Ranendra Das

Circulating MicroRNA-30d Is Associated With Response to Cardiac Resynchronization Therapy in Heart Failure and Regulates Cardiomyocyte Apoptosis A Translational Pilot Study

Background— Biomarkers that predict response to cardiac resynchronization therapy (CRT) in heart failure patients with dyssynchrony (HFDYS) would be clinically important. Circulating extracellular microRNAs (miRNAs) have emerged as novel biomarkers that may also play important functional roles, but their relevance as markers for CRT response has not been examined. Methods and Results— Comprehensive miRNA polymerase chain reaction arrays were used to assess baseline levels of 766 plasma miRNAs in patients undergoing clinically indicated CRT in an initial discovery set (n=12) with and without subsequent echocardiographic improvement at 6 months after CRT. Validation of candidate miRNAs in 61 additional patients confirmed that baseline plasma miR-30d was associated with CRT response (defined as an increase in left ventricular ejection fraction ≥10%). MiR-30d was enriched in coronary sinus blood and increased in late-contracting myocardium in a canine model of HFDYS, indicating cardiac origin with maximal expression in areas of high mechanical stress. We examined the functional effects of miR-30d in cultured cardiomyocytes and determined that miR-30d is expressed in cardiomyocytes and released in vesicles in response to mechanical stress. Overexpression of miR-30d in cultured cardiomyocytes led to cardiomyocyte growth and protected against apoptosis by targeting the mitogen-associated kinase 4, a downstream effector of tumor necrosis factor. In HFDYS patients, miR-30d plasma levels inversely correlated with high-sensitivity troponin T, a marker of myocardial necrosis. Conclusions— Baseline plasma miR-30d level is associated with response to CRT in HFDYS in this translational pilot study. MiR-30d increase in cardiomyocytes correlates with areas of increased wall stress in HFDYS and is protective against deleterious tumor necrosis factor signaling.

Use of standardised patients to assess antibiotic dispensing for tuberculosis by pharmacies in urban India: a cross-sectional study.

Summary Background Indias total antibiotic use is the highest of any country. Patients often receive prescription-only drugs directly from pharmacies. Here we aimed to assess the medical advice and drug dispensing practices of pharmacies for standardised patients with presumed and confirmed tuberculosis in India. Methods In this cross-sectional study in the three Indian cities Delhi, Mumbai, and Patna, we developed two standardised patient cases: first, a patient presenting with 2–3 weeks of pulmonary tuberculosis symptoms (Case 1); and second, a patient with microbiologically confirmed pulmonary tuberculosis (Case 2). Standardised patients were scheduled to present each case once to sampled pharmacies. We defined ideal management for both cases a priori as referral to a health-care provider without dispensing antibiotics or steroids or both. Findings Between April 1, 2014, and Nov 29, 2015, we sampled 622 pharmacies in Delhi, Mumbai, and Patna. Standardised patients completed 1200 (96%) of 1244 interactions. We recorded ideal management (defined as referrals without the use of antibiotics or steroids) in 80 (13%) of 599 Case 1 interactions (95% CI 11–16) and 372 (62%) of 601 Case 2 interactions (95% CI 58–66). Antibiotic use was significantly lower in Case 2 interactions (98 [16%] of 601, 95% CI 13–19) than in Case 1 (221 [37%] of 599, 95% CI 33–41). First-line anti-tuberculosis drugs were not dispensed in any city. The differences in antibiotic or steroid use and number of medicines dispensed between Case 1 and Case 2 were almost entirely attributable to the difference in referral behaviour. Interpretation Only some urban Indian pharmacies correctly managed patients with presumed tuberculosis, but most correctly managed a case of confirmed tuberculosis. No pharmacy dispensed anti-tuberculosis drugs for either case. Absence of a confirmed diagnosis is a key driver of antibiotic misuse and could inform antimicrobial stewardship interventions. Funding Grand Challenges Canada, Bill & Melinda Gates Foundation, Knowledge for Change Program, and World Bank Development Research Group.

