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Larry H Bernstein, MD, Curator

Leaders in Pharmaceutical Intelligence

 

Natriuretic Peptides (BNP and Amino-terminal proBNP)

Author: Larry Bernstein, M.D.,
(see Reviewers/Authors page)
Revised: 12 December 2010, last major update December 2010
Copyright: (c) 2003-2010, PathologyOutlines.com, Inc.
http://dx.doi.org:/PathologyOutlines.com/cardiac

General
=========================================================================

  • Brain natriuretic peptide (BNP), now known as B-type natriuretic peptide (also BNP),
    is a 32 amino acid polypeptide secreted by the cardiac ventricles in response to
    excessive stretching of cardiomyocytes (Wikipedia)
  • BNP was originally identified in extracts of porcine brain, although in humans
    it is produced mainly in the cardiac ventricles
  • BNP is co-secreted with a 76 amino acid N-terminal fragment (NT-proBNP),
    which is biologically inactive Indications

=========================================================================

  • Evaluation of dyspneic patient with suspected congestive heart failure,
    regardless of renal function (J Am Coll Cardiol 2006;47:91)
  • B-type natriuretic peptide levels are higher in patients with congestive heart
    failure than in dyspnea from other causes (J Am Coll Cardiol 2002;39:202,
    N Engl J Med 2004;350:647)
  • NT-proBNP measurement is a valuable addition to standard clinical
    assessment for the identification and exclusion of acute CHF in the
    emergency department setting (Am J Cardiol 2005;95:9480)

Clinical features
=========================================================================

  • Reduces misdiagnosis of congestive heart failure, which occurs
    50% to 75% of the time
  • NT-proBNP is superior to BNP for predicting mortality and morbidity for heart
    failure (Clin Chem 2006;52:1528), and coexisting renal disease and heart failure
    (Clin Chem 2007;53:1511)

Reference ranges
=========================================================================

  • BNP levels below 100 pg/mL indicate no heart failure

Limitations
=========================================================================

  • Determination of endogenous BNP with the AxSYM assay using frozen
    plasma samples may not be valid after 1 day, but NT-proBNP as
    measured by the Elecsys assay may be stored at -20 degrees C for
    at least four months without a relevant loss of the immunoreactive
    analyte (Clin Chem Lab Med 2004;42:942)

Additional references
=========================================================================

  • Clin Chem 2007;53:1928, Am J Kidney Dis 2005;46:610,
    Hypertension 2005;46:118, Hypertension 2006;47:874,
    Eur J Heart Fail 2004;6:269

Natriuretic peptides for risk stratification of patients with acute
coronary
 syndromes  
M Galvani,  D Ferrini, F Ottani. Eur J Heart Fail 2004;  6: 327–333.
http://eurjhf.oxfordjournals.org

Both BNP and NT-proBNP possess several characteristics of the ideal biomarker,
showing independent and incremental prognostic value above traditional clinical,
electrocardiographic, and biochemical (particularly troponin) risk indicators. Specifically,
in ACS patients, BNP and NT-proBNP have powerful prognostic value both in patients
without a history of previous heart failure or without clinical or instrumental signs of
left ventricular dysfunction on admission or during hospital stay.

Our results show that the prognostic value of natriuretic peptides is similar:
(1) both at short- and long-term;
(2) when natriuretic peptides are measured at first patient contact or during hospital stay;
(3) for BNP or NT-proBNP; and
(4) in patients with ST elevation myocardial infarction or no ST elevation ACS.

 

Steady-State Levels of Troponin and Brain Natriuretic Peptide for Prediction
of Long-Term
 Outcome after Acute Heart Failure with or without Stage 3 to 4
Chronic Kidney Disease

Y Endo, S Kohsaka, T Nagai, K Koide, M Takahashi, et al.
Br J Med Med Res 2012; 2(4): 490-500.
http://dx.doi.org:/10.9734/BJMMR/2012/1384

The population was predominantly male (69.3%), and the mean age was 66.6±15.3 years.
Patients with higher BNP levels or detectable TnT had a worse prognosis (BNP45.0% vs.
18.8%, p<0.001; TnT 43.8% vs. 25.1%, p=0.002, respectively). The primary event rate
was additively worse among patients with both increased BNP levels and detectable TnT
compared to those with increased levels of BNP or detectable TnT alone (log-rank p<0.001).
A similar trend was observed in the subgroup of patients with CKD stage III–V (n=172).

