Sivakumar Ardhanari

Impact of Obesity and Weight Loss on Cardiac Performance and Morphology in Adults

Obesity, particularly severe obesity is capable of producing hemodynamic alterations that predispose to changes in cardiac morphology and ventricular function. These include increased cardiac output, left ventricular hypertrophy and diastolic and systolic dysfunction of both ventricles. Facilitated by co-morbidities such as hypertension, the sleep apnea/obesity hypoventilation syndrome, and possibly certain neurohormonal and metabolic alterations, these abnormalities may predispose to left and right heart failure, a disorder known as obesity cardiomyopathy.

Adaptive mechanisms to compensate for overnutrition-induced cardiovascular abnormalities.

In conditions of overnutrition, cardiac cells must cope with a multitude of extracellular signals generated by changes in nutrient load (glucose, amino acids, and lipids) and the hormonal milieu [increased insulin (INS), ANG II, and adverse cytokine/adipokine profile]. Herein, we review the diverse compensatory/adaptive mechanisms that counter the deleterious effects of excess nutrients and growth factors. We largely focus the discussion on evidence obtained from Zucker obese (ZO) and Zucker diabetic fatty (ZDF) rats, which are useful models to evaluate adaptive and maladaptive metabolic, structural, and functional cardiac remodeling. One adaptive mechanism present in the INS-resistant ZO, but absent in the diabetic ZDF heart, involves an interaction between the nutrient sensor kinase mammalian target of rapamycin complex 1 (mTORC1) and ANG II-type 2 receptor (AT2R). Recent evidence supports a cardioprotective role for the AT2R; for example, suppression of AT2R activation interferes with antihypertrophic/antifibrotic effects of AT1R blockade, and AT2R agonism improves cardiac structure and function. We propose a scenario, whereby mTORC1-signaling-mediated increase in AT2R expression in the INS-resistant ZO heart is a cardioprotective adaptation to overnutrition. In contrast to the ZO rat, heart tissues of ZDF rats do not show activation of mTORC1. We posit that such a lack of activation of the mTOR↔AT2R integrative pathway in cardiac tissue under conditions of obesity-induced diabetes may be a metabolic switch associated with INS deficiency and clinical diabetes.

Renin Inhibition and AT1R blockade improve metabolic signaling, oxidant stress and myocardial tissue remodeling

OBJECTIVE Strategies that block angiotensin II actions on its angiotensin type 1 receptor or inhibit actions of aldosterone have been shown to reduce myocardial hypertrophy and interstitial fibrosis in states of insulin resistance. Thereby, we sought to determine if combination of direct renin inhibition with angiotensin type 1 receptor blockade in vivo, through greater reductions in systolic blood pressure (SBP) and aldosterone would attenuate left ventricular hypertrophy and interstitial fibrosis to a greater extent than either intervention alone. MATERIALS/METHODS We utilized the transgenic Ren2 rat which manifests increased tissue expression of murine renin which, in turn, results in increased renin-angiotensin system activity, aldosterone secretion and insulin resistance. Ren2 rats were treated with aliskiren, valsartan, the combination (aliskiren+valsartan), or vehicle for 21 days. RESULTS Compared to Sprague-Dawley controls, Ren2 rats displayed increased systolic blood pressure, elevated serum aldosterone levels, cardiac tissue hypertrophy, interstitial fibrosis and ultrastructural remodeling. These biochemical and functional alterations were accompanied by increases in the NADPH oxidase subunit Nox2 and 3-nitrotyrosine content along with increases in mammalian target of rapamycin and reductions in protein kinase B phosphorylation. Combination therapy contributed to greater reductions in systolic blood pressure and serum aldosterone but did not result in greater improvement in metabolic signaling or markers of oxidative stress, fibrosis or hypertrophy beyond either intervention alone. CONCLUSIONS Thereby, our data suggest that the greater impact of combination therapy on reductions in aldosterone does not translate into greater reductions in myocardial fibrosis or hypertrophy in this transgenic model of tissue renin overexpression.

