BSR 2.01 Biomarkers in Heart Disease.pdf

BASIC SCIENCE RESEARCH BIOMARKERS IN HEART DISEASE Block 2 Ma. Luisa G. Daroy, RCh, DPAM | August 30, 2024...

BASIC SCIENCE RESEARCH BIOMARKERS IN HEART DISEASE Block 2 Ma. Luisa G. Daroy, RCh, DPAM | August 30, 2024 Trans 2.01 OVERVIEW May be measured: I. Cardiovascular Disease C. C-Reactive Protein ○ On a biosample (e.g. blood, urine, or tissue test) A. Biomarker D. Interleukin-6 ○ As a recording obtained from a person (e.g. blood B. Coronary Heart V. Coagulation Markers ○ pressure, ECG, or Holter) Disease VI. Cardiac Troponins ○ An imaging test (e.g. echocardiogram or CT scan) C. Atherosclerosis VII. Brain Natriuretic Peptide B. Coronary Heart Disease (CHD) II. Biomarker Assays VIII. Cystatin C Major cause of death worldwide III. Lipoproteins IX. Clinical Impact of Atherosclerosis IV. Inflammatory Markers Biomarker Assays for A. Myeloperoxidase Cardiovascular Disease ○ Underlying cause of CHD B. Lipoprotein-Associated X. Conclusions ○ Starts early in life and progresses slowly and Phospholipase A2 XI. Article Q&A silently for decades LEGEND Clinical Manifestations: : Important information ○ Myocardial Infarction (MI) : Good-to-know info from lecturer ○ Stroke : Supplementary/Background Info ○ Angina : Exception ○ Sudden death at ages: 50-60 years old in men ABBREVIATIONS 60-70 years old in women CVD Cardiovascular Disease Cholesterol Screening CHD Coronary Heart Disease ○ Used to identify individuals at risk of developing PAD Peripheral Artery Disease future coronary events ACS Acute Coronary Syndrome ○ Fails to identify 50% of individuals who develop CAD Coronary Artery Disease MI each year who have either normal or LDL Low Density Lipoprotein moderately increased serum cholesterol levels HDL High Density Lipoprotein MPO Myeloperoxidase C. Atherosclerosis Not simply a disease of lipid deposits but systemic LP-PLA2 Lipoprotein-associated phospholipase A2 inflammation that plays a role in atherothrombotic CRP C-reactive Protein inception and progression hsCRP High Sensitivity C-reactive Protein Mononuclear cells, macrophages and T lymphocytes BNP Brain natriuretic peptide are prominent in atheromatous plaques in the arterial NT-proBNP N-terminal Pro–B-type Natriuretic Peptide wall. ECL Electrochemiluminescence Shoulder region of the plaque VLDL Very low Density Lipoprotein ○ Most vulnerable site for rupture in acute coronary IDL Intermediate Density Lipoprotein syndromes MI Myocardial Infarction ○ Heavily infiltrated with inflammatory cells Cytokines I. CARDIOVASCULAR DISEASE (CVD) ○ Shown to increase in acute coronary syndrome Leading cause of mortality and morbidity in the (ACS) even in the absence of myocardial necrosis Philippines and the rest of the world Cause de novo hepatic production of acute Life course disease phase reactants such as C-reactive protein ○ Begins with the evolution of risk factors that (CRP) contribute to the development of subclinical atherosclerosis, which culminates in overt disease Clinical assessment is the keystone of patient management, but it has its limitations ○ Clinicians have used additional tools to aid clinical assessment and to enhance their ability to identify the “vulnerable” patient at risk for CVD Biomarkers ○ Tool to better identify high-risk individuals Figure 1. Panel A shows a cross-sectioned coronary artery from a To diagnose disease conditions promptly and patient who died of a massive MI. Panel B is a high-power accurately micrograph of the area in Panel A indicated by the asterisk. To effectively prognosticate and treat patients with disease PANEL A A. Biomarker The artery in Panel A contains an occlusive thrombus A characteristic that is objectively measured and superimposed on a lipid-rich atherosclerotic plaque. evaluated as an indicator of normal biological The fibrous cap covering the lipid-rich core has processes, pathogenic processes, or pharmacologic ruptured (area between the arrows), exposing the responses to a therapeutic intervention (NIH working thrombogenic core to the blood. group, 2001) Trichrome stain was used, rendering luminal Page 1 of 13 | TH: ZOLETA, G | TF TG2 | DEL MUNDO, SUZUKI, ZARCILLA Checked and verified: TP LIM, A. GAMAD, MJ  BSR 2.01 Biomarkers in Heart Disease thrombus and intraplaque hemorrhage red and TC: 220 mg/dL collagen blue. HDL-C: 36 mg/dL PANEL B LDL-C: 140 mg/dL Shows that the contents of the atheromatous plaque TG: 220 mg/dL have seeped through the gap in the cap into the FBS: 120 mg/dL lumen ○ Suggesting that plaque rupture preceded What is WJC's 10-year absolute risk of fatal/nonfatal MI? thrombosis (the asterisk indicates cholesterol A 12% absolute risk is derived from points assigned in crystals). Framingham Risk Scoring, which considers: ○ Age: 6 ○ TC: 3 ○ HDL-C: 2 ○ SBP: 2 Total: 13 points In 1992 he exercised 14 minutes in a Bruce protocol exercise stress test to 91% of his maximum predicted heart rate without any abnormal ECG changes. He started on a statin in 2001. But in Sept 2004, he needed urgent coronary bypass surgery. Figure 2. Participation of inflammation in all stages of Table 1. Modified approach to CHD risk assessment atherosclerosis. Risk Designation designated as 0.01 mg/mL leads to: risks of 1.8 in men and 1.5 in women, attenuated to 1.5 ○ Survival level ≤ 40% after 6 to 8 years and 1.2 after risk factor adjustment VII. NATRIURETIC PEPTIDES Natriuretic peptide hormones: Family of vasoactive VI. CARDIAC TROPONIN peptides such as: Gold standard biomarker for diagnosis of acute ○ Atrial natriuretic peptide myocardial infarction (MI) ○ B-type natriuretic peptide (BNP) ○ E.g. Troponin-I (discovered in 1987) and ○ C-type natriuretic peptide Troponin-T (1989) Have hemodynamic and anti-remodelling actions in ○ High sensitivity and specificity for myocardial the cardiovascular system with favorable injury physiological effects such as: ○ Newer generations of high-sensitivity troponin ○ Diuretic assays can detect 10-fold lower concentrations of ○ Natriuretic troponin ○ Vasorelaxant Used for the diagnosis of MI, the assessment of ○ Anti-proliferative effects prognosis of individuals presenting with acute ○ Anti-hypertrophic effects coronary syndrome, and selection of those most Involved in pathogenic mechanisms when levels are likely to benefit from early invasive management altered, leading to major CVDs such as: Levels below diagnostic threshold for MI may signal ○ Heart failure presence of CAD and increased future CVD Risk ○ Coronary artery disease ○ Even mild troponin-I elevations may predict ○ Hypertension presence of angiographic CAD and future CVD ○ Left ventricular hypertrophy events including mortality ○ Cerebrovascular accidents ○ Elevated serum troponin had 3x risk of cardiac Important candidates for diagnostic tools and death or reinfarction at 30 days therapeutic agents in CVD ○ Blood levels of NPs have predictive value in History: Troponin diagnosis and prognostic stratification of heart Troponin I first described as a biomarker specific for AMI failure in 1987; Troponin T in 1989 ○ Provide clinical information in hypertension, and both stable / unstable coronary artery disease A. Brain Natriuretic Peptide Major source of BNP synthesis and secretion: Ventricular myocardium ○ Release may also be stimulated by proinflammatory cytokines and neurohormones Main stimulus is ventricular myocardial wall Page 6 of 13 | TH: ZOLETA, G | TF TG2 | DEL MUNDO, SUZUKI, ZARCILLA  BSR 2.01 Biomarkers in Heart Disease stress (e.g. volume or pressure overload that causes myocardial stretch) → prehormone (proBNP) is synthesized → released into circulation → cleaved in equal proportions into: ○ (1) Biologically active BNP ○ (2) Biologically inactive N-terminal proBNP (NT-proBNP) fragment Used as prognostic marker in acute coronary syndrome ○ Associated with increased risk of death at 10 months as concentration at 40 hours post-infarct increased ○ Associated with increased risk for new or recurrent MI Figure 8. BNP as predictor