The Effect of Correction of Mild Anemia in Severe, Resistant Congestive
Heart Failure
 Using Subcutaneous Erythropoietin and Intravenous Iron:
A Randomized Controlled Study

DS. Silverberg, D Wexler, D Sheps, M Blum, G Keren, et al.  JACC 2001; 37(7).
PII S0735-1097(01)01248-7  http://www.ncbi.nlm.nih.gov/pubmed/11401110

When anemia in CHF is treated with EPO and IV iron, a marked improvement in
cardiac and patient function is seen, associated with less hospitalization and renal
impairment and less need for diuretics. (J Am Coll Cardiol 2001;37:1775– 80)

 

 

 

Hemoglobin on NT proBNP

Hemoglobin on NT proBNP

 

 

 

 

What is the best approximation of reference normal for NT-proBNP?
Clinical levels for enhanced assessment
 of NT-proBNP (CLEAN) 

Larry H. Bernstein1*, Michael Y. Zions1,4, Mohammed E. Alam1,5, Salman A. Haq1,
John F. Heitner1, Stuart Zarich2, Bette Seamonds3 and Stanley Berger3
1New York Methodist Hospital, Brooklyn, NY; 2Bridgeport Hospital, Bridgeport, CT;
3Mercy Catholic Medical Center, Darby, Phila, PA;  4Touro College, &  5Medgar
Evers College, Brooklyn, NY
Journal of Medical Laboratory and Diagnosis 04/2011; 2:16-21.
http://www.academicjournals.org/jmld

The natriuretic peptides, B-type natriuretic peptide (BNP) and NT-proBNP that
have emerged as tools for diagnosing congestive heart failure (CHF) are affected
by age and renal insufficiency (RI).  NTproBNP is used in rejecting CHF and as a
marker of risk for patients with acute coronary syndromes. This observational study
was undertaken to evaluate the reference value for interpreting NT-proBNP
concentrations. The hypothesis is that increasing concentrations of NT-proBNP
are associated with the effects of multiple co-morbidities, not merely CHF,
resulting in altered volume status or myocardial filling pressures.

NT-proBNP was measured in a population with normal trans-thoracic echocardiograms
(TTE) and free of anemia or renal impairment. Exclusion conditions were the following
co-morbidities:

  • anemia as defined by WHO,
  • atrial fibrillation (AF),
  • elevated troponin T exceeding 0.070 mg/dl,
  • systolic or diastolic blood pressure exceeding 140 and 90 respectively,
  • ejection fraction less than 45%,
  • left ventricular hypertrophy (LVH),
  • left ventricular wall relaxation impairment, and
  • renal insufficiency (RI) defined by creatinine clearance < 60ml/min using
    the MDRD formula .

Study participants were seen in acute care for symptoms of shortness of breath
suspicious for CHF requiring evaluation with cardiac NTproBNP assay. The median
NT-proBNP for patients under 50 years is 60.5 pg/ml with an upper limit of 462 pg/ml,
and for patients over 50 years the median was 272.8 pg/ml with an upper limit of
998.2 pg/ml.
We suggest that NT-proBNP levels can be more accurately interpreted only after
removal of the major co-morbidities that affect an increase in this  peptide in serum.
The PRIDE study guidelines should be applied until presence or absence of
comorbidities is diagnosed. With no comorbidities, the reference range for normal
over 50 years of age remains steady at ~1000 pg/ml. The effect shown in previous
papers likely is due to increasing concurrent comorbidity with age.

NT-proBNP profile of combined population taken from 3 sites and donors.

