Posts Tagged ‘Heart disease’

Atherosclerosis Independence: Genetic Polymorphisms of Ion Channels Role in the Pathogenesis of Coronary Microvascular Dysfunction and Myocardial Ischemia (Coronary Artery Disease (CAD))

Reviewer and Co-Curator: Larry H Bernstein, MD, FCAP


Curator: Aviva Lev-Ari, PhD, RN

The role of ion channels in Na(+)-K(+)-ATPase: regulation of ion
transport across the plasma membrane has been studied by our Team in 2012 and 2013. This is article TWELVE in a 13 article series listed at the end of this article.

Chiefly, our sources of inspiration were the following:

1.            2013 Nobel work on vesicles and calcium flux at the neuromuscular junction

Machinery Regulating Vesicle Traffic, A Major Transport System in our Cells 

The 2013 Nobel Prize in Physiology or Medicine is awarded to Dr. James E. Rothman, Dr. Randy W. Schekman and Dr. Thomas C. Südhof for their discoveries of machinery regulating vesicle traffic, a major transport system in our cells. This represents a paradigm shift in our understanding of how the eukaryotic cell, with its complex internal compartmentalization, organizes the routing of molecules packaged in vesicles to various intracellular destinations, as well as to the outside of the cell. Specificity in the delivery of molecular cargo is essential for cell function and survival. 


Synaptotagmin functions as a Calcium Sensor: How Calcium Ions Regulate the fusion of vesicles with cell membranes during Neurotransmission

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN


2. Perspectives on Nitric Oxide in Disease Mechanisms

available on Kindle Store @ Amazon.com



3.            Professor David Lichtstein, Hebrew University of Jerusalem, Dean, School of Medicine

Lichtstein’s main research focus is the regulation of ion transport across the plasma membrane of eukaryotic cells. His work led to the discovery that specific steroids that have crucial roles, as the regulation of cell viability, heart contractility, blood pressure and brain function. His research has implications for the fundamental understanding of body functions, as well as for several pathological states such as heart failure, hypertension and neurological and psychiatric diseases.

Physiologist, Professor Lichtstein, Chair in Heart Studies at The Hebrew University elected Dean of the Faculty of Medicine at The Hebrew University of Jerusalem

Reporter: Aviva Lev-Ari, PhD, RN


4.            Professor Roger J. Hajjar, MD at Mount Sinai School of Medicine

Calcium Cycling (ATPase Pump) in Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension and Percutaneous Intra-coronary Artery Infusion for Heart Failure: Contributions by Roger J. Hajjar, MD

Aviva Lev-Ari, PhD, RN


5.            Seminal Curations by Dr. Aviva Lev-Ari on Genetics and Genomics of Cardiovascular Diseases with a focus on Conduction and Cardiac Contractility

Aviva Lev-Ari, PhD, RN

Aviva Lev-Ari, PhD, RN

Aviva Lev-Ari, PhD, RN and Larry H. Bernstein, MD, FCAP

Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

Other related research by the Team of Leaders in Pharmaceutical Business Intelligence published on the Open Access Online Scientific Journal


See References to articles at the end of this article on

  • ION CHANNEL and Cardiovascular Diseases


  • Calcium Role in Cardiovascular Diseases – The Role of Calcium Calmodulin Kinase  (CKCaII) and Ca(2) flux
  • Mitochondria and Oxidative Stress Role in Cardiovascular Diseases

Thus, the following article follows a series of articles on ion-channels and cardiac contractility mentioned, above. The following article is closely related to the work of Prof. Lichtstein.

These investigators studied the possible correlation between

  • Myocardial Ischemia (Coronary Artery Disease (CAD)) aka Ischemic Heart Disease (IHD) and
  • single-nucleotide polymorphisms  (SNPs) genes encoding several regulators involved in Coronary Blood Flow Regulation (CBFR), including
  • ion channels acting in vascular smooth muscle and/or
  • endothelial cells of coronary arteries.

They completely analyzed exon 3 of both KCNJ8 and KCNJ11 genes (Kir6.1 and Kir6.2 subunit, respectively) as well as

  • the whole coding region of KCN5A gene (Kv1.5 channel).
The work suggests certain genetic polymorphisms may represent a non-modifiable protective factor that could be used
  • to identify individuals at relatively low-risk for cardiovascular disease
  • an independent protective role of the
    • rs5215_GG against developing CAD and
    • a trend for rs5219_AA to be associated with protection against coronary microvascular dysfunction

Their findings are a lead into further investigations on ion channels and IHD affecting the microvasculature.

Role of genetic polymorphisms of ion channels in the pathophysiology of coronary microvascular dysfunction and ischemic heart disease

BasicResCardiol(2013)108:387   http//dx.dio.org/10.1007/s00395-013-0387-4

F Fedele1•M Mancone1•WM Chilian2•P Severino2•E Canali•S Logan•ML DeMarchis3•M Volterrani4•R Palmirotta3•F Guadagni3

1Department of Cardiovascular, Respiratory, Nephrology, Anesthesiology and Geriatric Sciences,Sapienza University of Rome, UmbertoI Policlinic, Rome, Italy  e-mail:francesco.fedele@uniroma1.it
2Department of Integrative Medical Sciences, Northeastern Ohio Universities College of Medicine, Rootstown,OH
3Department of Advanced Biotechnologies and Bioimaging, IRCCS San Raffaele Pisana,Rome,It
4Cardiovascular Research Unit, Department of Medical Sciences, Centre for Clinical and Basic Research, Raffaele Pisana, Rome, Italy (CBFR)

BasicResCardiol(2013)108:387   http//dx.dio.org/10.1007/s00395-013-0387-4
This article is published with open access at Springerlink.com


Conventionally,ischemic heart disease (IHD) study is equated with large vessel coronary disease (CAD). However, recent evidence has suggested

  • a role of compromised microvascular regulation in the etiology of IHD.

Because regulation of coronary blood flow likely involves

  • activity of specific ion-channels, and
  • key factors involved in endothelium-dependent dilation,

genetic anomalies of ion-channels or specific endothelial-regulators may underlie coronary microvascular disease.

We aimed to evaluate the clinical impact of single-nucleotide polymorphisms in genes encoding for

  • ion-channels expressed in the coronary vasculature and the possible
  • correlation with IHD resulting from microvascular dysfunction.

242 consecutive patients who were candidates for coronary angiography were enrolled. A prospective, observational, single-center study was conducted, 

  • analyzing genetic polymorphisms relative to

(1) NOS3 encoding for endothelial nitric oxide synthase (eNOS);
(2) ATP2A2 encoding for the Ca/H-ATP-ase pump (SERCA);
(3) SCN5A encoding for the voltage-dependent Na channel (Nav1.5);
(4) KCNJ8 and in KCNJ11 encoding for the Kir6.1and Kir6.2 subunits
of genetic K-ATP channels, respectively;and
(5) KCN5A encoding for the voltage-gated K channel (Kv1.5).

No significant associations between clinical IHD manifestations and

  • polymorphisms for SERCA, Kir6.1, and Kv1.5. were observed (p[0.05),

whereas specific polymorphisms detected in eNOS, as well as in Kir6.2 and Nav1.5 were found to be correlated with

  • IHD and microvascular dysfunction.

 Interestingly, genetic polymorphisms of ion-channels  seem to have an important clinical impact

  • influencing the susceptibility for microvascular dysfunction and (IHD,
  • independent of the presence of classic cardiovascular risk factors: atherosclerosis   


Keywords: Ion-channels, Genetic polymorphisms, Coronary microcirculation, Endothelium, Atherosclerosis Ischemic heart disease


Historically, in the interrogation of altered vascular function in patientswith ischemic heart disease (IHD), scientists have focused their attention on the correlation between

  • endothelial dysfunction and
  • atherosclerosis [11, 53, 6567].

The endothelium-independent dysfunction in coronary microcirculation and its possible correlations with  

  • atherosclerotic disease and
  • myocardial ischemia has not been extensively investigated.

In normal conditions, coronary blood flow regulation (CBFR) is mediated by several different systems, including

  • endothelial,
  • nervous,
  • neurohumoral,
  • myogenic, and
  • metabolic mechanisms [2, 10, 14, 15, 63, 64, 69].

Physiologic CBFR depends also on several ion channels, such as

  • ATP-sensitive potassium (KATP) channels,
  • voltage-gated potassium (Kv) channels,
  • voltage-gated sodium (Nav) channels, and others.

Ion channels regulate the concentration of calcium in both

  • coronary smooth muscle and endothelial cells, which
  • modulates the degree of contractile tone in vascular muscle and
  • the amount of nitric oxide that is produced by the endothelium

Ion channels play a primary role in the rapid response of both

  • the endothelium and vascular smooth muscle cells of coronary arterioles
  • to the perpetually fluctuating demands of the myocardium for blood flow
    [5, 6, 13, 18, 33, 45, 46, 51, 52, 61, 73, 75].

Despite this knowledge, there still exists an important gap about 

  • the clinical relevance and 
  • causes of microvascular dysfunction in IHD

By altering the overall

  • regulation of blood flow in the coronary system,
  • microvascular dysfunction could alter the normal distribution of shear forces in large coronary arteries

Proximal coronary artery stenosis could

  • contribute to microvascular dysfunction [29, 60]. But
  • ion channels play a critical role in microvascular endothelial
  • and smooth muscle function.

Therefore, we hypothesized  that alterations of coronary ion  channels could be the primary cause in a chain of events leading to

  • microvascular dysfunction and 
  • myocardial ischemia

independent of the presence of atherosclerosis.

Therefore, the objective of our study was to evaluate the possible correlation between

  • IHD and single-nucleotide polymorphisms  (SNPs) for genes encoding several regulators involved in CBFR, including
  • ion channels acting in vascular smooth muscle and/or
  • endothelial cells of coronary arteries.


Implications of the present work. This study describes the possible correlation of polymorphisms in genes encoding for CBFR effectors (i.e., ion channels, nitric oxide synthase, and SERCA) with the susceptibility for microcirculation dysfunction and IHD.

Our main findings are as follows: (Group 3 – Normal Patients – anatomically and functionally normal coronary arteries).

  • In Group 3, the genotype distribution of SNP rs5215 (Kir6.2/KCNJ11) moderately deviates from the HW equilibrium (p = 0.05).
  • In Group 1 (CAD), the polymorphism rs6599230 of Nav1.5/SCN5A showed deviation from HW equilibrium (p = 0.017).
  • The genotypic distribution of rs1799983 polymorphism for eNOS/NOS3 is inconsistent with the HW equilibrium in groups 1, 2, and 3 (p = 0.0001, p = 0.0012 and p = 0.0001, respectively).

Haplotype analyses revealed that there is no linkage disequilibrium between polymorphisms of the analyzed genes. There was no significant difference in the prevalence of T2DM (p = 0.185) or dyslipidemia (p = 0.271) between groups, as shown in Table2. In regards to genetic characteristics, no significant differences between the three.

1. A marked HW disequilibrium in the genotypic distribution of rs1799983 polymorphism for eNOS/NOS3 was observed in all three populations. Moreover, this SNP seems to be an independent risk factor for microvascular dysfunction, as evidenced by multivariate analysis;
2. The SNPs rs5215_GG, rs5218_CT, and rs5219_AA for Kir6.2/KCJ11 could reduce susceptibility to IHD, since they were present more frequently in patients with anatomically and functionally normal coronary arteries;
3. In particular, with regard to rs5215 for Kir6.2/KCJ11, we observed a moderate deviation from the HW equilibrium in the genotypic
distribution in the control group. In addition, this genotype appears to be an independent protective factor in the development of IHD, as evidenced by multivariate analysis;
4. Furthermore, the trend observed for the SNP  rs5219_AA of Kir6.2/KCNJ11 may suggest an independent protective factor  in the development of coronary microvascular dysfunction
5. The rs1805124_GG genotype of Nav1.5/SCN5A seems to play a role against CAD;
6. No association seems to exist between the polymorphisms of SERCA/ATP2A2, Kir6.1/KCNJ8, and Kv1.5/KCNA5 and the presence of IHD;
7. All groups are comparable regarding the cardiovascular risk factors of T2DM and dyslipidemia, illustrating a potentially important implication of genetic polymorphisms in the susceptibility to IHD.

It is important to underline that the control group (Group 3) is a high-risk population, because of their cardiovascular risk factors

  • hypertension = 17 %,
  • T2DM = 34.1 %,
  • dyslipidemia = 41.4 %,

with an appropriate indication for coronary angiography, in accordance with current guidelines. Nevertheless, these patients were demonstrated to have both anatomically and functionally normal coronary arteries. Moreover, as shown in Tables 2 and 3, we observed that

  • rs5215_GG, rs5218_CT and rs5219_AA for Kir6.2/KCNJ11 had a higher prevalence in this group,compared to patients with CAD
  • and patients with microvascular dysfunction.

Moreover, as shown in Table 4, the presence of the rs5215_GG polymorphism for the Kir6.2 subunit was

  • inversely correlated with the prevalence of cardiovascular risk factors and CAD,whereas
  • rs5219_AA of the Kir6.2 subunit trended towards an inverse correlation with coronary microvascular dysfunction.

On the other hand, the SNP rs1799983_GT of eNOS was

  • confirmed to be an independent risk factor for microvascular dysfunction.

Our data suggest that the presence of certain genetic polymorphisms may represent a non-modifiable protective factor that could be used

  • to identify individuals at relatively low-risk for cardiovascular disease,
  • regardless of the presence of T2DM and dyslipidemia.

Current Clinical and Research Context

In normal coronary arteries, particularly the coronary microcirculation, there are several different mechanisms of CBFR, including

  • endothelial, neural, myogenic, and metabolic mediators [2, 8, 10, 12, 14, 15, 37, 55, 63, 64, 69].

In particular, endothelium-dependent vasodilation acts mainly via eNOS-derived nitric oxide (NO) in response to acetylcholine and shear stress.

  • NO increases intracellular cyclic guanosine monophosphate. It also causes vasodilation via
  • activation of both K-Ca channels and K-ATP channels.

Recent data suggested a pathophysiologically relevant role for the polymorphisms of eNOS/NOS3 in human coronary vasomotion [40–43]. Our data suggest that rs1799983_GT at exon 7 (Glu298Asp, GAG-GAT) of eNOS/NOS3 represents

  • an independent risk factor for coronary micro-vascular dysfunction, which agrees with a recent meta-analysis reporting an
  • association of this SNP with CAD in Asian populations [74]. In addition,
  • this SNP has been associated with endothelial dysfunction, although the mechanisms are not well defined [30].

Consistently, a recent study performed on 60 Indian patients with documented history of CAD reported a significantly higher frequency of rs1799983 (p.05) compared to control subjects, indicating that

  • variations in NOS3 gene may be useful clinical markers of endothelial dysfunction in CAD [54].
Interestingly, another association between rs1799983_GT and impaired collateral development has been observed in patientswith a

  • high-grade coronary stenosis or occlusion [19].
As is well known, the significance of the mechanisms of CBFR is partly determined by the location within the coronary vasculature. For instance, for vessels with a diameter of < 200 µm—which comprise the coronary microcirculation—metabolic regulation of coronary blood flow is considered the most important mechanism [24, 63]. Importantly, many of these mediators of metabolic regulation act through specific ion channels. In particular, in both coronary artery smooth muscle cells and endothelial cells
  • potassium channels determine the resting membrane potential (Em) and serve as targets of endogenous and therapeutic vasodilators [9, 27].
Several types of K+ channels are expressed in the coronary tree.
  • The K-ATP channels couple cell metabolic demand to conductance, via pore-forming (Kir6.1 and/or Kir6.2) subunits and regulatory
    [sulphonylurea-binding (SUR 1, 2A, or 2B)] subunits.
  • Kir6.x allows for channel inhibition by ATP, while SURx is responsible for channel activation by ADP and Mg2+.
K-ATP channel activation results in an outward flux of potassium and

  • consequent hyperpolarization, resulting in
  • voltage-gated calcium channel closure,
  • decreased Ca2+ influx, and ultimately
  • vasodilation [1, 5, 18, 20, 21, 33, 61, 62, 73, 75].

Our data do not support any significant difference regarding the Kir6.1 subunit of the K-ATP channel. On the other hand, this study suggests

  • an important role of specific SNPs for the Kir6.2 subunit (Tables 2, 3)—i.e., rs5215, rs5219, and rs5218—

in the susceptibility to IHD and microvascular dysfunction. These SNPs are among the most studied K-ATP channel polymorphisms, especially in the context of diabetes mellitus. In fact, in both Caucasian and Asian populations, these three SNPs as well as other genetic polymorphisms for the KCNJ11 gene have been associated with diabetes mellitus [34, 35, 44, 50, 57, 58, 70].

Nevertheless, the precise

  • structure–function impacts of the various amino acid substitutions remain unclear.

The rs5215 and rs5219 polymorphisms, also known as I337V and E23K, respectively, are highly linked with reported

  • concordance rates between 72 and 100 % [22, 23, 56].

The high concordance between rs5219 and rs5215 suggests that these polymorphisms

  • may have originated in a common ancestor, further indicating a
  • possible evolutionary advantage to their maintenance in the general population [49].

In our study, multivariate analysis suggests both an independent protective role of the

  • rs5215_GG against developing CAD and
  • a trend for rs5219_AA to be associated with protection against coronary microvascular dysfunction (Table 4a, b).
  • The variant rs5215_GG is a missense SNP located in the gene KCNJ11 at exon 1009 (ATC-GTC) and results in
    the substitution of isoleucine (I) residue with valine (V) [23].

Future studies are necessary to better understand the influence of this single amino acid variant on the function of the channel.

In humans, vasodilation of the coronary microvasculature in response to hypoxia and K-ATP channel opening
  • are both impaired in diabetes mellitus [39].
It is also described that gain-of-function mutations of the KCNJ11 gene cause neonatal diabetes mellitus, and loss-of-function mutations lead to congenital hyperinsulinism [43]. Our study is not discordant with previous studies about the correlation of SNPs of the Kir6.2 subunit and diabetes mellitus. Rather, our findings show that these SNPs are correlated with anatomically and functionally normal coronary arteries,
  • independent of the presence of either diabetes mellitus or dyslipidemia.
These data suggest the possibility that these particular SNPs may identify individuals with decreased risk for coronary microcirculatory dysfunction and IHD,
  • regardless of the presence of T2DM and/or dyslipidemia.

However, further studies are necessary to confirm these findings. In this context, to better investigate the implications of genetic variation in the K-ATP channel,

  • future studies should include ion channel’s functional modification due to the SNPs and analysis of SUR subunits.

More than 40-kV channel subunits have been identified in the heart, and sections of human coronary smooth muscle cells demonstrate Kv1.5 immunoreactivity [16, 17, 27, 38]. Through constant regulation of smooth muscle tone, Kv channels contribute to the control of coronary microvascular resistance [4, 7]. Pharmacologic molecules that inhibit Kv1.5 channels such as

  • pergolide [25],
  • 4-amino-pyridine [32], and
  • correolide [17]

lead to coronary smooth muscle cell contraction and block the coupling between

  • cardiac metabolic demand and
  • coronary blood flow.

However, no significant differences were identified between the study groups in terms of the particular polymorphisms for Kv1.5 that were analyzed in this study. Expression of

  • the voltage-dependent Na+ channel (Nav) has been demonstrated in coronary microvascular endothelia cells [3, 66].

Our analysis reveals a possible implication of the polymorphism rs1805124_GG for Nav1.5 channel with the presence of anatomically and functionally normal coronary arteries. This SNP leads to a homozygous 1673A-G transition, resulting in a His558-to-Arg (H558R) substitution. It is important to underline that

  • our data are the first to correlate the polymorphism rs1805124_GG with IHD.

Further research is necessary to confirm the observed implication.

Finally, we have analyzed the sarco/endoplasmic reticulum calcium transporting Ca2+-ATPase (SERCA), which is fundamental in the regulation of intracellular Ca2+ concentration [6].

SERCA is an intracellular pump that

  • catalyzes the hydrolysis of ATP coupled with the
  • translocation of calcium from the cytosol into the lumen of the sarcoplasmic reticulum.

Although this pump plays a critical role in regulation of the contraction/relaxation cycle, our analysis did not reveal any apparent association between

  • genetic variants of SERCA and the
  • prevalence of microvascular dysfunction or IHD.


This pilot study is the first to compare the prevalence of SNPs in genes encoding coronary ion channels between patients
  • with CAD or microvascular dysfunction and those with both anatomically and functionally normal coronary arteries.
Taken together, these results suggest the possibility of associations between SNPs and IHD and microvascular dysfunction, although

  • the precise manners by which specific genetic polymorphisms affect ion channel function and expression
have to be clarified by further research involving larger cohorts.

Limitations and future perspectives

Notable limitations of this pilot study are as follows:

1. Due to the lack of pre-existing data, the power calculation was performed in advance on the basis of assumptions of allele frequencies and the population at risk.
2. The sample size for each group is small, mainly due to both the difficulty in enrolling patients with normal coronary arteries and normal microvascular function (group 3) and the elevated costs of the supplies such as Doppler flow wires.
3. There is a lack of ethnic diversity of our cohort.
4. Currently, there is an absence of supportive findings in another independent cohort or population. However, our pilot study included patients within a well-defined, specific population and was aimed to identify the presence of statistical associations between selected genetic polymorphisms and the prevalence of a specific disease.
5. There is a lack of functional characterization of the described genetic polymorphisms.
6. We have not identified any correlation between novel SNPs and IHD. Nevertheless, we completely analyzed exon 3 of both KCNJ8 and KCNJ11 genes (Kir6.1 and Kir6.2 subunit, respectively) as well as the whole coding region of KCN5A gene (Kv1.5 channel).  Moreover, we examined previously described SNPs since there are no data in the literature regarding the possible association of the prevalences of those polymorphisms in the examined population.More extensive studies are necessary to confirm our  findings, possibly with a larger number of patients. Future investigations are also required to confirm the roles of ion  channels in the pathogenesis of coronary microvascular dysfunction and IHD. These studies should involve analysis of both other subunits of the K-ATP channels

  • sulfonylurea receptor, SURx and further coronary ion channels (e.g., calcium-dependent K channels), as well as
  • in vitro evaluation of ion channel activity by patch clamp and analysis of channel expression in the human cardiac tissue.

Moreover, to better address the significance of microvascular dysfunction in IHD, it could be interesting to analyze

  • typical atherosclerosis susceptibility genes (e.g., PPAP2B, ICAM1, et al.).


In this prospective, observational, single-center study – 242 consecutive patients admitted to our department were enrolled with

  • the indication to undergo coronary angiography .

All patients matched inclusion criteria

  1. age [18];
  2. suspected or documented diagnosis of acute coronary syndrome or stable angina
  3. with indication(s) for coronary angiography, in accordance with current guidelines [36, 68], and
  4. the same ethno-geographic Caucasian origin) and

Exclusion Criteria

  1. previous allergic reaction to iodine contrast,
  2. renal failure,
  3. simultaneous genetic disease,
  4. cardiogenic shock,
  5. non- ischemic cardiomyopathy

All patients signed an informed consent document  –

prior to participation in the study, which included

  • acknowledgement of the testing procedures to be performed
    (i.e., coronary angiography; intracoronary tests; genetic analysis, and processing of personal data).

The study was approved by the Institution’s Ethics Committee.
All clinical and instrumental characteristics were collected in a dedicated  database.

 Study Design

(a)  Standard therapies were administered, according to current guidelines [36, 68].
(b) An echocardiography was performed before and after coronary angiography
(c)  Coronary angiography was performed using radial artery or femoral artery
Judkins approach via sheath insertion.
(d) In patients showing normal epicardial arteries, intracoronary functional tests
were performed through Doppler flow wire to evaluate

  1. both endothelium-dependent microvascular function
    [via intracoronary (IC) infusion of acetylcholine (2.5–10 lg)] and
  2. nonendothelium-dependent microvascular function
    [via IC infusion of adenosine (5 lg)] [31]. 

(e) In all enrolled patients, a peripheral blood sample for genetic analysis was taken. 

On the basis  of the  coronary angiography and the intracoronary functional tests, 

  • the 242 patients were divided into three groups (see also Fig. 1).
  1. Group 1: 155 patients with anatomic coronary alteration
    (comprising patients with acute coronary syndrome and chronic stable angina).

    • microvascular dysfunction defined as coronary flow reserve (CFR) \ 2.5
    • after IC infusion of acetylcholine and adenosine].
  2. Group 2: 46 patients with functional coronary alteration
    [normal coronary arteries as assessed by angiography, and

    • as assessed by angiography and with normal functional tests
      (CFR C 2.5 after intracoronary infusion of acetylcholine and adenosine) (Fig. 1).
  3. Group 3: 41 patients with anatomically and functionally normal coronary arteries

BRC 2013 fedele genetic polymorphisms of ion channels.pdf_page_2

Fig. 1 Study design: 242 consecutive not randomized patients matching inclusion and exclusion criteria were enrolled.
In all patients, coronary angiography was performed, according to current ESC/ACC/AHA guidelines. In patients with
angiographically normal coronary artery, intracoronary functional tests were performed. In 242 patients
(155 with coronary artery disease, 46 patients with micro-vascular dysfunction, endothelium and/or non-endothelium
dependent, and 41 patients with anatomically and functionally normal coronary arteries) genetic analysis was performed.

Genetic Analysis

In conformity with the study protocol, ethylenediaminetetraacetic acid (EDTA) whole blood samples were collected according
to the international guidelines reported in the literature [48]. Samples were transferred to the Interinstitutional Multidisciplinary
BioBank (BioBIM) of IRCCS San Raffaele Pisana (Rome) and stored at -80 C until DNA extraction. Bibliographic research by
PubMed and web tools OMIM (http://www.ncbi.nlm.nih.gov/omim), Entrez SNP (http://www.ncbi.nlm.nih.gov/snp), and
Ensembl (http://www.ensembl.org/index.html) were used to select variants of genes involved in signaling pathways

  • related to ion channels and/or reported to be associated with
  • microvascular dysfunction and/or myocardial ischemia and/or
  • diseases correlated to IHD, such as diabetes mellitus.
Polymorphisms for the following genes were analyzed:
  1. NOS3 (endothelial nitric oxide synthase, eNOS),
  2. ATP2A2 (Ca2+/H+-ATPase pump, SERCA2),
  3. SCN5A (voltage-dependent Na+ channel,
  4. Nav1.5),
  5. KCNJ11 (ATP-sensitive K+ channel, Kir6.2 subunit),
  6. KCNJ8 (ATP-sensitive K+ channel, Kir6.1 subunit) and
  7. KCNA5 (voltage-gated K+ channel, Kv1.5).

In particular, we completely analyzed by direct sequencing

  • exon 3 of KCNJ8 (Kir6.1 subunit), which includes eight SNPs, as well as
  • the whole coding region of KCNA5 (Kv1.5 channel), which includes 32 SNPs and
  • four previously described variants [26, 47, 71, 72].
We also examined
  • the whole coding region of KCNJ11 (Kir6.2 subunit), for which sequence variants are described [26, 28].

All SNPs and sequence variants analyzed—a total of 62 variants of 6 genes—are listed in Table 1.

BRC 2013 fedele genetic polymorphisms of ion channels_page_004
BRC 2013 fedele genetic polymorphisms of ion channels_page_005

DNA was isolated from EDTA anticoagulated whole blood using the MagNA Pure LC instrument and theMagNA Pure LC
total DNA isolation kit I (Roche Diagnostics, Mannheim, Germany) according to the manufacturer’s instructions. Standard
PCR was performed in a GeneAmp PCR System 9700 (Applied Biosystems, CA) using HotStarTaq Master Mix
(HotStarTaq Master Mix Kit, QIAGEN Inc, CA). PCR conditions and primer sequences are listed in Table 1.

In order to exclude preanalytical and analytical errors, all direct sequencing analyses were carried out on both
strands using Big Dye Terminator v3.1 Cycle Sequencing kit
(Applied Biosystems), run on an ABI 3130
Genetic Analyzer (Applied Biosystems), and repeated on PCR products obtained from new nucleic acid extractions.
All data analyses were performed in a blind fashion.

Statistical Analysis

This report, intended as pilot study, is the first to compare

  • the prevalence of SNPs in genes encoding  several effectors (including ion channels)
  • involved in CBFR between these groups of patients.

No definite sample size could be calculated to establish a power analysis. groups of patients. However, assuming

  • a 15 % prevalence of normal  macrovascular and microvascular coronary findings in unselected patients
    undergoing coronary angiography,

we estimated that

  • a sample size of at least 150 patients could enable the computation of two-sided 95 % confidence intervals for
    • such prevalence estimates ranging between -5.0 and + 5.0 %.

The significance of the differences of observed alleles and genotypes between groups, as well as

  • analysis of multiple inheritance models for SNPs were also tested
    (co-dominant, dominant, recessive, over-dominant and log-additive)
  • using a free web-based application (http://213. 151.99.166/index.php?module=Snpstats)
  • designed from a genetic epidemiology  point of view to analyze association studies.

Akaike Information Criterion (AIC) was used to determine the best-fitting inheritance model for analyzed SNPs,

  • with the model with the lowest AIC reflecting the best balance of  goodness-of-fit and parsimony.

Moreover,  the allelic frequencies were estimated by gene counting, and the genotypes were scored. For each gene,

  • the observed numbers of each genotype were compared with those expected for a population in Hardy–Weinberg (HW) equilibrium
  • using a free web-based application  ( [59].

Linkage disequilibrium coefficient (D0) and  haplotype analyses were assessed using  the  Haploview 4.1 program.
Statistical analysis was performed using SPSS software package for Windows v.16.0 (SPSS Inc., Chicago, IL).

All categorical variables are expressed as percentages, and all continuous variables as mean ± standard deviation.
Differences between categorical variables

  • were analyzed by Pearson’s Chi-SQ test.

Given the presence of three groups, differences  between continuous variables, were calculated using
(including the number of SNPs tested),

  • one-way ANOVA; a post-hoc analysis with Bonferroni correction was made for multiple comparisons.

Univariate and multivariate logistic regression analyses

  • the independent impact of genetic polymorphisms on
    • coronary artery disease and microvascular dysfunction,

were performed to assess the independent impact of

  • genetic polymorphisms on coronary artery disease
    and microvascular dysfunction

while adjusting for other confounding variables.  The following parameters were entered into the model:

  • age,
  • male gender,
  • type 2 diabetes mellitus (T2DM),
  • systemic arterial hypertension,
  • dyslipidemia,
  • smoking status, and
  • family history of myocardial infarction (MI).

Only variables with a p value < 0.10 after univariate analysis were entered

  • into the multivariable model as covariates.

A two-tailed p < 0.05 was considered statistically significant.

Definition of Cardiovascular Risk Factors

Patients were classified as having T2DM if they had

  • fasting levels of glucose of >126 mg/dL in two separate measurements or
  • if they were taking hypoglycemic drugs.

Systemic arterial hypertension was defined as

  • systolic blood pressure  > 140 mmHg / diastolic blood pressure > 90 mmHg
  • in two separate measurements or
  • if the patient was currently taking antihypertensive drugs.

Dyslipidemia was considered to be present if

  • serum cholesterol levels were>220 mg/dL or
  • if the patient was being treated with cholesterol-lowering drugs.

Family history of MI was defined as a first-degree relative with MI before the age of 60 years.


Sixty-two polymorphisms distributed among six genes coding for
  • nitric oxide synthase,
  • the SERCA pump, and
  • ion channels
    • were screened for sequence variations using PCR amplification and
    • direct DNA sequencing analysis

in the population of

  • 155 patients with CAD (group 1),
  • 46 patients with microvascular dysfunction (group 2), and
  • 41 patients with normal coronary arteries and
    • normal endothelium dependent and endothelium-independent vasodilation (group 3).
In Group 3, the genotype distribution of

  • SNP rs5215 (Kir6.2/KCNJ11) moderately deviates from the HW equilibrium (p = 0.05).
In Group 1 (CAD), the polymorphism

  • rs6599230 of Nav1.5/SCN5A showed deviation from HW equilibrium (p = 0.017).
The genotypic distribution of groups in terms of polymorphisms for
  • eNOS/NOS3, SERCA/ATP2A2, Nav1.5/SCN5A, Kir6.1/KCNJ8, or Kv1.5/KCNA5
were noticed. However, significant differences (p.05) for the SNPs
  • rs5215_GG, and
  • rs5219_AA of Kir6.2/KCNJ11 were observed,
as shown in Table 2. 