The mental health gender-gap in urban India: Patterns and narratives

Women report significantly higher levels of mental distress than men in community studies around the world. We provide further evidence on the origins of this mental health gender-gap using data from 789 adults, primarily spousal pairs, from 300 families in Delhi, India. These data were collected between 2001 and 2003. We first confirm that, like in other studies, women report higher levels of mental distress and that gender differences in education, household expenditures and age do not explain the mental health gender-gap. In contrast, women report significantly higher levels of distress than men in families with adverse reproductive outcomes, particularly the death of a child. Controlling for adverse reproductive outcomes sharply reduces the mental health gender-gap. Finally, mental health is strongly correlated with physical health for both men and women, but there is little evidence of a differential response by sex. We complement this empirical description with anthropological analysis based on ethnographic interviews with 100 men and 100 women. With the help of these ethnographic interviews we show how adverse life events for women are experienced as the inability to maintain the domestic, which seems to be at stake within their life worlds. We raise issues for further research on the apparent finding that the mental health of women and men are differentially affected by adverse reproductive events in the family in this sample.

Usefulness of Hemoglobin A1c to Predict Outcome After Cardiac Resynchronization Therapy in Patients With Diabetes Mellitus and Heart Failure

Patients with diabetes and heart failure (HF) have worse clinical outcomes compared to patients with HF without diabetes after cardiac resynchronization therapy (CRT). Patients with HF and diabetes represent a growing population at high risk for cardiovascular events and are increasingly treated with CRT. Although patients with diabetes and HF appear to benefit from CRT, their clinical outcomes are worse than those of patients without diabetes after CRT. The aim of this study was to identify clinical predictors that explain the differential hazard in patients with diabetes. We studied 442 patients (169 with diabetes) with systolic HF referred to the Massachusetts General Hospital CRT clinic from 2003 to 2010 to identify predictors of outcomes after CRT in patients with HF and diabetes. Patients with diabetes were more likely to have ischemic causes of HF than those without diabetes, but there was no difference in the left ventricular ejection fraction or HF classification at implantation. Patients with diabetes had poorer event-free survival (death or HF hospitalization) compared to those without diabetes (log-rank p = 0.04). The presence of diabetes was the most important independent predictor of differential outcomes in the entire population (hazard ratio 1.65, 95% confidence interval 1.10 to 2.51). Patients with diabetes receiving insulin therapy had poorer survival, whereas those not receiving insulin therapy had similar survival to patients without diabetes. Patients with peri-implantation glycosylated hemoglobin >7% had worse outcomes, whereas patients with glycosylated hemoglobin ≤7% had improved survival (hazard ratio 0.36, 95% confidence interval 0.15 to 0.86) equivalent to that of patients without diabetes. In conclusion, although the presence of diabetes, independent of other variables, increases the hazard of worse outcomes after CRT, there is additional risk conferred by insulin use and suboptimal peri-implantation glycemic control.

Cardiometabolic disease in South Asians: A global health concern in an expanding population

Cardiovascular disease (CVD) is one of the main causes of mortality and morbidity worldwide. As an emerging population, South Asians (SAs) bear a disproportionately high burden of CVD relative to underlying classical risk factors, partly attributable to a greater prevalence of insulin resistance and diabetes and distinct genetic and epigenetic influences. While the phenotypic distinctions between SAs and other ethnicities in CVD risk are becoming increasingly clear, the biology of these conditions remains an area of active investigation, with emerging studies involving metabolism, genetic variation and epigenetic modifiers (e.g., extracellular RNA). In this review, we describe the current literature on prevalence, prognosis and CVD risk in SAs, and provide a landscape of translational research in this field toward ameliorating CVD risk in SAs.

Hepatic steatosis is associated with cardiometabolic risk in a rural Indian population: A prospective cohort study.

BACKGROUND/OBJECTIVES While adiposity and hepatic steatosis are linked to cardiovascular risk in developed countries, their prevalence and impact in low-income countries are poorly understood. We investigated the association of anthropomorphic variables and hepatic steatosis with cardiometabolic risk profiles and subclinical cardiovascular disease (CVD) in a large rural Indian cohort. METHODS In 4691 individuals in the Birbhum Population Project in West Bengal, India, we performed liver ultrasonography, carotid ultrasound and biochemical and clinical profiling. We assessed the association of hepatic steatosis and anthropomorphic indices (BMI, waist circumference) with CVD risk factors (dysglycemia, dyslipidemia, hypertension) and subclinical CVD (by carotid intimal-medial thickness). RESULTS Rural Indians exhibited a higher visceral adiposity index and pro-atherogenic dyslipidemia at a lower BMI than Americans. Individuals with any degree of hepatic steatosis by ultrasound had a greater probability of dysglycemia (adjusted odds ratio, OR=1.67, 95% CI 1.31-2.12, P<0.0001) and pro-atherogenic dyslipidemia (OR=1.33, 95% CI 1.07-1.63, P=0.009). We observed a positive association between liver fat, adiposity and carotid intimal-medial thickness (CIMT) in an unadjusted model (β=0.02, P=0.0001); the former was extinguished after adjustment for cardiometabolic risk factors. CONCLUSIONS In a large population of rural Indians, hepatic steatosis and waist circumference were associated with prevalent cardiometabolic risk and subclinical CVD at lower BMI relative to multi-ethnic Americans, though the association of the former with subclinical CVD was extinguished after adjustment. These results underscore the emerging relevance of hepatic steatosis and adiposity in the developing world, and suggest efforts to target these accessible phenotypes for cardiometabolic risk prevention.

