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Atherosclerosis Independence: Genetic Polymorphisms of Ion Channels Role in the Pathogenesis of Coronary Microvascular Dysfunction and Myocardial Ischemia (Coronary Artery Disease (CAD))
Posted in Cardiovascular Pharmacogenomics, Diabetes Mellitus, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Genomic Testing: Methodology for Diagnosis, Ionic Transporters Na+, K, Molecular Genetics & Pharmaceutical, Na-K transport, Na-K-ATPase, Nitric Oxide in Health and Disease, Origins of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, Proteomics, tagged ATO2A@, ATPase, Aviva Lev-Ari, CAD, Coronary artery disease, Coronary circulation, coronary microvascular dysfunction, eNOS, genetic polymorphisms, Heart disease, Heart Failure, Hebrew University of Jerusalem, ion channels, ischemic heart diases (IHD), KCN5A gene (Kv1.5 channel), Kir6, Myocardial Ischemia, Nav 1.5, non-modifiable protective factor, NOS encoding, rs5215_GG, rs5219_AA, SCN5A, Thomas C. Südhof, voltage-gated K ion channel on December 21, 2013| Leave a Comment »
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
and
Curator: Aviva Lev-Ari, PhD, RN
Image created by Adina Hazan 06/30/2021
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.
http://www.nobelprize.org/nobel_prizes/medicine/laureates/2013/advanced-medicineprize2013.pdf
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
http://www.amazon.com/dp/B00DINFFYC
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
http://pharmaceuticalintelligence.com
See References to articles at the end of this article on
- ION CHANNEL and Cardiovascular Diseases
http://pharmaceuticalintelligence.com/?s=Ion+Channel
- 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
Abstract
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
http//dx.dio.org/10.1007/s00395-013-0387-4
Keywords: Ion-channels, Genetic polymorphisms, Coronary microcirculation, Endothelium, Atherosclerosis Ischemic heart disease
Introduction
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, 65, 67].
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.
Discussion
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.
Conclusions
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.).
Methods
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
- age [18];
- suspected or documented diagnosis of acute coronary syndrome or stable angina
- with indication(s) for coronary angiography, in accordance with current guidelines [36, 68], and
- the same ethno-geographic Caucasian origin) and
Exclusion Criteria
- previous allergic reaction to iodine contrast,
- renal failure,
- simultaneous genetic disease,
- cardiogenic shock,
- 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
- both endothelium-dependent microvascular function
[via intracoronary (IC) infusion of acetylcholine (2.5–10 lg)] and - 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).
- 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].
- 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).
- as assessed by angiography and with normal functional tests
- Group 3: 41 patients with anatomically and functionally normal coronary arteries
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:
- NOS3 (endothelial nitric oxide synthase, eNOS),
- ATP2A2 (Ca2+/H+-ATPase pump, SERCA2),
- SCN5A (voltage-dependent Na+ channel,
- Nav1.5),
- KCNJ11 (ATP-sensitive K+ channel, Kir6.2 subunit),
- KCNJ8 (ATP-sensitive K+ channel, Kir6.1 subunit) and
- 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.
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 (http://213.151.99.166/index.php?module=Snpstats) [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.
Results
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).
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.
SOURCE for TABLES
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.
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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
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Basic Res Cardiol (2013) 108:387 http://dx.doi.org/10.1007/s00395-013-0387-4
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Atrioventricular (AV) Conduction Disease (block): Human Mutations affecting the Voltage Clock
Posted in Cardiovascular Research, Chemical Genetics, Computational Biology/Systems and Bioinformatics, Congenital Heart Disease, Electrophysiology, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Origins of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, Proteomics, tagged Artificial cardiac pacemaker, Atrioventricular block, Brugada syndrome, Long QT syndrome, mutation, Nav1.5 on December 18, 2013| Leave a Comment »
Atrioventricular (AV) Conduction Disease (block): Human Mutations affecting the Voltage Clock
Reporter: Aviva Lev-Ari, PhD, RN
Human mutations affecting the voltage clock
-
(SCN5A and HCN4),
-
calcium clock (RYR2 and CASQ2), or both mechanisms
-
(ANKB) have been identified that negatively affect sinus node function.37,38
Diseases of Conduction Block Conduction block can occur at any level of the cardiac conduction system (CCS) and can manifest as sinoatrial exit block, atrioventricular block, infra-Hisian block, or bundle branch block. Impaired conduction can be caused by ion channel defects that alter action potential shape or by defective coupling between cardiomyocytes. Inherited defects in cardiac conduction have been linked to mutations in SCN5A and SCN1B (both affect phase 0) and KCNJ2 (affects phase 3 and 4).
The cardiac sodium channel consists of the pore-forming α-subunit (encoded by SCN5A) and a modulatory β-subunit (encoded by SCN1B). The α-subunit contains a voltage sensor that allows for rapid activation in response to membrane depolarization. After depolarization, the sodium channel undergoes a period of inactivation, in which it is refractory to further impulses. SCN5A requires membrane repolarization to relieve the inactivated state. The inward rectifier potassium channel, Kir2.1, encoded by KCNJ2, maintains the resting membrane potential. Therefore, proper functioning of Nav1.5 and Kir2.1 is necessary for normal cardiac excitability.
SCN5A
Progressive cardiac conduction defect, or Lev-Lenègre disease, is characterized by age-related, fibrosclerotic degeneration of the His-Purkinje system.6 Impulse propagation through the proximal ventricular conduction system progressively declines, resulting in bundle branch blocks and eventually complete atrioventricular block. An inherited form of Lev-Lenègre disease is associated with loss of function mutations in SCN5A and can exist alone or as overlap syndromes with Brugada or long QT syndrome 3.6 Inherited progressive cardiac conduction defect is associated with a high risk of complete atrioventricular block and Stoke-Adams syncope without ventricular dysrhythmia.7 Schott et al8 identified a mutation in SCN5A that cosegregates with Lenègre disease in a large French family. Affected individuals had variable degrees of conduction block requiring pacemaker implantation in 4 family members because of syncope or complete heart block. Linkage analysis and candidate gene sequencing identified a T>C substitution at position +2 of the donor splice site of intron 22 (IVS22+2 T>C), which results in a mutant lacking the voltage-sensitive segment.8 Functional analysis demonstrated no transient inward sodium current in response to depolarization, consistent with a loss-of-function mutation.6
SCN1B
The majority of patients with Brugada and conduction disease do not have SCN5Amutations. Therefore, modifiers of Nav1.5 expression or function have become the target of candidate gene sequencing approaches. Watanabe et al9 identified SCN1B mutations in 3 families with conduction disease with or without Brugada syndrome. Coexpression of mutant β-subunits with Nav1.5 resulted in diminished sodium current.