Table 3 displays 
significant differences between normal subjects (group 3) and
  • patients with either CAD (group 1) or microvascular dysfunction (group 2).

BRC 2013 fedele genetic polymorphisms of ion channels_page_006

When correcting for other covariates as risk factors, the rs5215_GG genotype of Kir6.2/KCNJ11 was found to be 

  • significantly associated with CAD after multivariate analysis (OR = 0.319, p = 0.047, 95 % CI = 0.100–0.991), evidencing
  • a ‘‘protective’’ role of this genotype, as shown in Table 4a.

Similarly, a trend that supports this role of Kir6.2/KCNJ11 was also observed

  • in microvascular dysfunction for rs5219 AA. In contrast,
  • rs1799983_GT for eNOS/NOS3 was identified as an independent risk factor

following multivariate analysis (Table 4b), which agrees with literature findings as described below. 

BRC 2013 fedele genetic polymorphisms of ion channels_page_007


BasicResCardiol(2013)108:387   http//dx.dio.org/10.1007/s00395-013-0387-4

Conflict of interest On behalf of all authors, the corresponding author states that there is no conflict of interest.
Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.


1. Alekseev AE, Hodgson DM, Karger AB, Park S, Zingman LV, Terzic A (2005) ATP-sensitive K? channel channel/enzyme multimer: metabolic gating in the heart. J Mol
Cell Cardiol 38:895–905. doi:10.1016/j.yjmcc.2005.02.022
2. Baumgart D, Naber C, Haude M, Oldenburg O, Erbel R, Heusch G, Siffert W (1999) G protein beta3 subunit 825T allele and enhanced coronary vasoconstriction on
alpha(2)-adrenoceptor activation. Circ Res 85:965–969. doi:10.1161/01.RES.85.10.965
3. Belardinelli L, Shryock JC, Fraser H (2006) Inhibition of the late sodium current as a potential cardioprotective principle: effects of the late sodium current inhibitor
ranolazine. Heart 92:6–14. doi:10.1136/hrt.2005.078790
4. Berwick ZC, Moberly SP, Kohr MC, Morrical EB, Kurian MM, Dick GM, Tune JD (2012) Contribution of voltage-dependent K+ and Ca2+ channels to coronary pressure-
flow autoregulation. Basic Res Cardiol 107:264. doi:10.1007/s00395-012-0264-6
5. Brayden JE (2002) Functional roles of KATP channels in vascular smooth muscle. Clin Exp Pharmacol Physiol 29:312–316. doi:10.1046/j.1440-1681.2002.03650.x
6. Brini M, Carafoli E (2009) Calcium pumps in health and disease. Physiol Rev 89:1341–1378. doi:10.1152/physrev.00032.2008
7. Chen TT, Luykenaar KD, Walsh EJ, Walsh MP, Cole WC (2006) Key role of Kv1 channels in vasoregulation. Circ Res 99:53–60. doi:10.1161/01.RES.0000229654.45090.57
8. Cohen KD, Jackson WF (2005) Membrane hyperpolarization is not required for sustained muscarinic agonist-induced increases in intracellular Ca2+ in arteriolar endothelial
cells. Microcirculation 12:169–182. doi:10.1080/10739680590904973
9. Daut J, Maier-Rudolph W, von Beckerath N, Mehrke G, Gu¨nter K, Goedel-Meinen L (1990) Hypoxic dilation of coronary arteries is mediated by ATP-sensitive potassium
channels. Science 247:1341–1344. doi:10.1126/science.2107575
10. Davidson SM, Duchen MR (2007) Endothelial mitochondria: contributing to vascular function and disease. Circ Res 100:1128–1141. doi:10.1161/01.RES.0000261970.18328.1d
…. 75

SOURCE for References 1-75

Basic Res Cardiol (2013) 108:387   http://dx.doi.org/10.1007/s00395-013-0387-4

Other related articles published on this Open Access Online Scientific Journal include the following: 

ION CHANNEL and Cardiovascular Diseases


Calcium Role in Cardiovascular Diseases

Part I: Identification of Biomarkers that are Related to the Actin Cytoskeleton

Larry H Bernstein, MD, FCAP


Part II: Role of Calcium, the Actin Skeleton, and Lipid Structures in Signaling and Cell Motility

Larry H. Bernstein, MD, FCAP, Stephen Williams, PhD and Aviva Lev-Ari, PhD, RN


Part III: Renal Distal Tubular Ca2+ Exchange Mechanism in Health and Disease

Larry H. Bernstein, MD, FCAP, Stephen J. Williams, PhD
 and Aviva Lev-Ari, PhD, RN


Part IV: The Centrality of Ca(2+) Signaling and Cytoskeleton Involving Calmodulin Kinases and Ryanodine Receptors in Cardiac Failure, Arterial Smooth Muscle, Post-ischemic Arrhythmia, Similarities and Differences, and Pharmaceutical Targets

Larry H Bernstein, MD, FCAP, Justin Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN


Part V: Ca2+-Stimulated Exocytosis:  The Role of Calmodulin and Protein Kinase C in Ca2+ Regulation of Hormone and Neurotransmitter

Larry H Bernstein, MD, FCAP
Aviva Lev-Ari, PhD, RN


Part VI: Calcium Cycling (ATPase Pump) in Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension and Percutaneous Intra-coronary Artery Infusion for Heart Failure: Contributions by Roger J. Hajjar, MD

Aviva Lev-Ari, PhD, RN


Part VII: Cardiac Contractility & Myocardium Performance: Ventricular Arrhythmias and Non-ischemic Heart Failure – Therapeutic Implications for Cardiomyocyte Ryanopathy (Calcium Release-related Contractile Dysfunction) and Catecholamine Responses

Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN


Part VIII: Disruption of Calcium Homeostasis: Cardiomyocytes and Vascular Smooth Muscle Cells: The Cardiac and Cardiovascular Calcium Signaling Mechanism

Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN


Part IX: Calcium-Channel Blockers, Calcium Release-related Contractile Dysfunction (Ryanopathy) and Calcium as Neurotransmitter Sensor

Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN


Part X: Synaptotagmin functions as a Calcium Sensor: How Calcium Ions Regulate the fusion of vesicles with cell membranes during Neurotransmission

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN


Part XI: Sensors and Signaling in Oxidative Stress

Larry H. Bernstein, MD, FCAP


Part XII: Atherosclerosis Independence: Genetic Polymorphisms of Ion Channels Role in the Pathogenesis of Coronary Microvascular Dysfunction and Myocardial Ischemia (Coronary Artery Disease (CAD))

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN


Mitochondria and Oxidative Stress Role in Cardiovascular Diseases

Reversal of Cardiac Mitochondrial Dysfunction

Larry H. Bernstein, MD, FCAP


Calcium Signaling, Cardiac Mitochondria and Metabolic Syndrome

Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN


Mitochondrial Dysfunction and Cardiac Disorders

Larry H. Bernstein, MD, FCAP

Mitochondrial Metabolism and Cardiac Function

Larry H. Bernstein, MD, FCAP


Mitochondria and Cardiovascular Disease: A Tribute to Richard Bing

Larry H. Bernstein, MD, FCAP


MIT Scientists on Proteomics: All the Proteins in the Mitochondrial Matrix Identified

Aviva Lev-Ari, PhD, RN


Mitochondrial Dynamics and Cardiovascular Diseases

Ritu Saxena, Ph.D.


Mitochondrial Damage and Repair under Oxidative Stress

Larry H Bernstein, MD, FCAP


Nitric Oxide has a Ubiquitous Role in the Regulation of Glycolysis -with a Concomitant Influence on Mitochondrial Function

Larry H. Bernstein, MD, FACP


Mitochondrial Mechanisms of Disease in Diabetes Mellitus

Aviva Lev-Ari, PhD, RN


Mitochondria Dysfunction and Cardiovascular Disease – Mitochondria: More than just the “Powerhouse of the Cell”

Ritu Saxena, PhD


Read Full Post »

Atrial Fibrillation: IL6R Polymorphism in Whites and African Americans

Reporter: Aviva Lev-Ari, PhD, RN

Large-Scale Candidate Gene Analysis in Whites and African Americans Identifies IL6R Polymorphism in Relation to Atrial Fibrillation

The National Heart, Lung, and Blood Institute’s Candidate Gene Association Resource (CARe) Project

Renate B. Schnabel, MD, MSc*Kathleen F. Kerr, PhD*Steven A. Lubitz, MD*,Ermeg L. Alkylbekova, MD*Gregory M. Marcus, MD, MAS, Moritz F. Sinner, MD,Jared W. Magnani, MD, Philip A. Wolf, MD, Rajat Deo, MD, Donald M. Lloyd-Jones, MD, ScM, Kathryn L. Lunetta, PhD, Reena Mehra, MD, MS, Daniel Levy, MD, Ervin R. Fox, MD, MPH, Dan E. Arking, PhD, Thomas H. Mosley, PhD, Martina Müller-Nurasyid, MSc, PhD, Taylor R. Young, MA, H.-Erich Wichmann, MD, PhD, Sudha Seshadri, MD,Deborah N. Farlow, PhD, Jerome I. Rotter, MD, Elsayed Z. Soliman, MD, MSc, MS,Nicole L. Glazer, PhD, James G. Wilson, MD, Monique M.B. Breteler, MD, Nona Sotoodehnia, MD, MPH, Christopher Newton-Cheh, MD, MPH, Stefan Kääb, MD, PhD,Patrick T. Ellinor, MD, PhD*Alvaro Alonso, MD*Emelia J. Benjamin, MD, ScM*,Susan R. Heckbert, MD, PhD* and for the Candidate Gene Association Resource (CARe) Atrial Fibrillation/Electrocardiography Working Group

Correspondence to Susan R. Heckbert, MD, PhD, Cardiovascular Health Research Unit, University of Washington, 1730 Minor Ave, Suite 1360, Seattle, WA 98101. E-mail heckbert@u.washington.edu; Emelia J. Benjamin, MD, ScM, Medicine andEpidemiology, Boston University Schools of Medicine and Public Health, The Framingham Heart Study, 73 Mount Wayte Ave, Framingham, MA 01702–5827. E-mail emelia@bu.edu; Renate B. Schnabel, MD, MSc, Department of Medicine 2, Cardiology, Johannes Gutenberg University, Langenbeckstr 1, 55131 Mainz, Germany. E-mail schnabelr@gmx.de

* These authors contributed equally to the manuscript.


Background—The genetic background of atrial fibrillation (AF) in whites andAfrican Americans is largely unknown. Genes in cardiovascular pathways have not been systematically investigated.

Methods and Results—We examined a panel of approximately 50 000 common single-nucleotide polymorphisms (SNPs) in 2095 cardiovascular candidate genesand AF in 3 cohorts with participants of European (n=18 524; 2260 cases) or African American descent (n=3662; 263 cases) in the National Heart, Lung, andBlood Institute’s Candidate Gene Association Resource. Results in whites were followed up in the German Competence Network for AF (n=906, 468 cases). The top result was assessed in relation to incident ischemic stroke in the Cohorts for Heartand Aging Research in Genomic Epidemiology Stroke Consortium (n=19 602 whites, 1544 incident strokes). SNP rs4845625 in the IL6R gene was associated with AF (relative risk [RR] C allele, 0.90; 95% confidence interval [CI], 0.85–0.95;P=0.0005) in whites but did not reach statistical significance in African Americans (RR, 0.86; 95% CI, 0.72–1.03; P=0.09). The results were comparable in the German AF Network replication, (RR, 0.71; 95% CI, 0.57–0.89; P=0.003). No association between rs4845625 and stroke was observed in whites. The known chromosome 4 locus near PITX2 in whites also was associated with AF in African Americans (rs4611994; hazard ratio, 1.40; 95% CI, 1.16–1.69; P=0.0005).

Conclusions—In a community-based cohort meta-analysis, we identified genetic association in IL6R with AF in whites. Additionally, we demonstrated that the chromosome 4 locus known from recent genome-wide association studies in whites is associated with AF in African Americans.


Circulation: Cardiovascular Genetics.2011; 4: 557-564

Published online before print August 16, 2011,

doi: 10.1161/ CIRCGENETICS.110.959197

Read Full Post »

Reporter: Aviva Lev-Ari, PhD, RN

We decided to include ACC/AHA Guidelines for Coronary Artery Bypass Graft Surgery in this Scientific Journal as a Reference resource to all our Experts, Authors, Writers.

Example of the Guidelines in use in this Journal:

Mitral Valve Repair: Who is a Patient Candidate for a Non-Ablative Fully Non-Invasive Procedure?



ACC/AHA Guidelines for Coronary Artery Bypass Graft Surgery


  • ACC/AHA Practice Guidelines

ACC/AHA Guidelines for Coronary Artery Bypass Graft Surgery: Executive Summary and Recommendations

A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1991 Guidelines for Coronary Artery Bypass Graft Surgery)

  1. Committee Members
  1. Kim A. Eagle, MD, FACC, Cochair;
  2. Robert A. Guyton, MD, FACC, Cochair;
  3. Ravin Davidoff, MB, BCh, FACC;
  4. Gordon A. Ewy, MD, FACC;
  5. James Fonger, MD;
  6. Timothy J. Gardner, MD, FACC;
  7. John Parker Gott, MD, FACC;
  8. Howard C. Herrmann, MD, FACC;
  9. Robert A. Marlow, MD, MA, FAAFP;
  10. William Nugent, MD;
  11. Gerald T. O’Connor, PhD, DSc;
  12. Thomas A. Orszulak, MD;
  13. Richard E. Rieselbach, MD, BS, FACP;
  14. William L. Winters, MD, FACC;
  15. Salim Yusuf, MB, BS, PhD
  1. Task Force Members
  1. Raymond J. Gibbons, MD, FACC, Chair;
  2. Joseph S. Alpert, MD, FACC;
  3. Kim A. Eagle, MD, FACC;
  4. Timothy J. Gardner, MD, FACC;
  5. Arthur Garson Jr, MD, MPH, FACC;
  6. Gabriel Gregoratos, MD, FACC;
  7. Richard O. Russell, MD, FACC;
  8. Thomas J. Ryan, MD, FACC;
  9. Sidney C. Smith Jr, MD, FACC

Key Words:

I. Introduction

The American College of Cardiology/American Heart Association (ACC/AHA) Task Force on Practice Guidelines was formed to make recommendations regarding the appropriate use of diagnostic tests and therapies for patients with known or suspected cardiovascular disease. Coronary artery bypass graft (CABG) surgery is among the most common operations performed in the world and accounts for more resources expended in cardiovascular medicine than any other single procedure. Since the original Guidelines were published in 1991, there has been considerable evolution in the surgical approach to coronary disease, and at the same time there have been advances in preventive, medical, and percutaneous catheter approaches to therapy. These revised guidelines are based on a computerized search of the English literature since 1989, a manual search of final articles, and expert opinion.

As with other ACC/AHA guidelines, this document uses ACC/AHA classifications I, II, and III as summarized below:

Class I: Conditions for which there is evidence and/or general agreement that a given procedure or treatment is useful and effective.

Class II: Conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness or efficacy of a procedure.

Class IIa: Weight of evidence/opinion is in favor of usefulness/efficacy.

Class IIb: Usefulness/efficacy is less well established by evidence/opinion.

Class III: Conditions for which there is evidence and/or general agreement that the procedure/treatment is not useful/effective and in some cases may be harmful.

II. Outcomes

A. Hospital Outcomes

Seven core variables (priority of operation, age, prior heart surgery, sex, left ventricular [LV] ejection fraction [EF], percent stenosis of the left main coronary artery, and number of major coronary arteries with significant stenoses) are the most consistent predictors of mortality after coronary artery surgery. The greatest risk is correlated with the urgency of operation, advanced age, and 1 or more prior coronary bypass surgeries. Additional variables that are related to mortality include coronary angioplasty during index admission; recent myocardial infarction (MI); history of angina, ventricular arrhythmias, congestive heart failure, or mitral regurgitation; and comorbidities such as diabetes, cerebrovascular disease, peripheral vascular disease, chronic obstructive pulmonary disease, and renal dysfunction. Table 1 shows a method by which key patient variables can be used to predict an individual patient’s operative risk of death, stroke, or mediastinitis.

B. Morbidity Associated With Bypass Surgery

1. Neurological Events

Neurological impairment after bypass surgery may be attributable to hypoxia, emboli, hemorrhage, and/or metabolic abnormalities. Postoperative neurological deficits have been divided into 2 types: type 1, associated with major, focal neurological deficits, stupor, or coma; and type 2, in which deterioration in intellectual function is evident. Adverse cerebral outcomes are observed in ≈6% of patients after bypass surgery and are equally divided between type 1 and type 2 deficits. Predictors of cerebral complications after bypass surgery include advanced age and a history of hypertension. Particular predictors of type 1 deficits include proximal aortic atherosclerosis as defined by the surgeon at operation, history of prior neurological disease, use of the intra-aortic balloon pump, diabetes, hypertension, unstable angina, and increased age. Predictors of type 2 deficits include a history of excess alcohol consumption; dysrhythmias, including atrial fibrillation; hypertension; prior bypass surgery; peripheral vascular disease; and congestive heart failure. Estimation of a patient’s risk for postoperative stroke can be calculated from Table 1.

2. Mediastinitis

Deep sternal wound infection occurs in 1% to 4% of patients after bypass surgery and carries a mortality of ≈25%. Predictors of this complication include obesity, reoperation, use of both internal mammary arteries at surgery, duration and complexity of surgery, and diabetes. An individual patient’s risk of postoperative mediastinitis can be estimated from Table 1.

3. Renal Dysfunction

Postoperative renal dysfunction occurs in as many as 8% of patients. Among patients who develop postoperative renal dysfunction (defined as a postoperative serum creatinine level >2.0 mg/dL or an increase in baseline creatinine level of >0.7 mg/dL), 18% require dialysis. Overall mortality among patients who develop postoperative renal dysfunction is 19% and approaches two thirds among patients requiring dialysis. Predictors of renal dysfunction include advanced age, a history of moderate or severe congestive heart failure, prior bypass surgery, type 1 diabetes, and prior renal disease. Table 2 can be used to estimate the risk for an individual patient. Patients with advanced preoperative renal dysfunction who undergo CABG surgery have an extraordinarily high rate of requiring postoperative dialysis. Among patients with a preoperative creatinine level >2.5 mg/dL, 40% to 50% require hemodialysis.

Table 2.

Risk of Postoperative Renal Dysfunction (PRD) After Coronary Artery Bypass Graft Surgery

C. Long-Term Outcomes

Predictors of poor long-term survival after bypass surgery include advanced age, poor LVEF, diabetes, number of diseased vessels, and female sex. In some studies, additional predictors include angina class, hypertension, prior MI, renal dysfunction, and clinical congestive heart failure. Predictors of the recurrence of angina, late MI, or any cardiac event also include obesity and lack of use of an internal mammary artery, as well as those factors identified above. Of these events, the return of angina is the most common and is primarily related to late vein-graft atherosclerosis and occlusion.

III. Comparison of Medical Therapy Versus Surgical Revascularization

The comparison of medical therapy with coronary surgical revascularization is primarily based on randomized, clinical trials and large registries. Although clinical trials have provided valuable insights, there are limitations to their interpretation in the current era. Patient selection had primarily included individuals ≤65 years of age, very few included large cohorts of women, and for the most part, the studies evaluated patients at low risk who were clinically stable. In addition, because the studies were done in the late 1970s and early 1980s, only 1 of the trials used arterial grafts, and even that trial had no arterial grafts in 86% of patients. Newer modalities of cardioprotection during cardiopulmonary bypass were not used, nor were minimally invasive or off-bypass techniques. Finally, medical therapy was not optimized in the trials. Lipid-lowering therapy had not yet become standard, aspirin was not widely used, and β-blockers were used in just half of the patients. Angiotensin-converting enzyme inhibitors were not being routinely used in patients with congestive heart failure or dilated cardiomyopathy. Accordingly, although the clinical trials have provided important insights, their interpretation must be viewed with caution, given the evolution in all types of coronary therapies.

For the most part, stratification of patients in the trials was based on the number of vessels with anatomically significant disease, whether or not the major epicardial obstruction was proximal, and the extent of LV dysfunction as determined by global EF. The end point of the trials was primarily survival.

Overview: Randomized Trials

There were 3 major, randomized trials and several smaller ones. A collaborative meta-analysis of 7 trials with a total enrollment of 2649 patients has allowed comparison of outcomes at 5 and 10 years (Tables 3, 4, and 5 and the Figure). Among all patients, the extension survival of CABG surgical patients compared with medically treated patients was 4.3 months at 10 years of follow-up. The benefit of CABG compared with medical therapy in various clinical subsets is presented below.

Figure 1.

Extension of survival after 10 years of follow-up in various subgroups of patients, from a meta-analysis of 7 randomized studies. LV indicates left ventricular; VA, Veterans Administration.

Table 3.

Total Mortality at 5 and 10 Years

Table 4.

Subgroup Results at 5 Years

Table 5.

Subgroup Analysis of 5-Year Mortality by Risk Stratum

1. Left Main Coronary Artery Disease

The trials defined significant left main coronary artery stenosis as a >50% reduction in lumen diameter. Median survival for surgically treated patients was 13.3 years versus 6.6 years in medically treated patients. Left main equivalent disease (≥70% stenosis in both the proximal left anterior descending [LAD] and proximal left circumflex arteries) appeared to behave similarly to true left main coronary artery disease. Median survival for surgical patients was 13.1 years versus 6.2 years for medically assigned patients. The benefit of surgery for left main coronary artery disease patients continued well beyond 10 years. By 15 years, it was estimated that two thirds of patients originally assigned to medical therapy and who survived would have had surgery. The 15-year cumulative survival for left main coronary artery disease patients having CABG surgery was 44% versus 31% for medical patients.

2. Three-Vessel Disease

If one defines 3-vessel disease as stenosis of 50% or more in all 3 major coronary territories, the overall extension of survival was 7 months in CABG patients compared with medically treated patients. Patients with class III or IV angina, those with more proximal and severe LAD stenosis, those with worse LV function, and/or those with more positive stress tests derived more benefit from surgery.

3. Proximal LAD Disease

In patients with severe, proximal LAD stenosis, the relative risk reduction due to bypass surgery compared with medical therapy was 42% at 5 years and 22% at 10 years. This was even more striking in patients with depressed LV function.

4. LV Function

In patients with mildly to moderately depressed LV function, the poorer the LV function, the greater was the potential advantage of CABG surgery. Although the relative benefit was similar, the absolute benefit was greater because of the high-risk profile of these patients.

5. Symptoms and Quality of Life

Improvement in symptoms and quality of life after bypass surgery parallels the outcome data regarding survival. Beyond survival, bypass surgery may be indicated to alleviate symptoms of angina above and beyond medical therapy or to reduce the incidence of nonfatal complications like MI, congestive heart failure, and hospitalization. Registry studies have shown a reduction in late MI among highest-risk patients, such as those with 3-vessel disease, and/or those with severe angina. In pooled analyses, a benefit on the incidence of MI was not evident. This result likely reflected an early increase in MI perioperatively after CABG, which was balanced by fewer MIs over the long term among CABG recipients. Antianginal medications were required less frequently after bypass surgery. At 5 years, two thirds of bypass patients were symptom-free compared with 38% of medically assigned patients. By 10 years, however, these differences were no longer significant. This result is related to the attrition of vein grafts in the bypass group as well as crossover of medically assigned patients to bypass surgery.

6. Loss of Benefit of Surgery

After 10 to 12 years of follow-up, there was a tendency for the bypass surgery and medical therapy curves to converge, in regard to both survival as well as nonfatal outcomes. This convergence is due to a number of factors. First, the reduced life expectancy of patients with coronary disease (regardless of treatment) leads to a steady attrition. Second, the increased event rate in the late follow-up period of surgically assigned patients was likely related to the progression of native coronary disease and graft disease over time. Finally, medically assigned patients crossed over to surgery late, thus allowing the highest-risk medically assigned patients to gain from the benefit of surgery later in the course of follow-up. By 10 years, 37% to 50% of medically assigned patients had crossed over to surgery. Tables 3, 4, and 5 and the Figure provide estimates of long-term outcomes among patients randomized in the trials. These tables and the Figure can be used to estimate the general survival expectations in various anatomic categories.

IV. Comparison of Bypass Surgery With Percutaneous Revascularization

The results of a number of randomized, clinical trials comparing angioplasty and bypass surgery have been published. The trials excluded patients in whom survival had already been shown to be longer with bypass surgery than with medical therapy. Also, none of the trials was sufficiently large to detect relatively modest differences in survival between the 2 techniques. Most of the trials did not have a long-term follow-up, ie, 5 to 10 years, and therefore were unable to provide clear inferences regarding long-term benefit of the 2 techniques in similar populations. Also, and perhaps most notably, only ≈5% of screened patients with multivessel disease at enrolling institutions were included in the trials. Half of the patients approached were ineligible owing to left main coronary artery disease, insufficient symptoms, or other reasons. Even among a large group of patients with multivessel disease suitable for enrollment, only half were actually randomized. It appeared that physicians elected not to enroll many patients with 3-vessel disease in the trials but rather refer them for bypass surgery, whereas patients with 2-vessel disease tended to be referred for angioplasty rather than be enrolled in the trials.

Overall, procedural complications were low for both procedures but tended to be higher with CABG surgery (Table 6). For patients randomized to angioplasty, CABG was needed in ≈6% during the index hospitalization and in nearly 20% by 1 year. The initial cost and length of stay were lower for angioplasty than for CABG. Patients having angioplasty returned to work sooner and were able to exercise more at 1 month. The extent of revascularization achieved by bypass surgery was generally higher than with angioplasty. Long-term survival was difficult to evaluate owing to the short period of follow-up and the small sample size of the trials. However, for the Bypass Angioplasty Revascularization Investigation (BARI) trial, bypass patients had a 5-year survival of 89.3% compared with 86.3% for angioplasty. Secondary analysis revealed that in treated diabetic patients in the BARI trials, CABG led to significantly superior survival compared with percutaneous transluminal coronary angioplasty (PTCA). However, this finding was not evident in other trials. In long-term follow-up, the most striking difference was the 4- to 10-fold-higher likelihood of reintervention after initial PTCA. Quality of life, physical activity, employment, and cost were similar by 3 to 5 years after both procedures. The BARI trial suggested higher mortality associated with PTCA in several high-risk groups, including those with diabetes, unstable angina, and/or non–Q wave MI, and in patients with heart failure.

Table 6.

CABG vs PTCA: Randomized Controlled Trials

An analysis of registries generally shows data similar to those of the trials. However, a recent analysis of ≈60 000 patients who were treated in New York State in the early 1990s provides a 3-year survival analysis of patients undergoing CABG and PTCA. After adjustment for various covariates, bypass surgery in the New York State registry experience was associated with longer survival in patients with severe proximal LAD stenosis and/or 3-vessel disease. Contrariwise, patients with 1-vessel disease not involving the proximal LAD had improved survival with PTCA. Table 7 summarizes survival data from the New York State registry with respect to various cohorts of patients undergoing angioplasty or bypass surgery. These data can be used to estimate 3-year survival expectations for patients with various anatomic features.

Table 7.

Three-Year Survival by Treatment in Each Anatomic Subgroup

V. Management Strategies

Reduction of Perioperative Mortality and Morbidity

1. Reducing the Risk of Type 1 Brain Injury After CABG

Postoperative neurological complications represent 1 of the most devastating consequences of CABG surgery. Type 1 injury, in which a significant, permanent, neurological injury is sustained, occurs in ≈3% of patients overall and is responsible for a 21% mortality.

Atherosclerotic Ascending Aorta

An important predictor of this complication is the surgeon’s identification of a severely atherosclerotic, ascending aorta before or during the bypass operation. Perioperative atheroembolism from aortic plaque is thought to be responsible for approximately one third of strokes after CABG. Atherosclerosis of the ascending aorta is strongly related to increased age. Thus, stroke risk is particularly increased in patients beyond 75 to 80 years of age. Preoperative, noninvasive testing to identify high-risk patients has variable accuracy. Computed tomography identifies the most severely involved aortas but underestimates mild or moderate involvement. Transesophageal echocardiography is useful for aortic arch examination, but examination of the ascending aorta may be limited by the intervening trachea. Intraoperative assessment with epiaortic imaging is superior to both methods. Intraoperative palpation underestimates the high-risk aorta. The highest-risk aortic pattern is a protruding or mobile aortic arch plaque. An aggressive approach to the management of patients with severely diseased ascending aortas identified by intraoperative echocardiographic imaging reduces the risk of postoperative stroke. For patients with aortic walls ≤3 mm thick, standard treatment is used. For aortas >3 mm thick, the cannulation, clamp, or proximal anastomotic sites may be changed, or a no-clamp, fibrillatory arrest strategy may be used. For high-risk patients with multiple or circumferential involvement or those with extensive middle ascending aortic involvement, replacement of the ascending aorta under hypothermic circulatory arrest may be indicated. Alternatively, a combined approach with off-bypass, in situ internal mammary grafting to the LAD and percutaneous coronary intervention to treat other vessel stenoses has conceptual merit.

Atrial Fibrillation and Stroke

Chronic atrial fibrillation is a hazard for perioperative stroke. Intraoperative surgical manipulation or spontaneous resumption of sinus rhythm during the early postoperative period may lead to embolism of a left atrial clot. One approach to reduce this risk is the performance of preoperative, transesophageal echocardiography. The absence of a left atrial clot would suggest that the operation may proceed with acceptable risk. For elective patients, if a left atrial clot is identified, 3 to 4 weeks of anticoagulation therapy followed by restudy and then subsequent surgery is reasonable. Few clinical trial data are available to assist clinicians in this circumstance.

New-onset postoperative atrial fibrillation occurs in ≈30% of post-CABG patients, particularly on the second and third postoperative days, and is associated with a 2- to 3-fold increased risk of postoperative stroke. Risk factors include advanced age, chronic obstructive pulmonary disease, proximal right coronary disease, prolonged operation, atrial ischemia, and withdrawal of β-blockers. The role of anticoagulants in patients who develop post-CABG atrial fibrillation is unclear. Aggressive anticoagulation and cardioversion may reduce the neurological complications associated with this arrhythmia. Early cardioversion within 24 hours of the onset of atrial fibrillation can probably be performed safely without anticoagulation. However, persistence of the arrhythmia beyond this time argues for the use of oral anticoagulants to reduce stroke risk in patients who remain in atrial fibrillation and/or in those for whom later cardioversion is planned.

Recent MI, LV Thrombus, and Stroke

Patients with a recent, anterior MI and residual wall-motion abnormality are at increased risk for the development of an LV mural thrombus and its potential for embolization. For patients undergoing surgical revascularization after sustaining an anterior MI, preoperative screening with echocardiography may be appropriate to identify the presence of a clot. Detection of an acute LV mural thrombus may call for long-term anticoagulation and reevaluation by echocardiography to ensure resolution or organization of the thrombus before coronary bypass surgery. Additionally, 3 to 6 months of anticoagulation therapy is appropriate for patients with persistent, anterior wall–motion abnormalities after coronary bypass surgery.

Recent, Antecedent Cerebrovascular Event

A recent, preoperative cerebrovascular accident represents a situation in which delaying surgery may reduce the perioperative neurological risk. In particular, evidence of a hemorrhagic component based on computed tomographic scan identifies high risk for the extension of neurological damage with cardiopulmonary bypass. It is generally believed that a delay of 4 weeks or more after a cerebrovascular accident is prudent, if coronary anatomy and symptoms permit, before proceeding with CABG.

Carotid Disease and Neurological Risk Reduction

Hemodynamically significant carotid stenoses are thought to be responsible for up to 30% of early postoperative strokes. The trend for coronary surgery to be performed in an increasingly elderly population and the increasing prevalence of carotid disease in this same group of patients underscore the importance of this issue. Perioperative stroke risk is thought to be <2% when carotid stenoses are <50%, 10% when stenoses are 50% to 80%, and 11% to 19% in patients with stenoses >80%. Patients with untreated, bilateral, high-grade stenoses and/or occlusions have a 20% chance of stroke. Carotid endarterectomy for patients with high-grade stenosis is generally done preceding or coincident with coronary bypass surgery and, with proper teamwork in high-volume centers, is associated with a low risk for both short- and long-term neurological sequelae. Carotid endarterectomy performed in this fashion carries a low mortality (3.5%) and reduces early postoperative stroke risk to <4%, with a concomitant 5-year freedom from stroke of 88% to 96%.