Age    Under 50 years 50-69 years 70 and over
NT-proBNP

Mean   
95% CI of Mean
Median   
95% CI of median
2.5-97.5 percentile   
25-75 percentile
209
35.9
29.8-43.3
27.6
24.8-33.6
5.0-1364
14.9-55.8
126
182.4
132.1-251.9
142.3
92.3-219.0
10.8-11604
42.1-565
82
611.7
425.2-880.1
564.2
419.7-1007.7
28.8-14242
210.2-2062

 

We observe the following changes with respect to NTproBNP and age:

(i) Sharp increase in NT-proBNP at over age 50

(ii) Increase in NT-proBNP at 7% per decade over 50

(iii) Decrease in eGFR at 4% per decade over 50

(iv) Slope of NT-proBNP increase with age is related to proportion of patients with
eGFR less than 90

(v) NT-proBNP increase can be delayed or accelerated based on disease
comorbidities

NT-proBNP sensitivity and specificity with RI prevalence

NT-proBNP sensitivity and specificity with RI prevalence

Figure 1. Plot of NT-proBNP sensitivity and specificity with RI prevalence.
GFRe scale: 0, > 120; 1, 90- 119; 2, 60-89; 3, 40-59; 4, 15-39; 5, under 15 ml/min.

NKF staging by GFRe interval and NT-proBNP (CHF removed).

NKF staging by GFRe interval and NT-proBNP (CHF removed).

 

Figure 2  plots the mean and 95% CI of NTproBNP (CHF removed) by the National Kidney Foundation
staging for eGFR interval (eGFR scale: 0, > 120; 1, 90 to 119;2, 60 to 89; 3, 40 to 59; 4, 15 to 39; 5,
under 15 ml/min). We created a new variable to minimize the effects of age and eGFR variability by
correcting these large effects in the whole sample population.

Adjustment of the NT-proBNP for eGFR and for age over 50 differences. We have
carried out a normalization to adjust for both eGFR and for age over 50:

(i) Take Log of NT-proBNP and multiply by 1000

(ii) Divide the result by eGFR (using MDRD9 or Cockroft Gault10)

(iii) Compare results for age under 50, 50-70, and over 70 years

(iv) Adjust to age under 50 years by multiplying by 0.66 and 0.56.

The equation does not require weight because the results are reported normalized
to 1.73 m2 body surface area, which is an accepted average adult surface area.

 

fn.log-NT-proBNP vs age

fn.log-NT-proBNP vs age

Figure 3.  Plot of 1000*log (NT-proBNP)/GFR vs age at  eGFR over 90  and 60 ml/min

scatterplot and regression line with centroid and confidence interval for fn.logNTproBNP vs age

scatterplot and regression line with centroid and confidence interval for fn.logNTproBNP vs age

Figure 4. Superimposed scatterplot and regression line with centroid and
confidence interval for 1000*log(NT-proBNP)/eGFR vs age (anemia removed)
at eGFR over 40 and 90 ml/min. (Black: eGFR > 90, Blue:  eGFR > 40)  

 

Ref Range NTpro NKLogNTpro

Ref Range NTpro NKLogNTpro

 

Reference range for NT-proBNP before and after adjusting

 

Amino-Terminal Pro-Brain Natriuretic Peptide, Renal Function, and
Outcomes in Acute Heart Failure
RRJ. van Kimmenade,  JL. Januzzi, JR,  AL. Baggish, et al. JACC 2006; 48(8).: 1621-7.

We sought to study the individual and integrative role of amino-terminal pro-brain natriuretic
peptide (NT-proBNP) and parameters of renal function for prognosis in heart failure. The
combination of NT-proBNP with measures of renal function better predicts short-term outcome
in acute heart failure than either parameter alone. Among heart failure patients, the objective
parameter of NT-proBNP seems more useful to delineate the “cardiorenal syndrome” than the
previous criteria of a clinical diagnosis of heart failure.

 

NT-proBNP testing for diagnosis and short-term prognosis in acute destabilized
heart failure: an international pooled analysis of 1256 patients The International
Collaborative of NT-proBNP Study
Januzzi, R van Kimmenade, J Lainchbury, A Bayes-Genis, J Ordonez-Llanos, et al.
Eur Heart J 2006; 27, 330–337. http://dx.doi.org:/10.1093/eurheartj/ehi631

Differences in NT-proBNP levels among 1256 patients with and without acute HF and the relationship
between NT-proBNPlevels and HF symptomswere examined.Optimal cut-points for diagnosis and
prognosis were identified and verified using bootstrapping and multi-variable logistic regression techniques.

