Ilan S. Wittstein

The cardiovascular toll of stress

Psychological stress elicits measurable changes in sympathetic-parasympathetic balance and the tone of the hypothalamic-pituitary-adrenal axis, which might negatively affect the cardiovascular system both acutely-by precipitating myocardial infarction, left-ventricular dysfunction, or dysrhythmia; and chronically-by accelerating the atherosclerotic process. We provide an overview of the association between stress and cardiovascular morbidity, discuss the mechanisms for this association, and address possible therapeutic implications.

PDE5A Inhibitor Treatment of Persistent Pulmonary Hypertension After Mechanical Circulatory Support

Background—Pulmonary hypertension (PH) secondary to left heart failure portends a poor prognosis and is a relative contraindication to heart transplantation at many centers. We tested the hypothesis that when PH persists after adequate left ventricle unloading via recent left ventricular assist device (LVAD) therapy, phosphodiesterase type 5A inhibition would decrease PH in this population. Methods and Results—We performed an open-label clinical trial using control patients not receiving therapy. Between 1999 and 2007, 138 consecutive patients undergoing cardiac transplantation evaluation with advanced left ventricular dysfunction, an elevated pulmonary capillary wedge pressure, and PH (defined by a pulmonary vascular resistance (PVR) >3 Woods Units), were treated with LVAD therapy. Fifty-eight of these patients reduced their pulmonary capillary wedge pressure to a value <15 mm Hg (11.8±2.0 mm Hg from baseline 23.2±6.2 mm Hg) 1 to 2 weeks after LVAD implantation, but despite this improvement, the PVR of these patients was only minimally affected (5.65±3.00 to 5.39±1.78 Wood Units). Twenty-six consecutive patients from this group with persistently elevated PVR were started on oral phosphodiesterase type 5A inhibition with sildenafil and titrated to an average of dose of 51.9 mg by mouth 3 times per day. The average PVR in the sildenafil-treated group fell from 5.87±1.93 to 2.96±0.92 Wood Units (P<0.001) and the mean pulmonary artery pressure fell from 36.5±8.6 to 24.3±3.6 mm Hg (P<0.0001) and was significantly lower when compared with the 32 LVAD recipients not receiving sildenafil at weeks 12 to 15 after the initial post-LVAD hemodynamic measurements (13 to 17 weeks post-LVAD implantation). In addition, hemodynamic measurements of right ventricular function in sildenafil-treated patients was also improved compared with patients not receiving sildenafil. Conclusions—In patients with persistent PH after recent LVAD placement, phosphodiesterase type 5A inhibition in this open-label trial resulted in a significant decrease in PVR when compared with control patients.

Stress cardiomyopathy: a syndrome of catecholamine-mediated myocardial stunning?

During the past few years, a novel syndrome of heart failure and transient left ventricular systolic dysfunction precipitated by acute emotional or physical stress has been described. While patients with “stress cardiomyopathy” (SCM) typically present with signs and symptoms that resemble an acute coronary syndrome, it has become clear that this syndrome has unique clinical features that can readily be distinguished from acute infarction. In particular, in contrast to the irreversible myocardial injury seen with infarction, the myocardial dysfunction of SCM is completely reversible and occurs in the absence of plaque rupture and coronary thrombosis. There is increasing evidence that exaggerated sympathetic stimulation may play a pathogenic role in the development of SCM. Plasma catecholamine levels have been found to be markedly elevated in some patients with SCM, and the syndrome has been observed in other clinical states of catecholamine excess such as central neurologic injury and pheochromocytoma. Further, intravenous catecholamines can precipitate SCM in humans and can reproduce the syndrome in animal models. The precise mechanism in which excessive sympathetic stimulation may result in transient left ventricular dysfunction remains controversial. Abnormal myocardial blood flow due to sympathetically mediated microvascular dysfunction has been suggested and is supported by decreased coronary flow reserve during the acute phase of this syndrome. An alternative explanation is the direct effect of catecholamines on cardiac myocytes, possibly through cyclic AMP-mediated calcium overload. This manuscript will review the clinical and diagnostic features of SCM and will summarize the evidence supporting a sympathetically mediated pathogenesis. Clinical risk factors that appear to increase susceptibility to SCM, possibly by modulating myocyte and microvascular sensitivity to catecholamines, will also be highlighted.

