Parul U. Gandhi

Incident Type 2 Myocardial Infarction in a Cohort of Patients Undergoing Coronary or Peripheral Arterial Angiography

Background: Despite growing recognition of type 2 myocardial infarction (T2MI; related to supply/demand mismatch), little is known about its risk factors or its association with outcome. Methods: A single-center cohort of patients undergoing coronary or peripheral angiography with or without intervention was prospectively enrolled and followed for incident type 1 and T2MI, and major adverse cardiovascular events (MACE, a composite of all-cause death, nonfatal myocardial infarction [MI], heart failure, stroke, transient ischemic attack, peripheral arterial complication, and cardiac arrhythmia), as well. T2MI was adjudicated using criteria from the Third Universal Definition of MI. Baseline characteristics, blood samples, and angiography information were obtained. Major end points subsequent to first MI were assessed using landmark analyses to compare the rates of first events only where everyone with a prior history of any MACE before MI were censored and adjusted for follow-up times. Cox proportional hazard models were used for time-to-event analyses with age and sex forced into all models and additional covariates evaluated by using the stepwise option for the selection. Results: One thousand two hundred fifty-one patients were enrolled and followed for a median of 3.4 years. Of these patients, 152 (12.2%) had T2MI during follow-up; T2MI was frequently recurrent. Multivariable predictors of T2MI were older age, lower systolic blood pressure, history of coronary artery disease, heart failure, chronic obstructive pulmonary disease, diabetes mellitus, nitrate use, and elevated concentrations of glucose, N-terminal pro-B type natriuretic peptide, and cystatin C. Patients with T2MI had higher rates of subsequent adverse events than those without T2MI (per 100 person-years: MACE, 53.7 versus 21.1, P<0.001; all-cause death, 23.3 versus 3.3, P<0.001; cardiovascular death, 17.5 versus 2.6, P<0.001; heart failure events, 22.4 versus 7.4, P<0.001); these rates are similar to those seen in patients with type 1 MI. Incident diagnosis of T2MI strongly predicted risk for subsequent MACE (adjusted hazard ratio, 1.90; 95% confidence interval, 1.46–2.48; P<0.001), all-cause death (adjusted hazard ratio, 2.96; 95% confidence interval, 2.01–4.36; P<0.001), and cardiovascular death (adjusted hazard ratio, 2.16; 95% confidence interval, 1.36–3.43; P=0.001). Conclusions: T2MI is common and associated with poor prognosis. Studies evaluating treatment strategies for management of T2MI are needed. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00842868.

Effects of Optimism and Gratitude on Physical Activity, Biomarkers, and Readmissions After an Acute Coronary Syndrome The Gratitude Research in Acute Coronary Events Study

Background—Positive psychological constructs, such as optimism, are associated with beneficial health outcomes. However, no study has separately examined the effects of multiple positive psychological constructs on behavioral, biological, and clinical outcomes after an acute coronary syndrome (ACS). Accordingly, we aimed to investigate associations of baseline optimism and gratitude with subsequent physical activity, prognostic biomarkers, and cardiac rehospitalizations in post-ACS patients. Methods and Results—Participants were enrolled during admission for ACS and underwent assessments at baseline (2 weeks post-ACS) and follow-up (6 months later). Associations between baseline positive psychological constructs and subsequent physical activity/biomarkers were analyzed using multivariable linear regression. Associations between baseline positive constructs and 6-month rehospitalizations were assessed via multivariable Cox regression. Overall, 164 participants enrolled and completed the baseline 2-week assessments. Baseline optimism was significantly associated with greater physical activity at 6 months (n=153; &bgr;=102.5; 95% confidence interval, 13.6–191.5; P=0.024), controlling for baseline activity and sociodemographic, medical, and negative psychological covariates. Baseline optimism was also associated with lower rates of cardiac readmissions at 6 months (n=164), controlling for age, sex, and medical comorbidity (hazard ratio, 0.92; 95% confidence interval, [0.86–0.98]; P=0.006). There were no significant relationships between optimism and biomarkers. Gratitude was minimally associated with post-ACS outcomes. Conclusions—Post-ACS optimism, but not gratitude, was prospectively and independently associated with superior physical activity and fewer cardiac readmissions. Whether interventions that target optimism can successfully increase optimism or improve cardiovascular outcomes in post-ACS patients is not yet known, but can be tested in future studies. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01709669.