The decision about who should undergo preoperative carotid screening is controversial. Predictors of important carotid stenosis include advanced age, female sex, known peripheral vascular disease, previous transient ischemic attack or stroke, a history of smoking, and left main coronary artery disease. Many centers screen all patients >65 years old. Patients with left main coronary disease are often screened, as are those with a previous transient ischemic attack or stroke. Preoperative central nervous system symptoms suggestive of vertebral basilar insufficiency should lead to an evaluation before elective CABG.

When surgery of both carotid and coronary disease is planned, the most common approach is to perform the operation in a staged manner, in which the patient first has carotid surgery followed by coronary bypass in 1 to 5 days. Alternatively, especially if the patient has compelling cardiac symptoms or coronary anatomy, the operations may be performed during a single period of anesthesia, with the carotid endarterectomy immediately preceding coronary bypass. Neither strategy has been established as being superior. Stroke risk is increased if a reversed-stage procedure is used, in which the coronary bypass operation precedes the carotid endarterectomy by ≥1 day.

2. Reducing the Risk of Type 2 Brain Injury

Type 2 neurological complications are seen in ≈3% of patients and are correlated with a 10% risk of postoperative death, with 40% of patients requiring additional care in a transitional facility after hospital discharge. Microembolization is thought to be a major contributor to the postoperative cerebral dysfunction after CABG. The release of microemboli during extracorporeal circulation, involving small gaseous or lipid emboli, may be responsible. The use of a 40-μm arterial-line filter on the heart-lung machine circuit and routine use of membrane oxygenators rather than bubble oxygenators may reduce such neurological injury. Additional maneuvers to reduce type 2 neurological injury include the maintenance of steady, cerebral blood flow during cardiopulmonary bypass, avoidance of cerebral hyperthermia during and after cardiopulmonary bypass, meticulous control of perioperative hyperglycemia, and avoidance and limitation of postoperative cerebral edema.

3. Reducing the Risk of Perioperative Myocardial Dysfunction

Protection in Patients With Normal LV Function

There is no universally applicable myocardial protection technique. Among patients with preserved preoperative cardiac function, no strong argument can currently be made for warm versus cold and crystalloid versus blood cardioplegia. However, certain techniques may offer a wider margin of safety for special patient subsets.

Myocardial Protection for Acutely Depressed Cardiac Function

Several studies have suggested that blood cardioplegia (compared with crystalloid) may offer a greater margin of safety during CABG performed on patients with acute coronary occlusion, failed angioplasty, urgent revascularization for unstable angina, and/or chronically impaired LV function.

Protection for Chronically Depressed LV Function

The use of a prophylactic intra-aortic balloon pump as an adjunct to myocardial protection may reduce mortality in patients having CABG in the setting of severe LV dysfunction (eg, LVEF <0.25). Placement of the intra-aortic balloon pump immediately before operation appears to be as effective as placement on the day preceding bypass surgery.

Adjuncts to Myocardial Protection

Although it is widely appreciated that use of the internal mammary artery leads to improved long-term survival after coronary bypass surgery, it has also been documented that use of the internal mammary artery influences operative mortality itself. Thus, internal mammary artery use should be encouraged in the elderly, emergent, or acutely ischemic patient and other patient groups.

Inferior Infarct With Right Ventricular Involvement

An acutely infarcted right ventricle is at great risk for severe, postoperative dysfunction and predisposes the patient to a higher postoperative mortality. During operation, loss of the pericardial constraint may lead to acute dilatation of the dysfunctional right ventricle, which then fails to recover even with optimal myocardial protection and revascularization. The best defense against right ventricular dysfunction is its recognition during preoperative evaluation. When possible, CABG should be delayed for ≥4 weeks to allow the right ventricle to recover.

4. Reducing the Systemic Consequences of Cardiopulmonary Bypass

A variety of measures have been tried to reduce the systemic consequences of cardiopulmonary bypass, which elicits a diffuse inflammatory response that may cause transient or prolonged multisystem organ dysfunction. Administration of corticosteroids before cardiopulmonary bypass may reduce complement activation and release of proinflammatory cytokines. Proper timing and duration of corticosteroid application are incompletely resolved. The administration of the serine protease inhibitor aprotinin may attenuate complement activation and cytokine release during extracorporeal circulation. Unfortunately, aprotinin is relatively expensive. Another method to reduce the inflammatory response is perioperative leukocyte depletion through hematologic filtration.

5. Reducing the Risk of Perioperative Infections

Several methods exist to reduce the risk of wound infections in patients undergoing CABG. These begin with interval reporting to individual surgeons regarding their respective wound infection rates and adherence to sterile operative techniques. Additional strategies include skin preparation with topical antiseptics, clipping rather than shaving the skin, avoidance of hair removal, reduction of operating room traffic, laminar-flow ventilation, shorter operation, minimization of electrocautery, avoidance of bone wax, use of double-glove barrier techniques for the operating room team, and routine use of a pleural pericardial flap. Aggressive, perioperative glucose control in diabetics through the use of continuous, intravenous insulin infusion reduces perioperative hyperglycemia and its associated infection risk. Avoidance of homologous blood transfusions after CABG may reduce the risk of both viral and bacterial infections. This is due to an immunosuppressive effect of transfusion. Leukodepletion of transfused blood also reduces this effect. This can be accomplished by regional blood blanks at the time of donation or at the bedside by use of a transfusion filter.

Preoperative antibiotic administration reduces the risk of postoperative infection 5-fold. Efficacy is dependent on adequate drug tissue levels before microbial exposure. Cephalosporins are currently the agents of choice. Table 8 identifies appropriate choices, doses, and routes of therapy. A 1-day course of intravenous antimicrobials is as effective as 48 hours or more. Therapy should be administered within 30 minutes of incision and again in the operating room if the operation exceeds 3 hours. Many centers deliver antibiotics just before incision. One fail-safe method is to have the anesthesiologist administer the cephalosporin after induction but before skin incision. If deep sternal wound infection does occur, aggressive surgical debridement and early vascularized muscle flap coverage are the most effective methods for treatment, along with long-term systemic antibiotics.

Table 8.

Prophylactic Antimicrobials for Coronary Artery Bypass Graft Surgery

6. Prevention of Postoperative Dysrhythmias

Postoperative atrial fibrillation increases the length of stay, cost, and most important, the risk of stroke. Atrial fibrillation occurs in up to 30% of patients, usually on the second or third postoperative day. Methods to avoid atrial fibrillation are several. First, withdrawal of preoperative β-blockers in the postoperative period doubles the risk of atrial fibrillation after CABG. Thus, early reinitiation of β-blockers is critical for avoidance of this complication. Virtually every study of patients receiving β-blockers prophylactically has shown benefit in lowering the frequency of atrial fibrillation. Most have used the drug in the postoperative period, but greater benefit may occur if β-blockade is begun before the operation. More recently, small studies of propafenone, sotalol, and amiodarone have also shown effectiveness in reducing the risk of postoperative atrial fibrillation. Table 9provides a review of pharmacological approaches in the randomized trials. Digoxin and calcium channel blockers have no consistent benefit for preventing atrial fibrillation after CABG, although they are frequently used to control its rate after it does occur. Currently, the routine preoperative or early postoperative administration of β-blockers is considered standard therapy to reduce the risk of atrial fibrillation after CABG.

Table 9.

Pharmacological Strategies for Prevention of Atrial Fibrillation (AF) After Coronary Artery Bypass Graft Surgery

7. Strategies to Reduce Perioperative Bleeding and Transfusion Risk

Transfusion Risk

Despite the increasing safety of homologous blood transfusion, concerns surrounding viral transmission during transfusion remain. Currently, the risks are likely very low and have been estimated to be 1/493 000 for human immunodeficiency virus, 1/641 000 for human T-cell lymphotrophic virus, 1/103 000 for hepatitis C virus, and 1/63 000 for hepatitis B virus.

Perioperative Bleeding

Risk factors for blood transfusion after CABG include advanced age, low preoperative red blood cell volume, preoperative aspirin therapy, urgent operation, duration of cardiopulmonary bypass, recent thrombolytic therapy, reoperation, and differences in heparin management. Institutional protocols that establish minimum thresholds for transfusion lead to a reduced number of units transfused and the percentage of patients requiring blood. Additional strategies can reduce the transfusion requirement after CABG. For stable patients, aspirin and other antiplatelet drugs may be discontinued 7 days before elective CABG. Aprotinin, a serum protease inhibitor with antifibrinolytic activity, also decreases postoperative blood loss and transfusion requirements in high-risk patients. Although there has been some concern that aprotinin may reduce early graft patency, recent studies have failed to document this effect. Routine use of aprotinin is limited by its high cost. Multidisciplinary approaches to conserve blood in single institutions appear to be effective.

For patients without exclusions, such as low hemoglobin values, heart failure, unstable angina, left main coronary artery disease, or advanced anginal symptoms, self-donation of 1 to 3 units of red blood cells over 30 days before operation reduces the need for homologous transfusion during or after operation. Donation immediately before cardiopulmonary bypass yields a higher platelet and hemoglobin count compared with simple hemodilution without pre–cardiopulmonary bypass blood harvesting.

8. Antiplatelet Therapy for Saphenous Vein Graft Patency

Aspirin significantly reduces vein graft closure during the first postoperative year. The aspirin should be started within 24 hours after surgery because its benefit on saphenous vein graft patency is lost when begun later. Dosing regimens from as little as 100 mg/d to as much as 325 mg TID appear to be efficacious. Ticlopidine offers no advantage over aspirin but is an alternative in truly aspirin-allergic patients. Life-threatening neutropenia is a rare but recognized side effect. Clopidogrel offers the potential for fewer side effects compared with ticlopidine as an alternative in aspirin-allergic patients. Its incidence of severe leukopenia is rare.

9. Pharmacological Management of Hyperlipidemia

Aggressive treatment of hypercholesterolemia reduces progression of atherosclerotic vein graft disease in patients after bypass surgery. Statin therapy has been shown to reduce saphenous vein graft disease progression over the ensuing years after bypass. Patients with unknown low-density lipoprotein (LDL) cholesterol levels after bypass should have cholesterol levels determined and treated pharmacologically if the LDL exceeds 100 mg/dL. Patients with treated LDL cholesterol should have their low-fat diet and cholesterol-lowering medications continued after bypass surgery to reduce subsequent graft attrition. Data regarding the benefit of cholesterol lowering after bypass surgery are most supported by studies that have used HMG CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors, particularly targeting LDL levels to <100 mg/dL.

10. Hormonal Manipulation

While observational studies have suggested that hormone replacement therapy in postmenopausal women leads to a reduction in all-cause mortality, a recent, randomized trial for secondary coronary prevention failed to show a beneficial effect on the overall rate of coronary events. Thus, hormone replacement therapy should be considered in postmenopausal women after bypass when, in the physician’s judgment, the potential coronary benefit is not offset by an increased risk of uterine or breast cancer.

11. Smoking Cessation

Smoking cessation is the single, most important risk-modification goal after CABG in patients who smoke. Smoking cessation leads to less recurrent angina, improved physical function, fewer admissions, maintenance of employment, and improved survival. Treatment individualized to the patient is crucial. Depression may be an important complicating factor and should be approached with behavioral and drug therapy. Nicotine replacement with a transdermal patch, nasal spray, gum, or inhaler is beneficial. A sustained-release form of bupropion, an antidepressant similar to selective serotonin reuptake inhibitors, reduces the nicotine craving and anxiety of smokers who quit. All smokers should receive educational counseling and be offered smoking cessation therapy after CABG (Table 10).

Table 10.

Proven Management Strategies to Reduce Perioperative and Late Morbidity and Mortality

Table 1.

12. Cardiac Rehabilitation

Cardiac rehabilitation, including early ambulation during hospitalization, outpatient prescriptive exercise, family education, and dietary and sexual counseling, has been shown to improve outcomes after CABG. The benefits include better physical mobility and perceived health. A higher proportion of rehabilitated patients are working at 3 years after CABG. The benefits of rehabilitation extend to the elderly and to women. Cardiac rehabilitation reinforces pharmacological therapy and smoking cessation and should be offered to all eligible patients after CABG.

13. Emotional Dysfunction and Psychosocial Considerations

Lack of social participation and low religious strength are independent predictors of death in elderly patients undergoing CABG. Although controversial, the high prevalence of depression after bypass surgery may reflect a high prevalence preoperatively. Cardiac rehabilitation has a highly beneficial effect in patients who are moderately or severely depressed. Evaluation of social supports and attempts to identify and treat underlying depression should be part of routine post-CABG care.

14. Rapid Sustained Recovery After Operation

Rapid recovery and early discharge are standard goals after CABG. The shortest in-hospital postoperative stays are followed by the fewest rehospitalizations. Important components of “fast-track” care are careful patient selection, patient and family education, early extubation, prophylactic antiarrhythmic therapy, dietary considerations, early ambulation, early outpatient telephone follow-up, and careful coordination with other physicians and healthcare providers.

15. Communication Between Caregivers

Maintenance of appropriate and timely communication between treating physicians regarding care of the patient is crucial. When possible, the primary care physician should follow up the patient during the perioperative course. The referral physician needs to provide clear, written reports of the findings and recommendations to the primary care physician, including discharge medications and dosages along with long-term goals.

VI. Impact of Evolving Technology

A. Less-Invasive Coronary Bypass Surgery

Technical modifications of CABG have been developed to decrease the morbidity of the operation, either by using limited incision or by eliminating cardiopulmonary bypass. Currently, “less-invasive” CABG surgery can be divided into 3 categories: (1) off-bypass CABG performed through a median sternotomy with a smaller skin incision, (2) minimally invasive direct CABG (MID-CAB) performed through a left anterior thoracotomy without cardiopulmonary bypass, and (3) port-access CABG with femoral-to-femoral cardiopulmonary bypass and cardioplegic arrest with limited incision.

Off-bypass coronary surgery is performed on a beating heart after reduction of cardiac motion with a variety of pharmacological and mechanical devices. These include slowing the heart with β-blockers and calcium channel blockers and use of a mechanical stabilizing device to isolate and stabilize the target vessel. Retraction techniques may elevate the heart to allow access to vessels on the lateral and inferior surfaces of the heart. Because this technique generally uses a median sternotomy, its primary benefit is the avoidance of cardiopulmonary bypass, not a less extensive incision.

MID-CAB refers to bypass surgery without median sternotomy and without the use of cardiopulmonary bypass. Generally, this is performed with a small left anterior thoracotomy, exposing the heart through the fourth intercostal interspace with access to the LAD and diagonal branches and occasionally, the anterior marginal vessels. The right coronary artery can be approached by using a right anterior thoracotomy. MID-CAB procedures are generally performed on only 1 or 2 coronary targets. Observational studies have suggested that MID-CAB is associated with a reduced average length of stay and an earlier return to work. Although initial reports of 2-year actuarial and event-free survival are encouraging, the data must be viewed with caution. Because the number of anastomoses performed on a beating heart is usually 1 or occasionally 2, the potential long-term effects of incomplete revascularization are unknown.

The closed-chest, port-access, video-assisted CABG operation uses cardiopulmonary bypass and cardioplegia of a globally arrested heart. Vascular access for cardiopulmonary bypass is achieved via the femoral artery and vein. A triple-lumen catheter with an inflatable balloon at its distal end is used to achieve endovascular aortic occlusion, cardioplegia delivery, and LV decompression. With cardiopulmonary bypass and cardioplegic arrest, CABG can be performed with video assistance on a still and decompressed heart through several small ports. In comparison with the MID-CAB, port access allows access to different areas of the heart, thus facilitating more complete revascularization, and the motionless heart may allow a more accurate anastomosis. Compared with conventional CABG, median sternotomy is avoided. However, potential morbidity of the port-access operation includes multiple wounds at port sites, the limited thoracotomy, and the groin dissection for femoral-femoral bypass. Vigorous scrutiny of the long-term benefits versus risks of port access is required.

B. Arterial and Alternate Conduits

Another area of evolving technology is the use of arterial and alternate conduits. The 5-year patency of coronary artery–vein bypass grafts is 74%, and at 10 years, just 41%. Contrariwise, patency rates of the internal mammary artery implanted into the LAD are as high as 83% at 10 years. As a consequence of improved patency, patients receiving an LAD graft with an internal mammary artery have improved survival compared with patients receiving only vein grafts. Currently, routine use of the left internal mammary artery for LAD grafting with supplemental saphenous vein grafts to other coronary lesions is generally accepted as a standard grafting method. The use of bilateral internal mammary arteries appears to be safe and efficacious. However, there is a higher rate of deep sternal wound infection when both internal mammary arteries are used. This is particularly true for patients with obesity and diabetes and perhaps for those requiring prolonged ventilatory support. The benefits of bilateral internal mammary artery use include lower rates of recurrent angina, MI, and need for reoperation and a trend for better survival. Recently, the radial artery has been used more frequently as a conduit for coronary bypass surgery. Five-year patency appears to be in the range of 85% (compared with nearly 90% for the internal mammary graft). In patients for whom mammary artery, radial artery, and standard vein conduits are unavailable, the in situ right gastroepiploic artery, the inferior epigastric free artery graft, and either lesser saphenous or upper-extremity vein conduits have been used. Long-term patency of these alternative grafts has not been extensively studied.

C. Percutaneous Technology

Technological improvements in percutaneous coronary angioplasty have included the introduction of new devices and improved medical therapy of patients in whom angioplasty is performed. The most notable improvement has been the introduction of intracoronary stents that have reduced late restenosis and the frequency with which emergency bypass surgery is required after PTCA. Intracoronary stents have been used to treat saphenous vein graft stenosis in patients with previous CABG. However, stented patients still have an ≈25% combined rate of death, MI, need for repeat CABG, or re-revascularization of the target vessel. For some patients, hybrid procedures may be the best choice, such as the combined use of CABG surgery and coronary angioplasty. Such an approach is relevant to the patient whose ascending aorta is involved with severe atherosclerosis, for which the implantation of free vein grafts or arterial grafts leads to risk for atheroembolism. In such a patient, the use of in situ internal mammary artery grafting without cardiopulmonary bypass combined with additional coronary angioplasty in other diseased vessels represents a strategy to provide complete revascularization without the concomitant risks of cardiopulmonary bypass and/or manipulation of the ascending aorta.

D. Transmyocardial Revascularization

A fourth area that is rapidly evolving is transmyocardial revascularization. The use of transmyocardial laser revascularization has generally been performed surgically for patients with severe angina refractory to medical therapy and who are not suitable candidates for standard surgical revascularization, PTCA, or heart transplant. While several studies have suggested improvement in angina severity with transmyocardial laser revascularization, the mechanism by which angina improves and the overall benefit on long-term angina and/or survival await further clarification.

VII. Special Patient Subsets

A. Elderly Patients

Elderly patients being considered for CABG have a higher average risk for mortality and morbidity in a direct relation to age, LV function, extent of coronary disease, and comorbid conditions and whether the procedure is urgent, emergent, or a reoperation. Nonetheless, functional recovery and sustained improvement in the quality of life can be achieved in the majority of such patients. The patient and physician together must explore the potential benefits of improved quality of life with the attendant risks of surgery versus alternative therapies that take into account baseline functional capacities and patient preferences. Age alone should not be a contraindication to CABG if it is thought that long-term benefits outweigh the procedural risk.

B. Women

A number of earlier reports had suggested that female sex was an independent risk factor for mortality and morbidity after CABG. More recent studies have suggested that women on average have a disadvantageous, preoperative clinical profile that accounts for much of this perceived difference. Thus, the issue is not necessarily sex itself but the comorbid conditions that are particularly associated with the later age at which women present for coronary surgery. Thus, CABG should not be delayed in or denied to women who have appropriate indications.

C. Diabetic Patients

Coronary heart disease is the leading cause of death among adult diabetics and accounts for 3 times as many deaths among diabetics as among nondiabetics. While CABG carries an increased morbidity and mortality in diabetics, data suggest that in appropriate candidates, the absolute risk reduction provided by successful revascularization remains high. The BARI trial suggested that diabetics with multivessel coronary disease derived advantage from bypass surgery compared with angioplasty. Several of the other randomized trials, albeit with smaller numbers of patients, failed to show this trend. Diabetics who are candidates for renal transplantation have a particularly high incidence of coronary artery disease, even in the absence of symptoms or signs. In appropriate candidates, CABG appears to offer morbidity and mortality benefit in such patients.

D. Patients With Chronic Obstructive Pulmonary Disease

Because CABG is associated with variable degrees of postoperative respiratory insufficiency, it is important to identify patients at particular risk for pulmonary complications. The intent is to treat reversible problems that may contribute to respiratory insufficiency in high-risk patients, with the hope of avoiding prolonged periods of mechanical ventilation after CABG. High-risk patients often benefit from preoperative antibiotics, bronchodilator therapy, a period of cessation from smoking, perioperative incentive spirometry, deep-breathing exercises, and chest physiotherapy. If pulmonary venous congestion or pleural effusions are identified, diuresis often improves lung performance.

Although preoperative spirometry directed to identifying patients with a low (eg, <1 L) 1-second forced expiratory volume has been used by some to qualify or disqualify candidates for CABG, clinical evaluation of lung function is likely as important if not more so. Patients with advanced chronic obstructive pulmonary disease are at particular risk for postoperative arrhythmias that may be fatal. While moderate to severe degrees of obstructive pulmonary disease represent a significant risk factor for early mortality and morbidity after CABG, it is also true that with careful preoperative assessment and treatment of the underlying pulmonary abnormality, many such patients are successfully carried through the operative procedure.

E. Patients With End-Stage Renal Disease

Coronary artery disease is the most important cause of mortality in patients with end-stage renal disease. Many of such patients have diabetes and other coronary risk factors, including hypertension, myocardial dysfunction, abnormal lipids, anemia, and increased plasma homocysteine levels. Although patients on chronic dialysis are at higher risk when undergoing coronary angioplasty or bypass, they are at even higher risk with conservative medical management. Thus, in patients with modest reductions in LV function, significant left main or 3-vessel disease, and/or unstable angina, coronary revascularization can lead to relief of coronary symptoms, improvement in overall functional status, and improved long-term survival in this select high-risk patient population.

F. Reoperative Patients

Operative survival and long-term benefit of reoperative CABG are distinctly inferior to first-time operations. Patients undergoing repeated CABG have higher rates of postoperative bleeding, perioperative MI, and neurological and pulmonary complications. Nevertheless, reasonable 5- and 10-year survival rates after reoperation for coronary disease can be achieved, and the operation is appropriate if the severity of symptoms and anticipated benefit justify the immediate risk. Data suggest that the need for reoperation is less common in patients undergoing internal mammary artery grafting to the LAD. More recently, short-term follow-up studies suggest that patients undergoing multiple arterial grafts have even lower rates of reoperation. These early results are consistent with the known superior graft patency of arterial conduits compared with vein grafts.

G. Concomitant Peripheral Vascular Disease

The presence of clinical and subclinical peripheral vascular disease is a strong predictor of increased hospital and long-term mortality rates in patients undergoing CABG. However, the absolute benefit offered by coronary revascularization is elevated in patients with peripheral vascular disease, particularly those with 3-vessel coronary disease, more advanced angina, and/or a depressed LVEF. Excess perioperative mortality in such patients is related to an increased incidence of heart failure and dysrhythmias rather than peripheral arterial complications.

H. Poor LV Function

Patients with severe LV dysfunction have increased perioperative and long-term mortality compared with patients with normal LV function. However, studies suggest that the beneficial effects of myocardial revascularization in patients with ischemic heart disease and severe LV dysfunction are sizeable when compared with medically treated patients of similar status in terms of symptom relief, exercise tolerance, and survival.

I. CABG in Acute Coronary Syndromes

Coronary bypass surgery offers a survival advantage compared with medical therapy in patients with unstable angina and LV dysfunction, particularly in the presence of 3-vessel disease. However, the risk of bypass surgery in patients with unstable or postinfarction angina or early after non–Q wave infarction and during acute MI is increased severalfold compared with patients with stable angina. Although this risk is not necessarily higher than that with medical therapy, it has led to the argument to consider angioplasty or to delay CABG in such patients if medical stabilization can be easily accomplished.

VIII. Institutional and Operator Competence

Studies suggest that mortality after CABG is higher when carried out in institutions that annually perform fewer than a minimum number of cases. Similar conclusions have been drawn regarding individual surgeons’ volumes. This observation strengthens the argument for careful outcome tracking and supports the monitoring of institutions or individuals who annually perform <100 cases. It is also true that there is a wide variation in risk-adjusted mortality rates in low-volume situations. Thus, some institutions and practitioners maintain excellent outcomes despite relatively low volumes.

Outcome reporting in the form of risk-adjusted mortality rates after bypass has been effective in reducing mortality rates nationwide. Public release of hospital and physician-specific mortality rates has not been shown to drive this improvement and has failed to effectively guide consumers or alter physician referral patterns.

IX. Cost-Effectiveness of Bypass Surgery

A variety of studies of CABG have found the technique to be cost-effective in patients for whom survival and/or symptomatic benefit is demonstrable. Within these subsets, the cost-effectiveness of CABG compares favorably with that of other accepted medical therapies.

When compared with PTCA, the initial hospital cost of CABG is significantly higher. However, by 5 years, the cumulative cost of PTCA compared with initial surgical therapy is within 5% of CABG, or a difference of <$3000. Observational studies showing a poorer survival effect of PTCA in patients with more advanced disease suggest that there may be a significant cost gradient for PTCA as the extent of disease increases, which is not apparent for coronary bypass surgery.

X. Indications

A. Indications for CABG in Asymptomatic or Mild Angina

Class I

1. Significant left main coronary artery stenosis.

2. Left main equivalent: significant (≥70%) stenosis of proximal LAD and proximal left circumflex artery.

3. Three-vessel disease. (Survival benefit is greater in patients with abnormal LV function; eg, with an EF <0.50.)

Class IIa

1. Proximal LAD stenosis with 1- or 2-vessel disease.*1

Class IIb

1. One- or 2-vessel disease not involving the proximal LAD.†2

Class III

See text.

B. Indications for CABG in Stable Angina

Class I

1. Significant left main coronary artery stenosis.

2. Left main equivalent: significant (≥70%) stenosis of proximal LAD and proximal left circumflex artery.

3. Three-vessel disease. (Survival benefit is greater when LVEF is <0.50.)

4. Two-vessel disease with significant proximal LAD stenosis and either EF <0.50 or demonstrable ischemia on noninvasive testing.

5. One- or 2-vessel coronary artery disease without significant proximal LAD stenosis, but with a large area of viable myocardium and high-risk criteria on noninvasive testing.

6. Disabling angina despite maximal medical therapy, when surgery can be performed with acceptable risk. If angina is not typical, objective evidence of ischemia should be obtained.

Class IIa

1. Proximal LAD stenosis with 1-vessel disease.*1

2. One- or 2-vessel coronary artery disease without significant proximal LAD stenosis, but with a moderate area of viable myocardium and demonstrable ischemia on noninvasive testing.

Class III

1. One- or 2-vessel disease not involving significant proximal LAD stenosis, in patients (1) who have mild symptoms that are unlikely due to myocardial ischemia or have not received an adequate trial of medical therapy and (A) have only a small area of viable myocardium or (B) have no demonstrable ischemia on noninvasive testing.

2. Borderline coronary stenoses (50% to 60% diameter in locations other than the left main coronary artery) and no demonstrable ischemia on noninvasive testing.

3. Insignificant (<50% diameter) coronary stenosis.

C. Indications for CABG in Unstable Angina/Non–Q Wave MI

Class I

1. Significant left main coronary artery stenosis.

2. Left main equivalent: significant (≥70%) stenosis of proximal LAD and proximal left circumflex artery.

3. Ongoing ischemia not responsive to maximal nonsurgical therapy.

Class IIa

1. Proximal LAD stenosis with 1- or 2-vessel disease.*1

Class IIb

2. One- or 2-vessel disease not involving the proximal LAD.†2

Class III

See text.

D. Indications for CABG in ST-Segment Elevation (Q-Wave) MI

Class I


Class IIa

1. Ongoing ischemia/infarction not responsive to maximal nonsurgical therapy.

Class IIb

1. Progressive LV pump failure with coronary stenosis compromising viable myocardium outside the initial infarct area.

2. Primary reperfusion in the early hours (≤6 to 12 hours) of an evolving ST-segment elevation MI.

Class III

1. Primary reperfusion late (≥12 hours) in evolving ST-segment elevation MI without ongoing ischemia.

E. Indications for CABG in Poor LV Function

Class I

1. Significant left main coronary artery stenosis.

2. Left main equivalent: significant (≥70%) stenosis of proximal LAD and proximal left circumflex artery.

3. Proximal LAD stenosis with 2- or 3-vessel disease.

Class IIa

1. Poor LV function with significant viable, noncontracting, revascularizable myocardium without any of the aforementioned anatomic patterns.

Class III

1. Poor LV function without evidence of intermittent ischemia and without evidence of significant revascularizable, viable myocardium.

F. Indications for CABG in Life-Threatening Ventricular Arrhythmias

Class I

1. Left main coronary artery stenosis.

2. Three-vessel coronary disease.

Class IIa

1. Bypassable 1- or 2-vessel disease causing life-threatening ventricular arrhythmias.‡3

2. Proximal LAD disease with 1- or 2-vessel disease.‡3

Class III

1. Ventricular tachycardia with scar and no evidence of ischemia.

G. Indications for CABG After Failed PTCA

Class I

1. Ongoing ischemia or threatened occlusion with significant myocardium at risk.

2. Hemodynamic compromise.

Class IIa

1. Foreign body in crucial anatomic position.

2. Hemodynamic compromise in patients with impairment of coagulation system and without previous sternotomy.

Class IIb

1. Hemodynamic compromise in patients with impairment of coagulation system and with previous sternotomy.

Class III

1. Absence of ischemia.

2. Inability to revascularize owing to target anatomy or no-reflow state.

H. Indications for CABG in Patients With Previous CABG

Class I

1. Disabling angina despite maximal noninvasive therapy. (If angina is not typical, then objective evidence of ischemia should be obtained.)

Class IIa

1. Bypassable distal vessel(s) with a large area of threatened myocardium on noninvasive studies.

Class IIb

1. Ischemia in the non-LAD distribution with a patent internal mammary graft to the LAD supplying functioning myocardium and without an aggressive attempt at medical management and/or percutaneous revascularization.

Class III

See text.


  • “ACC/AHA Guidelines for Coronary Artery Bypass Graft Surgery: Executive Summary and Recommendations: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1991 Guidelines for Coronary Artery Bypass Graft Surgery)” was approved by the American College of Cardiology Board of Trustees in March 1999 and by the American Heart Association Science Advisory and Coordinating Committee in July 1999.

  • When citing this document, the American College of Cardiology and the American Heart Association request that the following citation format be used: Eagle KA, Guyton RA, Davidoff R, Ewy GA, Fonger J, Gardner TJ, Gott JP, Herrmann HC, Marlow RA, Nugent W, O’Connor GT, Orszulak TA, Rieselbach RE, Winters WL, Yusuf S. ACC/AHA guidelines for coronary artery bypass graft surgery: executive summary and recommendations: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1991 Guidelines for Coronary Artery Bypass Graft Surgery). Circulation. 1999;100:1464-1480.

  • This document is available on the World Wide Web sites of the American College of Cardiology (www.acc.org) and the American Heart Association (www.americanheart.org). A single reprint of the executive summary and recommendations is available by calling 800-242-8721 (US only) or writing the American Heart Association, Public Information, 7272 Greenville Ave, Dallas, TX 75231-4596. Ask for reprint No. 71-0173. To obtain a reprint of the complete guidelines published in the October 1999 issue of the Journal of the American College of Cardiology, ask for reprint No. 71-0174. To purchase additional reprints (specify version and reprint number): up to 999 copies, call 800-611-6083 (US only) or fax 413-665-2671; 1000 or more copies, call 214-706-1466, fax 214-691-6342, or . To make photocopies for personal or educational use, call the Copyright Clearance Center, 978-750-8400.