Seven hundred and twenty subjects (57.3%) had acute HF, whose median NT-proBNP was considerably
higher than those without (4639 vs. 108 pg/mL, P < 0.001), and levels of NT-proBNP correlated with HF
symptom severity (P < 0.008). An optimal strategy to identify acute HF was to use age-related cut-points
of 450, 900, and 1800 pg/mL for ages < 50, 50–75, and  > 75, which yielded 90% sensitivity and 84% specificity
for acute HF. An age-independent cut-point of 300 pg/mL had 98% negative predictive value to exclude acute
HF. Among those with acute HF, a presenting NT-proBNP concentration > 5180 pg/mL was strongly predictive
of death by 76 days [odds ratio = 5.2, 95% confidence interval (CI) =2.2 – 8.1, P < 0.001].

Effect of B-type natriuretic peptide-guided treatment of chronic heart failure on total mortality
and hospitalization: an individual patient meta-analysis
RW. Troughton, CM. Frampton, HP Brunner-La Rocca, M Pfisterer, LW.M. Eurlings, et al.
Eur Heart J Mar 2014; 35, 1559–1567.
http://dx.doi.org:/10.1093/eurheartj/ehu090

We sought to perform an individual patient data meta-analysis to evaluate the effect of NP-guided treatment
of heart failure on all-cause mortality.  The survival benefit from NP-guided therapy was seen in younger (< 75
years) patients [0.62 (0.45–0.85); P = 0.004] but not older (≥75 years) patients [0.98 (0.75–1.27); P = 0.96].
Hospitalization due to heart failure [0.80 (0.67–0.94); P = 0.009] or cardiovascular disease [0.82 (0.67–0.99);
P = 0.048] was significantly lower in NP-guided patients with no heterogeneity between studies and no interaction
with age or LVEF.

 

Diagnostic and prognostic evaluation of left ventricular systolic heart failure by plasma N-terminal
pro-brain natriuretic peptide concentrations in a large sample of the general population

BA Groenning, I Raymond, PR Hildebrandt, JC Nilsson, M Baumann, F Pedersen.
Heart 2004; 90:297–303.  http://dx.doi.org:/10.1136/hrt.2003.026021

Value of NT-proBNP in evaluating patients with symptoms of heart failure and impaired left ventricular (LV) systolic
function; prognostic value of NT-proBNP for mortality and hospital admissions. In 38 (5.6%) participants LV ejection
fraction (LVEF) was ( 40%. NT-proBNP identified patients with symptoms of heart failure and LVEF ( 40% with a
sensitivity of 0.92, a specificity of 0.86, AUC of 0.94.  NT-proBNP was the strongest independent predictor of mortality
(hazard ratio (HR) = 5.70, p , 0.0001), hospital admissions for heart failure (HR = 13.83, p , 0.0001), and other cardiac
admissions (HR = 3.69, p , 0.0001). Mortality (26 v 6, p = 0.0003), heart failure admissions (18 v 2, p = 0.0002), and
admissions for other cardiac causes (44 v 13, p , 0.0001) were significantly higher in patients with NTproBNP above the
study median (32.5 pmol/l).

 

Testing for BNP and NT-proBNP in the Diagnosis and Prognosis of Heart Failure
Evidence Report/Technology Assessment – Number 142. Agency for Healthcare Research and Quality.
Prepared by: McMaster University Evidence-based Practice Center, Hamilton, ON, Canada
C Balion, PL. Santaguida, S Hill, A Worster, M McQueen, et al.
http://archive.ahrq.gov/downloads/pub/evidence/pdf/bnp/bnp.pdf

Question 1: What are the determinants of both BNP and NT-proBNP?
Question 2a: What are the clinical performance characteristics of both BNP and NTproBNP
measurement in patients with symptoms suggestive of HF or with known HF?
Question 2b: Does measurement of BNP or NT-proBNP add independent diagnostic information
to the traditional diagnostic measures of HF in patients with suggestive HF?
Question 3a: Do BNP or NT-proBNP levels predict cardiac events in populations at risk of CAD,
with diagnosed CAD and HF?
Question 3b: What are the screening performance characteristics of BNP or NT-proBNP in
general asymptomatic populations?
Question 4: Can BNP or NT-proBNP measurement be used to monitor response to therapy?        