Shared Genetic Predisposition in Peripartum and Dilated Cardiomyopathies

Background Peripartum cardiomyopathy shares some clinical features with idiopathic dilated cardiomyopathy, a disorder caused by mutations in more than 40 genes, including TTN, which encodes the sarcomere protein titin. Methods In 172 women with peripartum cardiomyopathy, we sequenced 43 genes with variants that have been associated with dilated cardiomyopathy. We compared the prevalence of different variant types (nonsense, frameshift, and splicing) in these women with the prevalence of such variants in persons with dilated cardiomyopathy and with population controls. Results We identified 26 distinct, rare truncating variants in eight genes among women with peripartum cardiomyopathy. The prevalence of truncating variants (26 in 172 [15%]) was significantly higher than that in a reference population of 60,706 persons (4.7%, P=1.3×10(-7)) but was similar to that in a cohort of patients with dilated cardiomyopathy (55 of 332 patients [17%], P=0.81). Two thirds of identified truncating variants were in TTN, as seen in 10% of the patients and in 1.4% of the reference population (P=2.7×10(-10)); almost all TTN variants were located in the titin A-band. Seven of the TTN truncating variants were previously reported in patients with idiopathic dilated cardiomyopathy. In a clinically well-characterized cohort of 83 women with peripartum cardiomyopathy, the presence of TTN truncating variants was significantly correlated with a lower ejection fraction at 1-year follow-up (P=0.005). Conclusions The distribution of truncating variants in a large series of women with peripartum cardiomyopathy was remarkably similar to that found in patients with idiopathic dilated cardiomyopathy. TTN truncating variants were the most prevalent genetic predisposition in each disorder.

The gene expression profile of patients with new-onset heart failure reveals important gender-specific differences

AIMS We sought to test the hypothesis that inherent biological factors contribute to gender differences in disease pathophysiology of new-onset heart failure (HF), which can be detected from the transcriptome of a single endomyocardial biopsy (EMB). METHODS AND RESULTS We analysed samples from male (n = 29) and female patients (n = 14) with idiopathic dilated cardiomyopathy (IDCM) and new-onset HF with U133 Plus 2.0 microarrays (Affymetrix) and significance analysis of microarrays (SAM). There were 35 overexpressed and 16 downregulated transcripts in men vs. women [q < 5%, fold change (FC) > 1.2]. In addition to overexpression of Y-chromosome-related transcripts (n = 18), such as USP9Y (FC > 13.1), DDX3Y (FC > 11.3), RPS4Y1 (FC > 9.9), and EIF1AY (FC > 11.8) in males, there was overexpression of CD24 (FC > 5.6) and KCNK1 (FC > 1.5). In females, XIST was highly overexpressed (FC > 28.9), together with X-linked zinc finger proteins (FC > 1.9) and autosomal genes GATAD1 (FC > 1.6), SLC2A12 (FC > 2.9), and PDE6B (FC > 1.5). Analysis of a public data set of end-stage IDCM (n = 15) resulted in approximately 85% overlap with our findings. CONCLUSION This is the first study that identified gender-specific transcriptomic differences in new-onset HF. Our findings may offer novel insights into fundamental biological differences in the pathophysiology of HF between sexes and provide a platform for personalized medicine.

Cardiac nitric oxide production due to angiotensin-converting enzyme inhibition decreases beta-adrenergic myocardial contractility in patients with dilated cardiomyopathy

OBJECTIVES This study tested the hypothesis that angiotensin-converting enzyme (ACE) inhibitors attenuate beta-adrenergic contractility in patients with idiopathic dilated cardiomyopathy (DCM) through nitric oxide (NO) myocardial signaling. BACKGROUND The ACE inhibitors increase bradykinin, an agonist of NO synthase (NOS). Nitric oxide inhibits beta-adrenergic myocardial contractility in patients with heart failure. METHODS The study patients were given the angiotensin-1 (AT-1) receptor antagonist losartan for one week. The hemodynamic responses to intravenous dobutamine were determined before and during intracoronary infusion of enalaprilat (0.2 mg/min) with and without the NOS inhibitor N(G)-monomethyl-L-arginine (L-NMMA, 5 mg/min). RESULTS In patients with DCM (n = 8), dobutamine increased the peak rate of rise of left ventricular pressure (+dP/dt) by 49 +/- 8% (p < 0.001) and ventricular elastance (Ecs) by 53 +/- 16% (p < 0.03). Co-infusion with enalaprilat decreased +dP/dt to 26 +/- 12% and Ecs to -2 +/- 17% above baseline (p < 0.05), and this anti-adrenergic effect was reversed by L-NMMA co-infusion (p < 0.05 vs. enalaprilat). In addition, intracoronary enalaprilat reduced left ventricular end-diastolic pressure (LVEDP), but not left ventricular end-diastolic volume, consistent with increased left ventricular distensibility. Infusion with L-NMMA before enalaprilat in patients with DCM (n = 5) prevented the reduction in +dP/dt, Ecs and LVEDP. In patients with normal left ventricular function (n = 5), enalaprilat did not inhibit contractility or reduce LVEDP during dobutamine infusion. CONCLUSIONS Enalaprilat attenuates beta-adrenergic contractility and enhances left ventricular distensibility in patients with DCM, but not in subjects with normal left ventricular function. This response is NO modulated and occurs in the presence of angiotensin receptor blockade. These findings may have important clinical and pharmacologic implications for the use of ACE inhibitors, AT-1 receptor antagonists and their combination in the treatment of heart failure.