KCNJ2
Mutations in KCNJ2 have been found in a rare autosomal dominant condition called Andersen-Tawil syndrome, characterized by periodic paralysis, dysmorphic features, polymorphic ventricular tachycardia, and cardiac conduction disease.10,11 ECG evaluation of 96 patients with Andersen-Tawil syndrome from 33 unrelated kindreds revealed conduction defects at multiple levels from the atrioventricular node to the distal conduction system.55 Cardiomyocytes expressing a dominant-negative subunit of Kir2.1 exhibited a 95% reduction in IK1, resulting in significant action potential prolongation. Mouse models of Andersen-Tawil syndrome exhibited a slower heart rate and significant slowing of conduction.56,57
Therapeutic Strategies
The current standard of care for symptomatic bradycardia due to conduction system disease is the implantation of an electronic pacemaker. Despite their success, electronic pacemakers have limitations, which include lead complications, finite battery life, potential for infection, lack of autonomic responsiveness, and size restriction in younger patients. These limitations have spurred on the development of biological pacemakers, the premise of which is to restore pacemaking activity with the use of viral-based or stem cell–based gene delivery systems.99 The identification and characterization of genes involved in generating pacemaker currents have allowed biological pacemaker technology to become a reality.
The restoration of sinus pacing rates can be achieved by modulating inward and outward currents to establish or increase the slope of diastolic depolarization in cardiac tissue. Increasing inward currents and/or decreasing outward currents increase the slope of diastolic depolarization and therefore the pacing rate. Genes that have been investigated or are under current investigation include the following: (1) β2-adrenergic receptor,100,101(2) dominant-negative Kir2.1 mutants,102 (3) adenylate cyclase type VI (ACVI),103,104and (4) HCN channels.105 The β2-adrenergic receptor and adenylate cyclase type VI both increase cAMP levels, leading to activation of endogenous HCN channels and calcium clock mechanisms. Although initial animal models using the β2-adrenergic receptor showed promise with transient increases in heart rate, the potential for proarrhythmia and the inability of this approach to establish de novo pacemaker activity limited its efficacy.101
Another approach focused on modifying ionic currents that convert working myocardial cells, which have relatively stable diastolic potentials, into cells with phase 4 diastolic depolarization. It was postulated that atrial and ventricular myocytes have the potential for automaticity, but that hyperpolarizing currents, such as IK1, prevent diastolic depolarization by stabilizing the resting membrane potential. Miake et al102 confirmed this hypothesis when they demonstrated that adenoviral delivery of a dominant-negative Kir2.1 construct into the left ventricle of guinea pigs resulted in conversion of quiescent myocytes into pacemaker cells. Unfortunately, significant action potential prolongation limited the clinical utility of this treatment strategy.102
Rosen and colleagues105,106 demonstrated that automaticity could be induced in quiescent myocardium with the use of heterologous expression of HCN channels that produce the pacemaker current If. Qu and Plotnikov et al demonstrated that stable autonomous rhythms could be generated when adenovirus encoding HCN2 was injected into the left atrium105 or left bundle branch106 of a canine heart. To bypass the limitations of viral-based systems, such as host immune response, several groups reported the successful use of cell-based delivery systems. Plotnikov et al107 reported the successful implantation of human mesenchymal stem cells expressing HCN2 in the left ventricle of a canine model of atrioventricular block. Dogs maintained stable ectopic pacemaker activity for >6 weeks without the use of immunosuppression.107 Human mesenchymal stem cells electronically couple to host myocardium through gap junctions; therefore, conditions with significant gap junction remodeling may affect the efficacy of this method.
Although standalone biological pacemakers may be far into the future, adjuvant biological pacemakers may find real-world utility for current deficiencies of electronic pacemakers, such as limited battery life and device infections. For example, biological preparations used in conjunction with device therapy may be used to extend battery life, decreasing the frequency of generator changes. Transient injectable pacemakers may also function as bridge therapy after lead extraction of an infected device. The need for adjuvant biological pacemakers is clear, but continued refinement of gene- and cell-based delivery systems will be necessary to make this technology a reality.99
Conclusion
Although rare, inherited arrhythmias have become an invaluable tool in identifying the genetic determinants of CCS function. Each new mutation enhances our understanding and appreciation of the biochemical and structural complexity needed for cardiac impulse generation and propagation. This methodology is hampered, however, by the relative scarcity of inherited conditions affecting the CCS. The addition of genome-wide association studies has broadened this search for novel genes beyond rare familial afflictions to include common, multifactorial conditions. It is hoped that this exciting new frontier will bring to light the complex interplay of genes and genetic/epigenetic modifiers that influence the prevalence of common diseases. These genetic screens will ultimately yield a bevy of new gene targets for pharmaceutical or gene-based therapeutics of the future.
REFERENCES
-
The Cardiac Conduction System
- David S. Park, MD, PhD;
- Glenn I. Fishman, MD
http://circ.ahajournals.org/content/123/8/904 [Circulation.2011; 123: 904-915 doi: 10.1161/CIRCULATIONAHA.110.942284]
- Genetics of Conduction Disease: Atrioventricular (AV) Conduction Disease (block): Gene Mutations – Transcription, Excitability, and Energy Homeostasis by Aviva Lev-Ari, PhD, RN
-
Benson DW Genetics of atrioventricular conduction disease in humans. Anat Rec A Discov Mol Cell Evol Biol. 2004 Oct;280(2):934-9.