Diagnosis: In all settings both BNP and NT-proBNP show good diagnostic properties as a rule out test for HF.
Prognosis: BNP and NT-proBNP are consistent independent predictors of mortality and other cardiac composite
endpoints for populations with risk of CAD, diagnosed CAD, and diagnosed HF. There is insufficient evidence to
determine the value of B-type natriuretic peptides for screening of HF.
Monitoring Treatment: There is insufficient evidence to demonstrate that BNP and NT-proBNP levels
show change in response to therapies to manage stable chronic HF patients.

Guide-IT Trial

Biomarker-Guided HF Therapy: Is It Cost-Effective
www.medscape.org/viewarticle/764686_transcript

Jan 29, 2013 – Uploaded by DCLRI
Michael Felker, MD, MHS
Associate Professor in the Division of Cardiology
Duke University Medical Center
www.youtube.com/watch?v=AW0480EE2kw

GUIDE-IT will last five years and involve approximately 45 trial sites in the United States. The first group of
patients will be enrolled by the end of 2012.

The trial tests NT-proBNP guided therapy with a COMPANION diagnostic biomarker used to optimize already
available and effective therapies for heart failure. It may identify  patients who will benefit from intensified therapy,
and  who would not have been known using only signs and symptoms of heart failure as it is currently the practice.
The NT-proBNP biomarker would enable doctors to create personalized treatment plans for patients to substantially
reduce mortality and morbidity

 Risk stratification in acute heart failure: Rationale and design of the
STRATIFY and DECIDE studies 

SP. Collins, CJ. Lindsell, CA. Jenkins, FE. Harrell, et al.
Am Heart J 2012;164:825-34.
http://dx.doi.org/10.1016/j.ahj.2012.07.033

Two studies (STRATIFY and DECIDE) have been funded by the National Heart Lung and Blood Institute with
the goal of developing prediction rules to facilitate early decision making in AHF. Using prospectively gathered
evaluation and treatment data from the acute setting (STRATIFY) and early inpatient stay (DECIDE), rules will
be generated to predict risk for death and serious complications.
A rigorous analysis plan has been developed to construct the prediction rules that will maximally extract both the
statistical and clinical properties of every data element. Upon completion of this study we will subsequently externally
test the prediction rules in a heterogeneous patient cohort.

N-terminal pro-B-type natriuretic peptide and the prediction of primary cardiovascular
events: results from 15-year follow-up of WOSCOPS

P Welsh, O Doolin, P Willeit, C Packard, P Macfarlane, S Cobbe, et al.
Eur Heart J Aug  2012.
http://dx.doi.org:/10.1093/eurheartj/ehs239

To test whether N-terminal pro-B-type natriuretic peptide (NT-proBNP) was independently associated with, and
improved the prediction of, cardiovascular disease (CVD) in a primary prevention cohort. N-terminal pro-B-type
natriuretic peptide predicts CVD events in men without clinical evidence of CHD, angina, or history of stroke,
and appears related more strongly to the risk for fatal events.
NT-proBNP was associated with an increased risk of all CVD [HR: 1.17 (95% CI: 1.11–1.23) per standard deviation
increase in log NT-proBNP] after adjustment for classical and clinical cardiovascular risk factors plus C-reactive protein.
N-terminal pro-B-type natriuretic peptide was more strongly related to the rsk of fatal [HR: 1.34 (95% CI: 1.19–1.52)]
than non-fatal CVD [HR: 1.17 (95% CI: 1.10–1.24)] (P = 0.022). The addition of NT-proBNP to traditional risk factors
improved the C-index (+0.013; P = 0.001). The continuous net reclassification index improved with the addition of NT-
proBNP by 19.8% (95% CI: 13.6–25.9%) compared with 9.8% (95% CI: 4.2–15.6%) with the addition of C-reactive protein.

