The paradox of hypothyroidism: elevated cardiac biomarkers without coronary artery disease

Coronavirus disease 2019 is delaying the diagnosis and management of chest pain, acute coronary syndromes, myocarditis and heart failure.

Cardiac biomarkers of necrosis provide clinicians with important “messages” from the heart. They are released into the interstitium of the myocardium after loss of the integrity of cardiac myocyte membranes. The pattern of the rise and fall of an individual biomarker (ie, its release kinetics) depends on its intracellular location in the myocyte, molecular weight, and clearance from the interstitium of the myocardium and ultimately the circulation.1 Cardiac biomarkers play an integral role in the clinical diagnosis of myocardial infarction (MI). Referring to the spontaneous occurrence of MI in patients, the World Health Organization required that at least 2 of the following be present to fulfill the criteria for MI: a history of ischemia-type chest discomfort, evolutionary changes on serially obtained ECG tracings, and a rise and fall in serum cardiac markers.2 Article see p 10 See Editorial Circulation . 2008;118:609–611 See Article Circulation . 2008;118:632–638 Several dramatic advances have occurred in the biomarker component of the diagnosis of MI. Analytes with greater specificity for the myocardium were introduced into clinical medicine, with creatine kinase-MB replacing total creatine kinase and subsequently cardiac-specific troponins replacing creatine kinase-MB as the biomarker of choice for diagnosing MI.3 Assay technology improved as clinical chemists moved from enzymatic activity assays for CK to highly specific immunoassays that can detect progressively smaller concentrations of cardiac troponins in the peripheral circulation.4 Although ST-elevation MI (STEMI) is easily identified on the 12-lead ECG, we now recognize that many patients previously diagnosed with unstable angina are more properly diagnosed as having non–ST-elevation MI (NSTEMI) on the basis of the detection of elevated levels of cardiac troponins in their blood.5 Cardiac biomarkers are used as a rough guide to the extent of myocardial necrosis. The higher the peak biomarker level after STEMI, the larger the …

The long-term cardiovascular outcomes of a population-based cohort presenting to the emergency department (ED) with chest pain and classified with a clinical risk stratification algorithm are not well documented. The Olmsted County Chest Pain Study is a community-based study that included all consecutive patients presenting with chest pain consistent with unstable angina presenting to all EDs in Olmsted County, Minnesota. Patients were classified according to the Agency for Health Care Policy and Research (AHCPR) criteria. Patients with ST elevation myocardial infarction and chest pain of noncardiac origin were excluded. Main outcome measures were major adverse cardiovascular and cerebrovascular events (MACCE) at 30 days and at a median follow-up of 7.3 years, and mortality through a median of 16.6 years.The 2271 patients were classified as follows: 436 (19.2%) as high risk, 1557 (68.6%) as intermediate risk, and 278 (12.2%) as low risk. Thirty-day MACCE occurred in 11.5% in the high-risk group, 6.2% in the intermediate-risk group, and 2.5% in the low-risk group (p < 0.001). At 7.3 years, significantly more MACCE were recorded in the intermediate-risk (hazard ratio [HR], 1.91; 95% confidence intervals [CI], 1.33-2.75) and high-risk groups (HR, 2.45; 95% CI, 1.67-3.58). Intermediate- and high-risk patients demonstrated a 1.38-fold (95% CI, 0.95-2.01; p = 0.09) and a 1.68-fold (95% CI, 1.13-2.50; p = 0.011) higher mortality, respectively, compared to low-risk patients at 16.6 years. At 7.3 and at 16.6 years of follow-up, biomarkers were not incrementally predictive of cardiovascular risk.In conclusion, a widely applicable rapid clinical algorithm using AHCPR criteria can reliably predict long-term mortality and cardiovascular outcomes. This algorithm, when applied in the ED, affords an excellent opportunity to identify patients who might benefit from a more aggressive cardiovascular risk factor management strategy.

