Sarcomeric gene variants among Indians with hypertrophic cardiomyopathy: A scoping review.

Hypertrophic cardiomyopathy (HCM) is a genetic heart muscle disease that frequently causes sudden cardiac death (SCD) among young adults. Several pathogenic mutations in genes encoding the cardiac sarcomere have been identified as diagnostic factors for HCM and proposed as prognostic markers for SCD. The objective of this review was to determine the scope of available literature on the variants encoding sarcomere proteins associated with SCD reported among Indian patients with HCM. The eligibility criteria for the scoping review included full text articles that reported the results of genetic screening for sarcomeric gene mutations in HCM patients of Indian south Asian ancestry. We systematically reviewed studies from the databases of Medline, Scopus, Web of Science core collection and Google Scholar. The electronic search strategy included a combination of generic terms related to genetics, disease and population. The protocol of the study was registered with Open Science Framework (https://osf.io/53gde/). A total of 19 articles were identified that reported pathogenic or likely pathogenic (P/LP) variants within MYH7, MYBPC3, TNNT2, TNNI3 and TPM1 genes, that included 16 singletons, one de novo and one digenic mutation (MYH7/ TPM1) associated with SCD among Indian patients. Evidence from functional studies and familial segregation implied a plausible mechanistic role of these P/LP variants in HCM pathology. This scoping review has compiled all the P/LP variants reported to-date among Indian patients and summarized their association with SCD. Single homozygous, de novo and digenic mutations were observed to be associated with severe phenotypes compared to single heterozygous mutations. The abstracted genetic information was updated with reference sequence ID (rsIDs) and compiled into freely accessible HCMvar database, available at https://hcmvar.heartfailure.org.in/. This can be used as a population specific genetic database for reference by clinicians and researchers involved in the identification of diagnostic and prognostic markers for HCM.

Charting a roadmap for heart failure research in India: Insights from a qualitative survey.

Background & objectives: Heart failure (HF) is emerging as a major health problem in India. The profile of HF in India is divergent from elsewhere in the world. While cardiologists must equip themselves with the requisite clinical management tools, scientists and health policymakers would need epidemiological data on HF and information on the resources required to meet the challenges ahead. The aim of this study was to identify the lacunae and to suggest recommendations to improve HF research. Methods: We surveyed a multidisciplinary group of HF experts using a two stage process. An email-based survey was conducted using a structured questionnaire, followed by an online discussion. The experts prioritized the major challenges in convergence research in India and inter-rater agreement values were calculated. In addition, they enlisted potential research gaps and barriers in the domains of epidemiology, diagnostics, management and technology and suggested recommendations to overcome those barriers. Results: The experts identified a paucity of data on HF burden, lack of state-of-the-art diagnostic facilities and trained personnel, overt dependence on imported devices/equipment/reagents, lack of interaction/awareness/information among stakeholders and lack of biobanks, as major barriers in HF research. Three fourths of the experts agreed that lack of interaction among stakeholders was the major challenge with the highest inter-rater agreement in both stages (19 out of 25 and 11 out of 17, respectively). The experts recommended the creation of multidisciplinary taskforces dedicated to population sciences, data sciences, technology development and patient management with short-, intermediate- and long-term strategies. Interpretation & conclusions: The study generated a wish list for advances in HF research and management, and proposed recommendations for facilitating convergence research as a way forward to reduce the burden of HF in India.

Clinical outcomes of bileaflet St. Jude Medical and tilting disc TTK Chitra mechanical heart valve prosthesis: A comparative study.

BACKGROUND: Comparative data on the clinical outcomes of TTK Chitra mechanical heart valve prosthesis (CHVP), an indigenously developed low-cost tilting disc valve and commonly used bileaflet valve, the St. Jude medical (SJM) prosthesis are sparse. METHODS: We conducted a retrospective follow-up study of consecutive patients undergoing mitral (MVR) and aortic valve replacement (AVR) with SJM or CHVP mechanical prostheses over a 6-year period at our institution. RESULTS: Seven hundred and thirty-five patients who underwent isolated MVR (n = 510) or AVR (n = 225) were included in the study. Patients with CHVP were younger and belonged to a lower socioeconomic class. The study cohort was followed-up for 2836 patient-years (SJM: 1865.1, CHVP: 971.0). All-cause mortality (p = 0.894), valve-related mortality (p = 0.681), prosthetic valve thrombosis (p = 0.155), embolism (p = 0.210), hemorrhage (p = 0.959) and infective endocarditis (IE, p = 0.084) were similar between both valve on follow-up. Estimated event free survival was 2302 ± 1 days in SJM as compared to 2484 ± 65 days in CHVP group (p = 0.393). Valve type was not an independent predictor of adverse events after adjusting for baseline data, time in therapeutic range and aspirin use. Subgroup analysis of patients who underwent MVR and AVR showed similar functional improvement and outcomes, except for a higher incidence of IE with SJM at the aortic position (p = 0.041). CONCLUSION: The indigenously developed, low-cost CHVP has comparable midterm clinical performance as SJM in aortic or mitral positions.