 

Utility of B-Natriuretic Peptide in Detecting Diastolic Dysfunction: Comparison With
Doppler Velocity Recordings
E Lubien, A DeMaria, P Krishnaswamy, P Clopton, J Koon…A Maisel.
http://circ.ahajournals.org/content/105/5/595
Circulation. 2002;105:595-601
http://dx.doi.org:/10.1161/hc0502.103010

Although Doppler echocardiography has been used to identify abnormal left ventricular (LV) diastolic filling dynamics,
inherent limitations suggest the need for additional measures of diastolic dysfunction. Because data suggest that B-natriuretic
peptide (BNP) partially reflects ventricular pressure, we hypothesized that BNP levels could predict diastolic abnormalities
in patients with normal systolic function. A rapid assay for BNP can reliably detect the presence of diastolic abnormalities
on echocardiography. In  patients with normal systolic function, elevated BNP levels and diastolic filling abnormalities might
help to reinforce the diagnosis diastolic dysfunction

Association of common variants in NPPA and NPPB with circulating natriuretic
peptides and blood pressure.
C Newton-Cheh, MG Larson, RS Vasan, D Levy, KD Bloch, et al.
Nat Genet. 2009 Mar; 41(3): 348–353.
http://dx.doi.org:/10.1038/ng.328

We examined the association of common variants at the NPPA-NPPB locus with circulating concentrations of the
natriuretic peptides, which have blood pressure–lowering properties. In 29,717 individuals, the alleles of rs5068
and rs198358 that showed association with increased circulating natriuretic peptide concentrations were also found
to be associated with lower systolic (P = 2 ×10−6 and 6 × 10−5, respectively) and diastolic blood pressure (P = 1 × 10−6
and 5 × 10−5), as well as reduced odds of hypertension (OR = 0.85, 95% CI = 0.79–0.92, P = 4 × 10−5; OR = 0.90, 95%
CI = 0.85–0.95, P = 2 × 10−4, respectively).

2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk
DC. Goff, Jr, DM. Lloyd-Jones, G Bennett, S Coady, RB. D’Agostino, Sr, et al.
Circulation. 2013;  http://circ.ahajournals.org/content/early/2013/11/11/01.cir.0000437741.48606.98.citation
http://dx.doi.org:/10.1161/01.cir.0000437741.48606.98

The ACC and AHA have collaborated with the National Heart, Lung, and Blood Institute (NHLBI) and stakeholder
and professional organizations to develop clinical practice guidelines for assessment of CV risk, lifestyle modifications
to reduce CV risk, and management of blood cholesterol, overweight and obesity in adults.
Although the Task Force led the final development of these prevention guidelines, they differ from other ACC/AHA
guidelines. First, as opposed to an extensive compendium of clinical information, these documents are significantly
more limited in scope and focus on selected CQs in each topic, based on the highest quality evidence available.
Recommendations were derived from randomized trials, meta-analyses, and observational studies evaluated for quality,
and were not formulated when sufficient evidence was not available. Second, the text accompanying each recommendation
is succinct, summarizing the evidence for each question. Third, the format of the recommendations differs from other
ACC/AHA guidelines. Each recommendation has been mapped from the NHLBI grading format to the ACC/AHA Class
of Recommendation/Level of Evidence (COR/LOE) construct (Table 1) and is expressed in both formats.

 

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Summary of Genomics and Medicine: Role in Cardiovascular Diseases


Summary of Genomics and Medicine: Role in Cardiovascular Diseases

Author: Larry H. Bernstein, MD, FCAP

The articles within Chapters and Subchapters you have just read have been organized into four interconnected parts.
  1. Genomics and Medicine
  2. Epigenetics – Modifyable Factors Causing CVD
  3. Determinants of CVD – Genetics, Heredity and Genomics Discoveries
  4. Individualized Medicine Guided by Genetics and Genomics Discoveries
The first part established the
  • rapidly evolving science of genomics
  • aided by analytical and computational tools for the identification of nucleotide substitutions, or combinations of them
that have a significant association with the development of
  • cardiovascular diseases,
  • hypercoagulable state,
  • atherosclerosis,
  • microvascular disease,
  • endothelial disruption, and
  • type-2DM, to name a few.
These may well be associated with increased risk for stroke and/or peripheral vascular disease in some cases,
  • essentially because the involvement of the circulation is systemic in nature.