  • 1 Becomes Class I if extensive ischemia documented by noninvasive study and/or an LVEF <0.50.

  • 2 If a large area of viable myocardium and high-risk criteria on noninvasive testing, becomes Class I.

  • 3 Becomes Class I if arrhythmia is resuscitated sudden cardiac death or sustained ventricular tachycardia.

  • CPB indicates cardiopulmonary bypass.

  • Data taken from (1) Townsend TR, Reitz BA, Bilker WB, Bartlett JG. Clinical trial of cefamandole, cefazolin, and cefuroxime for antibiotic prophylaxis in cardiac operations. J Thorac Cardiovasc Surg. 1993;106:664–670. (2) Antimicrobial prophylaxis in surgery. Med Lett Drugs Ther. 1997;39:97–101. (3) Vuorisalo S, Pokela R, Syrjala H. Comparison of vancomycin and cefuroxime for infection prophylaxis in coronary artery bypass surgery. Infect Control Hosp Epidemiol. 1998;19:234–239. (4) Romanelli VA, Howie MB, Myerowitz PD, Zvara DA, Rezaei A, Jackman DL, Sinclair DS, McSweeny TD. Intraoperative and postoperative effects of vancomycin administration in cardiac surgery patients: a prospective, double-blind, randomized trial. Crit Care Med. 1993;21:1124–1131.

Articles citing this article

  • Postoperative cognitive dysfunction after cardiac surgeryContin Educ Anaesth Crit Care Pain. 2013;0:mkt022v1-mkt022,
  • Atherosclerotic Changes in Common Carotid Artery, Common Femoral Artery, and Ascending Aorta/Aortic Arch in Candidates for Coronary Artery Bypass Graft SurgeryANGIOLOGY. 2012;63:630-631,
  • Impact of chronic obstructive pulmonary disease severity on surgical outcomes in patients undergoing non-emergent coronary artery bypass graftingEur J Cardiothorac Surg. 2012;42:108-113,
  • Impact of obesity on outcome of patients undergoing off-pump coronary artery bypass grafting using aorta no-touch techniqueInteract CardioVasc Thorac Surg. 2010;11:234-237,
  • Prevalence of Asymptomatic Coronary Artery Disease in Ischemic Stroke Patients: The PRECORIS StudyCirculation. 2010;121:1623-1629,
  • Is there any difference in carotid stenosis between male and female patients undergoing coronary artery bypass grafting?Interact CardioVasc Thorac Surg. 2009;9:823-826,
  • Selective Screening for Asymptomatic Carotid Artery Disease Prior to Isolated Heart Valve SurgeryANGIOLOGY. 2009;60:633-636,
  • Off-Pump Coronary Revascularization for Left Main Coronary Artery StenosisAsian Cardiovascular and Thoracic Annals. 2008;16:473-478,
  • Risk Stratification Models for Cardiac SurgerySEMIN CARDIOTHORAC VASC ANESTH. 2008;12:167-174,
  • Prognostic value of Doppler-derived mitral deceleration time on left ventricular reverse remodelling after undersized mitral annuloplastyEur Heart J Cardiovasc Imaging. 2008;9:631-640,
  • Medication Adherence following Coronary Artery Bypass Graft Surgery: Assessment of Beliefs and AttitudesAnn Pharmacother. 2008;42:192-199,
  • Staged Carotid Angioplasty and Stenting Followed by Cardiac Surgery in Patients With Severe Asymptomatic Carotid Artery Stenosis: Early and Long-Term ResultsCirculation. 2007;116:2036-2042,
  • Risk of Coronary and Other Nonstroke Vascular Death in Relation to the Presence and Extent of Atherosclerotic Disease at the Carotid BifurcationStroke. 2006;37:2904-2909,
  • Perioperative Amino Acid Infusion Improves Recovery and Shortens the Duration of Hospitalization After Off-Pump Coronary Artery Bypass GraftingAnesth. Analg.. 2006;103:1386-1393,
  • Assessment of Coronary Artery Disease by Cardiac Computed Tomography: A Scientific Statement From the American Heart Association Committee on Cardiovascular Imaging and Intervention, Council on Cardiovascular Radiology and Intervention, and Committee on Cardiac Imaging, Council on Clinical CardiologyCirculation. 2006;114:1761-1791,
  • Outcomes in off-pump vs. on-pump coronary artery bypass grafting stratified by pre-operative risk profile: an assessment using propensity scoreEur Heart J. 2006;27:2473-2480,
  • Isolated and Significant Left Main Coronary Artery Disease: Demographics, Hemodynamics and Angiographic FeaturesANGIOLOGY. 2006;57:464-477,
  • Risk factor awareness and secondary prevention of coronary artery disease: are we doing enough?Interact CardioVasc Thorac Surg. 2006;5:268-271,
  • Left Main Coronary Revascularization at the CrossroadsCirculation. 2006;113:2480-2484,
  • Impact of avoiding cardiopulmonary bypass for coronary surgery on perioperative cardiac enzyme release and survivalEur J Cardiothorac Surg. 2006;29:729-735,
  • Comparison of 19 pre-operative risk stratification models in open-heart surgeryEur Heart J. 2006;27:867-874,
  • Determinants of Morbidity and Intensive Care Unit Stay after Coronary SurgeryAsian Cardiovascular and Thoracic Annals. 2006;14:114-118,
  • Risk of Myocardial Infarction and Vascular Death After Transient Ischemic Attack and Ischemic Stroke: A Systematic Review and Meta-AnalysisStroke. 2005;36:2748-2755,
  • Assessing the risk of waiting for coronary artery bypass graft surgery among patients with stenosis of the left main coronary arteryCMAJ. 2005;173:371-375,
  • Mental Disorders and Revascularization Procedures in a Commercially Insured SamplePsychosom. Med.. 2005;67:568-576,
  • Left internal mammary artery use in patients with poor left ventricular ejection fraction: a propensity-matched analysis of mid-term survivalInteract CardioVasc Thorac Surg. 2005;4:184-188,
  • Influence of Racial Disparities in Procedure Use on Functional Status Outcomes Among Patients With Coronary Artery DiseaseCirculation. 2005;111:1284-1290,
  • 2004 Carolyn Sherif Award Address: Heart Disease and Gender InequityPsychology of Women Quarterly. 2005;29:15-23,
  • In vitro differences between venous and arterial-derived smooth muscle cells: potential modulatory role of decorinCardiovasc Res. 2005;65:702-710,
  • External validation of compliance to perfusion quality indicatorsPerfusion. 2004;19:295-299,
  • Expression of Angiogenic Factors During Acute Coronary Syndromes in Human Type 2 DiabetesDiabetes. 2004;53:2383-2391,
  • Influence of obesity on in-hospital and early mortality and morbidity after myocardial revascularizationEur J Cardiothorac Surg. 2004;26:535-541,
  • Concomitant Peripheral Arterial Disease and Coronary Artery Disease: Therapeutic OpportunitiesCirculation. 2004;109:3136-3144,
  • Factor V Leiden and Perioperative RiskAnesth. Analg.. 2004;98:1623-1634,
  • Isolated high-grade lesion of the proximal LAD: a stent or off-pump LIMA?Eur J Cardiothorac Surg. 2004;25:567-571,
  • Treatment of Inoperable Coronary Disease and Refractory Angina: Spinal Stimulators, Epidurals, Gene Therapy, Transmyocardial Laser, and CounterpulsationSEMIN CARDIOTHORAC VASC ANESTH. 2004;8:43-58,
  • The midlands trial of empirical amiodarone versus electrophysiology-guided interventions and implantable cardioverter-defibrillators (MAVERIC): a multi-centre prospective randomised clinical trial on the secondary prevention of sudden cardiac deathEuropace. 2004;6:257-266,
  • Patterns of Secondary Prevention in Older Patients Undergoing Coronary Artery Bypass Grafting During Hospitalization for Acute Myocardial InfarctionCirculation. 2003;108:II-24-II-28,
  • Coronary Risk Evaluation in Patients With Transient Ischemic Attack and Ischemic Stroke: A Scientific Statement for Healthcare Professionals From the Stroke Council and the Council on Clinical Cardiology of the American Heart Association/American Stroke AssociationCirculation. 2003;108:1278-1290,
  • Clinical Profiles and Outcomes of Acute Type B Aortic Dissection in the Current Era: Lessons From the International Registry of Aortic Dissection (IRAD)Circulation. 2003;108:II-312-II-317,
  • Coronary Risk Evaluation in Patients With Transient Ischemic Attack and Ischemic Stroke: A Scientific Statement for Healthcare Professionals From the Stroke Council and the Council on Clinical Cardiology of the American Heart Association/American Stroke AssociationStroke. 2003;34:2310-2322,
  • An evaluation of existing risk stratification models as a tool for comparison of surgical performances for coronary artery bypass grafting between institutionsEur J Cardiothorac Surg. 2003;23:935-942,
  • Validation of four different risk stratification systems in patients undergoing off-pump coronary artery bypass surgery: a UK multicentre analysis of 2223 patientsHeart. 2003;89:432-435,
  • The effect of obesity on mid-term survival following coronary artery bypass surgeryEur J Cardiothorac Surg. 2003;23:368-373,
  • Total arterial revascularisation as a primary strategy for coronary artery bypass graftingPostgrad. Med. J.. 2003;79:43-48,
  • Neurocognitive Sequelae Following Coronary Artery Bypass Graft: A Research Agenda for Behavioral ScientistsBehav Modif. 2003;27:68-82,
  • Risk of morbidity and in-hospital mortality in obese patients undergoing coronary artery bypass surgeryEur J Cardiothorac Surg. 2002;22:787-793,
  • The effect off-pump coronary artery bypass surgery on in-hospital mortality and morbidityEur J Cardiothorac Surg. 2002;22:255-260,
  • ACC/AHA Guideline Update for Perioperative Cardiovascular Evaluation for Noncardiac Surgery–Executive Summary A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1996 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery)Circulation. 2002;105:1257-1267,
  • Predicting Death in Patients With Acute Type A Aortic DissectionCirculation. 2002;105:200-206,
  • A Simple Method to Determine Anastomotic Quality of Coronary Artery Bypass Grafting in the Operating RoomVascular. 2001;9:499-503,
  • Admission Plasma Glucose: An independent risk factor in nondiabetic women after coronary artery bypass graftingDiabetes Care. 2001;24:1634-1639,
  • Stroke in Relation to Cardiac Procedures in Patients With Non-ST-Elevation Acute Coronary Syndrome: A Study Involving >18 000 PatientsCirculation. 2001;104:269-274,
  • Simple Bedside Additive Tool for Prediction of In-Hospital Mortality After Percutaneous Coronary InterventionsCirculation. 2001;104:263-268,
  • Off-pump coronary artery bypass surgery for critical left main stem disease: safety, efficacy and outcomeEur J Cardiothorac Surg. 2001;19:239-244,
  • Predicting the Risk of Death from Heart Failure After Coronary Artery Bypass Graft SurgeryAnesth. Analg.. 2001;92:596-601,
  • Guideline for the management of patients with acute coronary syndromes without persistent ECG ST segment elevationHeart. 2001;85:133-142,
  • Effects of a Residential Exercise Training on Baroreflex Sensitivity and Heart Rate Variability in Patients With Coronary Artery Disease : A Randomized, Controlled StudyCirculation. 2000;102:2588-2592,


Read Full Post »

Genetic Analysis of Atrial Fibrillation

Author and Curator: Larry H Bernstein, MD, FCAP  


Curator: Aviva-Lev Ari, PhD, RN

This article is a followup of the wonderful study of the effect of oxidation of a methionine residue in calcium dependent-calmodulin kinase Ox-CaMKII on stabilizing the atrial cardiomyocyte, giving protection from atrial fibrillation.  It is also not so distant from the work reviewed, mostly on the ventricular myocyte and the calcium signaling by initiation of the ryanodyne receptor (RyR2) in calcium sparks and the CaMKII d isoenzyme.

We refer to the following related articles published in pharmaceutical Intelligence:

Oxidized Calcium Calmodulin Kinase and Atrial Fibrillation
Author: Larry H. Bernstein, MD, FCAP and Curator: Aviva Lev-Ari, PhD, RN

Jmjd3 and Cardiovascular Differentiation of Embryonic Stem Cells

Author: Larry H. Bernstein, MD, FCAP and Curator: Aviva Lev-Ari, PhD, RN


Contributions to cardiomyocyte interactions and signaling
Author and Curator: Larry H Bernstein, MD, FCAP  and Curator: Aviva Lev-Ari, PhD, RN

Cardiac Contractility & Myocardium Performance: Therapeutic Implications for Ryanopathy (Calcium Release-related Contractile Dysfunction) and Catecholamine Responses
Editor: Justin Pearlman, MD, PhD, FACC, Author and Curator: Larry H Bernstein, MD, FCAP, and Article Curator: Aviva Lev-Ari, PhD, RN

Part I. Identification of Biomarkers that are Related to the Actin Cytoskeleton
Curator and Writer: Larry H Bernstein, MD, FCAP

Part II: Role of Calcium, the Actin Skeleton, and Lipid Structures in Signaling and Cell Motility
Larry H. Bernstein, MD, FCAP, Stephen Williams, PhD and Aviva Lev-Ari, PhD, RN

Part IV: The Centrality of Ca(2+) Signaling and Cytoskeleton Involving Calmodulin Kinases and Ryanodine Receptors in Cardiac Failure, Arterial Smooth Muscle, Post-ischemic Arrhythmia, Similarities and Differences, and Pharmaceutical Targets
Larry H Bernstein, MD, FCAP, Justin Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN

Part VI: Calcium Cycling (ATPase Pump) in Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension and Percutaneous Intra-coronary Artery Infusion for Heart Failure: Contributions by Roger J. Hajjar, MD
Aviva Lev-Ari, PhD, RN

Part VII: Cardiac Contractility & Myocardium Performance: Ventricular Arrhythmias and Non-ischemic Heart Failure – Therapeutic Implications for Cardiomyocyte Ryanopathy (Calcium Release-related Contractile Dysfunction) and Catecholamine Responses
Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

Part VIII: Disruption of Calcium Homeostasis: Cardiomyocytes and Vascular Smooth Muscle Cells: The Cardiac and Cardiovascular Calcium Signaling Mechanism
Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

Part IX: Calcium-Channel Blockers, Calcium Release-related Contractile Dysfunction (Ryanopathy) and Calcium as Neurotransmitter Sensor
Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

Part X: Synaptotagmin functions as a Calcium Sensor: How Calcium Ions Regulate the fusion of vesicles with cell membranes during Neurotransmission
Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

The material presented is very focused, and cannot be found elsewhere in Pharmaceutical Intelligence with respedt to genetics and heart disease.  However, there are other articles that may be of interest to the reader.

Volume Three: Etiologies of Cardiovascular Diseases – Epigenetics, Genetics & Genomics

Curators: Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

PART 3.  Determinants of Cardiovascular Diseases: Genetics, Heredity and Genomics Discoveries

3.2 Leading DIAGNOSES of Cardiovascular Diseases covered in Circulation: Cardiovascular Genetics, 3/2010 – 3/2013

The Diagnoses covered include the following – relevant to this discussion

  • MicroRNA in Serum as Bimarker for Cardiovascular Pathologies: acute myocardial infarction, viral myocarditis, diastolic dysfunction, and acute heart failure
  • Genomics of Ventricular arrhythmias, A-Fib, Right Ventricular Dysplasia, Cardiomyopathy
  • Heredity of Cardiovascular Disorders Inheritance

3.2.1: Heredity of Cardiovascular Disorders Inheritance

The implications of heredity extend beyond serving as a platform for genetic analysis, influencing diagnosis,

  1. prognostication, and
  2. treatment of both index cases and relatives, and
  3. enabling rational targeting of genotyping resources.

This review covers acquisition of a family history, evaluation of heritability and inheritance patterns, and the impact of inheritance on subsequent components of the clinical pathway.

SOURCE:   Circulation: Cardiovascular Genetics.2011; 4: 701-709.  http://dx.doi.org/10.1161/CIRCGENETICS.110.959379

3.2.2: Myocardial Damage MicroRNA in Serum as Biomarker for Cardiovascular Pathologies: acute myocardial infarction, viral myocarditis,  diastolic dysfunction, and acute heart failure

Increased MicroRNA-1 and MicroRNA-133a Levels in Serum of Patients With Cardiovascular Disease Indicate Myocardial Damage
Y Kuwabara, Koh Ono, T Horie, H Nishi, K Nagao, et al.
SOURCE:  Circulation: Cardiovascular Genetics. 2011; 4: 446-454   http://dx.doi.org/10.1161/CIRCGENETICS.110.958975 Circulating MicroRNA-208b and MicroRNA-499 Reflect Myocardial Damage in Cardiovascular Disease

MF Corsten, R Dennert, S Jochems, T Kuznetsova, Y Devaux, et al.
SOURCE: Circulation: Cardiovascular Genetics. 2010; 3: 499-506.  http://dx.doi.org/10.1161/CIRCGENETICS.110.957415 Large-Scale Candidate Gene Analysis in Whites and African Americans Identifies IL6R Polymorphism in Relation to Atrial Fibrillation

The National Heart, Lung, and Blood Institute’s Candidate Gene Association Resource (CARe) Project
RB Schnabel, KF Kerr, SA Lubitz, EL Alkylbekova, et al.
SOURCE:  Circulation: Cardiovascular Genetics.2011; 4: 557-564   http://dx.doi.org/10.1161/CIRCGENETICS.110.959197

 Weighted Gene Coexpression Network Analysis of Human Left Atrial Tissue Identifies Gene Modules Associated With Atrial Fibrillation

N Tan, MK Chung, JD Smith, J Hsu, D Serre, DW Newton, L Castel, E Soltesz, G Pettersson, AM Gillinov, DR Van Wagoner and J Barnard
From the Cleveland Clinic Lerner College of Medicine (N.T.), Department of Cardiovascular Medicine (M.K.C., D.W.N.), and Department of Thoracic & Cardiovascular Surgery (E.S., G.P., A.M.G.); and Department of Cellular & Molecular Medicine (J.D.S., J.H.), Genomic Medicine Institute (D.S.), Department of Molecular Cardiology (L.C.), and Department of Quantitative Health Sciences (J.B.), Cleveland Clinic Lerner Research Institute, Cleveland, OH
Circ Cardiovasc Genet. 2013;6:362-371; http://dx.doi.org/10.1161/CIRCGENETICS.113.000133
http://circgenetics.ahajournals.org/content/6/4/362   The online-only Data Supplement is available at http://circgenetics.ahajournals.org/lookup/suppl/doi:10.1161/CIRCGENETICS.113.000133/-/DC1

Background—Genetic mechanisms of atrial fibrillation (AF) remain incompletely understood. Previous differential expression studies in AF were limited by small sample size and provided limited understanding of global gene networks, prompting the need for larger-scale, network-based analyses.

Methods and Results—Left atrial tissues from Cleveland Clinic patients who underwent cardiac surgery were assayed using Illumina Human HT-12 mRNA microarrays. The data set included 3 groups based on cardiovascular comorbidities: mitral valve (MV) disease without coronary artery disease (n=64), coronary artery disease without MV disease (n=57), and lone AF (n=35). Weighted gene coexpression network analysis was performed in the MV group to detect modules of correlated genes. Module preservation was assessed in the other 2 groups. Module eigengenes were regressed on AF severity or atrial rhythm at surgery. Modules whose eigengenes correlated with either AF phenotype were analyzed for gene content. A total of 14 modules were detected in the MV group; all were preserved in the other 2 groups. One module (124 genes) was associated with AF severity and atrial rhythm across all groups. Its top hub gene, RCAN1, is implicated in calcineurin-dependent signaling and cardiac hypertrophy. Another module (679 genes) was associated with atrial rhythm in the MV and coronary artery disease groups. It was enriched with cell signaling genes and contained cardiovascular developmental genes including TBX5.

Conclusions—Our network-based approach found 2 modules strongly associated with AF. Further analysis of these modules may yield insight into AF pathogenesis by providing novel targets for functional studies. (Circ Cardiovasc Genet. 2013;6:362-371.)

Key Words: arrhythmias, cardiac • atrial fibrillation • bioinformatics • gene coexpression • gene regulatory networks • genetics • microarrays


trial fibrillation (AF) is the most common sustained car­diac arrhythmia, with a prevalence of ≈1% to 2% in the general population.1,2 Although AF may be an isolated con­dition (lone AF [LAF]), it often occurs concomitantly with other cardiovascular diseases, such as coronary artery disease (CAD) and valvular heart disease.1 In addition, stroke risk is increased 5-fold among patients with AF, and ischemic strokes attributed to AF are more likely to be fatal.1 Current antiarrhythmic drug therapies are limited in terms of efficacy and safety.1,3,4 Thus, there is a need to develop better risk pre­diction tools as well as mechanistically targeted therapies for AF. Such developments can only come about through a clearer understanding of its pathogenesis.

Family history is an established risk factor for AF. A Danish Twin Registry study estimated AF heritability at 62%, indicating a significant genetic component.5 Substantial progress has been made to elucidate this genetic basis. For example, genome-wide association studies (GWASs) have identified several susceptibil­ity loci and candidate genes linked with AF. Initial studies per­formed in European populations found 3 AF-associated genomic loci.6–9 Of these, the most significant single-nucleotide polymor-phisms (SNPs) mapped to an intergenic region of chromosome 4q25. The closest gene in this region, PITX2, is crucial in left-right asymmetrical development of the heart and thus seems promising as a major player in initiating AF.10,11 A large-scale GWAS meta-analysis discovered 6 additional susceptibility loci, implicating genes involved in cardiopulmonary development, ion transport, and cellular structural integrity.12

Differential expression studies have also provided insight into the pathogenesis of AF. A study by Barth et al13 found that about two-thirds of the genes expressed in the right atrial appendage were downregulated during permanent AF, and that many of these genes were involved in calcium-dependent signaling pathways. In addition, ventricular-predominant genes were upregulated in right atrial appendages of sub­jects with AF.13 Another study showed that inflammatory and transcription-related gene expression was increased in right atrial appendages of subjects with AF versus controls.14 These results highlight the adaptive responses to AF-induced stress and ischemia taking place within the atria.

Despite these advances, much remains to be discovered about the genetic mechanisms of AF. The AF-associated SNPs found thus far only explain a fraction of its heritability15; furthermore, the means by which the putative candidate genes cause AF have not been fully established.9,15,16 Additionally, previous dif­ferential expression studies in human tissue were limited to the right atrial appendage, had small sample sizes, and provided little understanding of global gene interactions.13,14 Weighted gene coexpression network analysis (WGCNA) is a technique to construct gene modules within a network based on correla­tions in gene expression (ie, coexpression).17,18 WGCNA has been used to study genetically complex diseases, such as meta­bolic syndrome,19 schizophrenia,20 and heart failure.21 Here, we obtained mRNA expression profiles from human left atrial appendage tissue and implemented WGCNA to identify gene modules associated with AF phenotypes.


Subject Recruitment

From 2001 to 2008, patients undergoing cardiac surgery at the Cleveland Clinic were prospectively screened and recruited. Informed consent for research use of discarded atrial tissues was ob­tained from each patient by a study coordinator during the presur­gical visit. Demographic and clinical data were obtained from the Cardiovascular Surgery Information Registry and by chart review. Use of human atrial tissues was approved by the Institutional Review Board of the Cleveland Clinic.

Table S1: Clinical definitions of cardiovascular phenotype groups

Criterion Type Mitral Valve (MV) Disease Coronary Artery Disease (CAD) Lone Atrial Fibrillation (LAF)
Inclusion Criteria Surgical indication – Surgical indication – History of atrial fibrillation
mitral valve repair or replacement coronary artery bypass graft
Surgical indication
– MAZE procedure
Preserved ejection fraction (≥50%)
Exclusion Criteria Significant coronary artery disease: Significant mitral valve disease: Significant
coronary artery
– Significant (≥50%) stenosis – Documented echocardiography disease:
 in at least finding of – Significant
one coronary artery  mitral regurgitation (≥3) or (≥50%) stenosis in
via cardiac catheterization mitral stenosis at least one
– History of revascularization – History of mitral valve coronary artery via
(percutaneous coronary intervention or coronary artery bypass graft surgery)  repair or replacement cardiac catheterization
– History of revascularization
(percutaneous coronary intervention or coronary artery bypass graft surgery)
Significant valvular heart disease:
-Documented echocardiography finding of valvular regurgitation (≥3) or stenosis
-History of valve repair or replacement

RNA Microarray Isolation and Profiling

Left atria appendage specimens were dissected during cardiac surgery and stored frozen at −80°C. Total RNA was extracted using the Trizol technique. RNA samples were processed by the Cleveland Clinic Genomics Core. For each sample, 250-ng RNA was reverse tran­scribed into cRNA and biotin-UTP labeled using the TotalPrep RNA Amplification Kit (Ambion, Austin, TX). cRNA was quantified using a Nanodrop spectrophotometer, and cRNA size distribution was as­sessed on a 1% agarose gel. cRNA was hybridized to Illumina Human HT-12 Expression BeadChip arrays (v.3). Arrays were scanned using a BeadArray reader.

Expression Data Preprocessing

Raw expression data were extracted using the beadarray package in R, and bead-level data were averaged after log base-2 transformation. Background correction was performed by fitting a normal-gamma deconvolution model using the NormalGamma R package.22 Quantile normalization and batch effect adjustment with the ComBat method were performed using R.23 Probes that were not detected (at a P<0.05 threshold) in all samples as well as probes with relatively lower vari­ances (interquartile range ≤log2[1.2]) were excluded.

The WGCNA approach requires that genes be represented as sin­gular nodes in such a network. However, a small proportion of the genes in our data have multiple probe mappings. To facilitate the representation of singular genes within the network, a probe must be selected to represent its associated gene. Hence, for genes that mapped to multiple probes, the probe with the highest mean expres­sion level was selected for analysis (which often selects the splice isoform with the highest expression and signal-to-noise ratio), result­ing in a total of 6168 genes.

Defining Training and Test Sets

Currently, no large external mRNA microarray data from human left atrial tissues are publicly available. To facilitate internal validation of results, we divided our data set into 3 groups based on cardiovascular comorbidities: mitral valve (MV) disease without CAD (MV group; n=64), CAD without MV disease (CAD group; n=57), and LAF (LAF group; n=35). LAF was defined as the presence of AF without concomitant structural heart disease, according to the guidelines set by the European Society of Cardiology.1 The MV group, which was the largest and had the most power for detecting significant modules, served as the training set for module derivation, whereas the other 2 groups were designated test sets for module reproducibility. To mini­mize the effect of population stratification, the data set was limited to white subjects. Differences in clinical characteristics among the groups were assessed using Kruskal–Wallis rank-sum tests for con­tinuous variables and Pearson x2 test for categorical variables.

Weight Gene Coexpression Network Analysis

WGCNA is a systems-biology method to identify and characterize gene modules whose members share strong coexpression. We applied previously validated methodology in this analysis.17 Briefly, pair-wise gene (Pearson) correlations were calculated using the MV group data set. A weighted adjacency matrix was then constructed. I is a soft-thresholding pa­rameter that provides emphasis on stronger correlations over weaker and less meaningful ones while preserving the continuous nature of gene–gene relationships. I=3 was selected in this analysis based on the criterion outlined by Zhang and Horvath17 (see the online-only Data Supplement).

Next, the topological overlap–based dissimilarity matrix was com­puted from the weighted adjacency matrix. The topological overlap, developed by Ravasz et al,24 reflects the relative interconnectedness (ie, shared neighbors) between 2 genes.17 Hence, construction of the net­work dendrogram based on this dissimilarity measure allows for the identification of gene modules whose members share strong intercon-nectivity patterns. The WGCNA cutreeDynamic R function was used to identify a suitable cut height for module identification via an adap­tive cut height selection approach.18 Gene modules, defined as branches of the network dendrogram, were assigned colors for visualization.

Network Preservation Analysis

Module preservation between the MV and CAD groups as well as the MV and LAF groups was assessed using network preservation statis­tics as described in Langfelder et al.25 Module density–based statistics (to assess whether genes in each module remain highly connected in the test set) and connectivity-based statistics (to assess whether con­nectivity patterns between genes in the test set remain similar com­pared with the training set) were considered in this analysis.25 In each comparison, a Z statistic representing a weighted summary of module density and connectivity measures was computed for every module (Zsummary). The Zsummary score was used to evaluate module preserva­tion, with values ≥8 indicating strong preservation, as proposed by Langfelder et al.25 The WGCNA R function network preservation was used to implement this analysis.25

Table S2: Network preservation analysis between the MV and CAD groups – size and Zsummary scores of gene modules detected.

Module Module Size


Black 275 15.52
Blue 964 44.79
Brown 817 12.80
Cyan 119 13.42
Green 349 14.27
Green-Yellow 215 19.31
Magenta 239 15.38
Midnight-Blue 83 15.92
Pink 252 23.31
Purple 224 16.96
Red 278 17.30
Salmon 124 13.84
Tan 679 28.48
Turquoise 1512 44.03

Table S3: Network preservation analysis between the MV and LAF groups – size and Zsummary scores of gene modules detected

Module Module Size ZSummary
Black 275 13.14
Blue 964 39.26
Brown 817 14.98
Cyan 119 11.46
Green 349 14.91
Green-Yellow 215 20.99
Magenta 239 18.58
Midnight-Blue 83 13.87
Pink 252 19.10
Purple 224 8.80
Red 278 16.62
Salmon 124 11.57
Tan 679 28.61
Turquoise 1512 42.07

Clinical Significance of Preserved Modules

Principal component analysis of the expression data for each gene module was performed. The first principal component of each mod­ule, designated the eigengene, was identified for the 3 cardiovascular disease groups; this served as a summary expression measure that explained the largest proportion of the variance of the module.26 Multivariate linear regression was performed with the module ei-gengenes as the outcome variables and AF severity (no AF, parox­ysmal AF, persistent AF, permanent AF) as the predictor of interest (adjusting for age and sex). A similar regression analysis was per­formed with atrial rhythm at surgery (no AF history, AF history in sinus rhythm, AF history in AF rhythm) as the predictor of interest. The false discovery rate method was used to adjust for multiple com­parisons. Modules whose eigengenes associated with AF severity and atrial rhythm were identified for further analysis.

In addition, hierarchical clustering of module eigengenes and se­lected clinical traits (age, sex, hypertension, cholesterol, left atrial size, AF state, and atrial rhythm) was used to identify additional module–trait associations. Clusters of eigengenes/traits were detected based on a dissimilarity measure D, as given by

D=1−cor(Vi,Vj),i≠j                                                                              (3)

where V=the eigengene or clinical trait.

Enrichment Analysis

Gene modules significantly associated with AF severity and atrial rhythm were submitted to Ingenuity Pathway Analysis (IPA) to determine enrichment for functional/disease categories. IPA is an application of gene set over-representation analysis; for each dis-ease/functional category annotation, a P value is calculated (using Fisher exact test) by comparing the number of genes from the mod­ule of interest that participate in the said category against the total number of participating genes in the background set.27 All 6168 genes in the current data set served as the background set for the enrichment analysis.

Hub Gene Analysis

Hub genes are defined as genes that have high intramodular connectivity17,20

Alternatively, they may also be defined as genes with high module membership21,25

Both definitions were used to identify the hub genes of modules associated with AF phenotype.

To confirm that the hub genes identified were themselves associ­ated with AF phenotype, the expression data of the top 10 hub genes (by intramodular connectivity) were regressed on atrial rhythm (ad­justing for age and sex). In addition, eigengenes of AF-associated modules were regressed on their respective (top 10) hub gene expres­sion profiles, and the model R2 indices were computed.

Membership of AF-Associated Candidate Genes From Previous Studies

Previous GWAS studies identified multiple AF-associated SNPs.8,9,12,15,28 We selected candidate genes closest to or containing these SNPs and identified their module locations as well as their clos­est within-module partners (absolute Pearson correlations).