Transition during radiofrequency ablation of manifest preexcitation. What is the mechanism?

A 45-year-old lady was evaluated for recurrent episodes of palpitation. Her 12­lead electrocardiogram (ECG) showed manifest but incomplete pre-excitation consistent with left sided accessory pathway. There was no structural heart disease by echocardiogram. She underwent an electrophysiology (EP) study after informed consent. A narrow QRS tachycardia consistent with orthodromic AV re-entry got induced. The accessory pathway was mapped to 2 'O clock of the mitral annulus (MA). While radio frequency ablation (RFA) was being performed at that site, an interesting phenomenon was observed (Figs. 1 & 2). What is the mechanism?

Clinical profile & long-term natural history of symptomatic coronary artery disease in young patients (<30 yr).

Background & objectives: Several studies have shown a high prevalence of cardiovascular risk factors in patients in the age group of 30-74 yr, but there is a paucity of data in young patients below 30 yr. We analyzed the clinical and coronary angiographic profile of patients <30 yr of age with symptomatic coronary artery disease (CAD) and also assessed their intermediate and long-term outcomes. Methods: All patients less than 30 yr of age who presented with symptomatic CAD from 1978 to 2017 in the department of Cardiology of a tertiary care hospital in south India, were studied for coronary risk factors and angiographic and treatment patterns, and the follow up data were collected. Results: The mean age of the 159 patients <30 yr of age was 26.7±3.29 yr. Male preponderance was observed (91.8%), 63.5 per cent patients were smokers and 88.3 per cent were dyslipidaemic. Acute myocardial infarction was the most common mode of presentation. Forty one per cent patients were non-adherent to medications. Risk factor control was inadequate with respect to smoking cessation, alcoholism, physical activity and dietary regulation. The predictors of long-term mortality were multivessel CAD [hazard ratio (HR): 1.927, 95% confidence interval (CI): 1.003-3.701] and reduction in ejection fraction (EF) (10% decrease in EF; HR: 1.349, 95% CI: 1.096-1.662). Overall mortality was 30 per cent at 10 yr and 48 per cent at 20 yr. Interpretation & conclusions: Decreasing EF and multivessel involvement were found to be the strong correlates for long-term mortality in young patients below 30 yr of age with CAD. High long-term mortality rates and poor risk factor control suggest the vast scope for the improvement of outcomes in these patients with aggressive risk factor control.

Incidentally detected right aortic arch with mirror image branching in a patient with rheumatic calcific mitral valve disease.

An isolated right-sided aortic arch with no congenital heart disease is extremely rare. We report an adult woman with longstanding rheumatic heart disease causing severe calcific mitral stenosis, moderate mitral regurgitation and moderate pulmonary hypertension, for which she underwent mitral valve replacement and tricuspid annuloplasty. On preoperative work-up, she was detected to have a right-sided aortic arch with mirror image branching along with a ductal dimple. However, there were no associated congenital cardiac defects.

Clinical exome sequencing unravels the diverse spectrum of genetic heterogeneity and genotype-phenotype correlations in hypertrophic cardiomyopathy.

BACKGROUND: Catalogues of pathogenic genetic mutations in hypertrophic cardiomyopathy (HCM) are disproportionately small when compared to that of the size of the population with South Asian ancestry and their collective increased risk of heart disease. METHODS: We conducted clinical exome sequencing of 200 HCM patients to identified cardiomyopathy-associated genetic mutations. The clinical and echocardiographic characteristics of genotype-positive and genotype-negative patients were compared, and the likelihood of detecting a positive genetic test result was evaluated. Allelic burden analysis was done to compare the minor allele frequencies (MAF) of the pathogenic or likely pathogenic (P/LP) variants and variants of uncertain significance (VUSs) identified in the cohort against various population genomics databases. RESULTS: The genetic yield was 40% for P/LP variants, with MYBPC3 and MYH7 as the predominant sarcomere genes. Younger age-at-diagnosis, family history of HCM, asymmetric hypertrophic (ASH) pattern, the ratio of the interventricular septum to posterior wall thickness (IVS/PW ratio), left atrial (LA) dimensions, severe mitral regurgitation grade (MR grade), late gadolinium enhancement (LGE) detected fibrosis and absence of hypertension were associated with an increased likelihood of HCM-associated variants. Patients who experienced ventricular tachycardia and premature cardiovascular death were significantly likely to carry MYBPC3 or loss-of-function variants. LA and interventricular septal (IVS) dimensions were associated with MYH7 variants. The rare variant burden for P/LP variants and VUSs was significantly enriched in HCM cases compared to population controls. CONCLUSION: Our study provides a comprehensive evaluation of HCM-associated genetic mutations from an Indian population. The identified genotype-phenotype associations could improve the yield of targeted genetic testing in HCM.