Usefulness of Mean Platelet Volume as a Biomarker for Long-Term Outcomes After Percutaneous Coronary Intervention

75-Year-Old Woman With Chest Pain and Shortness of Breath

The development of rapid, automated, and accurate laboratory testing for creatine kinase MB (CK-MB) revolutionized the treatment of patients with acute cardiac events in the 1970s and 1980s.1 To clinicians, CK-MB values augmented a thorough history, physical, and ECG findings, and elevations rapidly became the gold standard for identifying cardiac injury.1 CK-MB allowed earlier diagnosis of acute myocardial infarction (AMI), and detection of reinfarction, and measurements could be used to provide a facile clinical estimate of infarct size. Elevations of CK-MB were never intended to be synonymous with myocardial infarction, only indicative of cardiac injury.1 However, because of the relative insensitivity of measurements, increased concentrations occurred predominantly with larger insults such those associated with acute ischemic heart disease. For that reason, AMI was rarely diagnosed, assuming appropriate timing of the samples, in the absence of a CK-MB elevation.2,3 CK-MB assays initially relied on the measurement of enzyme activity, but over time, improved accuracy and ease of use were established by the use of mass assays. Mass assays allowed earlier detection of abnormal values and improved both clinical sensitivity and specificity. However, mass assays unmasked an increased frequency of CK-MB elevations due primarily to skeletal muscle injury because of their increased sensitivity.4–6 Clinical use of the percent relative index was then initiated. This approach improved the specificity of elevations for cardiac muscle injury but was insensitive when concurrent cardiac injury and skeletal muscle injury were present because elevations from skeletal muscle often are of a large magnitude.7–10 A large number of analytical confounds such as macrokinases and interfering substances also were substantial problems with these assays.10,11 Attempts to standardize assays12 have been partially successful, but differences still exist between manufacturers and even between the same testing antibodies used on different analytical platforms (ie, …

Acute regional myocarditis with normal ventricular wall motion diagnosed by two-dimensional speckle tracking imaging

Ischemic heart disease includes a wide spectrum of conditions, ranging from silent ischemia and exertion-induced angina, through unstable angina, to acute MI. Unstable angina occupies the center of this spectrum, causing disability and risk greater than that of chronic stable angina but less than that of acute MI1 (Fig 1⇓). Although non–Q-wave MI for many years was considered prognostically similar to unstable angina, recent longitudinal studies indicate that it is similar to Q-wave infarction2 3 (Fig 2⇓). Figure 1. Cumulative 6-month mortality from ischemic heart disease. Diagnosis on admission to hospital (n=21 761; 1985 to 1992). From Duke Cardiovascular Database. Reproduced with permission from Reference 1. Figure 2. Top, Cumulative 1-year combined death or MI among patients with Q-wave and non–Q-wave MI treated with fibrinolysis. Reproduced with permission from Reference 2. Bottom, Risk of subsequent cardiac events in stable convalescing patients after first non–Q-wave and Q-wave MI. Reproduced with permission from Reference 3. The concept of unstable angina has emerged from observations of frequent symptoms preceding acute MI, followed by prospective documentation that unstable symptoms frequently culminated in acute MI. The syndrome was rapidly accepted as a well-defined clinical entity as specific clinical manifestations, pathophysiological mechanisms, laboratory findings, and treatment became better characterized. Unstable angina is currently one of the leading causes of hospital admission for CAD, and non–Q-wave MI accounts for >30% of admissions for acute MI.1 4 Yet, the diagnosis of unstable angina remains clinical, based on symptom recognition. The physician caring for patients with unstable angina is in a privileged position of recognizing rapidly evolving CAD and being able to intervene to prevent irreversible left ventricular damage and progression of CAD. Unstable angina is classically described as a heterogeneous disease, referring to a wide spectrum of clinical manifestations from stable angina to MI, of disease …