Sensitivity Analysis of Soft-Thresholding Parameter

To verify that the key results obtained from the above analysis were robust with respect to the chosen soft-thresholding parameter (I=3), we repeated the module identification process using I=5. The eigen-genes of the detected modules were computed and regressed on atrial rhythm (adjusting for age and sex). Modules significantly associated with atrial rhythm in ≥2 groups of data set were compared with the AF phenotype–associated modules from the original analysis.


Subject Characteristics

Table 1 describes the clinical characteristics of the cardiac surgery patients who were recruited for the study. Subjects in the LAF group were generally younger and less likely to be a current smoker (P=2.0×10−4 and 0.032, respectively). Subjects in the MV group had lower body mass indices (P=2.7×10−6), and a larger proportion had paroxysmal AF compared with the other 2 groups (P=0.033).

Table 1. Clinical Characteristics of Study Subjects


MV Group (n=64)

CAD Group (n=57)

LAF Group (n=35)

P Value*

Age, median y (1st–3rd quartiles)

60 (51.75–67.25)

64 (58.00–70.00)

56 (45.50–60.50)


Sex, female (%) 19 (29.7) 6 (10.5)

7 (20.0)


BMI, median (1st–3rd quartiles)

25.97 (24.27–28.66)

29.01 (27.06–32.11)

29.71 (26.72–35.10)


Current smoker (%) 29 (45.3) 35 (61.4)

12 (21.1)


Hypertension (%) 21 (32.8) 39 (68.4)

16 (45.7)


AF severity (%)
No AF 7 (10.9) 7 (12.3)

0 (0.0)


Paroxysmal 19 (29.7) 10 (17.5)

7 (20.0)

Persistent 30 (46.9) 26 (45.6)

15 (42.9)

Permanent 8 (12.5) 14 (24.6)

13 (37.1)

Atrial rhythm at surgery (%)
No AF history in sinus rhythm 7 (10.9) 7 (12.3)

0 (0)


AF history in sinus rhythm 28 (43.8) 16 (28.1)

11 (31.4)

AF History in AF rhythm 29 (45.3) 34 (59.6)

24 (68.6)

Gene Coexpression Network Construction and Module Identificationsee document at  http://circgenetics.ahajournals.org/content/6/4/362

A total of 14 modules were detected using the MV group data set (Figure 1), with module sizes ranging from 83 genes to 1512 genes; 38 genes did not share similar coexpression with the other genes in the network and were therefore not included in any of the identified modules

Figure 1. Network dendrogram (top) and colors of identified modules (bottom).

Figure 1. Network dendrogram (top) and colors of identified modules (bottom). The dendrogram was constructed using the topological overlap matrix as the similarity measure. Modules corresponded to branches of the dendrogram and were assigned colors for visualization.

Network Preservation Analysis Revealed Strong Preservation of All Modules Between the Training and Test Sets

All 14 modules showed strong preservation across the CAD and LAF groups in both comparisons, with Z [summary]  scores of >10 in most modules (Figure 2). No major deviations in the Z [summary] score distributions for the 2 comparisons were noted, indicating that modules were preserved to a similar extent across the 2 groups

Figure 2. Preservation of mod-ules between mitral valve (MV) and coronary artery disease

Figure 2. Preservation of mod­ules between mitral valve (MV) and coronary artery disease (CAD) groups (left), and MV and lone atrial fibrillation (LAF) groups (right). A Zsummary sta­tistic was computed for each module as an overall measure of its preservation relating to density and connectivity. All modules showed strong pres­ervation in both comparisons with Zsummary scores >8 (red dot­ted line).

Regression Analysis of Module Eigengene Profiles Identified 2 Modules Associated With AF Severity and Atrial Rhythm

Table IV in the online-only Data Supplement summarizes the proportion of variance explained by the first 3 principal components for each module. On average, the first principal component (ie, the eigengene) explained ≈18% of the total variance of its associated module. For each group, the mod­ule eigengenes were extracted and regressed on AF severity (with age and sex as covariates). The salmon module (124 genes) eigengene was strongly associated with AF severity in the MV and CAD groups (P=1.7×10−6 and 5.2×10−4, respec­tively); this association was less significant in the LAF group (P=9.0×10−2). Eigengene levels increased with worsening AF severity across all 3 groups, with the greatest stepwise change taking place between the paroxysmal AF and per­sistent AF categories (Figure 3A). When the module eigen-genes were regressed on atrial rhythm, the salmon module eigengene showed significant association in all groups (MV: P=1.1×10−14; CAD: P=1.36×10−6; LAF: P=2.1×10−4). Eigen-gene levels were higher in the AF history in AF rhythm cat­egory (Figure 3B).

Table S4: Proportion of variance explained by the principal components for each module.












20.5% 22.2% 20.1% 21.8% 21.4% 22.8% 19.6%


4.1% 3.6% 4.8% 5.7% 4.5% 5.9% 3.9%


3.4% 3.1% 3.8% 4.4% 3.9% 3.7% 3.7%



12.5% 18.6% 7.1% 16.8% 12.2% 20.3% 12.8%


6.0% 5.5% 5.0% 7.0% 5.5% 6.1% 6.4%


4.9% 4.1% 4.4% 6.5% 4.8% 4.4% 4.8%



14.0% 16.6% 11.7% 14.3% 14.7% 20.8% 20.2%


8.9% 8.5% 7.6% 9.3% 7.3% 11.1% 6.9%


6.5% 6.3% 5.5% 8.2% 6.1% 5.3% 6.2%



Midnight- Blue









28.5% 22.6% 18.7% 20.5% 22.3% 19.0% 25.8%


4.6% 6.0% 4.7% 4.1% 6.9% 4.0% 3.5%


4.2% 4.2% 4.2% 3.5% 4.0% 3.6% 3.3%



23.4% 17.1% 15.5% 15.0% 18.0% 14.6% 18.2%


7.4% 8.6% 6.0% 6.4% 7.2% 5.8% 6.6%


5.1% 5.4% 5.3% 5.4% 6.2% 5.1% 4.5%



23.5% 18.4% 12.0% 15.9% 16.9% 13.7% 16.5%


7.9% 8.5% 9.8% 9.4% 9.5% 9.1% 9.6%


6.7% 7.0% 6.6% 6.0% 6.9% 6.8% 6.3%

Figure 3. Boxplots of salmon module eigengene expression levels with respect to atrial fibrillation (AF) severity (A) and atrial rhythm (B).

Figure 3. Boxplots of salmon module eigengene expression levels with respect to atrial fibrillation (AF) severity (A) and atrial rhythm (B).
A, Eigengene expression correlated positively with AF severity, with the largest stepwise increase between the paroxysmal AF and per­manent AF categories. B, Eigengene expression was highest in the AF history in AF rhythm category in all 3 groups. CAD indicates coro­nary artery disease; LAF, lone AF; and MV, mitral valve.

The regression analysis also revealed statistically significant associations between the tan module (679 genes) eigengene and atrial rhythm in the MV and CAD groups (P=5.8×10−4 and 3.4×10−2, respectively). Eigengene levels were lower in the AF history in AF rhythm category compared with the AF history in sinus rhythm category (Figure 4); this trend was also observed in the LAF group, albeit with weaker statistical evidence (P=0.15).

Figure 4. Boxplots of tan module eigengene expression levels with respect to atrial rhythm.

Figure 4. Boxplots of tan module eigengene expression levels with respect to atrial rhythm.
Eigengene expression levels were lower in the atrial fibrillation (AF) history in AF rhythm category compared with the AF history in sinus rhythm category. CAD indicates coronary artery disease; LAF, lone AF; and MV, mitral valve

Hierarchical Clustering of Eigengene Profiles With Clinical Traits

Hierarchical clustering was performed to identify relation­ships between gene modules and selected clinical traits. The salmon module clustered with AF severity and atrial rhythm; in addition, left atrial size was found in the same cluster, sug­gesting a possible relationship between salmon module gene expression and atrial remodeling (Figure 5A). Although the tan module was in a separate cluster from the salmon module, it was negatively correlated with both atrial rhythm and AF severity (Figure 5B).

Figure 5. Dendrogram (A) and correlation heatmap (B) of module eigengenes and clinical traits.

Figure 5. Dendrogram (A) and correlation heatmap (B) of module eigengenes and clinical traits

A, The salmon module eigengene but not the tan module eigengene clustered with atrial fibrillation (AF) severity, atrial rhythm, and left atrial size. B, AF severity and atrial rhythm at surgery correlated positively with the salmon module eigengene and negatively with the tan module eigengene. Arhythm indicates atrial rhythm at surgery; Chol, cholesterol; HTN, hypertension; and LASize, left atrial size.

IPA Enrichment Analysis of Salmon and Tan Modules

The salmon module was enriched in genes involved in cardio­vascular function and development (smallest P=4.4×10−4) and organ morphology (smallest P=4.4×10−4). In addition, the top disease categories identified included endocrine system disor­ders (smallest P=4.4×10−4) and cardiovascular disease (small­est P=2.59×10−3).

The tan module was enriched in genes involved in cell-to-cell signaling and interaction (smallest P=8.9×10−4) and cell death and survival (smallest P=1.5×10−3). Enriched disease categories included cancer (smallest P=2.2×10−4) and cardio­vascular disease (smallest P=4.5×10−4).

see document at  http://circgenetics.ahajournals.org/content/6/4/362

Hub Gene Analysis of Salmon and Tan Modules

We identified hub genes in the 2 modules based on intramod-ular connectivity and module membership. For the salmon module, the gene RCAN1 exhibited the highest intramodular connectivity and module membership. The top 10 hub genes (by intramodular connectivity) were significantly associated with atrial rhythm, with false discovery rate–adjusted P values ranging from 1.5×10−5 to 4.2×10−12. These hub genes accounted for 95% of the variation in the salmon module eigengene.

In the tan module, the top hub gene was CPEB3. The top 10 hub genes (by intramodular connectivity) correlated with atrial rhythm as well, although the statistical associations in the lower-ranked hub genes were relatively weaker (false discovery rate–adjusted P values ranging from 1.1×10−1 to 3.4×10−4). These hub genes explained 94% of the total varia­tion in the tan module eigengene.

The names and connectivity measures of the hub genes found in both modules are presented in Table 2.

Table 2. Top 10 Hub Genes in the Salmon (Left) and Tan (Right) Modules as Defined by Intramodular Connectivity and Module Membership

Salmon Module

Tan Module









RCAN1 8.2






DNAJA4 7.7






PDE8B 7.7












PTPN4 6.7






SORBS2 6.0






ADCY6 5.7






FHL2 5.7






BVES 5.4






TMEM173 5.3







A visualiza­tion of the salmon module is shown using the Cytoscape tool (Figure 6). A full list of the genes in the salmon and tan mod­ules is provided in the online-only Data Supplement.

Figure 6. Cytoscape visualization of genes in the salmon module.
Nodes representing genes with high intramodu-lar connectivities, such as RCAN1 and DNAJA4, appear larger in the network. Strong connections are visualized with darker lines, whereas weak connections appear more translucent

Figure 6. Cytoscape visualization of genes in the salmon module.

Membership of AF-Associated Candidate Genes From Previous Studies

The tan module contained MYOZ1, which was identified as a candidate gene from the recent AF meta-analysis. PITX2 was located in the green module (n=349), and ZFHX3 was located in the turquoise module (n=1512). The locations of other can­didate genes (and their closest partners) are reported in the online-only Data Supplement.

Sensitivity Analysis of Key Results

We repeated the WGCNA module identification approach using a different soft-thresholding parameter (β=5). One mod­ule (n=121) was found to be strongly associated with atrial rhythm at surgery across all 3 groups of data set, whereas another module (n=244) was associated with atrial rhythm at surgery in the MV and CAD groups. The first module over­lapped significantly with the salmon module in terms of gene membership, whereas most of the second modules’ genes were contained within the tan module. The top hub genes found in the salmon and tan modules remained present and highly connected in the 2 new modules identified with the dif­ferent soft-thresholding parameter.


To our knowledge, our study is the first implementation of an unbiased, network-based analysis in a large sample of human left atrial appendage gene expression profiles. We found 2 modules associated with AF severity and atrial rhythm in 2 to 3 of our cardiovascular comorbidity groups. Functional analy­ses revealed significant enrichment of cardiovascular-related categories for both modules. In addition, several of the hub genes identified are implicated in cardiovascular disease and may play a role in AF initiation and progression.

In our study, WGCNA was used to construct modules based on gene coexpression, thereby reducing the net-work’s dimensionality to a smaller set of elements.17,21 Relating modulewise changes to phenotypic traits allowed statistically significant associations to be detected at a lower false discovery rate compared with traditional differential expression studies. Furthermore, shared functions and path­ways among genes in the modules could be inferred via enrichment analyses.

We divided our data set into 3 groups to verify the repro­ducibility of the modules identified by WGCNA; 14 modules were identified in the MV group in our gene network. All were strongly preserved in the CAD and LAF groups, suggesting that gene coexpression patterns are robust and reproducible despite differences in cardiovascular comorbidities.

The use of module eigengene profiles as representative summary measures has been validated in a number of studies.20,26 Additionally, we found that the eigengenes accounted for a significant proportion (average 18%) of gene expression variability in their respective modules. Regression analysis of the module eigengenes found 2 modules associated with AF severity and atrial rhythm in ≥2 groups of data set. The association between the salmon module eigengene and AF severity was statistically weaker in the LAF group (adjusted P=9.0×10−2). This was probably because of its significantly smaller sample size compared with the MV and CAD groups. Despite this weaker association, the relationship between the salmon module eigengene and AF severity remained consistent among the 3 groups (Figure 3A). Similarly, the lack of statistical significance for the association between the tan module eigengene and atrial rhythm at surgery in the LAF group was likely driven by the smaller sample size and (by definition) lack of samples in the no AF category.

A major part of our analysis focused on the identifica­tion of module hub genes. Hubs are connected with a large number of nodes; disruption of hubs therefore leads to wide­spread changes within the network. This concept has powerful applications in the study of biology, genetics, and disease.29,30 Although mutations of peripheral genes can certainly lead to disease, gene network changes are more likely to be motivated by changes in hub genes, making them more biologically inter­esting targets for further study.17,29,31 Indeed,

  • the hub genes of the salmon and tan modules accounted for the vast majority of the variation in their respective module eigengenes, signaling their importance in driving gene module behavior.

The hub genes identified in the salmon and tan modules were significantly associated with AF phenotype overall. It was noted that this association was statistically weaker for the lower-ranked hub genes in the tan module. This highlights an important aspect and strength of WGCNA—to be able to capture module-wide changes with respect to disease despite potentially weaker associations among individual genes.

The implementation of WGCNA necessitated the selection of a soft-thresholding parameter 13. Unlike hard-thresholding (where gene correlations below a certain value are shrunk to zero), the soft-thresholding approach gives greater weight to stronger correlations while maintaining the continuous nature of gene–gene relationships. We selected a 13 value of 3 based on the criteria outlined by Zhang and Horvath.17 His team and other investigators have demonstrated that module identifica­tion is robust with respect to the 13 parameter.17,19–21 In our data, we were also able to reproduce the key findings reported with a different, larger 13 value, thereby verifying the stability of our results relating to 13.

The salmon module (124 genes) was associated with both AF phenotypes; furthermore, IPA analysis of its gene con­tents suggested enrichment in cardiovascular development as well as disease. Its eigengene increased with worsening AF severity, with the largest stepwise change occurring between the paroxysmal AF and persistent AF categories (Figure 3). Hence,

  • the gene expression changes within the salmon mod­ule may reflect the later stages of AF pathophysiology.

The top hub gene of the salmon module was RCAN1 (reg­ulator of calcineurin 1). Calcineurin is a cytoplasmic Ca2+/ calmodulin-dependent protein phosphatase that stimulates cardiac hypertrophy via its interactions with NFAT and L-type Ca2+ channels.32,33 RCAN1 is known to inhibit calcineurin and its associated pathways.32,34 However, some data suggest that RCAN1 may instead function as a calcineurin activator when highly expressed and consequently potentiate hypertrophic signaling.35 Thus,

  • perturbations in RCAN1 levels (attribut­able to genetic variants or mutations) may cause an aberrant switching in function, which in turn triggers atrial remodeling and arrhythmogenesis.

Other hub genes found in the salmon module are also involved in cardiovascular development and function and may be potential targets for further study.

  • DNAJA4 (DnaJ homolog, subfamily A, member 4) regulates the trafficking and matu­ration of KCNH2 potassium channels, which have a promi­nent role in cardiac repolarization and are implicated in the long-QT syndromes.36

FHL2 (four-and-a-half LIM domain protein 2) interacts with numerous cellular components, including

  1. actin cytoskeleton,
  2. transcription machinery, and
  3. ion channels.37

FHL2 was shown to enhance the hypertrophic effects of isoproterenol, indicating that

  • FHL2 may modulate the effect of environmental stress on cardiomyocyte growth.38
  • FHL2 also interacts with several potassium channels in the heart, such as KCNQ1, KCNE1, and KCNA5.37,39

Additionally, blood vessel epicardial substance (BVES) and other members of its family were shown to be highly expressed in cardiac pacemaker cells. BVES knockout mice exhibited sinus nodal dysfunction, suggesting that BVES regulates the development of the cardiac pacemaking and conduction system40 and may therefore be involved in the early phase of AF development.

The tan module (679 genes) eigengene was negatively correlated with atrial rhythm in the MV and CAD groups (Figure 4); this may indicate a general decrease in gene expres­sion of its members in fibrillating atrial tissue. IPA analysis revealed enrichment in genes involved in cell signaling as well as apoptosis. The top-ranked hub gene, cytoplasmic polyade-nylation element binding protein 3 (CPEB3), regulates mRNA translation and has been associated with synaptic plasticity and memory formation.41 The role of CPEB3 in the heart is currently unknown, so further exploration via animal model studies may be warranted.

Natriuretic peptide-precursor B (NPPB), another highly interconnected hub gene, produces a precursor peptide of brain natriuretic peptide, which

  • regulates blood pressure through natriuresis and vasodilation.42

(NPPB) gene variants have been linked with diabetes mellitus, although associations with cardiac phenotypes are less clear.42 TBX5 and GATA4, which play important roles in the embryonic heart development,43 were members of the tan module. Although not hub genes, they may also contribute toward developmental sus­ceptibility of AF. In addition, TBX5 was previously reported to be near an SNP associated with PR interval and AF in separate large-scale GWAS studies.12,28 MYOZ1, another candidate gene identified in the recent AF GWAS meta-analysis, was found to be a member as well; it associates with proteins found in the Z-disc of skeletal and cardiac muscle and may suppress calcineurin-dependent hypertrophic signaling.12

Some, but not all, of the candidate genes found in previous GWAS studies were located in the AF-associated modules. One possible explanation for this could be the difference in sample sizes. The meta-analysis involved thousands of indi­viduals, whereas the current study had <100 in each group of data set, which limited the power to detect significant differ­ences between levels of AF phenotype even with the module-wise approach. Additionally, transcription factors like PITX2 are most highly expressed during the fetal phase of develop­ment. Perturbations in these genes (attributable to genetic variants or mutations) may therefore initiate the development of AF at this stage and play no significant role in adults (when we obtained their tissue samples).

Limitations in Study

We noted several limitations in this study. First, no human left atrial mRNA data set of adequate size currently exists publicly. Hence, we were unable to validate our results with an external, independent data set. However, the network pres­ervation assessment performed within our data set showed strong preservation in all modules, indicating that our findings are robust and reproducible.

Although the module eigengenes captured a significant pro­portion of module variance, a large fraction of variability did remain unaccounted for, which may limit their use as repre­sentative summary measures.

We extracted RNA from human left atrial appendage tis­sue, which consists primarily of cardiomyocytes and fibro­blasts. Atrial fibrosis is known to occur with AF-associated remodeling.44 As such, the cardiomyocyte to fibroblast ratio is likely to change with different levels of AF severity, which in turn influences the amount of RNA extracted from each cell type. Hence, true differences in gene expression (and coexpression) within cardiomyocytes may be confounded by changes in cellular composition attributable to atrial remod­eling. Also, there may be significant regional heterogeneity in the left atrium with respect to structure, cellular composi­tion, and gene expression,45 which may limit the generaliz-ability of our results to other parts of the left atrium.

All subjects in the study were whites to minimize the effects of population stratification. However, it is recognized that the genetic basis of AF may differ among ethnic groups.9 Thus, our results may not be generalizable to other ethnicities.

Finally, it is possible for genes to be involved in multiple processes and functions that require different sets of genes. However, WGCNA does not allow for overlapping modules to be formed. Thus,

  • this limits the method’s ability to character­ize such gene interactions.


In summary, we constructed a weighted gene coexpression network based on RNA expression data from the largest collection of human left atrial appendage tissue specimens to date. We identified 2 gene modules significantly associated with AF severity or atrial rhythm at surgery. Hub genes within these modules may be involved in the initiation or progression of AF and may therefore be candidates for functional stud­ies.


1. European Heart Rhythm Association, European Association for Cardio-Thoracic Surgery, Camm AJ, Kirchhof P, Lip GY, Schotten U, et al. Guidelines for the management of atrial fibrillation: the task force for the management of atrial fibrillation of the European Society of Cardiology (ESC). Eur Heart J. 2010;31:2369–2429.

2. Lemmens R, Hermans S, Nuyens D, Thijs V. Genetics of atrial fibrilla­tion and possible implications for ischemic stroke. Stroke Res Treat. 2011;2011:208694.

3. Wann LS, Curtis AB, January CT, Ellenbogen KA, Lowe JE, Estes NA III, et al; ACCF/AHA/HRS. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (Updating the 2006 Guideline): a report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2011;57:223–242.

4. Dobrev D, Carlsson L, Nattel S. Novel molecular targets for atrial fibrilla­tion therapy. Nat Rev Drug Discov. 2012;11:275–291.

5. Christophersen IE, Ravn LS, Budtz-Joergensen E, Skytthe A, Haunsoe S, Svendsen JH, et al. Familial aggregation of atrial fibrillation: a study in Danish twins. Circ Arrhythm Electrophysiol. 2009;2:378–383.

6. Gudbjartsson DF, Arnar DO, Helgadottir A, Gretarsdottir S, Holm H, Sig-urdsson A, et al. Variants conferring risk of atrial fibrillation on chromo­some 4q25. Nature. 2007;448:353–357.

7. Ellinor PT, Lunetta KL, Glazer NL, Pfeufer A, Alonso A, Chung MK, et al. Common variants in KCNN3 are associated with lone atrial fibrillation. Nat Genet. 2010;42:240–244.

8. Benjamin EJ, Rice KM, Arking DE, Pfeufer A, van Noord C, Smith AV, et al. Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry. Nat Genet. 2009;41:879–881.

9. Sinner MF, Ellinor PT, Meitinger T, Benjamin EJ, Kääb S. Genome-wide association studies of atrial fibrillation: past, present, and future. Cardio-vasc Res. 2011;89:701–709.

10. Clauss S, Kääb S. Is Pitx2 growing up? Circ Cardiovasc Genet. 2011;4:105–107.

11. Kirchhof P, Kahr PC, Kaese S, Piccini I, Vokshi I, Scheld HH, et al. PITX2c is expressed in the adult left atrium, and reducing Pitx2c expres­sion promotes atrial fibrillation inducibility and complex changes in gene expression. Circ Cardiovasc Genet. 2011;4:123–133.

12. Ellinor PT, Lunetta KL, Albert CM, Glazer NL, Ritchie MD, Smith AV, et al. Meta-analysis identifies six new susceptibility loci for atrial fibrillation. Nat Genet. 2012;44:670–675.

13. Barth AS, Merk S, Arnoldi E, Zwermann L, Kloos P, Gebauer M, et al. Reprogramming of the human atrial transcriptome in permanent atrial fi­brillation: expression of a ventricular-like genomic signature. Circ Res. 2005;96:1022–1029.

Continues to 45.  see



Atrial fibrillation is the most common sustained cardiac arrhythmias in the United States. The genetic and molecular mecha­nisms governing its initiation and progression are complex, and our understanding of these mechanisms remains incomplete despite recent advances via genome-wide association studies, animal model experiments, and differential expression studies. In this study, we used weighted gene coexpression network analysis to identify gene modules significantly associated with atrial fibrillation in a large sample of human left atrial appendage tissues. We further identified highly interconnected genes (ie, hub genes) within these gene modules that may be novel candidates for functional studies. The discovery of the atrial fibrillation-associated gene modules and their corresponding hub genes provide novel insight into the gene network changes that occur with atrial fibrillation, and closer study of these findings can lead to more effective targeted therapies for disease management.

Read Full Post »

Myocardial Strain and Segmental Synchrony: Age and Gender in Speckle-tracking-based Echocardiographic Study

Reporter: Aviva Lev-Ari, PhD, RN

  • Original Article

Age- and Sex-based Reference Limits and Clinical Correlates of Myocardial Strain and Synchrony: The Framingham Heart Study

  1. Susan Cheng1*,
  2. Martin G. Larson2,
  3. Elizabeth L. McCabe3,
  4. Ewa Osypiuk4,
  5. Birgitta T. Lehman4,
  6. Plamen Stanchev4,
  7. Jayashri Aragam5,
  8. Emelia J. Benjamin6,
  9. Scott D. Solomon7 and
  10. Ramachandran S. Vasan8

+Author Affiliations

  1. 1Framingham Heart Study, Framingham, MA; Brigham and Women’s Hospital, Boston, MA

  2. 2Framingham Heart Study, Framingham, MA; Boston University, Boston, MA

  3. 3Boston University, Boston, MA

  4. 4Framingham Heart Study, Framingham, MA

  5. 5Veterans Administration Hospital, West Roxbury, MA

  6. 6Framingham Heart Study, Framingham, MA; Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA; Boston University School of Public Health, Boston, MA

  7. 7Brigham and Women’s Hospital, Boston, MA

  8. 8Framingham Heart Study, Framingham, MA; Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA
  1. * Brigham and Women’s Hospital, 75 Francis Street, PBB-119 Boston, MA 02115scheng3@partners.org


Background—There is rapidly growing interest in applying measures of myocardial strain and segmental synchrony in clinical investigations and in practice, but data are limited regarding their reference ranges in healthy individuals.

Methods and Results—We performed speckle-tracking-based echocardiographic measures of left ventricular (LV) myocardial strain and segmental synchrony in healthy Framingham Heart Study participants (n=738, mean age 63 years, 64% women) who were free of cardiovascular disease. Reference values (2.5th, 50th, 97.5th quantiles) were estimated using quantile regression. Age- and sex-based upper (97.5th quantile) limits were as follows:

  • 15.5% to -16.9% (women) and -14.5 to -15.4% (men) for longitudinal strain;
  • -21.9% to -24.3% (women) and -18.9% to -25.0% (men) for circumferential strain;
  • 114-158 msec (women) and 133-206 msec (men) for longitudinal segmental synchrony (SD of regional time-to-peak strains); and,
  • 204-224 msec (women) and 201-288 msec (men) for transverse segmental synchrony.

In multivariable analyses, women compared to men had

  • ~1.7% greater longitudinal strain,
  • ~2.2% greater transverse strain, and
  • ~3.2% greater circumferential strain (P<0.0001 for all).

Older age and higher diastolic blood pressure, even within the normal range, was associated with worse transverse segmental synchrony (P<0.001). Overall, clinical covariates contributed ≤12% of the variation in myocardial strain or synchrony in this healthy sample.

Conclusions—We estimated age- and sex-specific reference limits for echocardiographic measures of LV strain and synchrony in a healthy community-based sample, wherein clinical covariates contributed only a modest proportion of the variation. These data may facilitate interpretation of LV strain-based measures obtained in future clinical research and practice.

Key Words:

  • Received November 19, 2012.
  • Accepted July 18, 2013.


CIRCIMAGING.112.000627Published online before print August 5, 2013,doi: 10.1161/​CIRCIMAGING.112.000627

Read Full Post »

Orthotopic Heart Transplant (OHT): Effects of Autonomic Innervation / Denervation on Atrial Fibrillation (AF) Genesis and Maintenance

Author and Curator: Larry H. Bernstein, MD, FCAP


Curator: Aviva Lev-Ari, PhD, RN

Sympathetic stimulation increases heart rate (positive chronotropy), inotropy and conduction velocity (positive dromotropy), whereas parasympathetic stimulation of the heart has opposite effects.

Noheria A, Patel SM, Mirzoyev S, Madhavan M, Friedman PA, Packer DL, Daly RC, Kushwaha SS, Edwards BS, Asirvatham SJ.

Division of Cardiology, Cedars-Sinai Medical Center, Los Angeles, California.
Pacing Clin Electrophysiol. 2013 Jun;36(6):741-7. http://dx.doi.org/10.1111/pace.12102. Epub 2013 Feb 25.

ANS- autonomic innervation of heart

The medulla, located in the brainstem above the spinal cord, is the primary site in the brain for regulating sympathetic and parasympathetic (vagal) outflow to the heart and blood vessels. The nucleus tractus solitarius (NTS) of the medulla receives sensory input from different systemic and central receptors (e.g., baroreceptors and chemoreceptors).
The heart is innervated by vagal and sympathetic fibers. The right vagus nerve primarily innervates the SA node, whereas the left vagus innervates the AV node; however, there can be significant overlap in the anatomical distribution. Atrial muscle is also innervated by vagal efferents, whereas the ventricular myocardium is only sparsely innervated by vagal efferents. Sympathetic efferent nerves are present throughout the atria (especially in the SA node) and ventricles, including the conduction system of the heart.
Cardiac function is altered by neural activation. Sympathetic stimulation increases heart rate (positive chronotropy), inotropy and conduction velocity (positive dromotropy), whereas parasympathetic stimulation of the heart has opposite effects.  Sympathetic and parasympathetic effects on heart function are mediated by beta-adrenoceptors and muscarinic receptors, respectively.
The overall effect of sympathetic activation is to increase cardiac output, systemic vascular resistance (both arteries and veins), and arterial blood pressure. Enhanced sympathetic activity is particularly important during exercise, emotional stress, and during hemorrhagic shock.
The actions of autonomic nerves are mediated by the release of neurotransmitters that bind to specific cardiac receptors and vascular receptors. These receptors are coupled to signal transduction pathways that evoke changes in cellular function.

                                         Sympathetic                      Parasympathetic


Chronotropy (rate)

+ + +                                     − − −

Inotropy (contractility)

+ + +                                      − 1

 Lusitropy (relaxation)                              
                                             + + +                                     –  1 
Dromotropy (conduction velocity)

                                              + +                                       − − −


Arterial constriction    + + +                                    0

Venous constriction      + + +                                    0

Relative magnitude of responses indicated by number of + or – signs.
1 More pronounced in atria than ventricles.

CV Physiology: Autonomic Innervation of the Heart and Vasculature

Ablation Therapy for Cardiac Arrhythmias

By Richard N. Fogoros, M.D., About.com Guide Updated November 18, 2011
The most common form of ablation is done during a specialized form of cardiac catheterization, performed by a type of doctor known as a cardiac electrophysiologist (heart rhythm specialist). These procedures are sometimes called “trans-catheter ablations.”
During trans-catheter ablation procedures, specialized electrode catheters are positioned inside the heart, and the cardiac electrical system is mapped, showing the abnormal electrical pathways that are often responsible for producing the rapid heart rate. If these abnormal pathways are identified, the tip of the catheter (a tube) is placed on the abnormal pathway and the pathway is ablated (eliminated). The ablation itself is accomplished by transmitting some form of energy through the catheter (heat energy, freezing energy, or microwave energy), in order to damage the tissue at the tip of the catheter.

Decreased postoperative atrial fibrillation following cardiac transplantation: the significance of autonomic denervation.

