Justin A. Mariani

Sympathetic Neural Adaptation to Hypocaloric Diet With or Without Exercise Training in Obese Metabolic Syndrome Subjects

OBJECTIVE Sympathetic nervous system (SNS) overactivity contributes to the pathogenesis and target organ complications of obesity. This study was conducted to examine the effects of lifestyle interventions (weight loss alone or together with exercise) on SNS function. RESEARCH DESIGN AND METHODS Untreated men and women (mean age 55 ± 1 year; BMI 32.3 ± 0.5 kg/m2) who fulfilled Adult Treatment Panel III metabolic syndrome criteria were randomly allocated to either dietary weight loss (WL, n = 20), dietary weight loss and moderate-intensity aerobic exercise (WL+EX, n = 20), or no treatment (control, n = 19). Whole-body norepinephrine kinetics, muscle sympathetic nerve activity by microneurography, baroreflex sensitivity, fitness (maximal oxygen consumption), metabolic, and anthropometric measurements were made at baseline and 12 weeks. RESULTS Body weight decreased by −7.1 ± 0.6 and −8.4 ± 1.0 kg in the WL and WL+EX groups, respectively (both P < 0.001). Fitness increased by 19 ± 4% (P < 0.001) in the WL+EX group only. Resting SNS activity decreased similarly in the WL and WL+EX groups: norepinephrine spillover by −96 ± 30 and −101 ± 34 ng/min (both P < 0.01) and muscle sympathetic nerve activity by −12 ± 6 and −19 ± 4 bursts/100 heart beats, respectively (both P < 0.01), but remained unchanged in control subjects. Blood pressure, baroreflex sensitivity, and metabolic parameters improved significantly and similarly in the two lifestyle intervention groups. CONCLUSIONS The addition of moderate-intensity aerobic exercise training to a weight loss program does not confer additional benefits on resting SNS activity. This suggests that weight loss is the prime mover in sympathetic neural adaptation to a hypocaloric diet.

Blunted sympathetic neural response to oral glucose in obese subjects with the insulin-resistant metabolic syndrome

BACKGROUND Glucose ingestion stimulates sympathetic nervous system (SNS) activity in lean subjects, whereas blunted responses have been reported in the obese. OBJECTIVE The objective was to investigate the impact of insulin resistance on the SNS response to oral glucose. DESIGN Nineteen insulin-resistant (IR) and 12 insulin-sensitive (IS) obese subjects with the metabolic syndrome and matched for age, sex, and blood pressure participated. Simultaneous measurements of muscle sympathetic nerve activity (MSNA) by microneurography, whole-body norepinephrine spillover rate, cardiac baroreflex sensitivity (BRS), calf blood flow, and arterial blood pressure were made at baseline and 30, 60, 90, and 120 min after a 75-g glucose load. RESULTS IR subjects had a higher insulin area under the curve from 0 to 120 min (AUC(0-120): 13,468 +/- 677 compared with 6399 +/- 612 mU/L . min; P < 0.001), glucose AUC(0-120) (P < 0.05), and resting MSNA (41 +/- 3 compared with 31 +/- 3 bursts/min; P = 0.03) than did IS subjects. MSNA and the norepinephrine spillover rate increased from baseline (by 29 +/- 7% and 40 +/- 13%, respectively; P < or = 0.001 for both) in IS subjects after the glucose load. In contrast, there was a blunted and delayed sympathetic response in IR subjects. Cardiac BRS and diastolic blood pressure decreased, whereas calf blood flow increased after the glucose load and by a similar magnitude in both groups (P < 0.01). Body mass index, abdominal fat, and insulin AUC(0-120) were independent (inverse) predictors of the SNS response. CONCLUSIONS IR subjects with the metabolic syndrome have a blunted SNS response to oral glucose compared with IS subjects with the metabolic syndrome, which is related to central adiposity and the insulin response but not to differences in skeletal muscle vasodilation or BRS.

Bone Marrow-Derived Cells Contribute to Fibrosis in the Chronically Failing Heart

Cardiac fibrosis contributes significantly to the phenotype of the chronically failing heart. It is not clear whether in this setting the fibrosis is contributed by native cardiac fibroblasts or alternatively by recruitment of cells arising from the bone marrow. We aimed to determine the contribution of bone marrow-derived cells to cardiac fibrosis in the failing heart and to investigate potentially contributing cytokines. Bone marrow-derived fibrocyte recruitment to the failing heart was studied in a transgenic (Mst1 mice) model of dilated cardiomyopathy. In conjunction, we examined the role of stromal-derived factor-1 (SDF-1), a key chemoattractant, by assessing myocardial expression and secretion by cardiomyocytes and in clinical samples. Bone marrow-derived cells were recruited in significantly greater numbers in Mst1 versus control mice (P < 0.001), contributing 17 +/- 4% of the total fibroblast load in heart failure. Patients with heart failure had higher plasma levels of SDF-1 than healthy control subjects (P < 0.01). We found that cardiomyocytes constitutively secrete SDF-1, which is significantly up-regulated by angiotensin II. SDF-1 was shown to increases cardiac fibroblast migration by 59% (P < 0.05). Taken together, our data suggest that recruitment of bone marrow-derived cells under the influence of factors, including SDF-1, may play an important role in the pathogenesis of cardiac fibrosis in heart failure.