Identification of novel endogenous control miRNAs in heart failure for normalization of qPCR data.

MicroRNAs (miRNAs), a class of non-coding RNAs, are utilized as biomarkers for a wide range of disorders. Circulating miRNAs are proposed as potential markers in the clinical identification of heart failure (HF). However, identifying miRNA biomarkers in HF requires identification of robust endogenous control miRNAs for normalization in differential expression analysis. Hence, this study aimed to identify circulating miRNAs that can be utilized as endogenous controls in HF. We evaluated the expression of eight miRNAs, which were previously reported as endogenous controls in different pathological conditions. Total RNA, including miRNA, was extracted from the serum samples of 30 HF patients (15 HFrEF and 15 HFpEF) and their matched controls (n = 15). We used quantitative PCR to determine the miRNA expression. The stability of the selected endogenous miRNAs was assessed and compared using a standard set of criteria with the RefFinder software. Six of the eight miRNAs analyzed showed consistent expression among all sample groups. Stability analysis ranked hsa-let-7i-5p, hsa-miR-148b-3p, and hsa-miR-484 as the most stable miRNAs, indicating their potential as reliable endogenous controls.

Utility of 3D Echocardiography for Device Sizing During Transcatheter ASD Closure: A Comparative Study.

BACKGROUND: Two-dimensional (2D) transesophageal echocardiography (TEE) is commonly used for assessing patients undergoing transcatheter atrial septal defect (ASD) device closure. 3D TEE, albeit providing high resolution en-face images of ASD, is used in only a fraction of cases. We aimed to perform a comparative analysis between 3D and 2D TEE assessment for ASD device planning. METHODS: This was a prospective, observational study conducted over a period of one year. Patients deemed suitable for device closure underwent 2D and 3D TEE at baseline. Defect characteristics, assessed separately in both modalities, were compared. Using regression analysis, we aimed to derive an equation for predicting device size using 3D TEE parameters. RESULTS: Thirty patients were included in the study, majority being females (83%). The mean age of the study population was 40.5 ± 12.05 years. Chest pain, dyspnea and palpitations were the common presenting complaints. All patients had suitable rims on 2D TEE. A good agreement was noted between 2D and 3D TEE for measured ASD diameters. 3D TEE showed that majority of defects were circular in shape (60%). The final device size used had high degree of correlation with 3D defect area and circumference. An equation was devised to predict device size using 3D defect area and circumference. The mean device size obtained from the equation was similar to the actual device size used in the study population (p = 0.31). CONCLUSIONS: Device sizing based on 3D TEE parameters alone is equally effective for transcatheter ASD closure as compared to 2D TEE.

Culprit Lesion Morphology on Optical Coherence Tomography in ST-elevation Myocardial Infarction vs Non ST-elevation Myocardial Infarction - A Systematic Review of 7526 Patients.

Background: Patients with STEMI are postulated to have different culprit lesion morphology compared to NSTEMI. The use of OCT in ACS can help delineate lesion morphology. The aim of this systematic review was to analyze the available data on culprit plaque morphology in ACS patients. Methods: The available literature was systematically screened for studies on culprit lesion morphology in ACS patients. Data was extracted from the selected studies and analyzed for baseline characteristics as well as culprit lesion morphology on OCT. Lesion characteristics between STEMI and NSTEMI groups were compared. Results: A total of 32 studies were selected for the final analysis. The average age of the study population was 62.4 years. Majority of patients (66.6%) had STEMI on presentation. NSTEMI patients had a higher prevalence of diabetes compared to STEMI. Both STEMI and NSTEMI patients had similar prevalence of thin-cap fibroatheroma (44.9%). The mean fibrous cap thickness was 84.2 µm in the study. STEMI patients had higher prevalence of lipid plaques, macrophages and luminal thrombus as compared to NSTEMI patients. Plaque rupture was the predominant culprit lesion morphology in both STEMI and NSTEMI groups, with higher prevalence in STEMI patients. Plaque erosion was also more common in STEMI patients (34.4% vs 13.2%). Conclusion: Plaque rupture is the predominat culprit lesion morphology in both STEMI and NSTEMI patients, despite having differences in baseline characteristics. Use of OCT to determine plaque morphology in ACS patients can help guide management strategy in select cases. [PROSPERO CRD42021249742].