of risk in asymptomatic adults. Red: Highest BNP tertile exhibits highest incidence of death due to cardiovascular diseases ↑ BNP or NT-proBNP levels = ↑ long and short-term mortality in stable CAD and acute coronary syndrome ○ Increased risk for CVD death, MI, stroke, or revascularization (Figure 8, Table 6) Table 6. Association of increasing BNP levels and outcomes Hazard ratio for 1 End point SD increment in log BNP value Heart failure 1.77 Atrial Fibrillation Figure 7. Physiological effects of B-type natriuretic peptide 1.66 Systemic biological effects of BNP (Figure 7) Stroke or Transient ischemic ○ Peripheral vasodilation 1.53 attack ○ Inhibition of sympathetic nervous system First major CV event 1.28 ○ Inhibition of RAAS ↑ Natriuresis and diuresis Death 1.27 Coronary heart disease event 1.1 B. BNP and Heart Disease Both BNP and NT-proBNP act as predictors of CVD BNP and NT-proBNP can be used to rule out heart risk or death. They are biomarkers for myocardial patients in patients with shortness of breath (Table 7) stress caused by CVDs ○ Both are stable in whole blood and can be Table 7. Cut-off values for BNP and NT-proBNP for diagnosis of measured in clinical routine using fully automated heart failure of patients presenting with dyspnea commercially available assays RULE-OUT HF RULE-IN HF ○ Both provide prognostic information in patients Biomarker unlikely likely (pg/mL) with heart failure, CAD, and valvular heart disease (pg/mL) ○ Diagnostic performance the two markers are BNP 100 500 comparable and no meaningful difference NT-proBNP 300 450 Table 5. Clinical information that can be obtained from a BNP or Age < 50 years NT-proBNP assessment NT-proBNP Factor Diagnosis Severity Prognosis Decision Age > 50 years 300 900 Heart ++ ++ ++ + Failure Stable Role of BNP and NT-proBNP in Clinical Routine 0 + ++ 0 CAD BNP and NT-proBNP are reliable biomarkers for ACS 0 0 ++ 0 myocardial stress from cardiovascular diseases. Aortic Both markers are stable in whole blood and 0 + + 0 Stenosis measured with automated commercially available ++ : Strong evidence assays +: Evidence derived from smaller studies Their diagnostic performance is comparable, with no 0: No data available significant difference between them Page 7 of 13 | TH: ZOLETA, G | TF TG2 | DEL MUNDO, SUZUKI, ZARCILLA  BSR 2.01 Biomarkers in Heart Disease They are particularly useful in ruling out heart failure Cystatin in CAD [Batch 2027] in patients with shortness of breath in the emergency Patients with elevated cystatin C levels have been setting shown to be at highest risk for CVD, even with mild kidney dysfunction Those with the highest levels of cystatin C are older and have hypertension, dyslipidemia, high body mass index, and higher levels of high-sensitivity C-reactive protein. Cystatin in CAD (Shi et al., 2014) This study presented conflicting results: Reduction in Cystatin C leads to decreased CVD risk Cystatin C is: ○ Normally expressed in vascular smooth muscles ○ Severely reduced in both atherosclerotic and aneurysmal aortic lesions ↑ Abdominal aortic diameter in patients screened by Figure 9. Association of increasing BNP levels and outcomes ultrasonography correlated inversely with serum cystatin C levels VIII. CYSTATIN C ○ This is due to the imbalance between cysteine proteases and cystatin C in arterial wall remodeling CYSTATIN C [Batch 2027] Cystatin C deficiency occurs in vascular disease Protein encoded by the CST3 gene Used as a biomarker of kidney function and has also been studied for its role in predicting new-onset or Advancing Diagnostic Biomarkers for deteriorating CVD Cardiovascular Disease. Belongs to the type 2 cystatin family Scan the QR code or click this link: ○ As a cysteine protease inhibitor, it plays a https://youtu.be/lxQd-i0sJRA?si=cWq2UKFj pleiotropic role in human vascular KdhBUZPY pathophysiology. Elastolytic proteases and their inhibitors, in particular Brief exploration of on-going biomarker technology for CVD in cystatin C, have been