Part 1

establishes an important connection between RNA and disease expression.  This development has led to
  • the necessity of a patient-centric approach to patient-care.
When I entered medical school, it was eight years after Watson and Crick proposed the double helix.  It was also
  • the height of a series of discoveries elucidating key metabolic pathways.
In the period since then there have been treatments for some of the important well established metabolic diseases of
  • carbohydrate,
  • protein, and
  • lipid metabolism,
such as –  glycogen storage disease, and some are immense challenges, such as
  • Tay Sachs, or
  • Transthyretin-Associated amyloidosis.
But we have crossed a line delineating classical Mendelian genetics to
  • multifactorial non-linear traits of great complexity and
involving combinatorial program analyses to resolve.
The Human Genome Project was completed in 2001, and it has opened the floodgates of genomic discovery.  This resulted in the identification of
genomic alterations in
  • cardiovascular disease,
  • cancer,
  • microbial,
  • plant,
  • prion, and
  • metabolic diseases.
This has also led to
  • the identification of genomic targets
  • that are either involved in transcription or
  • are involved with cellular control mechanisms for targeted pharmaceutical development.
In addition, there is great pressure on the science of laboratory analytics to
  • codevelop with new drugs,
  • biomarkers that are indicators of toxicity or
  • of drug effectiveness.
I have not mentioned the dark matter of the genome. It has been substantially reduced, and has been termed dark because
  • this portion of the genome is not identified in transcription of proteins.
However, it has become a lightning rod to ongoing genomic investigation because of
  • an essential role in the regulation of nuclear and cytoplasmic activities.
Changes in the three dimensional structure of these genes due to
  • changes in Van der Waal forces and internucleotide distances lead to
  • conformational changes that could have an effect on cell activity.

Part 2

is an exploration of epigenetics in cardiovascular diseases.  Epigenetics is
  • the post-genomic modification of genetic expression
  • by the substitution of nucleotides or by the attachment of carbohydrate residues, or
  • by alterations in the hydrophobic forces between sequences that weaken or strengthen their expression.
This could operate in a manner similar to the conformational changes just described.  These changes
  • may be modifiable, and they
  • may be highly influenced by environmental factors, such as
    1. smoking and environmental toxins,
    2. diet,
    3. physical activity, and
    4. neutraceuticals.
While neutraceuticals is a black box industry that evolved from
  • the extraction of ancient herbal remedies of agricultural derivation
    (which could be extended to digitalis and Foxglove; or to coumadin; and to penecillin, and to other drugs that are not neutraceuticals).

The best examples are the importance of

  • n-3 fatty acids, and
  • fiber
  • dietary sulfur (in the source of methionine), folic acid, vitamin B12
  • arginine combined with citrulline to drive eNOS
  • and of iodine, which can’t be understated.
In addition, meat consumption involves the intake of fat that contains

  • the proinflammatory n-6 fatty acid.

The importance of the ratio of n-3/n-6 fatty acids in diet is not seriously discussed when

  • we look at the association of fat intake and disease etiology.
Part 2 then leads into signaling pathways and proteomics. The signaling pathways are
  • critical to understanding the inflammatory process, just as
  • dietary factors tie in with a balance that is maintained by dietary intake,
    • possibly gut bacteria utilization of delivered substrate, and
    • proinflammatory factors in disaease.
These are being explored by microfluidic proteomic and metabolomic technologies that were inconceivable a half century ago.
This portion extended into the diagnosis of cardiovascular disease, and
  • elucidated the relationship between platelet-endothelial interaction in the formation of vascular plaque.
It explored protein, proteomic, and genomic markers
  1. for identifying and classifying types of disease pathobiology, and
  2. for following treatment measures.

Part 3

connected with genetics and genomic discoveries in cardiovascular diseases.