BACKGROUND:  Endocardial ablation approaches have been proposed to targeting the retroatrial cardiac ganglia to treat atrial fibrillation (AF) . The potential value using this approach is unknown. Disruption of the autonomic inputs with orthotropic heart transplant (OHT) provides a unique opportunity to study the effects of autonomic innervation on AF genesis and maintenance.
The investigators hypothesized that due to denervation, the risk of postoperative AF would be lower following OHT compared to surgical maze even though both groups get isolation of the pulmonary veins.
METHODS:  We reviewed 155 OHTs (mean age 52 ± 11 years, 72% males) and used 1:1 age-, sex-, and date-of-surgery-matched two control groups from patients undergoing surgical maze or only coronary artery bypass grafting (CABG). Using conditional logistic regression we compared the odds of AF within 2 weeks following OHT versus controls.
RESULTS: Postoperative AF occurred in 10/155 (6.5%) OHT patients.
  1. The conditional odds of postoperative AF were lower for OHT as compared to controls (vs maze: odds ratio [OR] 0.27 [95% confidence interval (CI) 0.13-0.57], vs CABG: OR 0.38 [0.17-0.81], P = 0.003; and
  2. on additional adjustment for left atrial enlargement, vs maze: OR 0.28 [0.13-0.60], vs CABG: OR 0.14 [0.04-0.47], P = 0.0009).
Risk of postoperative AF is significantly lower with OHT as in comparison to surgical maze. As both surgeries entail isolation of the pulmonary veins but
  • only OHT causes disruption of autonomic innervation,
this observation supports a mechanistic role of autonomic nervous system in AF. The benefit of targeting the cardiac autonomic system to treat AF needs further investigation.

Other related articles published on this Open Access Online Scientific Journal, including the following:

Imbalance of Autonomic Tone: The Promise of Intravascular Stimulation of Autonomics

Aviva Lev-Ari, PhD, RN


Renal Sympathetic Denervation: Updates on the State of Medicine

Aviva Lev-Ari, PhD, RN


On Devices and On Algorithms: Prediction of Arrhythmia after Cardiac Surgery and ECG Prediction of an Onset of Paroxysmal Atrial Fibrillation

Justin D Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN

Xarelto (Rivaroxaban): Anticoagulant Therapy gains FDA New Indications and Risk Reduction for: (DVT) and (PE), while in use for Atrial fibrillation increase in Gastrointestinal (GI) Bleeding Reported

Aviva Lev-Ari, PhD, RN
Sustained Cardiac Atrial Fibrillation: Management Strategies by Director of the Arrhythmia Service and Electrophysiology Lab at The Johns Hopkins Hospital

Aviva Lev-Ari, PhD, RN
Stroke and Bleeding in Atrial Fibrillation with Chronic Kidney Disease

Aviva Lev-Ari, PhD, RN
Atrial Fibrillation: The Latest Management Strategies

Aviva Lev-Ari, PhD, RN
Genetics of Conduction Disease: Atrioventricular (AV) Conduction Disease (block): Gene Mutations – Transcription, Excitability, and Energy Homeostasis

Aviva Lev-Ari, PhD, RN

Minimally Invasive Structural CVD Repairs: FDA grants 510(k) Clearance to Philips’ EchoNavigator – X-ray and 3-D Ultrasound Image Fused

Aviva Lev-Ari, PhD, RN

Accurate Identification and Treatment of Emergent Cardiac Events

Larry Bernstein, MD, FCAP

Percutaneous Endocardial Ablation of Scar-Related Ventricular Tachycardia

Aviva Lev-Ari, PhD, RN


Sympathetic (red) and parasympathetic (blue) n...

Sympathetic (red) and parasympathetic (blue) nervous system Русский: Аанатомия иннервации вегетативной нервной системы. Системы: симпатическая (красным) и парасимпатическая (синим) Українська: Аанатомія іннервації вегетативної нервової системи. Симпатична (червоним) та парасимпатична (синім) гілки Polski: Układ autonomiczny: czerwony – sympatyczny, niebieski – parasympatyczny. (Photo credit: Wikipedia)

Scheme of atrial fibrillation (top) and sinus ...

Scheme of atrial fibrillation (top) and sinus rhythm (bottom). The purple arrow indicates a P wave, which is lost in atrial fibrillation. (Photo credit: Wikipedia)

English: A graphical representation of the Ele...

English: A graphical representation of the Electrical conduction system of the heart showing the Sinoatrial node, Atrioventricular node, Bundle of His, Purkinje fibers, and Bachmann’s bundle (Photo credit: Wikipedia)

Read Full Post »

CABG Survival in Multivessel Disease Patients: Comparison of Arterial Bypass Grafts vs Saphenous Venous Grafts

Writer and Curator: Larry H. Bernstein, MD, FCAP


Curator: Aviva Lev-Ari, PhD, RN 


This article examines 10-year to 15-year survivals from arterial bypass grafts using arterial vs saphenous venous grafts.

Locker C, Schaff HV, Dearani JA, Joyce LD, Park SJ, et al.
Division of Cardiovascular Surgery, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA. lekerlocker.chaim@mayo.edu
Circulation. 2012 Aug 28;126(9):1023-30.   PMID: 22811577 http://dx.doi.org/10.1161/CIRCULATIONAHA.111.084624. Epub 2012 Jul 18. Review.
Coronary artery bypass surgery (CABG) , is performed to relieve angina and reduce the risk of death from coronary artery disease. Arteries or veins from elsewhere in the patient’s body are grafted to the coronary arteries to bypass atherosclerotic narrowings and improve the blood supply to the coronary circulation supplying the myocardium. This surgery is usually performed with the heart stopped, necessitating the usage of cardiopulmonary bypass; techniques are available to perform CABG on a beating heart, so-called “off-pump” surgery.
Russian cardiac surgeon, Dr. Vasilii Kolesov, performed the first successful internal mammary artery–coronary artery anastomosis in 1964. Using a standard suture technique in 1964, and over the next five years he performed 33 sutured and mechanically stapled anastomoses in St. Petersburg, Russia.
Dr. René Favaloro, an Argentine surgeon, achieved a physiologic approach in the surgical management of coronary artery disease—the bypass grafting procedure—at the Cleveland Clinic in May 1967. His new technique used a saphenous vein autograft to replace a stenotic segment of the right coronary artery, and he later successfully used the saphenous vein as a bypassing channel, which has become the typical bypass graft technique we know today; in the U.S., this vessel is typically harvested endoscopically, using a technique known as endoscopic vessel harvesting (EVH). Soon Dr. Dudley Johnson extended the bypass to include left coronary arterial systems. In 1968, Doctors Charles Bailey, Teruo Hirose and George Green used the internal mammary artery instead of the saphenous vein for the grafting.
A person with a large amount of coronary artery disease (CAD) may receive fewer bypass grafts owing to the lack of suitable “target” vessels. A coronary artery may be unsuitable for bypass grafting if
  • it is small (< 1 mm or < 1.5 mm depending on surgeon preference),
  • heavily calcified (meaning the artery does not have a section free of CAD) or
  • intramyocardial (the coronary artery is located within the heart muscle rather than on the surface of the heart).
Similarly, a person with a single stenosis (“narrowing”) of the left main coronary artery requires only two bypasses (to the LAD and the LCX). However, a left main lesion places a person at the highest risk for death from a cardiac cause.
  • Both PCI and CABG are more effective than medical management at relieving symptoms, (e.g. angina, dyspnea, fatigue).
  • CABG is superior to PCI for some patients with multivessel CAD.
The Surgery or Stent (SoS) trial was a randomized controlled trial that compared CABG to PCI with bare-metal stents. The SoS trial demonstrated CABG is superior to PCI in multivessel coronary disease.
The SYNTAX trial was a randomized controlled trial of 1800 patients with multivessel coronary disease, comparing CABG versus PCI using drug-eluting stents (DES). The study found that
  • rates of major adverse cardiac or cerebrovascular events at 12 months were significantly higher in the DES group (17.8% versus 12.4% for CABG; P=0.002).
This was primarily driven by
  • higher need for repeat revascularization procedures in the PCI group with no difference in repeat infarctions or survival.
  • Higher rates of strokes were seen in the CABG group.




Left Internal Mammary Artery Usage in Coronary Artery Bypass Grafting: A Measure of Quality Control

S Karthik and BM Fabri
Ann R Coll Surg Engl 2008; 85(4):367-69.

Over the last two decades, many studies have shown better long-term patency rates and survival in patients undergoing coronary artery bypass grafting (CABG) with left internal mammary artery (LIMA) to the left anterior descending artery (LAD).
Although the current focus in the UK is on mortality rates, we believe that it will not be long before this will also include the incidence of major morbidity after CABG such as stroke, myocardial infarction (MI), renal failure and sternal wound problems. We also believe that we should now consider LIMA usage as a marker of quality control in CABG. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1964611/

This study very clearly demonstrated that:

  1. Approximately 4% of all patients undergoing first-time CABG do not need a graft to the LAD.
  2. Of the rest, about 92% receive LIMA to LAD.

Six sub-groups of patients in whom LIMA usage was significantly less were:

(i) the elderly (> 70 years of age);

(ii) females;

(iii) diabetics;

(iv) patients having emergency CABG;

(v) poor left ventricular (LV) function (ejection fraction [EF] < 30%); and

(vi) respiratory disease.

LIMA usage was also reduced in patients undergoing combined CABG and valve procedures.

Multiple arterial grafts improve late survival of patients undergoing CABG

BACKGROUND: Use of the left internal mammary artery (LIMA) in multivessel coronary artery disease improves survival after coronary artery bypass graft surgery; however, the survival benefit of multiple arterial (MultArt) grafts is debated. (Perhaps not without reason. One problem is the small size of the left circumflex artery, and where does the right coronary artery have a place?)
METHODS : We reviewed 8622 Mayo Clinic patients who had isolated primary coronary artery bypass graft surgery for multivessel coronary artery disease from 1993 to 2009. Patients were stratified by number of arterial grafts into the LIMA plus saphenous veins (LIMA/SV) group (n=7435) or the MultArt group (n=1187). Propensity score analysis matched 1153 patients.
RESULTS: Operative mortality was 0.8% (n=10) in the MultArt and 2.1% (n=154) in the LIMA/SV (P=0.005) group.This result was not statistically different (P=0.996) in multivariate analysis or the propensity-matched analysis (P=0.818).
Late survival was greater for MultArt versus LIMA/SV (10- and 15-year survival rates were 84% and 71% versus 61% and 36%, respectively [P<0.001], in unmatched groups and 83% and 70% versus 80% and 60%, respectively [P=0.0025], in matched groups). The large difference between the MultiArt versus the LIMA/SV appears to be the 61% and 36% in unmatched and 80% and 60% in matched, evident at 15-years, favorable for the MultiArt group.
MultArt subgroups with bilateral internal mammary artery/SV (n=589) and

  • bilateral internal mammary artery only (n=271) had improved 15-year survival (86% and 76%; 82% and 75% at 10 and 15 years [P<0.001]), and
  • bilateral internal mammary artery/radial artery (n=147) and LIMA/radial artery (n=169) had greater 10-year survival (84% and 78%; P<0.001) versus LIMA/SV.

In multivariate analysis, MultArt grafts remained a strong independent predictor of survival (hazard ratio, 0.79; 95% confidence interval, 0.66-0.94; P=0.007).


In patients undergoing isolated coronary artery bypass graft surgery with LIMA to left anterior descending artery,

  • arterial grafting of the non-left anterior descending vessels conferred a survival advantage at 15 years compared with Saphenous Venous (SV) grafting.

It is still unproven whether these results apply to higher-risk subgroups of patients.

Other related articles published on this Open Access Online Scientific Journal, include the following:

Competition in the Ecosystem of Medical Devices in Cardiac and Vascular Repair: Heart Valves, Stents, Catheterization Tools and Kits for Open Heart and Minimally Invasive Surgery (MIS) (Aviva Lev-Ari)
Bioabsorbable Drug Coating Scaffolds, Stents and Dual Antiplatelet Therapy (Aviva Lev-Ari)

Vascular Repair: Stents and Biologically Active Implants (larryhbern)

Drug Eluting Stents: On MIT’s Edelman Lab’s Contributions to Vascular Biology and its Pioneering Research on DES (larryhbern)

Coronary Artery Disease – Medical Devices Solutions: From First-In-Man Stent Implantation, via Medical Ethical Dilemmas to Drug Eluting Stents (Aviva Lev-Ari)

Survivals Comparison of Coronary Artery Bypass Graft (CABG) and Percutaneous Coronary Intervention (PCI) / Coronary Angioplasty (larryhbern)

Svelte Medical Systems’ Drug-Eluting Stent: 0% Clinically-Driven Events Through 12-Months in First-In-Man Study (Aviva Lev-Ari

Acute and Chronic Myocardial Infarction: Quantification of Myocardial Perfusion Viability – FDG-PET/MRI vs. MRI or PET alone (Justin Pearlman, Aviva Lev-Ari)

Biomaterials Technology: Models of Tissue Engineering for Reperfusion and Implantable Devices for Revascularization (larryhbern)

Revascularization: PCI, Prior History of PCI vs CABG (A Lev-Ari)

Accurate Identification and Treatment of Emergent Cardiac Events (larryhbern)

FDA Pending 510(k) for The Latest Cardiovascular Imaging Technology (A Lev-Ari)

The ACUITY-PCI score: Will it Replace Four Established Risk Scores — TIMI, GRACE, SYNTAX, and Clinical SYNTAX (A Lev-Ari)

CABG or PCI: Patients with Diabetes – CABG Rein Supreme (A Lev-Ari)

To Stent or Not? A Critical Decision (A Lev-Ari)

The internal mammary artery and its branches.

The internal mammary artery and its branches. (Photo credit: Wikipedia)

Coronary artery bypass surgery, the usage of c...

Coronary artery bypass surgery, the usage of cardiopulmonary bypass Русский: Коронарное шунтирование (Photo credit: Wikipedia)

A coronary angiogram that shows the LMCA, LAD ...

A coronary angiogram that shows the LMCA, LAD and LCX. (Photo credit: Wikipedia)

Micrograph of an artery that supplies the hear...

Micrograph of an artery that supplies the heart with significant atherosclerosis and marked luminal narrowing. Tissue has been stained using Masson’s trichrome. (Photo credit: Wikipedia)

Read Full Post »

Coronary Reperfusion Therapies: CABG vs PCI – Mayo Clinic preprocedure Risk Score (MCRS) for Prediction of in-Hospital Mortality after CABG or PCI

Author and Curator: Larry H. Bernstein, MD, FCAP 


Curator: Aviva Lev-Ari, PhD, RN


Published on Mar 27, 2012

Mayo Clinic cardiologist Charanjit Rihal, M.D. discusses a recent study conducted by Mayo Clinic that focuses on predicting operator outcomes in coronary angioplasty procedures.

“We’ve been interested in prediction of outcomes after coronary angioplasty and stent procedures for some time,” says Dr. Rihal. “Almost ten years ago, we published a paper called ‘The Mayo Clinic Risk Score for Prediction of Adverse Events following Coronary Angioplasty and Stent Procedures’. We’ve since refined into the ‘New Mayo Clinic Risk Score’, which includes seven key variables that predict bad outcomes following PCI procedures.”

The study, which was presented at the 2012 ACC Annual Scientific Session & Expo, presents a novel application of the Mayo Clinic Risk Score to predict operator specific outcomes in coronary angioplasty procedures.

“We looked at the outcomes of over 8000 procedures performed by 21 Mayo Clinic interventional cardiologists as predicted by the Mayo Clinic Risk Score,” says Dr. Rihal. “On an individual basis, we were able to calculate the expected mortality and adverse event rate and compare that to the actual observed mortality and adverse event rate. We were able to show that in our clinical practice of PCI, this risk score was very useful as a performance measure.

In a pleasant surprise, the study also discovered an outlier whose outcomes for instances of adverse event rates were much better than expected. “We don’t know exactly why this operator has such good results,” remarks Dr. Rihal, “But that will be the next phase of this analysis. We can compare procedural, pre-procedural, and post procedural practices of this operator and see if there are things that are translatable to the rest of us.”


Singh M, Gersh BJ, Li S, Rumsfeld JS, Spertus JA, O’Brien SM, Suri RM, Peterson ED.
Circulation. 2008 Jan 22;117(3):356-62.  http://dx.doi.org/10.1161/CIRCULATIONAHA.107.711523     Epub 2008 Jan 2.  PMID: 18172033
BACKGROUND:  Current risk models predict in-hospital mortality after either coronary artery bypass graft surgery or percutaneous coronary interventions. The overlap of models suggests that the same variables can define the risks of alternative coronary reperfusion therapies. We sought  a preprocedure risk model that can predict in-hospital mortality after either percutaneous coronary intervention or coronary artery bypass graft surgery.
METHODS AND RESULTS:  We tested the ability of the recently validated, integer-based Mayo Clinic Risk Score (MCRS) for percutaneous coronary intervention, which is based solely on preprocedure variables:
  • age,
  • creatinine,
  • ejection fraction,
  • myocardial infarction < or = 24 hours,
  • shock,
  • congestive heart failure
  • peripheral vascular disease
to predict in-hospital mortality among 370,793 patients in the Society of Thoracic Surgeons  (STS) database undergoing isolated coronary artery bypass graft surgery from 2004 to 2006. The median age of the STS database patients was 66 years (quartiles 1 to 3, 57 to 74 years), with 37.2% of patients > or = 70 years old. The high prevalence of comorbid conditions included
  • diabetes mellitus (37.1%)
  • hypertension (80.5%)
  • peripheral vascular disease (15.3%)
  • renal disease (creatinine > or = 1.4 mg/dL; 11.8%).
A strong association existed between the MCRS and the observed mortality in the STS database. The in-hospital mortality ranged between 0.3% (95% confidence interval 0.3% to 0.4%) with a score of 0 on the MCRS and 33.8% (95% confidence interval 27.3% to 40.3%) with an MCRS score of 20 to 24. The discriminatory ability of the MCRS was moderate, as measured by the area under the receiver operating characteristic curve (C-statistic = 0.715 to 0.784 among various subgroups); performance was inferior to the STS model for most categories tested.
CONCLUSIONS:  This model is based on the 7 preprocedure risk variables listed above. However, it  may be useful for providing patients with individualized, evidence-based estimates of procedural risk as part of the informed consent process before percutaneous or surgical revascularization.
It appears to this reviewer that the model might provide a better AUC if it were reconstructed as follows:
  1. age
  2. estimated creatinine clearance (which has been improved substantially by the Mayo Clinic)
  3. EF
  4. AMI < 24 hrs
  5. Decompensated CHF or shock
  6. PVD, or carotid artery disease, or PAD
  7. MAP
Mean arterial pressure (MAP) Calculator: Systolic BP: mm Hg: Diastolic BP: mm Hg Background: Equation: MAP = [(2 x diastolic)+systolic] / 3      http://www.globalrph.com/map.htm
There is another question that This reviewer has about the approach to prediction of post-procedural survival from pre-procedural information.
  • Age falls into interval classes that would suffice for use as classification variables.
  • Creatinine is a measurement that is a continuous variable, but I  call attention to the fact that eGFR would be preferred, as physicians tend to look at the creatinine roughly in relationship to age, gender, and body size or BMI.
  • The laboratory contribution as powerful information is underutilized.
On the one hand, CHF is important, but how is the distinction made between
  • stable CHF and
  • decompensated CHF, or degrees in between?
This is where the amino-terminal pro b-type natriuretic perptide, or the BNP has been used in isolation, but not in a multivariate model such as described.  There is a difference between them, but whether the difference makes a difference is unproved.
The BNP, derived from the propeptide is made by the myocardium as a hormonal mediator of sodium retention.  The BNP is degraded by the vascular endothelium, so it’s half time of disappearance would not reflect renal dysfunction, which is not the case for the NT proBNP.  This observation has nothing to do with the medical use of BNP.
Related articles

Other related articles were published on this Open Access Online Scientific Journal, including:

Survivals Comparison of Coronary Artery Bypass Graft (CABG) and Percutaneous Coronary Intervention (PCI) / Coronary Angioplasty

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN


Competition in the Ecosystem of Medical Devices in Cardiac and Vascular Repair: Heart Valves, Stents, Catheterization Tools and Kits for Open Heart and Minimally Invasive Surgery (MIS) (Aviva Lev-Ari)

Bioabsorbable Drug Coating Scaffolds, Stents and Dual Antiplatelet Therapy (Aviva Lev-Ari)

Vascular Repair: Stents and Biologically Active Implants (larryhbern)

Drug Eluting Stents: On MIT’s Edelman Lab’s Contributions to Vascular Biology and its Pioneering Research on DES (larryhbern)

Coronary Artery Disease – Medical Devices Solutions: From First-In-Man Stent Implantation, via Medical Ethical Dilemmas to Drug Eluting Stents (Aviva Lev-Ari)

Survivals Comparison of Coronary Artery Bypass Graft (CABG) and Percutaneous Coronary Intervention (PCI) / Coronary Angioplasty (larryhbern)
Trans-apical Transcatheter Aortic Valve Replacement in a Patient with Severe and Complex Left Main Coronary Artery Disease (LMCAD) (larryhbern)
Transcatheter Aortic Valve Replacement (TAVR): Postdilatation to Reduce Paravalvular Regurgitation During TAVR with a Balloon-expandable Valve (larryhbern)

Svelte Medical Systems’ Drug-Eluting Stent: 0% Clinically-Driven Events Through 12-Months in First-In-Man Study (Aviva Lev-Ari)

Acute and Chronic Myocardial Infarction: Quantification of Myocardial Perfusion Viability – FDG-PET/MRI vs. MRI or PET alone (Justin Pearlman, Aviva Lev-Ari)

Biomaterials Technology: Models of Tissue Engineering for Reperfusion and Implantable Devices for Revascularization (larryhbern)
Revascularization: PCI, Prior History of PCI vs CABG (A Lev-Ari)
Accurate Identification and Treatment of Emergent Cardiac Events (larryhbern)
FDA Pending 510(k) for The Latest Cardiovascular Imaging Technology (A Lev-Ari)
The ACUITY-PCI score: Will it Replace Four Established Risk Scores — TIMI, GRACE, SYNTAX, and Clinical SYNTAX (A Lev-Ari)
CABG or PCI: Patients with Diabetes – CABG Rein Supreme (A Lev-Ari)
New Drug-Eluting Stent Works Well in STEMI (A Lev-Ari)

Three coronary artery bypass grafts, a LIMA to...

Three coronary artery bypass grafts, a LIMA to LAD and two saphenous vein grafts – one to the right coronary artery (RCA) system and one to the obtuse marginal (OM) system. (Photo credit: Wikipedia)

Forrester-classification for classification of...

Forrester-classification for classification of Congestive heart failure ; Forrester-Klassifikation zur Einteilung einer akuten Herzinsuffizienz (Photo credit: Wikipedia)

Read Full Post »

Survivals Comparison of Coronary Artery Bypass Graft (CABG) and Percutaneous Coronary Intervention (PCI) / Coronary Angioplasty

Larry H. Bernstein, MD, Writer
Aviva Lev-Ari, PhD, RN, Curator


This is a summary of several studies, mostly reviewing one decade of work at Texas Heart Institute, Houston, TX.

Seminal treatments of the evolving methods, leading to a recent review of options for

  • Survival comparison of CABD vs PCI
  • Mitral valve repair or mitral valve replacement for the treatment of ischemic mitral regurgitation. This might further consolidate a series of articles in these chapters.


1. Bypass, Angioplasty Similar in Survival 10 Years After Heart Procedures, Survival Rates Differ Little. K Doheny. WebMD Health News   Oct. 15, 2007
3. Will Stent Revascularization Replace Coronary Artery Bypass Grafting? JM Wilson Tex Heart Inst J. 2012; 39(6): 856–859
4. Coronary Artery Bypass Surgery versus Coronary Stenting. Risk-Adjusted Survival Rates in 5,619 Patients. RP Villlareal,V-V Lee, MA Elayda, JM Wilson.  Tex Heart Inst J. 2002; 29(1): 3–9.
5. Should all ischemic mitral regurgitation be repaired? When should we replace?  DJ LaPar, IL Kron. Curr Opin Cardiol. 2011 March; 26(2): 113–117
6. Hybrid Cath Lab Combines Nonsurgical, Surgical Treatments

Bypass, Angioplasty Similar in Survival 10 Years After Heart Procedures

The survival rates 10 years after coronary artery bypass surgery and angioplasty are similar, according to a new analysis of nearly 10,000 heart patients. Five years after the procedures, 90.7% of the bypass patients and 89.7% of the angioplasty patients were still alive, says  Mark A. Hlatky, MD, senior author of the analysis and a professor of health research and policy and professor of medicine at Stanford University School of Medicine in Palo Alto.

Hlatky and colleagues stress that their analysis only applies to a select group of heart patients: those for whom either procedure would be considered a reasonable choice. For patients who are eligible for either heart intervention, “either is feasible,” Hlatky tells WebMD. The report is released early online and will be published in the Nov. 20 issue of the Annals of Internal Medicine.

CABG vs. Angioplasty

The researchers evaluated the results of 23 clinical trials in which 5,019 patients (average age 61 years; 73% men) were randomly assigned to get angioplasty with or without stents (PCI), and 4,944 were assigned to get coronary artery bypass graft surgery (CABG) In angioplasty, interventional cardiologists push a balloon-like device into the coronary arteries and inflate the balloon to widen the vessel. An expandable wire mesh tube called a stent may be inserted to keep the vessel open. Some stents are coated with drugs meant to help prevent the artery from clogging up. In 2005, about 645,000 angioplasty procedures were done in the U.S. In bypass surgery, cardiac surgeons harvest a segment of a healthy blood vessel from another part of the body and use it to bypass the clogged artery or arteries, rerouting the blood to improve blood flow to the heart. About 261,000 bypass procedures were done in the U.S. in 2005.


Besides similar survival rates overall, the researchers found no significant survival differences between the two procedures for patients with diabetes, although earlier research had seemed to favor bypass surgery. Similar numbers of patients suffered heart attacks within five years of the procedures. While 11.9 of those who got angioplasty had a heart attack within five years, 10.9% of those who got bypass did. Repeat procedures were more common in angioplasty patients. While 46.1% of angioplasty patients who didn’t get a stent needed repeat procedures, 40.1% of those who got a stent did. But just 9.8% of surgery patients needed another procedure.  The study didn’t include information on drug-coated stents.

Second Opinions

The new analysis is “very complete,” says Kim A. Eagle, MD, director of the Cardiovascular Center and Albion Walter Hewlett Professor of Internal Medicine at the University of Michigan, Ann Arbor. The study shows, he says, that if either procedure is considered appropriate for an individual patient, the decision can rest on patient attitudes and preferences. Patients preferences might be based on lower need to repeat in favor of surgery, or on avoidance of surgery in favor of angioplasty. But it is important to note, acoording to Curtis Hunter at Santa-Monica-UCLA, that the studies cover the least sick with heart disease, so the two procedures are shown to be equal in a very small subset of the patients.

Coronary Artery Bypass Surgery versus Coronary Stenting – Risk-Adjusted Survival Rates in 5,619 Patients  THIJ. 2002

We used the Texas Heart Institute Cardiovascular Research Database to retrospectively identify patients who had undergone their 1st revascularization procedure with coronary artery bypass surgery (CABG; n=2,826) or coronary stenting (n=2,793) between January 1995 and December 1999. Patients were classified into 8 anatomic groups according to the number of diseased vessels and presence or absence of proximal left anterior descending coronary artery disease. Mortality rates were adjusted with proportional hazards methods to correct for baseline differences in severity of disease and comorbidity.
We found that in-hospital mortality was significantly greater in patients undergoing CABG than in those undergoing stenting (3.6% vs 0.75%; adjusted OR 8.4; P <0.0001). At a mean 2.5-year follow-up, risk-adjusted survival was equivalent (CABG 91%, stenting 95%; adjusted OR 1.26; P = 0.06). When subgroups matched for severity of disease were compared, no differences in risk-adjusted survival were seen. A survival advantage of stenting was noted in 3 categories of patients: those >65 years of age (OR 1.33, P = 0.049), those with non-insulin-requiring diabetes (OR 2.06, P = 0.002), and those with any noncoronary vascular disease (OR 1.59, P = 0.009).
In this nonrandomized observational study, CABG had a higher periprocedural mortality rate than did percutaneous stenting. At 2.5 years, however, the survival advantage of stenting was no longer evident. These data suggest that there is no intermediate-term survival advantage of CABG over stenting in patients who have multivessel disease with lesions that can be treated percutaneously. (Tex Heart Inst J 2002;29:3–9)

Fig. 1 Adjusted and unadjusted survival rates in all patients treated with CABG or PCI-stenting

survival rates  of CABG or PCI-stenting

TABLE III. Multivariate Correlates of Intermediate-Term (2.5-Year) Mortality

Fig. 2 Adjusted odds ratios comparing the results of CABG and PCI-stenting in the 8 anatomic subgroups.

Adjusted odds ratios comparing the results of CABG and PCI-stenting in the 8 anatomic subgroups

TABLE IV. Intermediate-Term (2.5-Year) Survival According to Treatment in Each of the 8 Anatomic Groups

Intermediate-Term (2.5-Year) Survival According to Treatment in Each of the 8 Anatomic Groups

Fig. 3 Adjusted odds ratios comparing the results of CABG and PCI-stenting in the various prespecified subsets.

Adjusted odds ratios comparing the results of CABG and PCI-stenting in the various prespecified subsets.

Will Drug-Eluting Stents Replace Coronary Artery Bypass Surgery?


The growth of the PCI industry and the consequent decline in the number of patients referred for CABG has produced much speculation about the future role of each type of intervention. Because the new drug-eluting stents allow PCI to be performed with lower rates of early restenosis than do bare-metal stents or percutaneous transluminal coronary angioplasty (PTCA) alone, 2–8 some have predicted that surgical revascularization will soon be obsolete.

CABG vs Pharmaco-Therapy

Randomized clinical trials performed during the 1970s and early 1980s clearly established the advantages of CABG over medical therapy in patients with triple-vessel CAD, left main coronary artery stenosis, double-vessel CAD with proximal left anterior descending (LAD) coronary artery stenosis, or left ventricular dysfunction. Problems arose subsequently because of the limitations built into the trial so that the results were biased in favor of medical therapy.  These were:
  • stringent exclusion criteria that eliminated a large percentage of potential participants
  • left main CAD and an ejection fraction of less than 0.40, eliminated patients for whom CABG would have been beneficial
  • the high rate of crossover from the medical to the surgical groups

The numerous technical and technological advances made since these trials were completed limit the degree to which their results resemble those of the CAD treatments used today. The maximal medical therapy used during the trials did not routinely include lipid-lowering agents, β-blockers, angiotensin-converting enzyme (ACE) inhibitors, clopidogrel, or some of the other drugs currently used for CAD. Nor did the CABG groups benefit from advances that were subsequently made in preoperative imaging, perfusion and myocardial protection, anesthesia, and perioperative and intensive care practices. CABG did not then include the use of left internal mammary artery (LIMA) grafts, much less other arterial conduits. Finally, PCIs, including balloon angioplasty and stenting, were not included in these trials.


Randomized trials comparing PTCA with CABG revealed dramatically higher re-intervention rates in the PTCA groups and better angina relief in the CABG groups, although there were no significant differences in death or myocardial infarction rates. The Duke database study. 9 showed better survival rates with PTCA than with CABG in patients with single-vessel CAD, whereas CABG produced better survival than did PTCA in patients with severe, triple-vessel CAD.
These results are not necessarily representative of the results obtainable today with PTCA and CABG, for several reasons.
1.  stents were not used in the PTCA patients in these trials
2.  operative mortality rates for the CABG groups were higher than the rates currently found in the Society of Thoracic Surgeons (STS) database
3.  the inclusion/exclusion criteria of these studies eliminated a high percentage of those patients who might have benefited more from CABG than from PTCA

CABG vs Stents

The introduction of coronary artery stenting resulted in better outcomes than those produced by balloon angioplasty or by other adjuncts, including rotational atherectomy, brachytherapy, and laser angioplasty.  Since then, stent designs and delivery techniques have advanced considerably. The use of coronary stents has greatly decreased the necessity of emergent CABG for technical failure of PCI and for dissection or rupture of coronary arteries during PCI. Another major advance in the application of PCI is the use of the antiplatelet agent clopidogrel in addition to aspirin after PCI, as well as the use of glycoprotein (GP) IIb/IIIa receptor inhibitors during the procedure. These adjuncts have significantly reduced the incidence of acute and subacute thrombosis after PTCA with stenting.
Randomized trials comparing PTCA plus stenting with PTCA alone have shown that stenting significantly reduces rates of restenosis and re-intervention, as well as the frequency of emergent CABG.  On the other hand, randomized trials of stenting versus surgery have produced less conclusive results regarding the mid-term survival and freedom from adverse events.  For example, the Stent or Surgery (SOS) trial reported a greater need for repeat revascularization in the stent group (21%) than in the CABG group (6%) and a survival advantage in the CABG group (hazard ratio, 2.91; 95% CI, 1.29–6.53; P = 0.01) during the 3-year follow-up period. Additionally, angina and the use of anti-angina medications were less common in the CABG group at 1-year follow-up.
The ARTS and ERACI trials also reported an increased need for revascularization in the stent groups but did not show a survival advantage in the CABG groups. This was due in part to a higher operative mortality rate in the CABG group than reported in the STS database. Like the PCI versus CABG trials mentioned previously, these randomized trials involved a select group of patients with relatively low expected mortality rates and relatively high expected technical success with PCI.
Observational data in retrospective analyses of large patient databases comparing CABG with PCI plus stenting does indicate that, because of the greater invasiveness of surgical revascularization, CABG produces greater operative mortality than does PCI. However, in patients with multivessel CAD, the risk-adjusted survival rates at 2.5 years of follow-up are no better for PCI than for CABG, and 3 recent risk-adjusted observational studies showed that the CABG patients had a significant survival advantage at 3- to 8-year follow-up.   The CABG patients had significantly more preoperative risk factors than did the PCI patients in each study, so that unadjusted, the CABG groups in each study included significantly more patients with triple-vessel disease and fewer patients with double-vessel disease than did the PCI groups. Again, we have a moving target with recent advances in both surgery and PCI technology.