Galectin-3 and mineralocorticoid receptor antagonist use in patients with chronic heart failure due to left ventricular systolic dysfunction

BACKGROUND Galectin-3 is a prognostic heart failure biomarker associated with aldosterone-induced myocardial fibrosis; mineralocorticoid receptor antagonists (MRAs) may reduce such fibrosis. We sought to examine outcomes of patients with heart failure with reduced ejection fraction (HFrEF) as a function of galectin-3 and MRA therapy. METHODS A total of 151 patients with chronic HFrEF were categorized by baseline galectin-3 and subsequent MRA therapy trends with regard to cardiovascular (CV) events, left ventricular remodeling, safety, and quality of life, over a mean of 10 months. RESULTS Although galectin-3 >20 ng/mL was associated with doubling in adjusted risk for CV events, regardless of MRA treatment, there was no difference in CV event rates with regard to MRA use patterns, independent of galectin-3 concentrations. Specifically, in patients with elevated galectin-3 treated with intensified MRA therapy, a significant difference was not detected in CV event rates (P = .79) or the cumulative number of such events (P = .76). Adjusted analysis revealed no difference in time to first CV event if MRA was added/intensified in those with elevated galectin-3 (hazard ratio 0.99, 95% CI 0.97-1.02, P = .74); similarly, cumulative MRA dose was not a specific predictor of benefit. In those with elevated galectin-3, MRA therapy did not affect left ventricular remodeling indices or quality of life at follow-up; these patients had the highest rates of treatment-related adverse events with intensified MRA use. Regardless of MRA use, elevated galectin-3 was associated with more significant renal dysfunction. CONCLUSIONS Among patients with chronic HFrEF and elevated galectin-3 concentrations, we found no specific benefit from addition or intensification of MRA therapy.

Analysis of BAG3 plasma concentrations in patients with acutely decompensated heart failure.

BACKGROUND BCL-2-associated athanogene 3 (BAG3) is a protein implicated in the cardiomyocyte stress response and genesis of cardiomyopathy. Extracellular BAG3 is measurable in patients with heart failure (HF), but the relationship of BAG3 with HF prognosis is unclear. METHODS BAG3 plasma concentrations were measured in 39 acutely decompensated HF patients; the primary endpoint was death at 1 year. Baseline characteristics were compared by vital status and median BAG3 concentration. Correlation of BAG3 with left ventricular ejection fraction (LVEF) and other biomarkers was performed. Prognostic value was assessed using Cox proportional hazards regression and Kaplan-Meier analysis. RESULTS At baseline, median BAG3 was significantly higher in decedents (N=11) than survivors (N=28; 1489 ng/mL versus 50 ng/mL; P=0.04); decedents also had worse renal function and higher median natriuretic peptide (NP) and sST2. BAG3 was not significantly correlated with NPs, mid-regional pro-adrenomedullin, sST2, or eGFR, however. Mortality was increased in patients with supra-median BAG3 (>336 ng/mL; 42.1% versus 15.0%, P=0.06). In age and LVEF-adjusted Cox proportional hazards, BAG3 remained a significant mortality predictor (HR=3.20; 95% CI=1.34-7.65; P=0.02); those with supra-median BAG3 had significantly shorter time-to-death (P=0.04). CONCLUSION The stress response protein BAG3 is measurable in patients with ADHF and may be prognostic for death.