Part 4

is the tie between life style habits and disease etiology, going forward with
  • the pursuit of cardiovascular disease prevention.
The presentation of walking and running, and of bariatric surgery (type 2DM) are fine examples.
It further discussed gene therapy and congenital heart disease.  But the most interesting presentations are
  • in the pharmacogenomics for cardiovascular diseases, with
    1. volyage-gated calcium-channels, and
    2. ApoE in the statin response.

This volume is a splendid example representative of the entire collection on cardiovascular diseases.

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Diagnostic Value of Cardiac Biomarkers


Diagnostic Value of Cardiac Biomarkers

Author and Curator: Larry H Bernstein, MD, FCAP 

These presentations covered several views of the utilization of cardiac markers that have evolved for over 60 years.  The first stage was the introduction of enzymatic assays and isoenzyme measurements to distinguish acute hepatitis and acute myocardial infarction, which included lactate dehydrogenase (LD isoenzymes 1, 2) at a time that late presentation of the patient in the emergency rooms were not uncommon, with the creatine kinase isoenzyme MB declining or disappeared from the circulation.  The world health organization (WHO) standard definition then was the presence of two of three:

1. Typical or atypical precordial pressure in the chest, usually with radiation to the left arm

2. Electrocardiographic changes of Q-wave, not previously seen, definitive; ST- elevation of acute myocardial injury with repolarization;
T-wave inversion.

3. The release into the circulation of myocardial derived enzymes –
creatine kinase – MB (which was adapted to measure infarct size), LD-1,
both of which were replaced with troponins T and I, which are part of the actomyosin contractile apparatus.

The research on infarct size elicited a major research goal for early diagnosis and reduction of infarct size, first with fibrinolysis of a ruptured plaque, and this proceeded into the full development of a rapidly evolving interventional cardiology as well as cardiothoracic surgery, in both cases, aimed at removal of plaque or replacement of vessel.  Surgery became more imperative for multivessel disease, even if only one vessel was severely affected.

So we have clinical history, physical examination, and emerging biomarkers playing a large role for more than half a century.  However, the role of biomarkers broadened.  Patients were treated with antiplatelet agents, and a hypercoagulable state coexisted with myocardial ischemic injury.  This made the management of the patient reliant on long term followup for Warfarin with the international normalized ratio (INR) for a standardized prothrombin time (PT), and reversal of the PT required transfusion with thawed fresh frozen plasma (FFP).  The partial thromboplastin test (PPT) was necessary in hospitalization to monitor the heparin effect.

Thus, we have identified the use of traditional cardiac biomarkers for:

1. Diagnosis
2. Therapeutic monitoring

The story is only the beginning.  Many patients who were atypical in presentation, or had cardiovascular ischemia without plaque rupture were problematic.  This led to a concerted effort to redesign the troponin assays for high sensitivity with the concern that the circulation should normally be free of a leaked structural marker of myocardial damage. But of course, there can be a slow leak or a decreased rate of removal of such protein from the circulation, and the best example of this would be the patient with significant renal insufficiency, as TnT is clear only through the kidney, and TNI is clear both by the kidney and by vascular endothelium.  The introduction of the high sensitivity assay has been met with considerable confusion, and highlights the complexity of diagnosis in heart disease.  Another test that is used for the diagnosis of heart failure is in the class of natriuretic peptides (BNP, pro NT-BNP, and ANP), the last of which has been under development.

While there is an exponential increase in the improvement of cardiac devices and discovery of pharmaceutical targets, the laboratory support for clinical management is not mature.  There are miRNAs that may prove valuable, matrix metalloprotein(s), and potential endothelial and blood cell surface markers, they require

1. codevelopment with new medications
2. standardization across the IVD industry
3. proficiency testing applied to all laboratories that provide testing
4. the measurement  on multitest automated analyzers with high capability in proteomic measurement  (MS, time of flight, MS-MS)

nejmra1216063_f1   Atherosclerotic Plaques Associated with Various Presentations               nejmra1216063_f2     Inflammatory Pathways Predisposing Coronary Arteries to Rupture and Thrombosis.        atherosclerosis progression

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