Exercise augments weight loss induced improvement in renal function in obese metabolic syndrome individuals.

Objective Metabolic syndrome (MetS) obesity is an independent risk factor for chronic kidney disease. This study was conducted to examine the effects of lifestyle interventions on renal parameters and putative metabolic, neuroadrenergic and hemodynamic mediators of renal injury. Methods Untreated men and women (mean age 55 ± 1 years; BMI 32.7 ± 0.6 kg/m2) without pre-existing renal dysfunction, who fulfilled MetS criteria were randomized to dietary weight loss (WL, n = 13), weight loss combined with aerobic exercise (WL + EX, n = 13), or no treatment (control, n = 12). Estimated glomerular filtration rate (eGFR), 24 h urinary albumin excretion, plasma renin activity (PRA), muscle sympathetic nerve activity (MSNA), baroreflex sensitivity (BRS), anthropometric, metabolic and fitness variables were measured at baseline and week 12. Results Body weight decreased by −8.2 ± 0.8% in the WL and −10.7 ± 0.9% in the WL + EX groups (both P < 0.001). Fitness (maximal oxygen consumption) increased by 15 ± 5% and BRS by 5.5 ± 2.4 ms/mmHg in the WL + EX group only (P < 0.05). Serum creatinine decreased by −8.1 ± 4.8%, (WL, P = 0.016) and −14.9 ± 3.0% (WL + EX, P < 0.001). Estimated GFR increased commensurately but the increment was greater in the WL + EX group (P = 0.04). Albuminuria (P < 0.05) and MSNA (P < 0.001) decreased similarly in both groups, whereas PRA, high sensitivity C-reactive protein, uric acid and DBP decreased only in the WL + EX group (all P < 0.05). Conclusion Moderate weight loss in obese MetS patients is associated with a reduction in albuminuria and an improvement in eGFR which is augmented by exercise co-intervention.

Hemodynamic Determinants of Myocardial B-Type Natriuretic Peptide Release: Relative Contributions of Systolic and Diastolic Wall Stress

Although B-type natriuretic peptide (BNP) is widely used as a biomarker for heart failure, the in vivo mechanical stimulus for its cardiac release remains poorly defined. We aimed to characterize the hemodynamic determinants of the transcardiac BNP gradient as a measure of myocardial BNP release by performing a detailed hemodynamic assessment in subjects with a broad spectrum of systolic and diastolic left ventricular dysfunction. Forty-two subjects underwent a detailed transthoracic echocardiographic study, right heart catheterization, and simultaneous BNP measurement in arterial and coronary sinus plasma. The transcardiac BNP gradient was lowest in subjects with normal left ventricular ejection fraction/high peak early diastolic annular velocity (n=11), intermediate in those with normal left ventricular ejection fraction/low peak early diastolic annular velocity (n=13), and highest in those with low left ventricular ejection fraction/low peak early diastolic annular velocity (n=18; 29 ng/L (range: 15 to 78 ng/L) versus 88 ng/L (range: 34 to 172 ng/L) versus 1566 ng/L (range: 624 to 2349 ng/L; P<0.001). Across the range of patients, left ventricular end-systolic wall stress (r2=0.51) and peak systolic mitral annular velocity (r2=0.47) showed the strongest correlation with higher transcardiac BNP gradient. In contrast, the transcardiac BNP gradient was weakly related to indices of diastolic load, including pulmonary capillary wedge pressure (r2=0.27) and left ventricular end-diastolic wall stress (r2=0.21). Across this spectrum of pathophysiology, left ventricular end-systolic wall stress appears to be the key mechanical stimulus influencing cardiac BNP release.

Augmentation of left ventricular mechanics by recirculation-mediated AAV2/1-SERCA2a gene delivery in experimental heart failure.

Down‐regulation of sarcoplasmic reticulum calcium ATPase (SERCA2a) is a key molecular abnormality in heart failure (HF), which is not currently addressed by specific pharmacotherapy. We sought to evaluate, in detail, the impact of augmented SERCA2a expression on left ventricular (LV) mechanics in a large animal model of HF.

The transcardiac gradient of cardio-microRNAs in the failing heart

Differential microRNA expression in peripheral blood has been observed in patients with heart failure, suggesting their value as potential biomarkers and likely contributors to disease mechanisms. In the present study, we aimed to evaluate the transcardiac gradient of 84 cardio‐microRNAs in healthy and failing hearts to determine which microRNAs are released or absorbed by the myocardium in heart failure.