Effect of Weight Loss on Ventricular Repolarization in Normotensive Severely Obese Patients With and Without Heart Failure

Background:Obesity has been reported to be associated with delayed ventricular repolarization. The purpose of this study was to assess ventricular repolarization in normotensive severely obese subjects with and without heart failure (HF) and to assess the effect of weight loss on ventricular repolarization in such patients. Methods:Twenty-eight patients with and 39 patients without HF (body mass index ≥ 40 kg/m2) were studied before and after weight loss from bariatric surgery. Corrected QT interval (QTc) was measured on 12-lead electrocardiograms using Bazetts formula. QTc dispersion was calculated by subtracting the minimum from the maximum QTc on each 12-lead electrocardiogram. Electrocardiograms and transthoracic echocardiograms were performed preoperatively and at the nadir of postoperative weight loss. Results:Mean QTc and QTc dispersion were significantly longer/greater in subjects with HF than in those without HF (P < 0.0001). Weight loss produced significant reductions in mean QTc and QTc dispersion in both subgroups (P < 0.0001). Pre-weight loss left ventricular (LV) mass/height2.7 and presence or absence of HF independently predicted pre-weight loss QTc and QTc dispersion (P < 0.0001). Weight loss-induced decrease in LV mass/height2.7 independently predicted weight loss-induced decreases in QTc and QTc dispersion (P < 0.0001). Conclusions:HF independently predicts QTc and QTc dispersion in normotensive severely obese patients. Decrease in the LV mass resulting from weight loss independently predicts reduction in QTc and QTc dispersion in such patients.

Reduction in the Intensity Rate of Appropriate Shocks for Ventricular Arrhythmias With Statin Therapy

Higher rate of implantable cardioverter-defibrillator (ICD) shocks has been associated with increased mortality and morbidity. The aim of our study was to determine whether statins reduced the intensity rate of appropriate shock therapy for ventricular tachycardia/fibrillation in patients with an ICD placed for left ventricular systolic dysfunction. In this retrospective single center analysis, patients with an ejection fraction ≤35% who underwent ICD implantation were divided into treatment and control groups based on statin use. A zero-inflated negative binomial model was used to compare the intensity rate of appropriate ICD shocks between the 2 groups. Characteristics associated with shock-free follow-up were assessed using a stepwise logistic regression model. We found 699 patients eligible for inclusion, with 412 (59%) in the statin treatment group. The adjusted mean intensity rate of shocks was lower in patients on statin therapy (intensity rate ratio = 0.22; 95% confidence interval, 0.12-0.41; P < 0.001). Statin use was associated with a significantly higher probability of shock-free follow-up (odds ratio = 1.64; 95% confidence interval, 1.09-2.48; P = 0.019). In conclusion, statins reduced the intensity rate of appropriate shock therapy for ventricular tachycardia/fibrillation and increased probability of shock-free follow-up in patients with cardiomyopathy. Larger randomized trials are needed to confirm this relationship.

Statins reduce appropriate implantable cardioverter-defibrillator shocks in ischemic cardiomyopathy with no benefit in nonischemic cardiomyopathy

Statins have been hypothesized to decrease ventricular arrhythmias through a direct antiarrhythmic effect. Clinical studies have demonstrated a clear reduction only in populations with underlying ischemic heart disease. This study was designed to compare the effect of statins on appropriate shocks between ischemic and nonischemic cardiomyopathy. Patients with an ejection fraction 35% or less who received an implantable cardioverter–defibrillator and had follow-up for at least 1 month were included. The ischemic and nonischemic groups were divided into statin treatment and control subgroups and the occurrence of appropriate shocks was compared. The frequency of shocks was analyzed using negative binomial models to account for overdispersion of the “count” data (number of appropriate shocks) and an adjusted intensity rate ratio was calculated for statin use. A total of 676 patients were included, of which statins were used by 65% (329 of 506) of the ischemic and 42% (72 of 170) of the nonischemic groups. Occurrence of appropriate shocks was significantly reduced with statins in ischemic (13.4% vs 20.9%; relative risk 0.64, P = 0.028), but not in the patients with nonischemic cardiomyopathy. Similarly, although use of statins lowered the intensity rate of appropriate shocks in ischemic patients (intensity rate ratio, 0.23; 95% confidence interval, 0.12–0.47), no such benefit was noted in the nonischemic group (intensity rate ratio, 1.27; 95% confidence interval, 0.37–4.40). In conclusion, statins reduced the occurrence and frequency of appropriate shocks for ventricular arrhythmias in ischemic but not in nonischemic cardiomyopathy. Larger, randomized controlled trials are needed to confirm these findings.

Cardiovascular disease progression in female Zucker Diabetic Fatty rats occurs via unique mechanisms compared to males