http://www.ncbi.nlm.nih.gov/pubmed/15372490
- N Engl J Med 2013; 368:2335-2337 June 13, 2013DOI: 10.1056/NEJMc1300484
- Genomics & Genetics of Cardiovascular Disease Diagnoses: A Literature Survey of AHA’s Circulation Cardiovascular Genetics, 3/2010 – 3/2013 Aviva Lev-Ari, PhD, RN and Larry H. Bernstein, MD, FCAP
Adult Left Atrium: Reduction of Pitx2c Expression Promotes Atrial Fibrillation Inducibility and Complex Changes in Gene Expression
Posted in Congenital Heart Disease, Electrophysiology, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Genomic Testing: Methodology for Diagnosis, Origins of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, tagged Atrial fibrillation, Cardiac dysrhythmia, Kirchhof, Maastricht University on December 18, 2013| Leave a Comment »
Adult Left Atrium: Reduction of Pitx2c Expression Promotes Atrial Fibrillation Inducibility and Complex Changes in Gene Expression
Aviva Lev-Ari, PhD, RN
PITX2c Is Expressed in the Adult Left Atrium, and Reducing Pitx2c Expression Promotes Atrial Fibrillation Inducibility and Complex Changes in Gene Expression
Paulus Kirchhof, MD*, Peter C. Kahr*, Sven Kaese, Ilaria Piccini, PhD, Ismail Vokshi, BSc, Hans-Heinrich Scheld, MD, Heinrich Rotering, MD, Lisa Fortmueller, MD (vet),Sandra Laakmann, MD (vet), Sander Verheule, PhD, Ulrich Schotten, MD, PhD,Larissa Fabritz, MD and Nigel A. Brown, PhD
Author Affiliations
From the Department of Cardiology and Angiology (P.K., P.C.K., S.K., I.P., L.F., S.L., L.F.) and the Department of Thoracic and Cardiovascular Surgery (H.-H.S., H.R.), University Hospital Muenster, Germany; Division of Biomedical Sciences (P.C.K., I.V., N.A.B.), St. George’s, University of London, United Kingdom; and the Department of Physiology (S.V., U.S.), Maastricht University, The Netherlands.
Correspondence to Nigel A. Brown, PhD, Division of Biomedical Sciences, St George’s, University of London, Cranmer Terrace, London, SW17 0RE, UK. E-mail nbrown@sgul.ac.uk
↵* Drs Kirchhof and Kahr contributed equally to this work.
Abstract
Background— Intergenic variations on chromosome 4q25, close to the PITX2 transcription factor gene, are associated with atrial fibrillation (AF). We therefore tested whether adult hearts express PITX2 and whether variation in expression affects cardiac function.
Methods and Results— mRNA for PITX2 isoform c was expressed in left atria of human and mouse, with levels in right atrium and left and right ventricles being 100-fold lower. In mice heterozygous for Pitx2c (Pitx2c+/−), left atrial Pitx2c expression was 60% of wild-type and cardiac morphology and function were not altered, except for slightly elevated pulmonary flow velocity. Isolated Pitx2c+/−hearts were susceptible to AF during programmed stimulation. At short paced cycle lengths, atrial action potential durations were shorter in Pitx2c+/− than in wild-type. Perfusion with the β-receptor agonist orciprenaline abolished inducibility of AF and reduced the effect on action potential duration. Spontaneous heart rates, atrial conduction velocities, and activation patterns were not affected in Pitx2c+/− hearts, suggesting that action potential duration shortening caused wave length reduction and inducibility of AF. Expression array analyses comparing Pitx2c+/− with wild-type, for left atrial and right atrial tissue separately, identified genes related to calcium ion binding, gap and tight junctions, ion channels, and melanogenesis as being affected by the reduced expression of Pitx2c.
Conclusions— These findings demonstrate a physiological role for PITX2 in the adult heart and support the hypothesis that dysregulation of PITX2 expression can be responsible for susceptibility to AF.
SOURCE:
Circulation: Cardiovascular Genetics.2011; 4: 123-133
Published online before print January 31, 2011,
doi: 10.1161/ CIRCGENETICS.110.958058
North Americans With Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy: Genomics of Ventricular arrhythmias, A-Fib, Right Ventricular Dysplasia, Cardiomyopathy – Comprehensive Desmosome Mutation Analysis
Posted in Cardiomyopathy, Cardiovascular Research, Computational Biology/Systems and Bioinformatics, Congenital Heart Disease, Electrophysiology, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, HTN, Origins of Cardiovascular Disease, Pharmacogenomics, Population Health Management, Genetics & Pharmaceutical, Statistical Methods for Research Evaluation, tagged Arrhythmogenic right ventricular dysplasia, Cardiac dysrhythmia, Johns Hopkins School of Medicine, Johns Hopkins University, National Institutes of Health, University Medical Center Utrecht on December 18, 2013| Leave a Comment »
North Americans With Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy: Genomics of Ventricular arrhythmias, A-Fib, Right Ventricular Dysplasia, Cardiomyopathy – Comprehensive Desmosome Mutation Analysis
Reporter: Aviva Lev-Ari, PhD, RN
Genomics of Ventricular arrhythmias, A-Fib, Right Ventricular Dysplasia, Cardiomyopathy – Comprehensive Desmosome Mutation Analysis in North Americans With Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy
A. Dénise den Haan, MD, Boon Yew Tan, MBChB, Michelle N. Zikusoka, MD, Laura Ibañez Lladó, MS, Rahul Jain, MD, Amy Daly, MS, Crystal Tichnell, MGC, Cynthia James, PhD, Nuria Amat-Alarcon, MS, Theodore Abraham, MD, Stuart D. Russell, MD,David A. Bluemke, MD, PhD, Hugh Calkins, MD, Darshan Dalal, MD, PhD and Daniel P. Judge, MD
Author Affiliations
From the Department of Medicine/Cardiology (A.D.d.H., B.Y.T., M.N.Z., L.I.L., R.J., A.D., C.T., C.J., N.A.-A., T.A., S.D.R., H.C., D.D., D.P.J.), Johns Hopkins University School of Medicine, Baltimore, Md; Department of Cardiology, Division of Heart and Lungs (A.D.d.H.), University Medical Center Utrecht, Utrecht, The Netherlands; and National Institutes of Health, Radiology and Imaging Sciences (D.A.B.), Bethesda, Md.
Correspondence to Daniel P. Judge, MD, Johns Hopkins University, Division of Cardiology, Ross 1049; 720 Rutland Avenue, Baltimore, MD 21205. E-mail djudge@jhmi.edu
Abstract
Background— Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited disorder typically caused by mutations in components of the cardiac desmosome. The prevalence and significance of desmosome mutations among patients with ARVD/C in North America have not been described previously. We report comprehensive desmosome genetic analysis for 100 North Americans with clinically confirmed or suspected ARVD/C.