Variations in the quality of tuberculosis care in urban India: A cross-sectional, standardized patient study in two cities

Background India has the highest burden of tuberculosis (TB). Although most patients with TB in India seek care from the private sector, there is limited evidence on quality of TB care or its correlates. Following our validation study on the standardized patient (SP) method for TB, we utilized SPs to examine quality of adult TB care among health providers with different qualifications in 2 Indian cities. Methods and findings During 2014–2017, pilot programs engaged the private health sector to improve TB management in Mumbai and Patna. Nested within these projects, to obtain representative, baseline measures of quality of TB care at the city level, we recruited 24 adults to be SPs. They were trained to portray 4 TB “case scenarios” representing various stages of disease and diagnostic progression. Between November 2014 and August 2015, the SPs visited representatively sampled private providers stratified by qualification: (1) allopathic providers with Bachelor of Medicine, Bachelor of Surgery (MBBS) degrees or higher and (2) non-MBBS providers with alternative medicine, minimal, or no qualifications. Our main outcome was case-specific correct management benchmarked against the Standards for TB Care in India (STCI). Using ANOVA, we assessed variation in correct management and quality outcomes across (a) cities, (b) qualifications, and (c) case scenarios. Additionally, 2 micro-experiments identified sources of variation: first, quality in the presence of diagnostic test results certainty and second, provider consistency for different patients presenting the same case. A total of 2,652 SP–provider interactions across 1,203 health facilities were analyzed. Based on our sampling strategy and after removing 50 micro-experiment interactions, 2,602 interactions were weighted for city-representative interpretation. After weighting, the 473 Patna providers receiving SPs represent 3,179 eligible providers in Patna; in Mumbai, the 730 providers represent 7,115 eligible providers. Correct management was observed in 959 out of 2,602 interactions (37%; 35% weighted; 95% CI 32%–37%), primarily from referrals and ordering chest X-rays (CXRs). Unnecessary medicines were given to nearly all SPs, and antibiotic use was common. Anti-TB drugs were prescribed in 118 interactions (4.5%; 5% weighted), of which 45 were given in the case in which such treatment is considered correct management. MBBS and more qualified providers had higher odds of correctly managing cases than non-MBBS providers (odds ratio [OR] 2.80; 95% CI 2.05–3.82; p < 0.0001). Mumbai non-MBBS providers had higher odds of correct management than non-MBBS in Patna (OR 1.79; 95% CI 1.06–3.03), and MBBS providers’ quality of care did not vary between cities (OR 1.15; 95% CI 0.79–1.68; p = 0.4642). In the micro-experiments, improving diagnostic certainty had a positive effect on correct management but not across all quality dimensions. Also, providers delivered idiosyncratically consistent care, repeating all observed actions, including mistakes, approximately 75% of the time. The SP method has limitations: it cannot account for patient mix or care-management practices reflecting more than one patient–provider interaction. Conclusions Quality of TB care is suboptimal and variable in urban India’s private health sector. Addressing this is critical for India’s plans to end TB by 2025. For the first time, we have rich measures on representative levels of care quality from 2 cities, which can inform private-sector TB interventions and quality-improvement efforts.