Disadvantages of Stenting

The Achilles’ heel of PCI is restenosis and the need for repeat revascularization. Stents have decreased the rate of acute and subacute  periprocedural thrombosis. The newer, drug-eluting stents (DESs) have improved in-stent restenosis rates, especially in the carefully selected patient populations studied in the early DES trials. In the RAVEL trial, the early reports of zero in-stent restenosis compared favorably with the 27% in-stent restenosis rates in the bare-metal stent control group at 6-month follow-up. However, the RAVEL trial excluded patients with lesions longer than 18 mm, ostial targets, calcified or thrombosed targets, or target arteries less than 2.5 mm in diameter.
The media frenzy that followed the release of these findings created a public demand for these new “miracle” stents that apparently did not re-occlude. Stories of CAD patients refusing conventional PCI and CABG —instead, adding their names to the list of patients waiting for U.S. Food and Drug Administration (FDA) approval of DESs—appeared to change the practice patterns of cardiologists and cardiac surgeons overnight.  And then there were the calls for class-action lawsuits and recall of various DES models. After the FDA approved the Cordis Cypher™ DES (Cordis Corporation, a Johnson & Johnson company; Miami Lakes, Fla), a few reports of subacute thrombosis and hypersensitivity reactions prompted the FDA to release a public health notification on 29 October 2003.
The SIRIUS trial had slightly less strict exclusion criteria than did the RAVEL trial, admitting patients with target lesions 2.5 to 3.5 mm in diameter and 15 to 30 mm long, as well as patients with diabetes mellitus (who constituted 26% of the total group).  The SIRIUS trial also differed from the RAVEL trial in that the reported end-point was in-segment restenosis, rather than in-stent restenosis. The results showed a significant advantage of DESs over bare-metal stents for preventing in-segment restenosis (9.2% vs 32.3%) and target failures (10.5% vs 19.5%), but major adverse cardiac events were more frequent in the DES group than in the bare-metal stent group (3.7% vs 1.0%). Interestingly, the 6-month restenosis rates of the bare-metal stents in the RAVEL and SIRIUS control groups were much higher than the 19% 12-month restenosis rate associated with bare-metal stents in an earlier study comparing bare-metal stents with PTCA. In fact, the restenosis rates in the RAVEL and SIRIUS control groups more closely resembled the 40% restenosis rate reported for the PTCA control group in the earlier study.
The practical advantages of DESs over bare-metal stents are evident; nonetheless, we still do not have sufficient mid-term or long-term clinical data to argue that PTCA with DESs is preferable to CABG in “real-world” patients who require revascularization. Although DESs will likely provide better outcomes than bare-metal stents for many patients for whom stenting is indicated, a general extrapolation of existing data to justify the use of DESs in patients for whom CABG is currently indicated is unknown, perhaps undeterminable because the lesion and patient characteristics that lead to the failure of PCI are multifactorial, and the size of the population with lesions having unfavorable characteristics , such as,
  • longer
  • total occlusion
  • branch
  • small-diameter
  • calcified
  • multiple
  • left main
  • ostial, and
  • diffuse lesions
are being treated with PCI more often, as well as diabetics, multiple lesions, and patients with multiple comorbidities.

Advantages of CABG

Over the last 4 decades, surgical coronary artery revascularization techniques and technology have advanced significantly. As a result, despite an increasingly older and sicker patient population, CABG outcomes continue to improve. Observed operative mortality rates have decreased because advances in preoperative evaluation, including more precise coronary artery and myocardial imaging and diagnostic techniques, have allowed more appropriate patient selection and surgical planning. In addition, preoperative, intraoperative, and postoperative monitoring and therapeutic interventions have made CABG safer, even for critically ill and high-risk patients. Improvements in cardiopulmonary perfusion and careful myocardial protection, as well as the use of off-pump and on-pump beating- heart techniques in selected patients, have also decreased perioperative morbidity and mortality rates.

LIMA-to-LAD Long-Term Patency

The long-term benefits of CABG with regard to survival and quality of life are dependent on prolonged graft patency. The LIMA-to-LAD bypass, which is now performed in more than 90% of CABG procedures, shows excellent patency in 10- to 20-year angiographic follow-up studies, setting the gold standard with which other revascularization strategies should be compared. Tatoulis et al. reported that LIMA-to-LAD grafts had a 97.1% patency rate in patients who underwent angiography for cardiac symptoms. Those authors also found high patency rates at 5-year (98%), 10-year (95%), and 15-year (88%) follow-up. However, there are not yet long-term data on bare-metal stents or DESs, and by the time 10- or 20-year data are available, DESs probably will have been replaced by a newer, more advanced technology.
Because of the reported success of the LIMA-to-LAD bypass, other types of arterial conduits are also being used much more frequently. Conduit selection has become an area of great interest to cardiac surgeons, and conduit studies are expanding our understanding of the mechanisms of graft failure and ways to improve bypass graft patency. For example, studies have shown that patients who undergo CABG with both LIMA and right internal mammary artery (RIMA) conduits have better results than those who undergo CABG with one IMA and one or more saphenous vein grafts.

Techniques to Improve Conduit Patency

To maximize the odds of long-term graft patency, surgeons carefully harvest the graft as a pedicled or skeletonized conduit using “no touch” techniques. Using careful anastomotic technique to avoid excessive turbulence at the anastomosis site will prolong graft patency, and the quality of the conduit is crucial. Long-term graft patency depends not only on the conduit chosen but also on the target artery and the degree of stenosis proximal to the anastomosis. Maintaining flow patterns in the native artery, including residual flow (that is, competitive flow) and outflow, is important to avoid stasis in the graft, turbulence at the anastomosis, and vasospasm, especially in arterial conduits. Studies have shown an inverse relationship between the degree of proximal stenosis and graft patency. Targeting the LAD produces the highest patency rates. The characteristics of the target artery also determine graft patency, including –
1. the diameter of the target artery,
2. the presence or absence of diffuse disease within the artery,
3. whether or not the artery requires endarterectomy
Surgeons can avoid atheroembolic events by handling the aorta carefully or not at all. They can also improve safety by
1. using aggressive myocardial protection techniques;
2. avoiding the induction of inflammatory mediators; and
3. carefully controlling
  • blood pressure,
  • body temperature, and
  • electrolyte and glucose levels.
Although there have been major innovations that have enabled surgeons to perform cardiac surgery (including CABG) less invasively, minimally invasive surgical procedures are useful only if they are at least as efficacious as conventional surgery. New technology is being developed to enhance the evolving field of minimally invasive coronary bypass surgery.

Hybrid Coronary Revascularization

As PCI technology improves and techniques of LIMA-to-LAD grafting become less invasive, hybrid coronary revascularization is becoming a distinct possibility. For example, a minimally invasive, off-pump, direct LIMA-to-LAD anastomosis can be combined with DES placement in a focal mid-right-coronary-artery lesion in a patient with complex proximal LAD lesions. Hybrid coronary revascularization procedures are currently being performed, with promising early results. A few centers now have hybrid operating rooms with cardiac surgical and coronary angiographic capabilities that make it possible to perform simultaneous hybrid coronary revascularizations.

Although coronary artery bypass grafting (CABG) remains the treatment of choice for certain types of coronary artery disease (CAD), percutaneous coronary intervention (PCI)—particularly coronary angioplasty with stenting—has become the most popular nonmedical treatment approach to CAD. Some have speculated that, with the advent of drug-eluting stents (DESs), PCI will replace CABG entirely. However, the complete disappearance of CABG is both unlikely and unwarranted, for several reasons. Published randomized trials of CABG, PCI, and medical approaches to CAD compared only highly selected subgroups of patients because of strict exclusion criteria that often favored the PCI cohorts. Therefore, their results do not constitute sufficient evidence for the superiority of PCI over CABG in all CAD patients requiring revascularization. As PCI indications broaden to include more complex lesions and more high-risk patients, outcomes will not remain as favorable. In addition, although PCI is less invasive than surgery, CABG offers more complete revascularization and better freedom from repeat revascularization. Furthermore, no long-term patency data on DESs yet exist, whereas excellent 10- and 20-year patency rates have been reported for the left internal mammary artery-to-left anterior descending artery graft used in most CABG procedures. While PCI has been changing, CABG has not been stagnant; recently, advances in many aspects of the CABG procedure have improved short- and long-term outcomes in CABG patients. Both CABG and PCI technologies will continue to advance, not necessarily exclusive of one another, but no data yet exist to suggest that DESs will render CABG obsolete any time soon. 

Will Stent Revascularization Replace Coronary Artery Bypass Grafting?

When we discuss revascularization outcomes, we are talking about 3 major endpoints: death, myocardial infarction, and symptom control. With respect to death, we know that revascularization benefits patients who have severe multivessel disease and left ventricular dysfunction or other physiologic indicators of high risk. 2-vessel disease with proximal left anterior descending coronary artery (LAD) stenosis has been accepted as an indication for revascularization, even though the supporting data come from a small subgroup in a single trial. There has been no success in proving that endovascular treatment has a positive impact on stable CAD, but it is relevant because we leave the native arteries relatively intact. Attempts to improve graft performance beyond the relatively spectacular performance of the pedicled internal mammary artery (IMA) graft to the LAD have been disappointing.

Fig. 1 Graph of graft patency shows deterioration rates over 10 years and the comparative superiority of using the internal mammary artery (IMA) instead of the saphenous vein (SVG).http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3528239/bin/25FF1.gif

graft patency of IMA vs SVG

Percutaneous Transluminal Coronary Angioplasty

When angioplasty was introduced, the hope was for a method of revascularization that would rival coronary artery bypass grafting. However, the results were mixed. Angioplasty worked well in patients with no major risk factors, such as diabetes mellitus, but failed miserably in diabetic patients. In fact, the Bypass Angioplasty Revascularization Investigation (BARI)  taught us this: if revascularization is needed, regardless of physiologic markers of high risk, the use of percutaneous coronary intervention (PCI) is potentially harmful in comparison with an IMA bypass for the LAD.

Stents and Short-Term Outcomes

The use of stents drastically reduced the probability of emergent surgery after attempted; however, the probability of new lesion formation or restenosis after intervention did not decrease.

Fig. 2 Diagrams  show the calculated success (after percutaneous revascularization) of A) percutaneous transluminal coronary angioplasty (PTCA), and B) bare-metal and C) drug-eluting stenting in patients with 3-vessel coronary artery disease (CAD).

At the same time, surgeons got better. Myocardial preservation techniques improved, and the use of the pedicled IMA graft changed the game. As a result, successful revascularization, meaning long-term success, became the domain of the surgeon. We at the Texas Heart Institute/St. Luke’s Episcopal Hospital (THI/SLEH) examined our long-term outcomes after stenting or surgery, and we initially reported that stenting was just as beneficial as surgery. This was in accord with the results of several trials: whenever placing a stent was feasible, stent therapy and surgery had the same outcome.


success after PTCA vs bare-metal and drug-eluting stents

Stents and Long-Term Outcomes

Later, when we looked at longer-term follow-up data and the effects of multiple procedures, this picture began to change. Stented patients underwent more procedures. When the risk of one surgical procedure was compared with that of multiple endovascular procedures, the outcomes became more similar, especially in patients with bifurcation lesions or lesions with severe calcification. Drug-eluting stents, with their promise of no restenosis, substantially increased interventional cardiologists’ reach, but not their grasp. In patients with multivessel disease and high-risk lesions, DES placement was almost as risky as surgery and did not yield the same long-term benefit.

Nevertheless, we found locally that the introduction of the DES, with its lower risk of restenosis, was treated as a blessing to proceed with stenting (Table I). This did not follow the data, but cardiologists continued anyway, given the promise of less restenosis. Early risk was discounted, glycoprotein IIb/IIIa inhibitor use declined overnight, and the rate of endovascular procedural complications rose to meet that of surgery without the promise of an IMA graft in our future.

Table I. Independent Predictors of 30-Day Major Adverse Cardiac Events and 3-Year Survival after Drug-Eluting Stent Placement

Comparing Stenting and Surgery

For decades, methods have been sought to quantify lesion complexity in order to compare the early and late risks associated with stenting versus surgery. Although no perfect system has been devised, the SYNTAX was an important step forward. The SYNTAX score is a simple, computer-based tool for evaluating the risk of complications or failure after PCI. And there are other tools for estimating the same complications after surgery. These estimates enable cardiologists to give patients objective advice regarding the revascularization method that has the best short- and long-term probability of success.
In the patient with non-life-threatening disease (that is, not left main or severe multivessel CAD with left ventricular dysfunction or severely impaired function), stent revascularization has become a reasonable, although not ideal, alternative to surgical revascularization. However, this is true only if stenting is confined to patients whose anatomy and physiology are suited to it—considerations that are well quantified in the SYNTAX score. Whenever questions arise as to the most appropriate therapy, the SYNTAX score should be weighed against clinical characteristics that affect surgical risk. This will guide discussions between the cardiologist, cardiovascular surgeon, patient, and treating physician.
I think that our THI risk is more useful than the other available scores. It uses simple clinical data and can be easily calibrated to the geographic location of its use. Other scores require data that might not be available at the time of clinical decision-making or at all—making such predictions hazardous, at best.


With regard to the chosen mode of revascularization, it is perhaps safe to say that the decision goes beyond the individual physician and must become collective. When a patient has multivessel disease, a reasoned approach must be taken, using these predictive tools and considering the patient’s wishes. Treatment decisions should include all interested parties: the patient, cardiologist, cardiovascular surgeon, and anesthesiologist. The time of ad hoc angioplasty for the patient with multivessel CAD has passed.

Should all ischemic mitral regurgitation be repaired? When should we replace?   Curr Opin Cardiol. 2011


Purpose of review

Ischemic mitral regurgitation (IMR) is a major source of morbidity and mortality. Although mitral valve repair has become recently popularized for the treatment of IMR, select patients may derive benefits from replacement. The purpose of this review is to describe current surgical options for IMR and to discuss when mitral valve replacement (MVR) may be favored over mitral valve repair.

Recent findings

Current surgical options for the treatment of IMR include surgical revascularization alone, mitral valve repair, or MVR. Although surgical revascularization alone may benefit patients with mild–moderate IMR, most surgeons advocate the performance of revascularization in combination with either mitral valve repair or replacement. In the current era, mitral valve repair has proven to offer improved short-term and long-term survival, decreased valve-related morbidity, and improved left ventricular function compared with MVR. However, MVR should be considered for high-risk patients and those with specific underlying mechanisms of IMR.


In the absence of level one evidence, mitral valve repair offers an effective and durable surgical approach to the treatment of mitral insufficiency and remains the operation of choice for IMR. MVR, however, is preferred for select patients. Future randomized, prospective clinical trials are needed to directly compare these surgical techniques.


Ischemic mitral regurgitation (IMR) describes insufficiency of the mitral valve in the setting of myocardial ischemia, resulting from coronary artery disease. Although IMR may present in the acute setting, usually as a papillary rupture (Carpentier type II), it is usually a consequence of chronic myocardial ischemia that typically presents weeks following a complete infarction. IMR describes mitral insufficiency in the absence of degenerative (structural) mitral valve disease. The underlying pathophysiologic mechanisms of IMR are often complex, resulting from several different structural changes involving left ventricular geometry, the mitral annulus, and the valvular/subvalvular apparatus. Although changes to any one component may result in detectable mitral valve insufficiency, moderate-to-severe IMR requiring surgical correction often involves the complex interplay of several co-existent anatomic changes. These underlying mechanisms result in clinically significant valve incompetence due to the combined effects of decreased ventricular function and restricted motion of the valve itself due to tethering.
IMR is a major source of patient morbidity and mortality. Although the frequency of IMR differs based upon imaging modality, estimates have suggested that nearly 20–30% of patients experience mitral insufficiency following myocardial infarction. Furthermore, its intimate association with heart failure and poor outcomes for suboptimal medical management further complicates the management of clinically significant IMR. Recent evidence suggests that moderate or severe mitral regurgitation may be associated with a three-fold increase in the adjusted risk of heart failure and a 1.6-fold increase in risk-adjusted mortality at 5-year follow-up. In addition, unfavorable patient profiles and co-existing comorbid disease, including renal failure, chronic obstructive pulmonary disease, diabetes, and impaired left ventricular function, further complicate the clinical picture for those with IMR. Consequently, surgical correction of this condition is often required.
The purpose of this review is to analyze published results for the surgical correction of IMR and to provide current opinion regarding the selection of mitral valve procedure in the setting of myocardial ischemia. Herein, we review current surgical options for IMR and discuss when MVR may be favored over mitral valve repair.

Surgical options for ischemic mitral regurgitation: surgical revascularization alone

Surgical revascularization alone with CABG may be beneficial for some patients. Although CABG alone may be performed in cases of mild-to-moderate IMR, for the treatment of severe IMR, evidence supports performance of CABG with a mitral valve. In fact, a lack of evidence exists to support the performance of CABG alone for severe IMR. In one retrospective review of propensity-matched cohorts, Diodato et al. suggested that addition of a mitral valve procedure to patients undergoing CABG for moderately severe to severe IMR did not increase mortality or improve survival over the performance of CABG alone. This study, however, was limited by small sample sizes (51 CABG + mitral valve repair vs. 51 CABG alone) and 3-year follow-up. To the contrary, substantial evidence exists to support the performance of surgical revascularization alone in cases of mild-to-moderate IMR.
A study by Aklog et al. investigated the role of CABG alone in the correction of moderate IMR. In their series of 136 patients with moderate IMR, they demonstrated that performance of revascularization alone conferred improvement of mitral regurgitation in 51% of patients with complete resolution in an additional 9%. Despite these results, 40% of patients remained with 3–4+ mitral regurgitation, leading the authors to conclude that CABG alone may not be the optimal therapy for most patients and suggest that concomitant mitral annuloplasty may improve results. Other series similarly suggest that complete resolution of functional IMR is uncommon following revascularization alone. Despite the presence of residual mitral regurgitation following revascularization, the impact of performance of CABG without a valve procedure on long-term survival remains ill defined. Currently, on-going prospective evaluation may help to define the potential role of revascularization alone for patients with moderate IMR. Until the completion of these trials, however, evidence supports the performance of surgical revascularization combined with a mitral valve procedure for moderate-to-severe mitral regurgitation.

Surgical revascularization with a mitral valve procedure

The majority of patients with moderate-to-severe IMR require surgical revascularization with a concomitant mitral valve procedure (MVR or mitral valve repair). Historically, these procedures have been associated with high morbidity and mortality as well as poor long-term. However, improved surgical techniques and postoperative management have improved contemporary outcomes. Those favoring mitral valve repair promote its beneficial effects on survival, preserved ventricular function, and the avoidance of long-term anticoagulation, whereas those favoring MVR argue that it ensures long-term freedom from recurrent mitral insufficiency.

Mitral valve replacement vs. mitral valve repair

The use of MVR for IMR eliminates the possibility of recurrent IMR. In addition, previous literature suggests improvements in surgical technique for MVR 29–32. For patients with IMR, MVR with preservation of the subvalvular apparatus using a chordal sparing technique has been shown to be beneficial 33. David and Ho 33 demonstrated a significant survival benefit for patients undergoing MVR with preservation of chordae tendineae (89%) compared with complete excision of the mitral valves (59%) in a cohort of 51 patients with IMR. In addition, Cohn et al. suggested disproportionate survival benefits favoring MVR in a cohort of 150 patients with both functional and structural IMR, concluding that survival following performance of mitral valve procedures for IMR was more dependent on underlying pathophysiology rather than surgical technique. More recently, series have suggested equivalent results for the MVR and mitral valve repair. Mantovani et al. report that prosthetic MVR and mitral valve repair offer very similar results for chronic IMR, demonstrating similar operative mortality and 5-year actuarial survival for both techniques. In a similar report, Magne et al.•• compared short-term and long-term outcomes for 370 patients undergoing mitral valve repair (n = 186) and MVR (n = 184) for IMR. Although operative mortality was lower for mitral valve repair compared with MVR (9.7 vs. 17.4%, P = 0.03), 6-year survival was similar for both operations (73 ± 4 vs. 67 ± 4%, P = 0.17). Type of procedure was also not an independent predictor of mortality following risk adjustment. As a result, the authors suggest that mitral valve repair is not superior to MVR for patients with IMR.
In contrast, other series favor the performance of mitral valve repair for functional IMR. Although several repair techniques exist, restrictive annuloplasty remains the most commonly performed operation 37• and has been shown to be beneficial in both functional and chronic IMR 38•. The purported benefits of improved survival, decreased valve-related morbidity, and improved left ventricular function have been previously established, and several series have reported lower hospital mortality with mitral valve repair compared with MVR.
The Cleveland Clinic published a landmark review of 482 patients undergoing mitral valve procedures for IMR to study the influence of mitral valve procedure type on survival 1. In this series, propensity-matched cohorts were compared: mitral valve repair (n = 397) vs. MVR (n = 85). Concomitant CABG was performed in 95% of operations, and annuloplasty for repair occurred in 98% of cases. After matching, patients were risk stratified into five quintiles. Group 1 represented the highest-risk patients with higher degrees of heart failure and emergent operations, and group 5 represented the lowest-risk patients. Subsequent survival analysis revealed that overall 5-year survival was poor for patients with IMR (58% mitral valve repair vs. 36% MVR, P = 0.08). Moreover, within matched quintiles, the highest-risk patients (quintile 1) had the worst survival, but survival was similar (P = 0.4) despite mitral valve procedure type. In contrast, survival favored mitral valve repair over replacement for quintiles III–V (P = 0.003).
In the absence of published randomized trials, two recently published meta-analyses provide more robust comparisons of the influence of surgical mitral valve repair or replacement. Shuhaiber and Anderson  compared outcomes of 29 studies, including over 10 000 patients. Study groups were stratified based upon mitral valve etiology into ischemic, degenerative/myxomatous, rheumatic, and mixed groups. Summary analyses indicated worse overall survival for MVR (early mortality odds ratio = 2.24 and total survival hazard ratio = 1.58) compared with repair. Mitral valve repair was also associated with lower rates of thromboembolism. Moreover, a nonsignificant trend toward lower 30-day mortality favored mitral valve repair for those with IMR. The most recent meta-analysis to date compared short-term and long-term survival of mitral valve repair vs. replacement specifically for IMR ••. In this analysis, nine studies were included based upon stringent exclusion criteria to ensure direct comparisons of survival for mitral valve procedures exclusively performed for IMR. Interestingly, in this series, although patients undergoing MVR were older, those undergoing repair often had higher rates of hypertension and diabetes with lower ejection fractions. Further, the proportion of patients with severe ventricular dysfunction was similar between procedure groups. These findings conflict with a common assumption that an inherent selection bias exists within published studies for the performance of mitral valve repair in healthier patients. Nevertheless, MVR was associated with worse short-term mortality (odds ratio = 2.667) and long-term mortality (hazard ratio = 1.35) compared with mitral valve repair, and the authors advocate that choice in mitral procedure should be based upon individual patient profile.

When not to repair ischemic mitral regurgitation?

Within the context of published literature and current dogma among practicing surgeons, the fundamental question of when not to repair an ischemic mitral valve remains. For several years, accumulated evidence supports the performance of mitral valve repair over replacement for the surgical treatment of functional IMR. The aforementioned benefits of repair include improved long-term survival, durability and efficacy, improved ventricular function, and avoidance of chronic anticoagulation therapy. Nevertheless, MVR still plays a select role in the treatment of IMR.
With respect to the performance of MVR, the use of bioprosthetic valves and the avoidance of mechanical valve replacement are preferred. This choice is largely driven by the avoidance of complications due to long-term anticoagulation use as well as by the belief that it is unlikely that the majority of patients requiring MVR are likely to encounter bioprosthetic deterioration in their lifetime. In addition, MVR with techniques to preserve the subvalvular apparatus should be performed when possible.


Undoubtedly, the debate regarding when to perform repair or replacement for IMR remains unsettled. In the recent era, mitral valve repair has proven efficacious and remains the preferred surgical strategy for most cases of IMR. MVR should be considered for severe tethering, complex or uncertain mechanisms of mitral insufficiency, regurgitation due to papillary muscle rupture, and perhaps for the sickest and highest-risk patients.
The present review was supported by Award Number 2T32HL007849-11A1 (D.J.L.) from the National Heart, Lung, and Blood Institute. The content is solely the responsibility of the authors.
Hybrid Cath Lab Combines Nonsurgical, Surgical Treatments  2008
A new cardiac treatment facility that couples the benefits of interventional cardiology with cardiothoracic surgery for critically ill newborns, children and adults has opened at Rush University Medical Center, Chicago.  Toshiba’s new biplane hybrid cardiac suite, which is one of only three facilities of its kind in the U.S., is equipped with the latest in continuous, real-time imaging technology and radio frequency identification (RFID) technology which allows “all-in-one-room” care. The suite allows collaboration between the surgeon and interventional cardiologist on complex heart problems. For example, fixing a very large hole in the heart can be done by inserting a catheter through a small incision in the chest rather than relying on major surgery to open the chest to reach the heart. “Now, interventional cardiologists and cardiothoracic surgeons working together in this suite will reduce the amount of time required to correct complex heart problems and reduce the emotional and physical stress placed on a patient and their family – which translates into less pain, less scarring and a faster recovery time,” Ziyad Hijazi, M.D., director of the new Rush Center for Congenital and Structural Heart Disease. The hybrid suite is equipped with the latest technology for minimally invasive interventional cardiology that involves the use of a catheter and an image-guidance system to thread tiny instruments through blood vessels to repair the heart. Through these special catheters, physicians at Rush can implant stents, artificial heart valves and insert patches for holes in the heart. In many complex cardiac cases, patients who would otherwise have no other option but to undergo open-heart bypass surgery can now have minimally invasive procedures that would otherwise not be available to them. “We can now communicate with colleagues and obtain their expertise in real time for very complex situations,” said Dr. Hijazi. “If physicians decide another procedure is needed, even surgery, the suite can be converted into an operating room and the surgical team can be assembled in the new suite ”Patients at Rush will stay in one place in the new hybrid cardiac suite where all the imaging technology and implantable devices that might be needed are stored and located. The additional ability it gives us to provide surgical treatments allows us to provide the most comprehensive care in the most sensitive manner for patients with often extremely fragile conditions.”  The new hybrid cardiac catheterization suite has the most advanced imaging technologies and can still get a precise, optimal image of any region of the heart regardless of the size or complexity of congenital heart disease. The imaging system also features eight-inch cardiac flat panel detectors designed to deliver distortion-free images. The suite also includes intravascular ultrasound machines, which takes real-time images to allow physicians to see the progress of the procedure taking place inside the patient’s body. A high-tech, automated clinical resource management system located in the suite stores and tracks the medication, surgical tools, medical devices, and implantable devices and supplies using the latest RFID enabled technology.

Hybrid Cath Lab/ORs Are the Way of the Future

Recent developments in cardiac surgery and interventional cardiology with new percutaneous alternatives for aneurysm repair, valve replacements, shunt closure devices and aortic arch reconstruction have led to the creation of integrated, hybrid cath lab/operating rooms (OR) that allow both surgical and intravascular procedures. These rooms offer both surgical equipment and high-end angiographic equipment. Creating such rooms requires special planning and design from both surgical and interventional cardiologists working closely together. Cath labs have high-quality fluoroscopy equipment, but generally are smaller rooms and lack the sterile requirements and equipment needed for surgical procedures. ORs tend to use lower quality mobile C-arms, which are not ideal for interventional procedures. The hybrids aim to provide the best of both worlds. The trend toward hybrid labs has been reinforced by digital angiography manufacturers partnering with surgical equipment companies to create easy-to-integrate hybrid room solutions with coordinated installation. Philips partners with both Skytron and Steris. Toshiba partners with MAQUET. GE Healthcare, Siemens and Toshiba also offer hybrid installations. Philips said while some hospitals want to combine interventional procedures with minimally invasive surgeries, they also want a properly equipped room in case emergency surgery is needed.
Philips said hybrids also allow hospitals with lower PCI numbers to get a bigger bang for their buck by allowing the same room to serve the needs of surgeons. Penn Presbyterian Medical Center in Philadelphia, PA, created a hybrid lab with help from Siemens, which opened in November. Wilson Szeto, M.D., cardio-thoracic surgeon, and William Matthai, M.D., interventionalist, both from Penn Presbyterian said hybrid labs are ideally suited for procedures that require both percutaneous and surgical interventions, percutaneous valve replacements, deploying percutaneous septal occluders or installing aortic stent grafts. Interventionalists can also be called in after cardiac surgery to perform a completion angiography.

