Mitchell S. Finkel

Platelet/Endothelial Biomarkers in Depressed Patients Treated With the Selective Serotonin Reuptake Inhibitor Sertraline After Acute Coronary Events. The Sertraline AntiDepressant Heart Attack Randomized Trial (SADHART) Platelet Substudy

Background—Depression after acute coronary syndromes (ACSs) has been identified as an independent risk factor for subsequent cardiac death. Enhanced platelet activation has been hypothesized to represent 1 of the mechanisms underlying this association. Selective serotonin reuptake inhibitors (SSRIs) are known to inhibit platelet activity. Whether treatment of depressed post-ACS patients with SSRIs alters platelet function was not known. Accordingly, we serially assessed the release of established platelet/endothelial biomarkers in patients treated with sertraline vs placebo in the Sertraline AntiDepressant Heart Attack Randomized Trial (SADHART). Methods and Results—Plasma samples (baseline, week 6, and week 16) were collected from patients randomized to sertraline (n=28) or placebo (n=36). Anticoagulants, aspirin, and ADP-receptor inhibitors were permitted in this study. Platelet factor 4, &bgr;-thromboglobulin (&bgr;TG), platelet/endothelial cell adhesion molecule-1, P-selectin, thromboxane B2, 6-ketoprostaglandin F1a, vascular cell adhesion molecule-1, and E-selectin were measured by ELISA. Treatment with sertraline was associated with substantially less release of platelet/endothelial biomarkers than was treatment with placebo. These differences attained statistical significance for &bgr;TG (P =0.03) at weeks 6 and 16 and for P-selectin (P =0.04) at week 16. Repeated-measures ANOVA revealed a significant advantage for sertraline vs placebo for diminishing E-selectin and &bgr;TG concentrations across the entire treatment period. Conclusions—Treatment with sertraline in depressed post-ACS patients is associated with reductions in platelet/endothelial activation despite coadministration of widespread antiplatelet regimens including aspirin and clopidogrel. The antiplatelet and endothelium-protective properties of SSRIs might represent an attractive additional advantage in patients with depression and comorbid coronary artery and/or cerebrovascular disease.

Cytokines and nitric oxide synthase inhibitor as mediators of adrenergic refractoriness in cardiac myocytes

We have previously proposed that pro-inflammatory cytokines and nitric oxide (NO) contributed to reversible myocardial depression in patients with sepsis and congestive heart failure. Sepsis and heart failure are also associated with refractoriness to beta-adrenoceptor agonists. Therefore, the chronotropic effects of cytokines and the NO synthase inhibitor, NG-methyl-L-arginine (NMA), on beta-adrenoceptor stimulation of neonatal cardiac myocytes were studied. Tumor necrosis factor alpha, interleukin-1 beta and interleukin-6 but not interleukin-4 or interleukin-5 significantly enhanced spontaneous beating rates compared to untreated myocytes in serum-free media for 48 h (P < 0.01; n = 12 for each). NMA also significantly enhanced spontaneous beating rates (P < 0.01; n = 12 for each). Only interleukin-1 beta treatment resulted in significant nitrite production, immunohistochemical staining for inducible nitric oxide synthase and detection of inducible NO synthase messenger RNA by reverse transcriptase-polymerase chain reaction (RT-PCR). However, tumor necrosis factor alpha, interleukin-1 beta, interleukin-6, and NMA each completely blocked the positive chronotropic effects of the beta-adrenoceptor agonist, isoproterenol (P < 0.01; n = 12 for each). These findings are most consistent with an inducible NO synthase-independent effect of cytokines and NMA on the chronotropic responses of neonatal cardiac myocytes to beta-adrenoceptor stimulation. This effect of cytokines and NMA on adrenergic signaling may involve a myocardial constitutive NO synthase or an NO-independent mechanism.