78-Year-Old Woman With Intermittent Chest Pain and Palpitations

Brain (B-type) natriuretic peptide (BNP) is a 32 amino acid peptide that is synthesized and released predominantly from ventricular myocardium in response to myocyte stretch. Like atrial natriuretic peptide (ANP), BNP seems to have almost exclusively beneficial physiological properties, including balanced vasodilation, natriuresis, and inhibition of both the sympathetic nervous system and the renin-angiotensin-aldosterone axis. Attempts to exploit these properties for therapeutic benefit has led to the development of recombinant human BNP (nesiritide) for the acute treatment of decompensated heart failure, and also of novel compounds that inhibit neutral endopeptidase, an enzyme that is partially responsible for BNP degradation. See p 2913 In patients with heart failure, the cardiac neurohormonal system is activated, and circulating plasma levels of ANP, BNP, and the N-terminal fragments of their prohormones (N-proANP and N-proBNP) are elevated. Compared with ANP and N-proANP, BNP and N-proBNP undergo a greater proportional rise in disease states (ie, higher “signal-to-noise” ratio), and thus have emerged as the preferred biomarkers for clinical development. With commercially available assays now available, measurement of BNP or N-proBNP can be integrated readily into the care of patients with suspected heart failure. Although data are limited, BNP and N-proBNP seem to provide qualitatively similar information, and for purposes of this editorial, will be referred to interchangeably. Incorporation of BNP measurement into the clinical evaluation facilitates the diagnosis of heart failure due to either left ventricular (LV) systolic or diastolic dysfunction; a normal BNP level virtually rules out the diagnosis of decompensated heart failure, whereas a markedly elevated BNP has a high positive predictive value for heart failure.1 Although BNP levels are correlated with age, sex, intracardiac filling pressures, LV mass and ejection fraction (LVEF), renal function, and symptoms, BNP provides prognostic information in patients with heart failure that is independent of these variables.2 …

Poststroke cognitive impairment is a severe and common clinical complication that constitutes a substantial global health burden. We aimed to evaluate the association of 3 cardiac biomarkers in combination with poststroke cognitive impairment and their prognostic significance. This prospective study included 566 patients with ischemic stroke. Cardiac biomarkers, including sST2 (soluble suppression of tumorigenicity-2 receptor), GDF-15 (growth differentiation factor-15), and NT-proBNP (N-terminal pro-B-type natriuretic peptide), were measured. Cognitive impairment was defined as a Mini-Mental State Examination score of <27 or a Montreal Cognitive Assessment score of <25 at 3 months after ischemic stroke. Odds of cognitive impairment 3 months after ischemic stroke increased with the number of elevated cardiac biomarkers (sST2, GDF-15, and NT-proBNP; Ptrend<0.001). The multivariable adjusted odds ratios (95% CIs) of cognitive impairment defined by the Mini-Mental State Examination and Montreal Cognitive Assessment were 2.45 (1.48-4.07) and 1.86 (1.10-3.14) for the participants with ≥2 elevated cardiac biomarkers, respectively, compared with those without any elevated cardiac biomarker. Additionally, higher cardiac biomarker scores were associated with an increased risk of cognitive impairment (Ptrend<0.05). Simultaneously adding all 3 cardiac biomarkers to the basic model with traditional risk factors significantly improved the risk prediction of Mini-Mental State Examination-defined cognitive impairment (net reclassification improvement=34.99%, P<0.001; integrated discrimination index=2.67%, P<0.001). Similar findings were observed using the Montreal Cognitive Assessment scores. An increased number of elevated novel cardiac biomarkers were associated with an increased odds of poststroke cognitive impairment, suggesting that a combination of these cardiac biomarkers may improve the risk prediction of cognitive impairment. URL: https://www.clinicaltrials.gov; Unique identifier: NCT01840072.

COVID-19-Associated Stress (Takotsubo) Cardiomyopathy.