Characterization and Prediction of Adverse Events From Intensive Chronic Heart Failure Management and Effect on Quality of Life: Results From the Pro-B-Type Natriuretic Peptide Outpatient-Tailored Chronic Heart Failure Therapy (PROTECT) Study

BACKGROUND Serious adverse events (SAEs) from heart failure (HF) therapy are frequent; however, techniques to identify at-risk patients are inadequate. Furthermore, the relationship between SAEs, quality of life (QOL), and cardiac structure are unknown. METHODS AND RESULTS 151 symptomatic patients with systolic HF were followed for a mean of 10 months. In this post hoc analysis, treatment-related SAEs included acute renal failure, dizziness, hypo/hyperkalemia, hypotension, and syncope. At 1 year, 21 treatment-related SAEs occurred. No difference in SAEs existed between the N-terminal pro-B-type natriuretic peptide (NT-proBNP)-guided arm and the standard of care arm (P = .20). At baseline, patients who suffered SAEs were less likely to be receiving beta-blockers (85.7% vs 97.7%; P = .009) and had worse functional class and lower chloride levels. Patients who experienced SAEs had less improvement in their Minnesota Living With Heart Failure Questionnaire scores and had a trend toward reduced echocardiographic reverse remodeling over the follow-up period. Univariable and multivariable analyses were conducted to develop a risk score for SAE prediction; patients in the highest risk quartile had the shortest time to first cardiovascular event (P = 0.01). CONCLUSIONS NT-proBNP-guided HF care is safe. Experiencing treatment-related SAEs is associated with worse QOL and potentially reduced reverse remodeling. A risk score to prospectively predict SAEs in aggressive HF management was developed.

Management of chronic heart failure: biomarkers, monitors, and disease management programs.

BACKGROUND The management of patients with heart failure has been evolving given the complex nature of the disease and the increasing number of patients. FINDINGS Biomarkers, and in particular the natriuretic peptides, have been studied to assist with diagnosis, chronic management, and prognosis in patients with heart failure. Several new biomarkers are emerging and may be used individually or in combination with the natriuretic peptides. The use of cardiac monitoring devices and disease management programs is being established to assist in the care of patients with chronic heart failure. Interventions using phone calls, telemedicine devices, intracardiac pressure monitors, and implantable cardioverter defibrillators have been investigated. CONCLUSIONS The combination of biomarkers, monitoring devices, and disease management programs shows promise for improving care in this challenging patient population.

The Current and Potential Clinical Relevance of Heart Failure Biomarkers

Heart failure is a growing epidemic, and our understanding of the intricacies of its pathophysiology continues to evolve. Over the last decade, biomarkers of heart failure have been extensively investigated, particularly for diagnosis and risk stratification. While the natriuretic peptides remain the gold standard heart failure biomarker, they are plagued by their non-specific nature; furthermore, the strategy of natriuretic peptide-guided care remains elusive. Multiple candidate markers indicative of other physiologic aspects of heart failure have been identified and studied, including soluble ST2, galectin-3, and high-sensitivity cardiac troponins. Each of these biomarkers has the potential to provide unique therapeutically relevant information. Ultimately, a multi-marker approach may be applied to improve care of patients with heart failure. Definitive clinical trials and the use of advanced statistical analytic techniques are needed to truly determine the optimal strategy of biomarker-assisted diagnosis, prognostication, and management of patients who suffer from this devastating condition.

Design and baseline data from the Gratitude Research in Acute Coronary Events (GRACE) study

BACKGROUND Positive psychological constructs, especially optimism, have been linked with superior cardiovascular health. However, there has been minimal study of positive constructs in patients with acute coronary syndrome (ACS), despite the prevalence and importance of this condition. Furthermore, few studies have examined multiple positive psychological constructs and multiple cardiac-related outcomes within the same cohort to determine specifically which positive construct may affect a particular cardiac outcome. MATERIALS AND METHODS The Gratitude Research in Acute Coronary Events (GRACE) study examines the association between optimism/gratitude 2weeks post-ACS and subsequent clinical outcomes. The primary outcome measure is physical activity at 6months, measured via accelerometer, and key secondary outcome measures include levels of prognostic biomarkers and rates of nonelective cardiac rehospitalization at 6months. These relationships will be analyzed using multivariable linear regression, controlling for sociodemographic, medical, and negative psychological factors; associations between baseline positive constructs and subsequent rehospitalizations will be assessed via Cox regression. RESULTS Overall, 164 participants enrolled and completed the baseline 2-week assessment; the cohort had a mean age of 61.5+/?10.5years and was 84% men; this was the first ACS for 58% of participants. CONCLUSION The GRACE study will determine whether optimism and gratitude are prospectively and independently associated with physical activity and other critical outcomes in the 6months following an ACS. If these constructs are associated with superior outcomes, this may highlight the importance of these constructs as independent prognostic factors post-ACS.