Effect of Antidepressant Switching vs Augmentation on Remission Among Patients With Major Depressive Disorder Unresponsive to Antidepressant Treatment: The VAST-D Randomized Clinical Trial

Importance Less than one-third of patients with major depressive disorder (MDD) achieve remission with their first antidepressant. Objective To determine the relative effectiveness and safety of 3 common alternate treatments for MDD. Design, Setting, and Participants From December 2012 to May 2015, 1522 patients at 35 US Veterans Health Administration medical centers who were diagnosed with nonpsychotic MDD, unresponsive to at least 1 antidepressant course meeting minimal standards for treatment dose and duration, participated in the study. Patients were randomly assigned (1:1:1) to 1 of 3 treatments and evaluated for up to 36 weeks. Interventions Switch to a different antidepressant, bupropion (switch group, n = 511); augment current treatment with bupropion (augment-bupropion group, n = 506); or augment with an atypical antipsychotic, aripiprazole (augment-aripiprazole group, n = 505) for 12 weeks (acute treatment phase) and up to 36 weeks for longer-term follow-up (continuation phase). Main Outcomes and Measures The primary outcome was remission during the acute treatment phase (16-item Quick Inventory of Depressive Symptomatology-Clinician Rated [QIDS-C16] score ⩽5 at 2 consecutive visits). Secondary outcomes included response (≥50% reduction in QIDS-C16 score or improvement on the Clinical Global Impression Improvement scale), relapse, and adverse effects. Results Among 1522 randomized patients (mean age, 54.4 years; men, 1296 [85.2%]), 1137 (74.7%) completed the acute treatment phase. Remission rates at 12 weeks were 22.3% (n = 114) for the switch group, 26.9% (n = 136)for the augment-bupropion group, and 28.9% (n = 146) for the augment-aripiprazole group. The augment-aripiprazole group exceeded the switch group in remission (relative risk [RR], 1.30 [95% CI, 1.05-1.60]; P = .02), but other remission comparisons were not significant. Response was greater for the augment-aripiprazole group (74.3%) than for either the switch group (62.4%; RR, 1.19 [95% CI, 1.09-1.29]) or the augment-bupropion group (65.6%; RR, 1.13 [95% CI, 1.04-1.23]). No significant treatment differences were observed for relapse. Anxiety was more frequent in the 2 bupropion groups (24.3% in the switch group [n = 124] vs 16.6% in the augment-aripiprazole group [n = 84]; and 22.5% in augment-bupropion group [n = 114]). Adverse effects more frequent in the augment-aripiprazole group included somnolence, akathisia, and weight gain. Conclusions and Relevance Among a predominantly male population with major depressive disorder unresponsive to antidepressant treatment, augmentation with aripiprazole resulted in a statistically significant but only modestly increased likelihood of remission during 12 weeks of treatment compared with switching to bupropion monotherapy. Given the small effect size and adverse effects associated with aripiprazole, further analysis including cost-effectiveness is needed to understand the net utility of this approach. Trial Registration clinicaltrials.gov Identifier: NCT01421342

TNF-α enhances cardiac myocyte NO production through MAP kinase-mediated NF-κB activation

We have previously reported that interleukin-1beta (IL-1beta) alone induced nitric oxide (NO) production by neonatal rat cardiac myocytes (CM). The effects of tumor necrosis factor-alpha (TNF-alpha) on inducible NO synthase (iNOS) were not characterized. Unlike IL-1beta, TNF-alpha alone failed to enhance NO production in CM. However, the addition of TNF-alpha to IL-1beta significantly enhanced iNOS mRNA expression, iNOS protein synthesis, and NO production (NO(-)(2)). TNF-alpha enhancement of IL-1beta-induced NO(-)(2) production was blocked by PD-98059, a selective mitogen-activated protein (MAP) kinase kinase inhibitor, but not calphostin C (Cal C), a protein kinase C inhibitor. TNF-alpha-enhanced MAP kinase activity was associated with an increase in IL-1beta-stimulated NF-kappaB activity. PD-98059, but not Cal C, inhibited both TNF-alpha-enhanced MAP kinase and NF-kappaB activities. Thus TNF-alpha enhancement of IL-1beta-induced NO production is associated with MAP kinase-mediated activation of NF-kappaB.

CXCR4 receptor antagonist blocks cardiac myocyte p38 MAP kinase phosphorylation by HIV gp120.