NT-proBNP (N-terminal pro-B-type natriuretic peptide), high-sensitivity cardiac troponin T (hs-troponin T), and high-sensitivity cardiac troponin I (hs-troponin I) have been widely recognized as significant cardiac biomarkers, and are increasingly being recommended for early risk identification in cardiovascular high-risk populations. The aim of our study was to evaluate the prevalence of elevated cardiac biomarkers (NT-proBNP, hs-troponin T, hs-troponin I) and their association with the risk of hyperuricemia in the general US adults without known cardiovascular disease. We further studied whether elevated cardiac biomarkers are associated with an increased risk of all-cause and cardiovascular mortality in individuals with or without hyperuricemia. The study population came from the adults (age ≥20y) without prevalent cardiovascular disease in NHANES (National Health and Nutrition Examination Survey) 1999 to 2004. We evaluated the prevalence of elevated cardiac biomarkers among adults with or without hyperuricemia, and conducted a comprehensive multivariate logistic regression analysis to ascertain the association between elevated cardiac biomarkers and hyperuricemia risk. Multivariate Cox regression model and Kaplan-Meier curve, risk competition model and Cumulative Incidence Function(CIF) were used respectively to examine the associations between elevated cardiac biomarkers with all-cause and cardiovascular mortality. In general US adults without known cardiovascular disease, the prevalence of hyperuricemia was 16.35%. The age-adjustd prevalence of elevated NT-proBNP (≥125 pg/mL), hs-troponin T (≥6 ng/L), and hs-troponin I (male ≥6, female ≥4 ng/L) was 16.70%, 49.80%, and 11.91%, respectively, among adults with hyperuricemia. Adjusted multivariable logistic regression analysis revealed a statistically significant association between elevated levels of NT-proBNP, hs-troponin T, and hs-troponin I and hyperuricemia, and different clinical categories observed grade differences on the same cardiac biomarker. Elevated NT-proBNP, hs-troponinT and hs-troponinI were each significantly positively associated with the cumulative incidence of all-cause and cardiovascular mortality in adults with or without hyperuricemia. Compared to those with elevated cardiac biomarkers only, adults with hyperuricemia and elevated cardiac biomarkers faced the highest risk of all-cause and cardiovascular mortality. Our study identified that elevated cardiac biomarkers pose a high burden on hyperuricemia risk in the general population without known cardiovascular disease, and further provides important information on long-term mortality risk in these populations. Routine testing of cardiac biomarkers may be useful for early risk identification and prognostic assessment in adults with hyperuricemia.

Objectives: This study aimed to assess the frequency of hypomagnesemia among patients presenting with acute coronary syndrome (ACS) and to evaluate its correlation with biochemical markers of cardiac injury—specifically Troponin-I (Trop-I), Creatine Kinase-MB (CK-MB), and Brain Natriuretic Peptide (BNP)—as well as associated clinical outcomes. Methodology: A total of 185 patients diagnosed with ACS were enrolled. Serum magnesium levels were measured within 24 hours of hospital admission. Hypomagnesemia was defined as serum magnesium &lt;1.7 mg/dL. Cardiac biomarkers (Trop-I, CK-MB, BNP) were assessed on admission and monitored during hospitalization. Clinical outcomes including in-hospital mortality, arrhythmias, heart failure, recurrent ischemia, and other complications were recorded and analyzed. Results: Hypomagnesemia was detected in 60 of the 185 patients (32.4%). Patients with hypomagnesemia exhibited significantly higher levels of Trop-I, CK-MB, and BNP compared to those with normal magnesium levels (p &lt; 0.05). Hypomagnesemia was also associated with significantly higher rates of mortality (20% vs. 6.4%, p = 0.05), heart failure (41.7% vs. 28%, p = 0.04), recurrent ischemia (16.7% vs. 4%, p = 0.03), and other complications (25% vs. 8%, p = 0.04). No significant difference was observed in the incidence of arrhythmias between the two groups (p = 0.32). Conclusion: Hypomagnesemia is commonly observed in ACS patients and is significantly associated with elevated cardiac biomarkers and worse clinical outcomes, including increased mortality and complications. These findings suggest that magnesium deficiency may exacerbate myocardial injury and negatively impact prognosis in ACS. Magnesium supplementation presents a potential therapeutic intervention and warrants further investigation in larger, controlled studies.

52-Year-Old Woman With Fever, Diaphoresis, and Abdominal Pain