Methods and Results— In 82 individuals with ARVD/C and 18 people with suspected ARVD/C, DNA sequence analysis was performed on PKP2, DSG2, DSP, DSC2, and JUP. In those with ARVD/C, 52% harbored a desmosome mutation. A majority of these mutations occurred in PKP2. Notably, 3 of the individuals studied have a mutation in more than 1 gene. Patients with a desmosome mutation were more likely to have experienced ventricular tachycardia (73% versus 44%), and they presented at a younger age (33 versus 41 years) compared with those without a desmosome mutation. Men with ARVD/C were more likely than women to carry a desmosome mutation (63% versus 38%). A mutation was identified in 5 of 18 patients (28%) with suspected ARVD. In this smaller subgroup, there were no significant phenotypic differences identified between individuals with a desmosome mutation compared with those without a mutation.
Conclusions— Our study shows that in 52% of North Americans with ARVD/C a mutation in one of the cardiac desmosome genes can be identified. Compared with those without a desmosome gene mutation, individuals with a desmosome gene mutation had earlier-onset ARVD/C and were more likely to have ventricular tachycardia.
SOURCE:
Circulation: Cardiovascular Genetics.2009; 2: 428-435
Published online before print June 3, 2009,
doi: 10.1161/ CIRCGENETICS.109.858217
Heart and Aging Research in Genomic Epidemiology: 1700 MIs and 2300 coronary heart disease events among about 29 000 eligible patients: Design of Prospective Meta-Analyses of Genome-Wide Association Studies From 5 Cohorts
Posted in Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Cardiovascular Pharmacogenomics, Computational Biology/Systems and Bioinformatics, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Genomic Testing: Methodology for Diagnosis, Origins of Cardiovascular Disease, Pharmacogenomics, Population Health Management, Genetics & Pharmaceutical, Reproductive Andrology, Embryology, Genomic Endocrinology, Preimplantation Genetic Diagnosis and Reproductive Genomics, Statistical Methods for Research Evaluation, tagged Boston University School of Public Health, Cedars-Sinai Medical Center, Coronary disease, Framingham Heart Study, Rotterdam Study on December 18, 2013| Leave a Comment »
Heart and Aging Research in Genomic Epidemiology: 1700 MIs and 2300 coronary heart disease events among about 29 000 eligible patients: Design of Prospective Meta-Analyses of Genome-Wide Association Studies From 5 Cohorts
Reporter: Aviva Lev-Ari, PhD, RN
Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium
Heart and Aging Research in Genomic Epidemiology: 1700 MIs and 2300 coronary heart disease events among about 29 000 eligible patients: Design of Prospective Meta-Analyses of Genome-Wide Association Studies From 5 Cohorts
Bruce M. Psaty, MD, PhD, Christopher J. O’Donnell, MD, MPH, Vilmundur Gudnason, MD, PhD, Kathryn L. Lunetta, PhD, Aaron R. Folsom, MD, Jerome I. Rotter, MD,André G. Uitterlinden, PhD, Tamara B. Harris, MD, Jacqueline C.M. Witteman, PhD,Eric Boerwinkle, PhD and on Behalf of the CHARGE Consortium
Author Affiliations
From the Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services (B.M.P.), University of Wash; Center for Health Studies, Group Health (B.M.P.), Seattle, Wash; the National Heart, Lung and Blood Institute and the Framingham Heart Study (C.J.O.D.), Framingham, Mass; Icelandic Heart Association and the Department of Cardiovascular Genetics (Y.G.), University of Iceland, Reykjavik, Iceland; Department of Biostatistics (K.L.), Boston University School of Public Health, Mass; Division of Epidemiology and Community Health (A.R.F.), University of Minnesota, Minneapolis; Medical Genetics Institute (J.I.R.), Cedars-Sinai Medical Center, Los Angeles, Calif; Departments of Internal Medicine (A.G.U.) and Epidemiology (A.G.U., J.C.M.W.), Erasmus Medical Center, Rotterdam, The Netherlands; Laboratory of Epidemiology, Demography, and Biometry (T.B.H.), Intramural Research Program, National Institute on Aging, Bethesda, Md; and Human Genetics Center and Division of Epidemiology (E.B.), University of Texas, Houston.
Guest editor for this article was Elizabeth R. Hauser, PhD.
Abstract
Background— The primary aim of genome-wide association studies is to identify novel genetic loci associated with interindividual variation in the levels of risk factors, the degree of subclinical disease, or the risk of clinical disease. The requirement for large sample sizes and the importance of replication have served as powerful incentives for scientific collaboration.
Methods— The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium was formed to facilitate genome-wide association studies meta-analyses and replication opportunities among multiple large population-based cohort studies, which collect data in a standardized fashion and represent the preferred method for estimating disease incidence. The design of the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium includes 5 prospective cohort studies from the United States and Europe: the Age, Gene/Environment Susceptibility—Reykjavik Study, the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study. With genome-wide data on a total of about 38 000 individuals, these cohort studies have a large number of health-related phenotypes measured in similar ways. For each harmonized trait, within-cohort genome-wide association study analyses are combined by meta-analysis. A prospective meta-analysis of data from all 5 cohorts, with a properly selected level of genome-wide statistical significance, is a powerful approach to finding genuine phenotypic associations with novel genetic loci.
Conclusions— The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium and collaborating non-member studies or consortia provide an excellent framework for the identification of the genetic determinants of risk factors, subclinical-disease measures, and clinical events.
Example of Coronary Heart Disease
The cohort-study methods papers provide detail about many of the phenotypes listed in Table 2. For coronary heart disease, investigators knowledgeable about the phenotype in each study decided to focus on fatal and nonfatal myocardial infarction (MI) as the primary outcome because the MI criteria differed in only trivial ways among the studies. There were some minor differences in the definition of the composite outcome of MI, fatal coronary heart disease, and sudden death, which became the secondary outcome. Only subjects at risk for an incident event were included in the analysis. MI survivors whose DNA was drawn after the event were not eligible. The primary analysis was restricted to Europeans or European Americans. Patients entered the analysis at the time of the DNA blood draw, and were followed until an event, death, loss to follow up, or the last visit. The main recommendations of the Analysis Committee were adopted, and a threshold of 5×10−8 was selected for genome-wide statistical significance. Analyses in progress include about 1700 MIs and 2300 coronary heart disease events among about 29 000 eligible patients. Each cohort conducted its own analysis, and results were uploaded to a secure share site for the fixed-effects meta-analysis. Even with this number of events (Supplemental Figure 2), power is good for only for relatively high minor allele frequencies (>0.25) and large relative risks (>1.3).