Key References:

1. Davis KB, Alderman EL, Kosinski AS, Passamani E, Kennedy JW. Early mortality of acute myocardial infarction in patients with and without prior coronary revascularization surgery. A Coronary Artery Surgery Study Registry Study. Circulation 1992;85(6):2100–9. [PubMed]
2. Peduzzi P, Detre K, Murphy ML, Thomsen J, Hultgren H, Takaro T. Ten-year incidence of myocardial infarction and prognosis after infarction. Department of Veterans Affairs Cooperative Study of Coronary Artery Bypass Surgery. Circulation 1991;83(3):747–55. [PubMed]
3. Myocardial infarction and mortality in the coronary artery surgery study (CASS) randomized trial. N Engl J Med 1984; 310(12):750–8. [PubMed]
4. Long-term results of prospective randomised study of coronary artery bypass surgery in stable angina pectoris. European Coronary Surgery Study Group. Lancet 1982;2(8309):1173–80. [PubMed]
5. Frimerman A, Rechavia E, Eigler N, Payton MR, Makkar R, Litvack F. Long-term follow-up of a high risk cohort after stent implantation in saphenous vein grafts. J Am Coll Cardiol 1997;30(5):1277–83. [PubMed]
6. Comparison of coronary bypass surgery with angioplasty in patients with multivessel disease. The Bypass Angioplasty Revascularization Investigation (BARI) Investigators [published erratum appears in N Engl J Med 1997;336(2):147]. N Engl J Med 1996;335(4):217–25. [PubMed]
7. Coronary angioplasty versus coronary artery bypass surgery: the Randomized Intervention Treatment of Angina (RITA) trial. Lancet 1993;341:573–80. [PubMed]
8. Rodriguez A, Boullon F, Perez-Balino N, Paviotti C, Liprandi MI, Palacios IF. Argentine randomized trial of percutaneous transluminal coronary angioplasty versus coronary artery bypass surgery in multivessel disease (ERACI): in-hospital results and 1-year follow-up. ERACI Group. J Am Coll Cardiol 1993;22:1060–7. [PubMed]
9. Hamm CW, Reimers J, Ischinger T, Rupprecht HJ, Berger J, Bleifeld W. A randomized study of coronary angioplasty compared with bypass surgery in patients with symptomatic multivessel coronary disease. German Angioplasty Bypass Surgery Investigation (GABI). N Engl J Med 1994;331: 1037–43. [PubMed]
10. King SB 3rd, Lembo NJ, Weintraub WS, Kosinski AS, Barnhart HX, Kutner MH, et al. A randomized trial comparing coronary angioplasty with coronary bypass surgery. Emory Angioplasty versus Surgery Trial (EAST). N Engl J Med 1994;331:1044–50. [PubMed]
11 First-year results of CABRI (Coronary Angioplasty versus Bypass Revascularisation Investigation). CABRI Trial Participants. Lancet 1995;346:1179–84. [PubMed]
12. Carrie D, Elbaz M, Puel J, Fourcade J, Karouny E, Fournial G, Galinier M. Five-year outcome after coronary angioplasty versus bypass surgery in multivessel coronary artery disease: results from the French Monocentric Study. Circulation 1997; 96(9 Suppl):II-1–6. [PubMed]
13. Altmann DB, Racz M, Battleman DS, Bergman G, Spokojny A, Hannan EL, Sanborn TA. Reduction in angioplasty complications after the introduction of coronary stents: results from a consecutive series of 2242 patients. Am Heart J 1996;132:503–7. [PubMed]
14. Rankin JM, Spinelli JJ, Carere RG, Ricci DR, Penn IM, Hilton JD, et al. Improved clinical outcome after widespread use of coronary-artery stenting in Canada. N Engl J Med 1999;341:1957–65. [PubMed]
15. Jones RH, Kesler K, Phillips HR 3rd, Mark DB, Smith PK, Nelson CL, et al. Long-term survival benefits of coronary artery bypass grafting and percutaneous transluminal angioplasty in patients with coronary artery disease. J Thorac Cardiovasc Surg 1996;111:1013–25. [PubMed]
16. Hannan EL, Racz MJ, McCallister BD, Ryan TJ, Arani DT, Isom OW, Jones RH. A comparison of three-year survival after coronary artery bypass graft surgery and percutaneous transluminal coronary angioplasty. J Am Coll Cardiol 1999; 33:63–72. [PubMed]
17. Topol EJ, Mark DB, Lincoff AM, Cohne E, Burton J, Kleiman N, et al. Outcomes at 1 year and economic implications of platelet glycoprotein IIb/IIIa blockade in patients undergoing coronary stenting: results from a multicentre randomised trial. EPISTENT Investigators. Evaluation of Platelet IIb/IIIa Inhibitor for Stenting [published erratum appears in Lancet 2000;355:1104]. Lancet 1999;354:2019–24. [PubMed]
18. Serruys PW, de Jaegere P, Kiemeneij F, Macaya C, Rutsch W, Heyndrickx G, et al. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. Benestent Study Group. N Engl J Med 1994;331:489–95. [PubMed]
19. Fischman DL, Leon MB, Baim DS, Schatz RA, Savage MP, Penn I, et al. A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. Stent Restenosis Study Investigators. N Engl J Med 1994;331:496–501. [PubMed]
20. Coronary-artery bypass surgery in stable angina pectoris: survival at two years. European Coronary Surgery Study Group. Lancet 1979;1:889–93. [PubMed]
21.  Coronary artery surgery study (CASS): a randomized trial of coronary artery bypass surgery: quality of life in patients randomly assigned to treatment groups. Circulation 1983; 68:951–60. [PubMed]
22. Takaro T, Hultgren HN, Lipton MJ, Detre KM. The VA cooperative randomized study of surgery for coronary arterial occlusive disease II. Subgroup with significant left main lesions. Circulation 1976;54:III107–17. [PubMed]
23. Hueb WA, Bellotti G, de Oliveira SA, Arie S, de Albuquerque CP, Jatene AD, et al. The Medicine, Angioplasty or Surgery Study (MASS): a prospective, randomized trial of medical therapy, balloon angioplasty or bypass surgery for single proximal left anterior descending artery stenoses. J Am Coll Cardiol 1995;26:1600–5. [PubMed]
24. Nordmann AJ, Hengstler P, Leimenstoll BM, Harr T, Young J, Bucher HC. Clinical outcomes of stents versus balloon angioplasty in non-acute coronary artery disease: a meta-analysis of randomized controlled trials. Eur Heart J 2004;25:69–80. [PubMed]
25. Versaci F, Gaspardone A, Tomai F, Crea F, Chiariello L, Gioffre PA. A comparison of coronary-artery stenting with angioplasty for isolated stenosis of the proximal left anterior descending coronary artery. N Engl J Med 1997;336:817–22. [PubMed]
26. Krumholz HM, Cohen DJ, Williams C, Baim DS, Brinker J, Cabin HS, et al. Health after coronary stenting or balloon angioplasty: results from the Stent Restenosis Study. Am Heart J 1997;134:337–44. [PubMed]
27. Villareal RP, Lee VV, Elayda MA, Wilson JM. Coronary artery bypass surgery versus coronary stenting: risk-adjusted survival rates in 5,619 patients. Tex Heart Inst J 2002;29:3–9. [PMC free article] [PubMed]
28. van Domburg RT, Takkenberg JJ, Noordzij LJ, Saia F, van Herwerden LA, Serruys PW, et al. Late outcome after stenting or coronary artery bypass surgery for the treatment of multivessel disease: a single-center matched-propensity controlled cohort study. Ann Thorac Surg 2005;79:1563–9. [PubMed]
29. Brener SJ, Lytle BW, Casserly IP, Schneider JP, Topol EJ, Lauer MS. Propensity analysis of long-term survival after surgical or percutaneous revascularization in patients with multivessel coronary artery disease and high-risk features. Circulation 2004;109:2290–5. [PubMed]
30. Al-Ruzzeh S, Ambler G, Asimakopoulos G, Omar RZ, Hasan R, Fabri B, et al. Off-pump coronary artery bypass (OPCAB) surgery reduces risk-stratified morbidity and mortality: a United Kingdom multi-center comparative analysis of early clinical outcome. Circulation 2003;108 Suppl 1:II1–8. [PubMed]
31. Puskas JD, Williams WH, Mahoney EM, Huber PR, Block PC, Duke PG, et al. Off-pump vs conventional coronary artery bypass grafting: early and 1-year graft patency, cost, and quality-of-life outcomes: a randomized trial. JAMA 2004;291:1841–9. [PubMed]
32. Goldman S, Zadina K, Moritz T, Ovitt T, Sethi G, Copeland JG, et al. Long-term patency of saphenous vein and left internal mammary artery grafts after coronary artery bypass surgery: results from a Department of Veterans Affairs Cooperative Study. J Am Coll Cardiol 2004;44:2149–56. [PubMed]
33. Shah PJ, Durairaj M, Gordon I, Fuller J, Rosalion A, Seevanayagam S, et al. Factors affecting patency of internal thoracic artery graft: clinical and angiographic study in 1434 symptomatic patients operated between 1982 and 2002. Eur J Cardiothorac Surg 2004;26:118–24. [PubMed]
34. Arima M, Kanoh T, Suzuki T, Kuremoto K, Tanimoto K, Oigawa T, et al. Serial angiographic follow-up beyond 10 years after coronary artery bypass grafting. Circ J 2005;69: 896–902. [PubMed]
35. Tatoulis J, Buxton BF, Fuller JA. Patencies of 2127 arterial to coronary conduits over 15 years. Ann Thorac Surg 2004; 77:93–101. [PubMed]
36. Beauford RB, Saunders CR, Lunceford TA, Niemeier LA, Shah S, Karanam R, et al. Multivessel off-pump revascularization in patients with significant left main coronary artery stenosis: early and midterm outcome analysis. J Card Surg 2005;20:112–8. [PubMed]
37. Banning AP, Westaby S, Morice MC, Kappetein AP, Mohr FW, Berti S, et al. Diabetic and nondiabetic patients with left main and/or 3-vessel coronary artery disease: comparison of outcomes with cardiac surgery and paclitaxel-eluting stents. J Am Coll Cardiol 2010;55(11):1067–75. [PubMed]
38. Laham RJ, Carrozza JP, Berger C, Cohen DJ, Kuntz RE, Baim DS. Long-term (4- to 6-year) outcome of Palmaz-Schatz stenting: paucity of late clinical stent-related problems. J Am Coll Cardiol 1996;28(4):820–6. [PubMed]
39. Rodriguez A, Bernardi V, Navia J, Baldi J, Grinfeld L, Martinez J, et al. Argentine Randomized Study: Coronary Angioplasty with Stenting versus Coronary Bypass Surgery in patients with Multiple-Vessel Disease (ERACI II): 30-day and one-year follow-up results. ERACI II Investigators [published erratum appears in J Am Coll Cardiol 2001;37(3):973–4]. J Am Coll Cardiol 2001;37(1):51–8. [PubMed]
40. Serruys PW, Unger F, Sousa JE, Jatene A, Bonnier HJ, Schonberger JP, et al. Comparison of coronary-artery bypass surgery and stenting for the treatment of multivessel disease. N Engl J Med 2001;344(15):1117–24. [PubMed]
41. Goy JJ, Kaufmann U, Goy-Eggenberger D, Garachemani A, Hurni M, Carrel T, et al. A prospective randomized trial comparing stenting to internal mammary artery grafting for proximal, isolated de novo left anterior coronary artery stenosis: the SIMA trial. Stenting vs Internal Mammary Artery. Mayo Clin Proc 2000;75(11):1116–23. [PubMed]
42. SoS Investigators. Coronary artery bypass surgery versus percutaneous coronary intervention with stent implantation in patients with multivessel coronary artery disease (the Stent or Surgery trial): a randomised controlled trial. Lancet 2002;360 (9338):965–70. [PubMed]
43. Reul RM. Will drug-eluting stents replace coronary artery bypass surgery? Tex Heart Inst J 2005;32(3):323–30. [PMC free article] [PubMed]
44. Sianos G, Morel MA, Kappetein AP, Morice MC, Colombo A, Dawkins K, et al. The SYNTAX Score: an angiographic tool grading the complexity of coronary artery disease. EuroIntervention 2005;1(2):219–27. [PubMed]
45. Madan P, Elayda MA, Lee VV, Wilson JM. Predicting major adverse cardiac events after percutaneous coronary intervention: the Texas Heart Institute risk score. Am Heart J 2008; 155(6):1068–74. [PubMed]
46. Gillinov AM, Wierup PN, Blackstone EH, et al. Is repair preferable to replacement for ischemic mitral regurgitation? J Thorac Cardiovasc Surg. 2001;122:1125–1141. [PubMed]
47. Grigioni F, Enriquez-Sarano M, Zehr KJ, et al. Ischemic mitral regurgitation: long-term outcome and prognostic implications with quantitative Doppler assessment. Circulation. 2001;103:1759–1764. [PubMed]
48. Lamas GA, Mitchell GF, Flaker GC, et al. Clinical significance of mitral regurgitation after acute myocardial infarction. Survival and Ventricular Enlargement Investigators. Circulation. 1997;96:827–833. [PubMed]
49. Bursi F, Enriquez-Sarano M, Nkomo VT, et al. Heart failure and death after myocardial infarction in the community: the emerging role of mitral regurgitation. Circulation. 2005;111:295–301. [PubMed]
50. Adams DH, Filsoufi F, Aklog L. Surgical treatment of the ischemic mitral valve. J Heart Valve Dis. 2002;11 (Suppl 1):S21–S25. [PubMed]
51. Filsoufi F, Salzberg SP, Adams DH. Current management of ischemic mitral regurgitation. Mt Sinai J Med. 2005;72:105–115. [PubMed]
52. Micovic S, Milacic P, Otasevic P, et al. Comparison of valve annuloplasty and replacement for ischemic mitral valve incompetence. Heart Surg Forum. 2008;11:E340–E345. [PubMed]
53. Aklog L, Filsoufi F, Flores KQ, et al. Does coronary artery bypass grafting alone correct moderate ischemic mitral regurgitation? Circulation. 2001;104 (12 Suppl 1):I68–I75. [PubMed]
54. Lam BK, Gillinov AM, Blackstone EH, et al. Importance of moderate ischemic mitral regurgitation. Ann Thorac Surg. 2005;79:462–470. discussion 462–470. [PubMed]
55. Ryden T, Bech-Hanssen O, Brandrup-Wognsen G, et al. The importance of grade 2 ischemic mitral regurgitation in coronary artery bypass grafting. Eur J Cardiothorac Surg. 2001;20:276–281. [PubMed]
56•. Goland S, Czer LS, Siegel RJ, et al. Coronary revascularization alone or with mitral valve repair: outcomes in patients with moderate ischemic mitral regurgitation. Tex Heart Inst J. 2009;36:416–424. This series documents current outcomes for the performance of CABG alone with/without concomitant mitral valve repair for ischemic mitral regurgitation. The authors report similar 5-year survival rates for both techniques; however, revascularization with repair resulted in significantly reduced mitral regurgitation grade, improved left ventricular function, and functional class compared with revascularization alone. This study provides an important comparison of these two techniques in the current surgical era. [PMC free article] [PubMed]
57••. Magne J, Girerd N, Senechal M, et al. Mitral repair versus replacement for ischemic mitral regurgitation: comparison of short-term and long-term survival. Circulation. 2009;120(11 Suppl):S104–S111. In this study, the authors compare postoperative outcomes for mitral valve repair and replacement for ischemic mitral regurgitation. Despite lower operative mortality following mitral valve repair, long-term survival was equivalent between surgical groups. This study adds important long-term comparisons of mitral valve procedures to accumulating data examining surgical treatments for ischemic mitral regurgitation. [PubMed]
58. Silberman S, Klutstein MW, Sabag T, et al. Repair of ischemic mitral regurgitation: comparison between flexible and rigid annuloplasty rings. Ann Thorac Surg. 2009;87:1721–1726. discussion 1726–1727. This study provides a contemporary comparison between the use of flexible and rigid annuloplasty rings for the surgical treatment of IMR. The authors report significantly improved clinical and hemodynamic results for rigid mitral annuloplasty rings compared with flexible rings. [PubMed]
59•. Tekumit H, Cenal AR, Uzun K, et al. Ring annuloplasty in chronic ischemic mitral regurgitation: encouraging early and midterm results. Tex Heart Inst J. 2009;36:287–292. This study reports early and midterm results for the use of flexible annuloplasty rings for the surgical treatment of chronic IMR. The authors demonstrate that use of flexible mitral valve annuloplasty conferred a reduction in left ventricular diameter with improved New York Heart Association functional class. This study reports current, encouraging results and provides a context for future investigations comparing flexible and rigid annuloplasty rings for chronic IMR. [PMC free article] [PubMed]
60. Shuhaiber J, Anderson RJ. Meta-analysis of clinical outcomes following surgical mitral valve repair or replacement. Eur J Cardiothorac Surg. 2007;31:267–275. [PubMed]
61••. Vassileva CM, Boley T, Markwell S, Hazelrigg S. Meta-analysis of short-term and long-term survival following repair versus replacement for ischemic mitral regurgitation. Eur J Cardiothorac Surg. 2010 [Epub ahead of print] This meta-analysis provides a comparison of nine published series specifically addressing the performance of mitral valve repair vs. replacement for IMR. The authors demonstrate worse short-term and long-term mortality for MVR. Their analysis offers an up-to-date and robust comparison of these two surgical techniques. [PubMed]

Other Related articles  published on this Open Access Online Scientific Journal, include the following:

Cardiac Surgery Theatre in China vs. in the US: Cardiac Repair Procedures, Medical Devices in Use, Technology in Hospitals, Surgeons’ Training and Cardiac Disease Severity”    https://pharmaceuticalintelligence.com/2013/01/08/cardiac-surgery-theatre-in-china-vs-in-the-us-cardiac-repair-procedures-medical-devices-in-use-technology-in-hospitals-surgeons-training-and-cardiac-disease-severity/

Heart Remodeling by Design – Implantable Synchronized Cardiac Assist Device: Abiomed’s Symphony                                                                                     https://pharmaceuticalintelligence.com/2012/07/23/heart-remodeling-by-design-implantable-synchronized-cardiac-assist-device-abiomeds-symphony/
Acute Chest Pain/ER Admission: Three Emerging Alternatives to Angiography and PCI    https://pharmaceuticalintelligence.com/2013/03/10/acute-chest-painer-admission-three-emerging-alternatives-to-angiography-and-pci/
Dilated Cardiomyopathy: Decisions on implantable cardioverter-defibrillators (ICDs) using left ventricular ejection fraction (LVEF) and Midwall Fibrosis: Decisions on Replacement using late gadolinium enhancement cardiovascular MR (LGE-CMR)
Clinical Trials on transcatheter aortic valve replacement (TAVR) to be conducted by American College of Cardiology and the Society of Thoracic Surgeons
FDA Pending 510(k) for The Latest Cardiovascular Imaging Technology
PCI Outcomes, Increased Ischemic Risk associated with Elevated Plasma Fibrinogen not Platelet Reactivity
The ACUITY-PCI score: Will it Replace Four Established Risk Scores — TIMI, GRACE, SYNTAX, and Clinical SYNTAX
Coronary artery disease in symptomatic patients referred for coronary angiography: Predicted by Serum Protein Profiles
Ablation Devices Market to 2016 – Global Market Forecast and Trends Analysis by Technology, Devices & Applications
Heart Renewal by pre-existing Cardiomyocytes: Source of New Heart Cell Growth Discovered
Cardiovascular Risk Inflammatory Marker: Risk Assessment for Coronary Heart Disease and Ischemic Stroke – Atherosclerosis.
To Stent or Not? A Critical Decision
Endothelin Receptors in Cardiovascular Diseases: The Role of eNOS Stimulation
Transcatheter Aortic-Valve Replacement for Inoperable Severe Aortic Stenosis
Imbalance of Autonomic Tone: The Promise of Intravascular Stimulation of Autonomics
New Definition of MI Unveiled, Fractional Flow Reserve (FFR)CT for Tagging Ischemia
Ethical Considerations in Studying Drug Safety — The Institute of Medicine Report
New Drug-Eluting Stent Works Well in STEMI
Expected New Trends in Cardiology and Cardiovascular Medical Devices
Minimally Invasive Structural CVD Repairs: FDA grants 510(k) Clearance to Philips’ EchoNavigator – X-ray and 3-D Ultrasound Image Fused.
Drug Eluting Stents: On MIT’s Edelman Lab’s Contributions to Vascular Biology and its Pioneering Research on DES

Related articles

Diagram of coronary angioplasty and stent plac...

Diagram of coronary angioplasty and stent placement (Photo credit: Wikipedia)

Denton A. Cooley, MD

Denton A. Cooley, MD (Photo credit: Wikipedia)

English: A thoracic surgeon performs a mitral ...

English: A thoracic surgeon performs a mitral valve replacement at the Fitzsimons Army Medical Center. Slovenščina: Kirurgi med operacijo. (Photo credit: Wikipedia)

Read Full Post »

Ventricular Assist Device (VAD): A Recommended Approach to the Treatment of Intractable Cardiogenic Shock

Writer: Larry H Bernstein, MD, FCAP


Curator: Aviva Lev-Ari, PhD, RN

A ventricular assist device (VAD) is an implantable mechanical pump that helps pump blood from the lower chambers of your heart (the ventricles) to the rest of your body. VADs are used in people who have weakened hearts or heart failure. Although VADs can be placed in the left, right or both ventricles of your heart, they are most frequently used in the left ventricle. When placed in the left ventricle they are called left ventricular assist devices (LVADs).

You may have a VAD implanted while you wait for a heart transplant or for your heart to become strong enough to effectively pump blood on its own. Your doctor may also recommend having a VAD implanted as a long-term treatment if you have heart failure and you’re not a good candidate for a heart transplant.

The procedure to implant a VAD requires open-heart surgery and has serious risks. However, a VAD can be lifesaving if you have severe heart failure.


This is an assessment of the development and progression of cardiogenic shock  and review of the use of ventricular assist devices in that setting.  It is another piece of the chapter on cardiothoracic surgical management at Columbia University Medical Center, New York, NY.

A stepwise progression in the treatment of cardiogenic shock.

Pollack AUriel NGeorge IKodali STakayama HNaka YJorde U.


Department of Medicine, New York Presbyterian Hospital/Columbia University Medical Center, New York, New York, USA.


Cardiogenic shock remains a deadly complication of acute myocardial infarction (MI). Early revascularization, inotropic support, and intraaortic balloon counterpulsation are the mainstays of treatment, but these are not always sufficient. New mechanical approaches, both percutaneous and surgical, are available in this high-risk population. We present a case of a young woman with a massive anterior wall MI and subsequent cardiogenic shock who was treated with advanced mechanical circulatory support. This case serves as an illustration of the stepwise escalation of mechanical support that can be applied in a patient with an acute MI complicated by refractory cardiogenic shock. We also review the literature with regard to the use of percutaneous left ventricular assist devices in the setting of cardiogenic shock.

Copyright © 2012 Elsevier Inc. All rights reserved.

PMID: 22608034

Care of the Critically Ill:  A Stepwise Progression in the Treatment of Cardiogenic Shock.

Pollack A, Uriel N, George I, Kodali S, Takayama H, Naka Y, Jorde U
J Heart & Lung 2012; 41:500-504.

Initial Presentation

 A 21-year-old woman with a history of migraine headaches was admitted to the hospital with nonradiating substernal chest pain onset that morning. When she presented to another hospital she had a normal electrocardiogram (EKG) and was discharged. When the patient’s chest discomfort became crushing  she presented again to the same hospital where her EKG revealed ST-segment elevations in an anterolateral distribution. Her peak (hs) troponin was 229 ng/mL and peak creatinine kinase was 6900 U/L.  This was an elevation of CK far out of proportion to the troponin increase (suggestive of decreased peripheral circulation with massive release of CK from muscle). There was no family history of early myocardial infarction (MI), sudden cardiac death, clotting disorders, or hypercholesterolemia. She had been taking amitriptyline for migraines and oral contraceptives for 3 years.  The patient developed significant hypotension, after she was given metoprolol and morphine, for which dobutamine and dopamine were administered. Medication was switched to norepinephrine because of excessive tachycardia. Cardiac catheterization was performed emergently approximately 12 hours after the onset of the patient’s chest pain.
Thrombectomy of an angiographically identified clot in the proximal portion of the left anterior descending artery was performed, followed by placement of a bare metal stent with no residual occlusion. An intraaortic balloon bump (IABP) was placed. The initial transthoracic echocardiogram revealed an ejection fraction of 25% and global hypokinesis with regional wall motion abnormalities, worst in the anterior, apical, and lateral walls. She was intubated and required significant hemodynamic support with norepinephrine. Her antiplatelet regimen consisted of oral aspirin, clopidogrel, and intravenous eptifibatide. The patient was transferred to the New York Presbyterian Hospital/Columbia University Medical Center approximately 12 hours after revascularization.

Transfer to  NY Presbyteran Columbia Hospital

On arrival, the patient was intubated and sedated. Her blood pressure was 80/51mmHg, pulse rate was 140 beats/min, and oral temperature was 101F. On examination, she was tachycardic with warm extremities. The jugular veins were not distended. Her lactate was 7.0 mmol/L. (If she was so severely hypotensive with lactic acidemia, possibly from impaired liver and/or muscle circulation with aerobic glycolysis, then why was the temperature 101 deg F?)  The patient was not tested for procalcitonin (Brahms, BioMerieux), but sepsis is now considered bacterial or abacterial.  Whether there was release of bacterial endotoxin secondary to poor decreased circulation in the superior mesenteric artery is not known, which complicates the situation more.  In a study of acute phase changes in liver proteins by Bernstein and associates [Transthyretin as a marker to predict outcome in critically ill patients. Devakonda A, George L, Raoof S, Esan A, Saleh A, Bernstein LH.   Clin Biochem 2008; 41(14-15):1126-1130. ICID: 939927], and another on  procalcitonin and sepsis [The role of procalcitonin in the diagnosis of sepsis and patient assignment to medical intensive care. Bernstein LH, Devakonda A, Engelman E, Pancer G,  Ferrar J, Rucinski J, Raoof S,  George L, Melniker L.  J Clin Ligand Assay] there was a notable case of negative bacterial culture in a patient with highly elevated procalcitonin, considered a reliable early indicator of sepsis.sepsis classification with PCT and MAP
Procalcitonin (PCT) is a sensitive and specific inflammation marker, which can be used to detect both inflammatory infections and noninflammatory complications in postsurgical monitoring of patients after cardiac surgery using extracorporeal circulation. The optimum cut-off value for PCT levels, as a predictor of postoperative complications, appears to be 1.2 ng/mL with a sensitivity of 80% and a specificity of 90%. PCT may be used to monitor response to therapy because blood concentrations increase in an inflammatory disease relapse. Importance of procalcitonin in post-cardiosurgical patients. Topolcan O, Bartunek L, Holubec Jr L,  Polivkova V, eta al. Journal of Clinical Ligand Assay 2008; 31(1-4): 57-60.]This might be expected to be associated with a CRP increase over 50-70 mg/ml.  In addition, the hemogram would have been of some interest, perhaps raising the question of whether the cardiovascular impairment triggered other events [Validation and Calibration of the Relationship between Granulocyte Maturation and the Septic State. Bernstein LH and Rucinski J.  Clin Chem Lab Med 2011; 49. Walter de Gruyter . http://dx.doi.org/10.1515cclm.2011.688Converting Hematology Based Data into an Inferential Interpretation. Bernstein LH, David G, Rucinski J and Coifman RR.  In Hematology – Science and Practice, 2012. Chapter 22, pp 541-552. InTech Open Access Publ. Croatia]. 
A chest radiograph showed pulmonary edema. Her EKG revealed sinus tachycardia at 121 beats/min with ST-segment elevation of 3 mm in leads V1 to V4 and poor R-wave progression throughout the precordial leads with pathologic Q waves in V1 to V6, I, and aVL. Eptifibatide (Integrilin, Merck & Co., Inc., Whitehouse Station, NJ) was stopped, and norepinephrine was continued at 20 mg/min. Dobutamine 2.5 mg/min and broad-spectrum antibiotics were administered. During the next 4 hours, the patient’s mean arterial pressure fluctuated between 60 and 70 mm Hg with a heart rate between 120 and 140 beats/min on 20 mg/min of norepinephrine, 2.5 mg/min of dobutamine, and the IABP. Rapid escalation of mechanical support with a left ventricular assist device (LVAD) was deemed necessary.  Right-sided heart catheterization after placement of an Impella 2.5 assist device (ABIOMED, Inc.) revealed a cardiac output of 3.3 L/min and a cardiac index (CI) of 2.1 L/min/m2, despite addition of 3 ug/min and 4 U/h of vassopressin.

Day 2

On the second day after transfer she was severely hyponatremic, but her plasma sodium stabilized at 131 to 138 mmol/L after discontinuing the vasopressin. She also developed significant bleeding at the site of the Impella and hemolysis requiring several blood transfusions. Her hemoglobin on transfer was 10.4 g/dL, which trended down to 7.8 g/dL after Impella placement. The patient’s lactate dehydrogenase was 1980 U/L (probably reflecting poor liver perfusion), and total bilirubin was 2.6 mg/dL on day 2 of her hospitalization compared with 1.1 mg/dL on transfer.

Day 3

After the Impella device was removed on day 3 because of persistent bleeding, the patient’s hemoglobin, bilirubin, and platelet count stabilized, but while the patient was able to maintain end-organ perfusion initially as manifested by a normal creatinine, as the day progressed, the patient’s systemic blood pressure trended downward and urine output decreased, and she could not tolerate discontinuation of the vasoactive agents being administered. Pulmonary hypertension developed with a rate-dependent cardiac output as manifested by persistent tachycardia, and had an ejection fraction of 20% with severe hypokinesis of all segments except the basal inferior and inferolateral walls. As a consequence of the enduring cardiogenic shock and the low likelihood for recovery of left ventricular function, it was evident the patient required long-term mechanical support. A continuous flow LVAD (HeartMate II; Thoratec Corporation) was implanted as a rescue therapy, and the patient was emergently listed for transplantation.


A comprehensive heart failure regimen was introduced, and the patient was discharged with warfarin 25 days after her transfer. A comprehensive hypercoagulability workup performed while the patient was receiving anticoagulation with negative results. Aside from oral contraceptive use, no other obvious risk factor for an acute arterial thrombosis could be identified, which is not surprising given that up to 40% of all thrombotic events occur in patients without a recognizable risk factor. Early revascularization, inotropic support, and intraaortic balloon counterpulsation are the mainstays of treatment, but these are not always sufficient.  New mechanical approaches, both percutaneous and surgical, are available in this high-risk population. This case serves as an illustration of the stepwise escalation of mechanical support that can be applied in a patient with an acute MI complicated by refractory cardiogenic shock. We also review the literature with regard to the use of percutaneous left ventricular assist devices in the setting of cardiogenic shock.


The authors recommend the following protocol for patients with cardiogenic shock superimposed on acute MI.    Treatment of cardiogenic shock.  PCI, percutaneous coronary intervention; IABP, intraaortic balloon pump; VAD, ventricular assist device; VA-ECMO, venoarterial extracorporeal membrane oxygenation; OHT, orthotopic heart transplantation; pVAD, percutaneous ventricular assist device. It is important to note that it includes immediate revascularization in conjunction with IABP placement. In patients with refractory cardiogenic shock who are unable to be weaned from the IABP, mechanical circulatory support using a percutaneous or surgical device is the next essential measure to be taken. The type of mechanical support to be used depends on many factors, including the reversibility of the shock state, chances of ventricular recovery, and risk of bleeding. Mechanical circulatory support with left ventricular assists devices can improve cardiac performance and reduce myocardial ischemic injury. Principle mechanisms include unloading of the left ventricle, thereby decreasing myocardial oxygen demand and improvement of systemic hypotension, thus increasing coronary perfusion.
Although there were complications related to the use of the device, its deployment resulted in the improvement of the patient’s surgical candidacy by virtue of maintaining her end-organ function.  After the removal of the Impella device, we thought the left ventricle in this patient would not recover, and for this reason, we chose a definitive surgical procedure as opposed to alternative temporary support device.  Clinical studies focusing on the use of VA-ECMO in refractory cardiogenic shock after an acute MI are limited. Observational and retrospective series have thus far demonstrated a high mortality rate in these patients.  However, a recent retrospective study of 33 patients who received ECMO support for advanced refractory cardiogenic shock after an acute MI demonstrated a mortality rate of 46% and 52% at 30 days and 1 year, respectively. In addition to mny complications with VA-ECMO, the procedure also can lead to increased afterload from the retrograde flow of peripheral cannulation., which may to lead to increased left ventricular pressure and wall stress, thereby compromising myocardial recovery and worsening pulmonary edema, both of which were major concerns
in this patient.


This case demonstrates that a sequential approach using percutaneous mechanical support as a bridge to surgical mechanical support is feasible in this high-risk population (Figure ). Advantages of percutaneous mechanical support include its rapid and straightforward placement. Disadvantages include its limited cardiac output and bleeding. Future technology should focus on a device that is capable of providing significant cardiac output and that can be easily placed, like the Impella. Such a device could alter the natural history of intractable cardiogenic shock.

Other related articles published on this Open Access Online Scientific Journal include the following:

Implantable Synchronized Cardiac Assist Device Designed for Heart Remodeling: Abiomed’s Symphony

Aviva Lev-Ari, PhD, RN, 7/11/2012


Biomaterials Technology: Models of Tissue Engineering for Reperfusion and Implantable Devices for Revascularization

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN


Foreseen changes in Guideline of Treatment of Cardiogenic Shock with Intra-aortic Balloon counterPulsation (IABP)

Evidence for Overturning the Guidelines in Cardiogenic Shock

Clinical Indications for Use of Inhaled Nitric Oxide (iNO) in the Adult Patient Market: Clinical Outcomes after Use, Therapy Demand and Cost of Care

Aviva Lev-Ari, PhD, RN, 6/3/2013

English: Ventricular assist device

English: Ventricular assist device (Photo credit: Wikipedia)

English: Simulation of a wave pump human ventr...

English: Simulation of a wave pump human ventricular assist device (Photo credit: Wikipedia)

myocardial infarction - Myokardinfarkt - scheme

myocardial infarction – Myokardinfarkt – scheme (Photo credit: Wikipedia)

English: Graphic presentation of an LVAD, left...

English: Graphic presentation of an LVAD, left ventricular assist device. (Photo credit: Wikipedia)

Read Full Post »

« Newer Posts - Older Posts »