shown to be directly involved in first-world hospitals in other countries. the atherosclerotic process. IX. CLINICAL IMPACT OF BIOMARKER ASSAYS A. Renal Dysfunction and CVD FOR CVD Patients with chronic kidney disease are at high risk A. Translation from Lab to Clinic for developing CVD and CV events For biomarkers of CV risk to make the transition from Cystatin C clinical research to the routine clinical setting, several ○ A protease inhibitor synthesized in all nucleated important issues must be satisfied: cells 1. The availability of population-based cutpoints for ○ More sensitive than serum creatinine in interpretation and risk assessment diagnosing mild reductions in glomerular filtration I.e. CVD information system is available in rate and assessing renal function SLMC. It holds the records of 150,000 patients. Plasma cystatin C concentration is influenced by 2. The existence of potential therapeutic and risk factors such as: assessment ○ Age I.e. Using biomarkers to looks at the progress ○ BMI of disease in a patient ○ Sex 3. The reliability of the analytical systems used for ○ Smoking status measurement ○ High CRP concentrations I.e. Looking at the quality of lab devices, personnel, and operation B. Cystatin in CAD To be clinically useful, biomarkers must change Associated with increased CV risk management ○ High levels had increased risk for all-cause ○ Ex. If Clinton had his biomarkers screened, he mortality, CV events, and incident heart failure might not have been required to have coronary Better predictor of coronary artery calcium heart surgery progression than serum creatinine or glomerular Assessment of CV risk vs. extending this to modifying filtration rate treatment as a result of biomarker data Cystatin C has also been shown to be directly ○ Examples: involved in the atherosclerotic process (being an Rosiglitazone inhibitor of protease) Statin: individuals without prevalent CVD who may not be indicated for statin therapy but Page 8 of 13 | TH: ZOLETA, G | TF TG2 | DEL MUNDO, SUZUKI, ZARCILLA  BSR 2.01 Biomarkers in Heart Disease who are at increased CV risk due to elevated XI. ARTICLE[Batch 2027] hsCRP level may benefit from rosuvastatin treatment. TP Note: The article was not discussed during the lecture, but we have added it as nice-to-know information from the 2027 B. Multi-biomarker Approach transcript for additional context. Whether use of multiple biomarkers improves CV risk stratification in the outpatient setting of CAD cases Prognostic Value of Biomarkers in Heart remains unknown (Shlipak et al. 2009) Failure: Application of Novel Methods in Ideal scheme might combine traditional risk factors the Community known to promote atherosclerosis (hyperglycemia, Scan the QR code or click this link: dyslipidemia, smoking etc.) with: https://www.ahajournals.org/doi/epub/10.11 ○ Measures of inflammation (CRP, IL-6) 61/CIRCHEARTFAILURE.109.849299 ○ Myocyte necrosis (troponins) ○ Hemodynamic stress (BNP or NT-proBNP) Abstract: The biomarkers CRP, BNP, and cardiac troponin T were ○ Renal dysfunction/vascular damage (creatinine, measured in Olmsted County residents presenting with heart cystatin C, microalbuminuria) failure in order to determine if the use of a multimarker strategy will improve the 1-year mortality risk prediction model. It was C. Prognostic Significance found that adding two or more biomarkers to the model greatly improved the 1-year mortality risk prediction as compared to the Prognostic information on CAD cases could be useful use of a single biomarker as shown via an increase in measured in: c-statistic, integrated discrimination improvement, and net ○ Evaluating the risk/benefit tradeoff of possible reclassification improvement. However, there is no added benefit intervention strategies of the addition of a third biomarker compared to a two-biomarker ○ For counseling patients about their prognosis combination. ○ For making decisions about non-CV prevention strategies, such as cancer screening Presence of