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
Discussion
In thousands of published papers, the 5 CHARGE cohort studies and many of the collaborating studies have already characterized the risk factors for and the incidence and prognosis of a variety of aging-related and cardiovascular conditions. The analysis of the incident MI, for instance, is free from the survival bias typically associated with cross-sectional or case-control studies. The methodologic advantages of the prospective population-based cohort design, the similarity of phenotypes across 5 studies, the availability of genome-wide genotyping data in each cohort, and the need for large sample sizes to provide reliable estimates of genotype-phenotype associations have served as the primary incentives for the formation of the CHARGE consortium, which includes GWAS data on about 38 000 individuals. The consortium effort relies on collaborative methods that are similar to those used by the individual contributing cohorts.
Phenotype experts who know the studies and the data well are responsible for phenotype-standardization across cohorts. The coordinated prospectively planned meta-analyses of CHARGE provide results that are virtually identical to a cohort-adjusted pooled analysis of individual level data. This approach–the within-study analysis followed by a between-study meta-analysis–avoids the human subjects issues associated with individual-level data sharing.
Editors, reviewers, and readers expect replication as the standard in science.6 The finding of a genetic association in one population with evidence for replication in multiple independent populations provides moderate assurance against false-positive reports and helps to establish the validity of the original finding. In a single experiment, the discovery-replication structure is traditionally embodied in a 2-stage design. The CHARGE consortium includes up to 5 independent replicate samples as well as additional collaborating studies for some phenotype working groups, so that it would have been possible to set up analysis plans within CHARGE to mimic the traditional 2-stage design for replication. For instance, the 2 largest cohorts could have served as the discovery set and the others as the replication set. However, attaining the extremely small probability values expected in GWAS requires large sample sizes. For any phenotype, a prospective meta-analysis of all participating cohorts, with a properly selected level of genome-wide statistical significance to minimize the chance of false-positives, is the most powerful approach to finding new genuine associations for genetic loci.25 When findings narrowly miss the prespecified significance threshold, genotyping individuals in other independent populations provides additional evidence about the association. For findings that substantially exceed pre-established significance thresholds, the results of a CHARGE meta-analysis effectively provide evidence of a multistudy replication.
The effort to assemble and manage the CHARGE consortium has provided some interesting and unanticipated challenges. Participating cohorts often had relationships with outside study groups that predated the formation of CHARGE. Timelines for genotyping and imputation have shifted. Purchases of new computer systems for the volume of work were sometimes necessary. Each cohort came to the consortium with their own traditions for methods of analysis, organization, and authorship policies that, while appropriate for their own work, were not always optimal for collaboration with multiple external groups. Within each cohort, the investigators had often formed working groups that divided up the large number of available phenotypes in ways that made sense locally but did not necessarily match the configuration that had been adopted by other cohorts. The Research Steering Committee has attempted to create a set of CHARGE working groups that accommodate the needs and the conventions of the various cohorts. Transparency, disclosure, and professional collaborative behavior by all participating investigators have been essential to the process.
Resource limitations are another challenge. Grant applications that funded the original single-study genome-wide genotyping effort typically imagined a much simpler design. The CHS whole-genome study had as its primary aim, for instance, the analysis of data on 3 endpoints, coronary disease, stroke and heart failure. With a score of active phenotype working groups, the CHARGE collaboration broadened the scope of the short-term work well beyond initial expectations for all the participating cohorts.
One of the premier challenges has been communications among scores of investigators at a dozen sites. CHS and ARIC are themselves multi-site studies. To be successful, the CHARGE collaboration has required effective communications: (1) within each cohort; (2) between cohorts; (3) within the CHARGE working groups; and (4) among the major CHARGE committees. In addition to the traditional methods of conference calls and email, the CHARGE “wiki,” set up by Dr J. Bis (Seattle, Wash), has provided a crucial and highly functional user-driven website for calendars, minutes, guidelines, working group analysis plans, manuscript proposals, and other documents. In the end, there is no substitute for face-to-face meetings, especially at the beginning of the collaboration, and this complex meta-organization has benefited from several CHARGE-wide meetings.
The major emerging opportunity is the collaboration with other studies and consortia. Many working groups have already incorporated nonmember studies into their efforts. Several working groups have coordinated submissions of initial manuscripts with the parallel submission of manuscripts from other studies or consortia. Several working groups have embarked on plans for joint meta-analyses between CHARGE and other consortia. CHARGE has tried to acknowledge and reward the efforts of champions, who assume leadership responsibility for moving these large complex projects forward and who are often hard-working young investigators, the key to the future success of population science.
The CHARGE Consortium represents an innovative model of collaborative research conducted by research teams that know well the strengths, the limitations, and the data from 5 prospective population-based cohort studies. By leveraging the dense genotyping, deep phenotyping and the diverse expertise, prospective meta-analyses are underway to identify and replicate the major common genetic determinants of risk factors, measures of subclinical disease, and clinical events for cardiovascular disease and aging.
SOURCE:
Circulation: Cardiovascular Genetics.2009; 2: 73-80
doi: 10.1161/ CIRCGENETICS.108.829747
On Genes and On Drug Response: Every Genome to have its own Personal Antidepressant
Posted in Cerebrovascular and Neurodegenerative Diseases, Chemical Genetics, Genome Biology, Genomic Testing: Methodology for Diagnosis, Innovations in Neurophysiology & Neuropsychology, Neurodegenerative Diseases, Personalized and Precision Medicine & Genomic Research, Pharmaceutical R&D Investment, Pharmacogenomics, Population Health Management, Genetics & Pharmaceutical, tagged Antidepressant, Sackler Faculty of Medicine, Selective serotonin reuptake inhibitor, Tel Aviv University on December 18, 2013| Leave a Comment »
Every Genome to have its own Personal Antidepressant
Reporter: Aviva Lev-Ari, PhD, RN
A Personal Antidepressant for Every Genome
Monday, December 9, 2013
TAU researchers discover gene that may predict human responses to specific antidepressants
Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed antidepressants, but they don’t work for everyone. What’s more, patients must often try several different SSRI medications, each with a different set of side effects, before finding one that is effective. It takes three to four weeks to see if a particular antidepressant drug works. Meanwhile, patients and their families continue to suffer.