The prognosis for patients with human immunodeficiency virus (HIV) infection has improved remarkably as a result of effective antiretroviral therapy. This has resulted in an increased awareness of cardiac complications from HIV infection, including cardiomyopathy and overt heart failure. Mechanisms responsible for HIV cardiomyopathy and heart failure are unknown, but may include direct effects of HIV proteins on the heart. We have previously reported that the HIV envelope glycoprotein, gp120, has a p38 MAP kinase-dependent negative inotropic effect on adult rat ventricular myocytes (ARVM). This signaling pathway presumably results from the binding of gp120 to a specific receptor on the surface of cardiac myocytes. HIV gp120 has been shown to bind to CD4, CXCR4, and CCR5 receptors on lymphocytes and macrophages. Accordingly, we sought to determine if HIV gp120 regulated its negative inotropic effect through activation of one of these binding sites on cardiac myocytes. AMD3100, a highly selective CXCR4 receptor antagonist, reversed HIV gp120-induced negative inotropic effect on ARVM. AMD3100 also blocked HIV gp120 phosphorylation of both p38 MAP kinase and Troponin I. The binding of gp120 to the CXCR4 receptor on ARVM was confirmed by co-immunoprecipitation. We conclude that the negative inotropic effect of HIV gp120 is mediated by a novel signaling pathway that begins with binding to a cardiac myocyte CXCR4 receptor, followed by phosphorylation of both p38 MAP kinase and Troponin I.

Nitric Oxide and Viral Cardiomyopathy

The report by Badorff et al1 in this issue of Circulation provides an opportunity to reflect on the enormous impact that the discovery of nitric oxide (NO) has already had in furthering our understanding of the basic biology of human disease processes. This report also helps to illustrate how basic insights coupled with clinical observations will ultimately lead to redefining previously unrelated clinical conditions along more pathophysiologically relevant lines. The 1998 Nobel Prize for Medicine or Physiology was awarded to Louis J. Ignarro, Ferid Murad, and Robert Furchgott for the discovery of the role of NO as a signaling molecule in the cardiovascular system.2 Ignarro studied the mechanism of action of nitroglycerin, which was first synthesized by Sobrero more than 150 years ago, and discovered that it mediates its effects through NO. Murad discovered that NO mediates effects through that “other,” less appreciated (ie, not cAMP), cyclic nucleotide, cGMP. Furchgott’s simple experiments with rabbit aortas provided physiological relevance by revealing that vascular endothelium normally produces a relaxing factor, endothelium-derived relaxing factor, which Ignarro showed to be NO. Shortly thereafter, inhibitors were identified, enzyme proteins isolated, and NO synthases (NOS) successively cloned from neurons (type 1), macrophages (type 2), and endothelial cells (type 3).3 It was clear from the beginning that the constitutive, basal production of small quantities of NO by NOS types 1 and 3 played a critical role in normal physiological processes. What has been less obvious, however, is the benefits conferred by the production of much larger quantities of NO by NOS 2 in response to cytokines. Sepsis has served as the paradigm for cytokine-induced expression of NO.3 Much unsuccessful effort has been invested in regulating the presumed exclusively deleterious effects of cytokine-induced NO production in sepsis. This view of cytokine-induced NO production appears …

Emotional Stress and Reversible Myocardial Dysfunction

A growing body of clinical and experimental literature supports a strong association between emotional stress and adverse outcomes from CVD. Effects of emotional stress on coronary blood flow and cardiac arrhythmias provide only a partial explanation. A direct impact of emotional stress on myocardial function has recently received attention as a result of reports of patients presenting with new onset of unexplained reversible heart failure following episodes of emotional stress. Potential mechanisms responsible for myocardial dysfunction following emotional stress remain to be elucidated. This review will explore potential pathophysiologic mechanisms linking emotional stress to adverse cardiovascular outcomes beginning with primary and secondary risk factors and leading to direct effects of emotional stress on reversible myocardial dysfunction.

Diastolic dysfunction following HIV infection.

The development of myocardial dysfunction in patients following HIV infection continues to be widely reported [1–6]. Compelling evidence of surprisingly frequent diastolic dysfunction followed by systolic dysfunction is observed in both the pediatric and adult populations [1–6]. Basic mechanisms proposed to explain these clinical observations include direct effects of HIV proteins, or indirect effects of cytokines, co-infection, autoimmunity and antiretroviral toxicity [1,7]. The advent of highly active antiretroviral therapies (HAART) has prolonged survival, but has been considered a potential source of cardiovascular complications of HIV infection [1]. Recent clinical studies in countries lacking universal access to HAART have provided some insights into the relative importance of HIV infection as opposed to its pharmacotherapy in HIV cardiomyopathy. These recent studies indicate that HIV cardiomyopathy is more prevalent among patients with HIV alone compared with those patients with HIV who also received HAART [1–6]. Thus, HIV infection appears to contribute more to HIV cardiomyopathy than does its treatment. Human autopsy data identifying gp120 in the hearts of HIV cardiomyopathy patients prior to HAART also support its potential pathogenic role in this condition [8].