Response to Letter Regarding Article, “Circulating MicroRNA-30d Is Associated With Response to Cardiac Resynchronization Therapy in Heart Failure and Regulates Cardiomyocyte Apoptosis: A Translational Pilot Study”

We thank Sardu and colleagues for their comments. Our report demonstrates that baseline levels of microRNA-30d (miR-30d) are correlated with response to cardiac resynchronization therapy and that miR-30d was dynamically regulated by mechanical stress.1 Moreover, miR-30d appeared to be an adaptive response and was cardioprotective against tumor necrosis factor-α–mediated apoptosis. Similar to our study, Marfella et al2 noted differential expression of several plasma miRNAs in cardiac resynchronization therapy responders versus nonresponders 1 year after cardiac resynchronization therapy. The lack of significant overlap between the sets of extracellular miRNAs reflects some of the ongoing issues in extracellular RNA research. The first issue is differences in patient populations and small sample sizes. The second is variances in methodology. Several groups, including …

Circulating MicroRNA-30d Is Associated With Response to Cardiac Resynchronization Therapy in Heart Failure and Regulates Cardiomyocyte Apoptosis

Background— Biomarkers that predict response to cardiac resynchronization therapy (CRT) in heart failure patients with dyssynchrony (HFDYS) would be clinically important. Circulating extracellular microRNAs (miRNAs) have emerged as novel biomarkers that may also play important functional roles, but their relevance as markers for CRT response has not been examined. Methods and Results— Comprehensive miRNA polymerase chain reaction arrays were used to assess baseline levels of 766 plasma miRNAs in patients undergoing clinically indicated CRT in an initial discovery set (n=12) with and without subsequent echocardiographic improvement at 6 months after CRT. Validation of candidate miRNAs in 61 additional patients confirmed that baseline plasma miR-30d was associated with CRT response (defined as an increase in left ventricular ejection fraction ≥10%). MiR-30d was enriched in coronary sinus blood and increased in late-contracting myocardium in a canine model of HFDYS, indicating cardiac origin with maximal expression in areas of high mechanical stress. We examined the functional effects of miR-30d in cultured cardiomyocytes and determined that miR-30d is expressed in cardiomyocytes and released in vesicles in response to mechanical stress. Overexpression of miR-30d in cultured cardiomyocytes led to cardiomyocyte growth and protected against apoptosis by targeting the mitogen-associated kinase 4, a downstream effector of tumor necrosis factor. In HFDYS patients, miR-30d plasma levels inversely correlated with high-sensitivity troponin T, a marker of myocardial necrosis. Conclusions— Baseline plasma miR-30d level is associated with response to CRT in HFDYS in this translational pilot study. MiR-30d increase in cardiomyocytes correlates with areas of increased wall stress in HFDYS and is protective against deleterious tumor necrosis factor signaling.

Circulating MicroRNA-30d Is Associated With Response to Cardiac Resynchronization Therapy in Heart Failure and Regulates Cardiomyocyte ApoptosisCLINICAL PERSPECTIVE

Background— Biomarkers that predict response to cardiac resynchronization therapy (CRT) in heart failure patients with dyssynchrony (HFDYS) would be clinically important. Circulating extracellular microRNAs (miRNAs) have emerged as novel biomarkers that may also play important functional roles, but their relevance as markers for CRT response has not been examined. Methods and Results— Comprehensive miRNA polymerase chain reaction arrays were used to assess baseline levels of 766 plasma miRNAs in patients undergoing clinically indicated CRT in an initial discovery set (n=12) with and without subsequent echocardiographic improvement at 6 months after CRT. Validation of candidate miRNAs in 61 additional patients confirmed that baseline plasma miR-30d was associated with CRT response (defined as an increase in left ventricular ejection fraction ≥10%). MiR-30d was enriched in coronary sinus blood and increased in late-contracting myocardium in a canine model of HFDYS, indicating cardiac origin with maximal expression in areas of high mechanical stress. We examined the functional effects of miR-30d in cultured cardiomyocytes and determined that miR-30d is expressed in cardiomyocytes and released in vesicles in response to mechanical stress. Overexpression of miR-30d in cultured cardiomyocytes led to cardiomyocyte growth and protected against apoptosis by targeting the mitogen-associated kinase 4, a downstream effector of tumor necrosis factor. In HFDYS patients, miR-30d plasma levels inversely correlated with high-sensitivity troponin T, a marker of myocardial necrosis. Conclusions— Baseline plasma miR-30d level is associated with response to CRT in HFDYS in this translational pilot study. MiR-30d increase in cardiomyocytes correlates with areas of increased wall stress in HFDYS and is protective against deleterious tumor necrosis factor signaling.