Now researchers at Tel Aviv Universityhave discovered a gene that may reveal whether people are likely to respond well to SSRI antidepressants, both generally and in specific formulations. The new biomarker, once it is validated in clinical trials, could be used to create a genetic test, allowing doctors to provide personalized treatment for depression.
Doctoral students Keren Oved and Ayelet Morag led the research under the guidance of Dr. David Gurwitz of the Department of Molecular Genetics and Biochemistryat TAU’s Sackler Faculty of Medicine and Dr. Noam Shomron of the Department of Cell and Developmental Biology at TAU’s Sackler Faculty of Medicine and Sagol School of Neuroscience. Sackler faculty members Prof. Moshe Rehavi of theDepartment of Physiology and Pharmacology and Dr. Metsada Pasmnik-Chor of the Bioinformatics Unit were coauthors of the study, published in Translational Psychology.
“SSRIs only work for about 60 percent of people with depression,” said Dr. Gurwitz. “A drug from other families of antidepressants could be effective for some of the others. We are working to move the treatment of depression from a trial-and-error approach to a best-fit, personalized regimen.”
Good news for the depressed
More than 20 million Americans each year suffer from disabling depression that requires clinical intervention. SSRIs such as Prozac, Zoloft, and Celexa are the newest and the most popular medications for treatment. They are thought to work by blocking the reabsorption of the neurotransmitter serotonin in the brain, leaving more of it available to help brain cells send and receive chemical signals, thereby boosting mood. It is not currently known why some people respond to SSRIs better than others.
To find genes that may be behind the brain’s responsiveness to SSRIs, the TAU researchers first applied the SSRI Paroxetine — brand name Paxil — to 80 sets of cells, or “cell lines,” from the National Laboratory for the Genetics of Israeli Populations, a biobank of genetic information about Israeli citizens located at TAU’s Sackler Faculty of Medicine and directed by Dr. Gurwitz. The TAU researchers then analyzed and compared the RNA profiles of the most and least responsive cell lines. A gene called CHL1 was produced at lower levels in the most responsive cell lines and at higher levels in the least responsive cell lines. Using a simple genetic test, doctors could one day use CHL1as a biomarker to determine whether or not to prescribe SSRIs.
“We want to end up with a blood test that will allow us to tell a patient which drug is best for him,” said Oved. “We are at the early stages, working on the cellular level. Next comes testing on animals and people.”
Rethinking how antidepressants work
The TAU researchers also wanted to understand why CHL1 levels might predict responsiveness to SSRIs. To this end, they applied Paroxetine to human cell lines for three weeks — the time it takes for a clinical response to SSRIs. They found that Paroxetine caused increased production of the gene ITGB3 — whose protein product is thought to interact with CHL1 to promote the development of new neurons and synapses. The result is the repair of dysfunctional signaling in brain regions controlling mood, which may explain the action of SSRI antidepressants.
This explanation differs from the conventional theory that SSRIs directly relieve depression by inhibiting the reabsorption of the neurotransmitter serotonin in the brain. Dr. Shomron adds that the new explanation resolves the longstanding mystery as to why it takes at least three weeks for SSRIs to ease the symptoms of depression when they begin inhibiting reabsorption after a couple days — the development of neurons and synapses takes weeks, not days.
The TAU researchers are working to confirm their findings on the molecular level and with animal models. Adva Hadar, a master’s student in Dr. Gurwitz’s lab, is using the same approach to find biomarkers for the personalized treatment of Alzheimer’s disease.
For more psychology and psychiatry news from Tel Aviv University, click here.
Keep up with the latest AFTAU news on Twitter: http://www.twitter.com/AFTAUnews.
SOURCE
Physiologist, Professor Lichtstein, Chair in Heart Studies at The Hebrew University elected Dean of the Faculty of Medicine at The Hebrew University of Jerusalem
Posted in Bio Instrumentation in Experimental Life Sciences Research, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Biomedical Measurement Science, BioSimilars, Cardiovascular Pharmacogenomics, Cardiovascular Research, Cell Biology, Signaling & Cell Circuits, Cerebrovascular and Neurodegenerative Diseases, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Drug Delivery Platform Technology, Electrophysiology, Frontiers in Cardiology and Cardiovascular Disorders, Human Sensation and Cellular Transduction: Physiology and Therapeutics, Ionic Transporters Na+, Na-K transport, Origins of Cardiovascular Disease, Pharmacotherapy and Cell Activity, Pharmacotherapy of Cardiovascular Disease, Scientist: Career considerations, Technology Transfer: Biotech and Pharmaceutical, Translational Research, Translational Science, Water Transporters, tagged Hebrew University of Jerusalem, pharmacology, Roche Institute of Molecular Biology on December 18, 2013| Leave a Comment »
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
Professor David Lichtstein Elected Dean of Hebrew University’s Faculty of Medicine
December 2, 2013
Jerusalem — Professor David Lichtstein has been elected dean of the Faculty of Medicine at The Hebrew University of Jerusalem. Professor Lichtstein is the Walter & Greta Stiel Chair in Heart Studies at The Hebrew University. He replaces Professor Eran Leitersdorf, who recently completed his four-year term as dean.
According to Professor Lichtstein, “The Hebrew University’s Faculty of Medicine is devoted to creating innovative teaching, research and patient care programs that will meet the demands of 21st century health care. As global health care moves towa
rd prevention, wellness and cost effectiveness, we are adapting how we train the next generation of physicians, nurses, pharmacists and biomedical researchers. Through fruitful collaborations between preclinical and clinical faculty, we are also translating basic biomedical insights into clinical treatments. Thus, the Faculty of Medicine is well-positioned to maintain its leading role in the scientific community of Israel and the world.”