Population studies have shown that compared to diabetic men, diabetic women are at a higher risk of cardiovascular disease. However, the mechanisms underlying this gender disparity are unclear. Our studies in young murine models of type 2 diabetes mellitus (T2DM) and cardiovascular disease show that diabetic male rats develop increased cardiac fibrosis and suppression of intracardiac anti-fibrotic cytokines, while premenopausal diabetic female rats do not. This protection from cardiac fibrosis in female rats can be an estrogen-related effect. However, diabetic female rats develop early subclinical myocardial deformation, cardiac hypertrophy via elevated expression of pro-hypertrophic miR-208a, myocardial damage, and suppression of cardio-reparative Angiotensin II receptor 2 (Agtr2). Diabetic rats of both sexes exhibit a reduction in cardiac capillary density. However, diabetic female rats have reduced expression of neuropilin 1 that attenuates cardiomyopathy compared to diabetic male rats. A combination of cardiac hypertrophy and reduced capillary density likely contributed to increased myocardial structural damage in diabetic female rats. We propose expansion of existing cardiac assessments in diabetic female patients to detect myocardial deformation, cardiac hypertrophy and capillary density via non-invasive imaging, as well as suggest miR-208a, AT2R and neuropilin 1 as potential therapeutic targets and mechanistic biomarkers for cardiac disease in females.

Mineralocorticoid and Apparent Mineralocorticoid Syndromes of Secondary Hypertension

The mineralocorticoid aldosterone is a key hormone in the regulation of plasma volume and blood pressure in man. Excessive levels of this mineralocorticoid have been shown to mediate metabolic disorders and end-organ damage more than what can be attributed to its effects on blood pressure alone. Inappropriate excess levels of aldosterone contribute significantly to the cardiorenal metabolic syndrome and target organ injury that include atherosclerosis, myocardial hypertrophy, fibrosis, heart failure, and kidney disease. The importance of understanding the role of excess mineralocorticoid hormones such as aldosterone in resistant hypertension and in those with secondary hypertension should be visited. Primary aldosteronism is one of the commonly identified causes of hypertension and is treatable and/or potentially curable. We intend to review the management of mineralocorticoid-induced hypertension in the adult population along with other disease entities that mimic primary aldosteronism.

Systematic review of non-invasive cardiovascular imaging in the diagnosis of constrictive pericarditis

Background Diagnosis of constrictive pericarditis (CP) can be challenging. It can be nearly impossible to distinguish CP from other causes of right heart failure. Although various imaging modalities help in the diagnosis, no test is definitive. Several reviews have addressed the role of various imaging techniques in the diagnosis of CP but a systematic review has not yet been published. Objective Our intention was to study the ability of various non-invasive imaging modalities to diagnose CP in patients with surgically confirmed disease and to apply our findings to develop a clinically useful diagnostic algorithm. Methods A PubMed (NLM) search was performed with MeSH term “constrictive pericarditis”. Original articles that investigated the ability of various cardiovascular imaging modalities to noninvasively diagnose surgically confirmed CP were included in our review. Investigations that included any cases without surgical confirmation were excluded. Results The PubMed search yielded 3001 results with MeSH term “constrictive pericarditis” (January 8, 2016). We identified (40) studies on CP that matched our inclusion criteria. We summarized our results sorted by individual non-invasive CV imaging modalities – echocardiography, cardiac computed tomography (CT), and magnetic resonance imaging (MRI). Under each imaging modality, we grouped our discussion based on different parameters useful in CP diagnosis. Conclusions In conclusion, contemporary diagnosis of CP is based on clinical features and echocardiography. Cardiac MRI is recommended in patients where echocardiography is not diagnostic. Both cardiac MRI and CT can guide surgical planning but we prefer MRI as it provides both structural and functional information.

Cardiac stimulation with electronic control device application.

BACKGROUND Electronic control devices (ECDs) are weapons used to incapacitate violent subjects. Subjects have died suddenly after ECD application, but because cardiac dysrhythmias have been inconsistently observed during ECD application in animals, the cause for death is uncertain. OBJECTIVES The objective was to identify the factors contributing to cardiac stimulation during ECD application detected by transesophageal echocardiography. METHODS Four Yorkshire pigs were anesthetized, paralyzed with vecuronium, and restrained in a supine position. A GE 6T echo probe was placed in the esophagus to directly visualize left ventricular function. M-mode echocardiography was used to estimate heart rate. Two dart locations, chest and abdomen, were assessed. ECD applications were delivered from one of five commercially available devices (Taser X26, Singer S200 AT, Taser M26, Taser X3, and Taser C2) in random order to each pig, four times in each orientation. RESULTS Cardiac stimulation, characterized by multiple PVCs or the sudden increase in ventricular contraction rate during application, did not occur with abdominal dart location. With chest dart application in small pigs, cardiac stimulation occurred with all ECDs except with the Taser X3 (p < 0.0001). In large pigs, cardiac stimulation occurred only during chest application of the S200 AT (chest vs. abdomen: 207 beats/min, vs. 91 beats/min, p < 0.0001). CONCLUSION Cardiac stimulation occurs during ECD application in pigs, and is dependent upon subject size, dart orientation, and ECD. The Taser X3 did not result in cardiac stimulation in small or large pigs.