Prognostic Value of Insulin-Like Growth Factor-Binding Protein 7 in Patients with Heart Failure and Preserved Ejection Fraction

BACKGROUND The prognostic merit of insulin-like growth factor-binding protein 7 (IGFBP7) is unknown in heart failure and preserved ejection fraction (HFpEF). METHODS AND RESULTS Baseline IGFBP7 (BL-IGFBP7; n = 302) and 6-month change (Δ; n = 293) were evaluated in the Irbesartan in Heart Failure and Preserved Ejection Fraction (I-PRESERVE) trial. Primary outcome was all-cause mortality or cardiovascular hospitalization with median follow-up of 3.6 years; secondary outcomes included HF events. Median BL-IGFBP7 concentration was 218 ng/mL. BL-IGFBP7 was significantly correlated with age (R2 = 0.13; P < .0001), amino-terminal pro-B-type NP (R2 = 0.22; P < .0001), and estimated glomerular filtration rate (eGFR; R2 = 0.14; P < .0001), but not with signs/symptoms of HFpEF. BL-IGFBP7 was significantly associated with the primary outcome (hazard ratio [HR] = 1.007 per ng/mL; P < .001), all-cause mortality (HR = 1.008 per ng/mL; P < .001), and HF events (HR = 1.007 per ng/mL; P < .001). IGFBP7 remained significant for each outcome after adjustment for ln amino-terminal pro-B-type NP and eGFR but not all variables in the I-PRESERVE prediction model. After 6 months, IGFBP7 did not change significantly in either treatment group. ΔIGFBP7 was significantly associated with decrease in eGFR in patients randomized to irbesartan (R2 = 0.09; P = .002). ΔIGFBP7 was not independently associated with outcome. CONCLUSIONS Higher concentrations of IGFBP7 were associated with increased risk of cardiovascular events, but after multivariable adjustment this association was no longer present. Further studies of IGFBP7 are needed to elucidate its mechanism. CLINICAL TRIAL REGISTRATION www.clinicaltrials.gov, NCT00095238.

Can copeptin emerge from the growing shadow of the troponins

This editorial refers to ‘Early discharge using single cardiac troponin and copeptin testing in patients with suspected acute coronary syndrome (ACS): a randomized, controlled clinical process study.’, by M. Mockel et al. on page doi:10.1093/eurheartj/ehu178 The brightest flame casts the darkest shadow.George R.R. Martin1 Evaluation of suspected acute coronary syndrome (ACS) accounts for a staggering 10 million emergency department visits per year in Europe2 and >8 million in the USA.3 Many patients that undergo evaluation for suspected ACS unfortunately spend countless hours waiting for the results of diagnostic evaluation to determine their fate: discharge, continued observation, or admission, with the possibility of supplementary testing to explore their presentation further. While patients anxiously and eagerly await their results, the harried emergency department physician continues to triage more patients with similar complaints and various acuities; in this context, both patients and physicians alike watch the emergency department fill and often overflow. Clearly, how suspected ACS is evaluated needs serious reconsideration. Historically, the means by which physicians have evaluated patients with suspected acute myocardial infarction (MI) or unstable angina pectoris (UAP) evolved rapidly over the later decades of the last century, particularly with the development of adjunctive diagnostic biomarker testing to augment clinical evaluation. In particular, with the emergence of cardiac troponin (Tn) testing in the 1990s, clinicians had more accurate tools to identify and exclude acute MI. However, until recently, methods for Tn measurement remained reasonably insensitive and were only diagnostic after a period of time had passed since onset of cardiac injury (the ‘troponin blind’ interval); furthermore, by definition, UAP is associated with a Tn in the normal range, leaving this diagnosis to be based on clinical judgement and electrocardiography (ECG). These issues often rendered physicians unable to make rapid decisions about triaging patients with chest pain …