Professor Lichtstein was born in Lodz, Poland, and immigrated to Israel with his family in 1957. As a student at The Hebrew University, he completed a Bachelor’s degree in Physiology and Zoology in 1970, followed by a Master’s degree in Physiology in 1972 and a Ph.D. in Physiology in 1977. He joined the Department of Physiology of The Hebrew University-Hadassah Medical School in 1980 as a lecturer, and received full professorship in 1994. Prof. Lichtstein has held many roles at The Hebrew University and its Faculty of Medicine, including Chairman of the Neurobiology Teaching Division, Chairman of the Department of Physiology, Chairman of the Institute for Medical Sciences and, until recently, Chairman of the Faculty of Medicine. From 2007 to 2011, Professor Lichtstein was the Jacob Gitlin Chair in Physiology at The Hebrew University. In 2011 he was named the Walter & Greta Stiel Chair in Heart Studies at The Hebrew University. He also served as the President of the Israel Society for Physiology and Pharmacology from 1996 to 1999.
From 1977-1979 Professor Lichtstein was a Postdoctoral Fellow at the Roche Institute of Molecular Biology in New Jersey. He was a visiting scientist at the National Institute of Child Health and Human Development (1985-1986) and the Eye Institute (1997-1998) at the National Institutes of Health in Maryland, and a visiting professor at the Toledo School of Medicine in Ohio (2007).
Professor. 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 were known to be present in plants and amphibians are actually normal constituents of the human body and have crucial roles, such 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.
SOURCE
http://www.afhu.org/professor-david-lichtstein-elected-dean-hebrew-universitys-faculty-medicine
Field of Study
Regulation of ion transport across the plasma membrane:
The primary focus of the research in my laboratory is the regulation of ion transport across the plasma membrane of eukaryotic cells. In particular, we study the main transport system for sodium and potassium, the sodium-potassium-ATPase, and its regulation by cardiac steroids.
Specific areas of interest:
Identification of endogenous cardiac steroids in mammalian tissue; The biological consequences of the interaction of cardiac steroids with the sodium-potassium-ATPase; Biosynthesis of the cardiac steroids in the adrenal gland; Effects of endogenous sodium-potassium-ATPase inhibitors on cell differentiation; Determination of the levels of endogenous sodium-potassium-ATPase inhibitors in pathological states, including hypertension, preeclampsia; malignancies (cancer) and manic depressive illnesses; Involvement of the sodium-potassium–ATPase/cardiac steroids system in depressive disorders; Involvement of the sodium-potassium-ATPase/cardiac steroids system in cardiac function; Involvement of intestinal signals in the regulation of phosphate homeostasis; Volume regulation and its involvement in the mitogenic response.
Cardiac Steroids and the Na+, K+-ATPase and Cardiac Steroids
Cardiac steroids, such as ouabain, digoxin and bufalin are hormones synthesized by and released from the adrenal gland and the hypothalamus. These compounds, the structure of which resembles that of plant and amphibian and butterfly steroids, interact only with the plasma membrane Na+, K+-ATPase (Figure 1). This interaction elicits numerous specific biological responses affecting the function of cells and organs.
Topics Currently under investigation include
Cardiac Steroids
- Ouabain
- Bufalin
- Dogoxin
Involvement of the sodium-potassium–ATPase/cardiac steroids system in depressive disorders
Depressive disorders, including major depression, dysthymia and bipolar disorder, are a serious and devastating group of diseases that have a major impact on the patients’ quality of life, and pose a significant concern for public health. The etiology of depressive disorders remains unclear. The Monoaminergic Hypothesis, suggesting that alterations in monoamine metabolism in the brain are responsible for the etiology of depressive disorders, is now recognized as insufficient to explain by itself the complex etiology of these diseases. Data from our and other laboratories has provided initial evidence that endogenous cardiac steroids and their only established receptor, the Na+, K+-ATPase, are involved in the mechanism underlining depressive disorders, and BD in particular. Our study (Biol. Psychiatry. 60:491-499, 2006) has proven that Na+, K+-ATPase and DLC are involved in depressive disorders particularly in manic-depression. We have also shown that specific genetic alterations in the Na+, K+-ATPase α isoforms are associated with bipolar disorders (Biol. Psychiatry, 65:985-991, 2009). Our recent study in this project (Eur. Neuropsychopharmacol. 22:72-729, 2012) showed that drugs affecting the Na+, K+-ATPase/cardiac steroids system are beneficial for the treatment of depression. Hence our work is in accordance to the proposition that mal functioning of the Na+, K+-ATPase/cardiac steroids system may be involved in manifestation of depressive disorders and identify new compounds as potential drug for the treatment of these maladies.
Involvement of the sodium-potassium-ATPase/cardiac steroids system in cardiac function
The classical and best documented effect of cardiac steroids, as their name implies, is to increase the force of contraction of heart muscle. Indeed, cardiac steroids were widely used in Western and Eastern clinical practices for the treatment of heart failure and atrial fibrillation. Despite extensive research, the mechanism underlying cardiac steroids actions have not been fully elucidated. The dogmatic explanation for cardiac steroids-induced increase in heart contractility is that the inhibition of Na+, K+-ATPase by the steroids causes an increase in intracellular Na+ which, in turn, attenuates the Na+/Ca++ exchange, resulting in an increased intracellular Ca++ concentration, and hence greater contractility. However, recent observations led to the hypothesis that the ability of cardiac steroids to modulate a number of intracellular signaling processes may be responsible for both short- and long-term changes in CS action on cardiac function. We are addressing this hypothesis using the zebrafish model and our ability to quantify heart function in-vivo. Heart contractility measurements were performed using a series of software tools for the analysis of high-speed video microscopic images, allowing the determination of ventricular heart diameter and perimeter during both diastole and systole. The ejection fraction (EF) and fractional area changes (FAC) were calculated from these measurements, providing two independent parameters of heart contractility (see attached movie bellow). We are currently testing the effect of cardiac steroids in the presence and absence of intracellular signaling pathways (MAP, AKT, IP3R) inhibitors. Reduction in the steroids ability to increase the force of contraction will serve as the first evidence, in-vivo, for the participation of the signaling processes in the molecular mechanisms responsible for the action of cardiac steroids on heart muscle.
Laboratory Techniques
We employ a broad range of preparations and techniques. These include isolated organs (arterial rings, smooth and cardiac muscle strips) and isolated nerve endings, as well as primary and established tissue-cultured cells. Our studies involve the application of biochemical and immunological techniques (transport and enzymatic activity measurements, RIA, ELISA), molecular biological techniques (e.g., Western and Northern blotting, and PCR), protein purification (HPLC), cellular techniques muscle contractility, cell proliferation and differentiation’ in-vivo measurements of heart contractility and blood flow in Zebrafish and behavior measurements in rodents.