Evaluating the Utility of Circulating Biomarkers of Collagen Synthesis in Hypertrophic Cardiomyopathy

Background— In hypertrophic cardiomyopathy (HCM), accumulation of myocardial collagen may play a central role in the pathogenesis of diastolic dysfunction and arrhythmia. Previous studies have suggested that peripheral levels of byproducts of collagen synthesis are reflective of myocardial extracellular matrix metabolism, although this has not been validated in detail. Given the potential clinical utility of such biomarkers, we sought to validate the assumed relationship between peripheral markers and myocardial fibrosis in HCM. Methods and Results— Fifty patients with HCM and 25 healthy controls underwent peripheral venous sampling to determine plasma concentrations of key collagen precursors (procollagen I and III N-terminal propeptides [PINP, PIIINP]). Contrast-enhanced cardiac magnetic resonance imaging was performed to quantify regional (by late-gadolinium enhancement) and diffuse (by T1 mapping) myocardial fibrosis. Nineteen subjects also underwent simultaneous arterial and coronary sinus blood sampling (to derive transcardiac concentration gradients of PINP, PIIINP, and C-terminal telopeptide of type I collagen) and right heart catheterization. Despite cardiac magnetic resonance evidence of regional (late-gadolinium enhancement quantity, 6.4±8.0%) and diffuse (T1 time, 478±79 ms) myocardial fibrosis in patients with HCM, peripheral levels of collagen precursors were similar compared with control subjects (PINP, 45.9±22.9 versus 53.4±25.9 &mgr;g/L; P=0.21; PIIINP, 4.8±1.7 versus 4.4±1.1 &mgr;g/L; P=0.26). No significant net positive transcardiac concentration gradient was detected for either biomarker of collagen synthesis. Conclusions— The cardiac contribution to peripheral levels of byproducts of collagen synthesis in patients with HCM is insignificant. Furthermore, peripheral levels of these biomarkers do not accurately reflect myocardial collagen content in these patients.

Utility of Myocardial Fibrosis and Fatty Infiltration Detected by Cardiac Magnetic Resonance Imaging in the Diagnosis of Arrhythmogenic Right Ventricular Dysplasia—A Single Centre Experience

INTRODUCTION Cardiac magnetic resonance imaging (CMR) has evolved as a major diagnostic tool to evaluate arrhythmogenic right ventricular dysplasia (ARVD). However, there is a lack of consensus in the interpretation of findings such as fatty infiltration or myocardial fibrosis. We examined the diagnostic utility of these two features in the diagnosis of ARVD. METHODS We performed fast imaging employing steady-state acquisition cine imaging, T(1)-weighted black blood imaging with and without fat suppression and post-contrast delayed enhancement on a 1.5-T scanner to evaluate ventricular function and morphology, fatty infiltration and regional myocardial fibrosis in 52 subjects with suspected ARVD. RESULTS Eight subjects met the international diagnostic criteria for ARVD. Right ventricle (RV) delayed hyper-enhancement was found in 7 of 8 (88%) ARVD subjects compared to 6 of 44 (14%) subjects without ARVD (p<0.001). Fatty infiltration was only identified in 1 ARVD patient, and 1 non-ARVD patient. On multiple logistic regression analysis RV enhancement remained an independent predictor for the diagnosis of ARVD (p<0.05). CONCLUSION RV delayed enhancement is common in patients with ARVD, whereas detection of fatty infiltration of the right ventricle was rare in our patient population. The inclusion of RV fibrosis on CMR as a feature of ARVD may improve the diagnostic accuracy of this condition.

Impaired myocardial oxygen availability contributes to abnormal exercise hemodynamics in heart failure with preserved ejection fraction

Background Hypertension is a frequent risk factor for the development of heart failure with preserved ejection fraction (HFPEF). Progressive extracellular matrix accumulation has been presumed to be the fundamental pathophysiologic mechanism that leads to the transition to impaired diastolic reserve. However, the contribution of other mechanisms affecting active and passive components of diastolic function has not been comprehensively assessed. In this study, we investigated the potential role of impaired myocardial oxygen delivery in the pathophysiology of HFPEF. Methods and Results Patients with HFPEF, those with controlled hypertension, and healthy controls underwent simultaneous right‐heart catheterization, echocardiography, and paired arterial and coronary sinus blood gas sampling at rest and during supine‐cycle ergometry. Despite a lower workload (HFPEF vs control, hypertension: 43±8 versus 114±12, 87±14 W; P<0.001 and P<0.05, respectively), peak exercise pulmonary capillary wedge pressure was markedly higher in HFPEF patients compared with healthy and hypertensive controls (32±2 versus 16±1 and 17±1 mm Hg, both P<0.001). During exercise, the transcardiac oxygen gradient increased significantly in all groups; however, the peak transcardiac oxygen gradient was significantly lower in HFPEF patients (P<0.05). In addition, the left ventricular–work corrected transcardiac oxygen gradient remained significantly lower in HFPEF patients compared with controls (P<0.001). Conclusion The current study provides unique data suggesting that the abnormal diastolic reserve observed during exertion in HFPEF patients may, in part, be explained by impaired myocardial oxygen delivery due possibly to microvascular dysfunction. Further studies are required to confirm the structural and functional basis of these findings and to investigate the influence of potential therapies on this abnormality.