Increased levels of uric acid predict haemodynamic compromise in patients with heart failure independently of B-type natriuretic peptide levels

Heart failure is a leading cause of mortality in the USA and Europe, and the ability to predict prognosis is essential for optimal allocation of treatments. Biomarkers offering prognostic information in patients with heart failure have recently entered practice. Although B-type natriuretic peptide (BNP) is an established biomarker,1 uric acid may also have prognostic value.2,3 Increases in BNP results primarily from increasing cardiac filling pressures, whereas increases in uric acid are associated with increased vascular tone4 and depressed myocardial contractility via increased xanthine oxidase activity.5 Thus, uric acid, like BNP, could be associated with haemodynamic compromise in heart failure. We tested the hypothesis that increased uric acid levels are associated with worsening haemodynamic compromise in patients with heart failure independent of BNP. Study patients were referred for right heart catheterisation between 1 January 2003 and 1 July 2004. Right atrial, pulmonary arterial and pulmonary capillary wedge (PCW) pressures were measured using a balloon-tipped, flow-directed catheter. Cardiac output was determined by thermodilution. Heart transplant recipients or patients currently receiving synthetic human BNP were excluded. Uric acid and N-terminal proBNP (NT-proBNP) levels were drawn during the right heart catheterisation. The study was approved by the Johns Hopkins Institutional Review Board. Patients were divided into groups on the basis of the median serum uric acid and NT-proBNP levels: low uric acid and low NT-proBNP (n = 27), high uric acid and low NT-proBNP (n = 24), low uric acid and high NT-proBNP (n = 22), and high uric acid and high NT-proBNP (n = 33). We compared haemodynamic parameters between groups using linear …

Transcriptomic Biomarkers for the Accurate Diagnosis of Myocarditis

Background— Lymphocytic myocarditis is a clinically important condition that is difficult to diagnose and distinguish. We hypothesized that the transcriptome obtained from an endomyocardial biopsy would yield clinically relevant and accurate molecular signatures. Methods and Results— Microarray analysis was performed on samples from patients with histologically proven lymphocytic myocarditis (n=16) and idiopathic dilated cardiomyopathy (n=32) to develop accurate diagnostic transcriptome-based biomarkers using multiple classification algorithms. We identified 9878 differentially expressed genes in lymphocytic myocarditis versus idiopathic dilated cardiomyopathy (fold change >1.2; false discovery rate <5%) from which a transcriptome-based biomarker containing 62 genes was identified that distinguished myocarditis with 100% sensitivity (95% confidence interval, 46 to 100) and 100% specificity (95% confidence interval, 66 to 100) and was generalizable to a broad range of secondary cardiomyopathies associated with inflammation (n=27), ischemic cardiomyopathy (n=8), and the normal heart (n=11). Multiple classification algorithms and quantitative real-time reverse-transcription polymerase chain reaction analysis further reduced this subset to a highly robust molecular signature of 13 genes, which still performed with 100% accuracy. Conclusions— Together, these findings demonstrate that transcriptomic biomarkers from a single endomyocardial biopsy can improve the clinical detection of patients with inflammatory diseases of the heart. This approach advances the clinical management and treatment of cardiac disorders with highly variable outcome.

Incidence and clinical characteristics of takotsubo cardiomyopathy post-aneurysmal subarachnoid hemorrhage

a Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States b Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA, United States c Division of Internal Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, GA, United States d Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA, United States e Department Neurology, Emory University School of Medicine, Atlanta, GA, United States

The Change in B-Type Natriuretic Peptide Levels Over Time Predicts Significant Rejection in Cardiac Transplant Recipients

BACKGROUND B-type natriuretic peptide (BNP) correlates with cardiac filling pressures and outcomes in patients with heart failure. In heart transplant recipients, we hypothesize that a within-individual change in BNP over time would be more helpful than absolute BNP in detecting International Society of Heart and Lung Transplantation (ISHLT) grade 2R or greater rejection. METHODS N-terminal pro-BNP (NT-proBNP) levels were measured in 146 consecutive transplant recipients undergoing routine endomyocardial biopsies. In the cross-sectional analysis, multiple observations per individual were accounted for using generalized estimation equations. RESULTS A cross-sectional analysis demonstrated a weak association between NT-proBNP levels and rejection, with an odds ratio (OR) of 1.01 for every 100-pg/mL increase in NT-proBNP (p = 0.02). However, with a doubling of an individuals NT-proBNP level, the OR for significant rejection was 2.9 (95% confidence interval [CI] 1.2-7.0), the OR with a 5-fold increase was 9.1 (95% CI, 2.7-31.5), and the OR with a 10-fold increase was 27.7 (95% CI, 5.9-129). A 10-fold increase in NT-proBNP offered a negative predictive value of 95% for the diagnosis of rejection. The relationship between within-individual increases in NT-proBNP and rejection persisted after adjusting for a fall in ejection fraction and a rise pulmonary capillary wedge pressure, and was a stronger predictor than changes in these parameters. CONCLUSIONS There is a strong, graded relationship between the within-individual increase in NT-proBNP and the odds of significant rejection independent of hemodynamic parameters. These results suggest that the change in NT-proBNP rather than absolute BNP levels may offer a non-invasive approach to detect rejection.