Biography
Education
| 1970 |
B.Sc. in Physiology and Zoology, The Hebrew University, Jerusalem, Israel
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| 1970-1972 | M.Sc. in Physiology, Department of Physiology, The Hebrew University, Hadassah Medical School, Jerusalem, Israel. |
|
1973-1977
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Ph.D., Department of Physiology, Hebrew University Hadassah Medical School, Jerusalem, Israel. (Thesis: “Increased Production of Gamma Aminobutyryl choline in Cerebral Cortex Caused by Afferent Electrical Stimulation” (Thesis Advisors: Prof. J. Dobkin and Prof. J. Magnes). |
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1977-1979
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Postdoctoral Fellow, Department of Physiological Chemistry and Pharmacology, Roche Institute of Molecular Biology, Nutley, New Jersey, U.S.A. |
Positions held
|
1970-1972
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Teaching and Research Assistant, Department of Physiology, The Hebrew University, Hadassah Medical School, Jerusalem, Israel |
| 1972-1974 | Assistant Instructor, Department of Physiology, The Hebrew University, Hadassah Medical School, Jerusalem, Israel |
| 1975-1977 | Instructor, Department of Physiology, The Hebrew University, Hadassah Medical School, Jerusalem, Israel |
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1977-1979
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Postdoctoral Fellow, Department of Physiological Chemistry and Pharmacology, Roche Institute of Molecular Biology, Nutley, New Jersey, U.S.A. |
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1979-1983
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Lecturer, (REVSON fellowship) Department of Physiology, The Hebrew University, Hadassah Medical School, Jerusalem, Israel |
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1981 (summer)
|
Visiting Scientist, Department of Physiological Chemistry and Pharmacology, Roche Institute of Molecular Biology, Nutley, New Jersey, USA |
| 1983-1987 | Senior Lecturer, Department of Physiology, The Hebrew University Hadassah Medical School, Jerusalem, Israel. |
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1985-1986
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Visiting Scientist, Laboratory of Theoretical and Physical Biology, NICHD, National Institutes of Health, Bethesda, Maryland, USA |
| 1988-1994 | Associate Professor, Department of Physiology, The Hebrew University Hadassah Medical School, Jerusalem, Israel |
| 1994-present | Professor of Physiology, Department of Physiology, The Hebrew University Hadassah Medical School, Jerusalem, Israel |
| 1997-1998 | Visiting Scientist, Laboratory of Mechanisms of Ocular Diseases, NEI, National Institutes of Health, Bethesda, Maryland, USA |
|
2007 (summer)
|
Visiting Professor, Department of Physiology, Pharmacology, Metabolism and cardiovascular Sciences, Medical Center University of Toledo, Toledo, Ohio, USA |
| 2007-2011 | Jacob Gitlin Chair in Physiology, The Hebrew University, Jerusalem, Israel |
| 2011-present | Walter & Greta Stiel Chair in Heart Studies, The Hebrew University, Jerusalem |
Professional Membership
| 1979-present | International Society of Neurochemistry |
| 1979-present | Israel Society for Physiological and Pharmacological |
| 1980-present | Society of Neurosciences (Europe) |
| 1986-present | The American Society of Hypertension |
| 1992-present | Israeli Society for Neurosciences |
| 1999-present | The American Physiological Society |
Editorial Tasks
| Serving as a Reviewer for the scientific journals: | ||||
| • | American Journal of Hypertension | • | Journal of Neural Transmission | |
| • | American Journal of Physiology | • | Journal of Neurochemistry | |
| • | Apoptosis | • | Journal of Pharmacology and Experimental Therapeutics | |
| • | Biochemical and Biophysical Research Communications | • | Life Sciences | |
| • | Basic Journal of Physiology and Pharmacology | • | NANO | |
| • | Brain Research | • | Neurochemistry International | |
| • | Bioconjugate Chemistry | • | Neuroscience | |
| • | Cell Calcium | • | Neurotoxicity Research | |
| • | Clinical Science | • | Pathophysiology | |
| • | Endocrinology | • | Physiology and Behavior | |
| • | European Neuropsychopharmacology | • | PNAS | |
| • | General and Comparative Endocrinology | • | Psychiatry Research | |
| • | Hypertension | • | Translational Research | |
| • | Journal of Cell Sciences | |||
University and Other Activities
| 1982-1985 | Chairman of the Neurobiology Teaching Division, The Hebrew University, Jerusalem |
| 1988-1994 | Elected representative of the Senior Lecturers and Associate Professors for the University Senate |
| 1989-1997 | Member of the admission committee of the Medical School, The Hebrew University, Jerusalem |
| 1990-1996 | Member of the Committee for cellular biology of the graduate studies, The Hebrew University, Jerusalem |
| 1992-1996 | Member of the Teaching Committee, Faculty of Medicine, The Hebrew University, Jerusalem |
| 1992-1996 |
Chairman, Department of Physiology, The Hebrew University, Hadassah Medical School, Jerusalem
|
| 1994-1997 | Member of the Committee for graduate studies, The Hebrew University, Jerusalem |
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1992-2002
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Member of the Management Committee of The Institute for Medical Sciences, Faculty of Medicine, The Hebrew University, Jerusalem
|
| 1996-1999 |
President of the Israel Society for Physiology and Pharmacology
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| 1998- 2002 | Chairman, Institute of Medical Sciences, The Hebrew University, Hadassah Medical School, Jerusalem |
| 1999-2002 | Member of the Planning and Development Committee of the Faculty of Medicine, The Hebrew University, Jerusalem |
| 2007–Present | Elected representative of the Professors for the executive University Senate |
| 2008-2012 | Member of the Planning and Development Committee of the Faculty of Medicine, The Hebrew University, Jerusalem |
| 2008-2012 | Chairman, Institute for Medical Research Israel-Canada, The Hebrew University, Hadassah Medical School, Jerusalem |
| 2009 – Present | Elected member of the Senate to the Executive Committee of the Hebrew University |
PUBLICATIONS 2006 – 2012
Use link below for earlier publications
https://medicine.ekmd.huji.ac.il/En/Publications/publications/Pages/default.aspx?aut=Lichtstein,%20D
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|
SOURCE
https://medicine.ekmd.huji.ac.il/En/Publications/publications/Pages/default.aspx?aut=Lichtstein,%20D
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