elevated NT-proBNP → earlier initiation TG Note: The article was not discussed by Doc, but posted on of ACE inhibitors and beta blockers (in controlling NeoLMS. This part of the trans is from Batch 2027. hypertension) Kidney damage by either increased albuminuria or What are the objectives of the study? cystatin C → trigger use of RAAS inhibitors or more ○ To identify the risk of heart failure through the use aggressive systolic blood pressure control of biomarker approach aside from the traditional Inflammatory biomarkers like CRP and IL-6 have been risk classifications consistently predictive of CV outcomes, but may not ○ To evolve or devise new methods of analyzing be modifiable in either primary or secondary these results prevention settings Because the conventional ROC curve/C-statistic may not be optimal in X. CONCLUSION assessing models that predict future risk and Standard risk factors alone or in combination do not should not be the sole determinant of clinical predict global risk well enough utility ○ Too many events in too many lower risk Wanted to do novel measures of predictive individuals ability such as reclassification tables and ○ Modest screening performance (not very sensitive) integrated discrimination improvement (IDI) Measurement of certain biomarkers such as hs-CRP Why did the researchers use CRP, BNP, and cardiac may be useful in conjunction with global risk troponin T? assessment to improve risk classification ○ The following are cardiac biomarkers: However, insufficient data at the present time to CRP indicates inflammation recommend novel biomarkers to screen the BNP indicates cardiac stress population at large, but selected intermediate risk Cardiac troponin T (TNT) indicates myocyte populations may be appropriate injury and helps with contraction Individual biomarkers do not markedly improve risk What was the result/main finding? prediction ○ The use of biomarkers improved risk prediction of ○ Markers of existing disease are the most heart diseases and events, especially when a promising (including imaging tools) combination of them is employed. Combining individual markers that reflect distinct ○ Addition of two (2) or more biomarkers have biological pathways is a promising strategy, with greatly improved the 1-year mortality risk several caveats: prediction → multimarker ○ Combining multiple mediocre markers will not work ○ Not close to ready for clinical application Cost-effectiveness and outcome studies needed Page 9 of 13 | TH: ZOLETA, G | TF TG2 | DEL MUNDO, SUZUKI, ZARCILLA  BSR 2.01 Biomarkers in Heart Disease measurements when comparing values, because the trend would be able to prognosticate ○ Statement “Although each biomarker provides incremental prognostic value about established risk factors the combined use of more biomarkers confers substantial improvement.” is unclear and does not specify what “incremental” refers to ○ Researchers mentioned potential limitations which includes the relatively small number of deaths If you were a clinician, would you pursue this approach? ○ Student: Since most of the participants are white (raced), it would be nice to apply this study in the Philippines, it would be beneficial to conduct knowing that the number one cause of mortality Figure 10. Reclassification of participants by 1-year mortality status using model with CRP and BNP and morbidity in the country are cardiovascular Source: Dunlay et al., 2009 diseases. Dr Daroy: That’s true, however the problem in ○ Figure 10 shows the 3x3 table of the 1-year the Philippines is collecting the data on the mortality status with the traditional risk factors established risk factors. Need to work with and the model with the traditional risk factors, different agencies to see if the data is CRP, and BNP available. ○ For the model with the established risk factors, ↪ Study used electronic medical records (i.e. only where participants were dead at 1 year (n = death certificates) of the patients for data. 122), 10 were at