Prevalence and Risk Factors of Periodontal Disease among Rural and Urban Residents of a South Indian City: A Cross-Sectional Study.

Background: The prevalence of oral diseases has been increasing alarmingly in the state of Kerala. Screening for periodontal disease (PD) is crucial due to its negative impact on oral and overall health. Since the occurrence and severity of PD depend on its risk factors, a structured survey in randomly selected districts in the state can be a valuable tool for policymakers to envisage strategies to enhance oral health care and control shared systemic illnesses. Data on the prevalence and risk factors of PD among the residents of the Thiruvananthapuram district of Kerala is not currently available in the public domain. This data could also be representative of the other 13 districts with more or less similar topographical, cultural, and lifestyle characteristics. Aim: To study the prevalence of PD and its risk factors among the residents of the Thiruvananthapuram district of Kerala and to compare the urban-rural differences. Materials and Methods: In this community-based cross-sectional study, a multistage cluster random sampling method was used to select the participants. Among the 1285 participants, 560 were from urban areas, and 725 were from rural areas. A modification of the Ramfjord PD index was used to assess periodontal health. The epidemiological risk factors were evaluated using sociodemographic data, personal histories, and physical and biochemical parameters. Multivariate logistic regression was used to determine the relationship of PD with independent variables. Mediation analysis was performed to examine the mediating effects of independent factors. Results: The rural population (61.4%) had a higher frequency of PD than the urban (35.5%) and an overall prevalence of 50%. Aging, poor oral hygiene, and low educational level (EL) were significant risk factors for PD in urban and rural settings, with hypertension only being significant in the latter. A higher odds ratio (9.07-29.68) with a confidence interval of (5.45-48.94) for poor oral hygiene was noted. Poor oral hygiene and tobacco use had mediating effects between low EL and PD. Conclusions: In this study, the overall prevalence of PD was 50%, with the rural population being more afflicted. Poor oral hygiene has been identified as a modifiable risk factor for PD in urban and rural populations. Poor oral hygiene and tobacco use have been demonstrated to be mediators of the strong link between low EL and PD. Therefore, this study reiterates the need for better oral health awareness and treatment facilities to minimize the impact of the above risk factors on the periodontium. A shared risk relationship between PD and hypertension in the rural population emphasizes the need for an integrated approach to public health by including oral health as part of noncommunicable disease prevention and intervention programs.

Development and validation of heart failure-specific quality-of-life measurement tool in India.

Objective: To develop and validate a sensitive tool for assessment of quality of life (QoL) in heart failure (HF) patients in Indian settings. Methods: The authors conducted literature review, in depth interviews, clinical observations and designed the first draft of the QoL tool. The tool was validated using content and face validity by a panel of experts. For internal consistency reliability, the questionnaire was administered among 270 HF patients. Test-retest reliability was assessed in 20 HF patients. Principal component factor analysis with varimax rotation was employed to assess the dimensionality and to reduce the number of items. Cronbach's alpha, and Intra-class correlation coefficients (ICCs) were employed to investigate reliability of questionnaire. The responsiveness data were collected 6 months after the baseline data collection from 30 HF patients. IBM® SPSS® Statistics Version 21 was used for statistical analysis. Results: The principal component factor analysis revealed mainly 5 domains. The final tool included 25 items. Cronbach's alpha (α) for the overall tool was 0.915. Intra-class correlation coefficients (ICCs) based on test-retest was 0.734. The final tool showed good responsiveness to changes with a mean ± SD of the change in response of 46 ± 12.4 and a standardized mean response of 3.7 within six-months. Conclusion: The HF specific QoL tool developed for Indian patients is a valid and reliable instrument and it can be applied in daily clinical practice, and research. Short summary: We had developed and validated a quality-of-life tool for heart failure patients in India. This is the first ever attempt to develop a measure for heart failure patients in India. We had used a mixed methodology approach to identify all the domains in the tool. The newly developed tool is a valid, reliable, sensitive and responsive tool to measure quality of life in HF patients in India. This tool can be applied in daily clinical practice, research and health system for patients with HF in India.

Team based collaborative care model, facilitated by mHealth enabled and trained nurses, for management of heart failure with reduced ejection fraction in India (TIME-HF): design and rationale of a parallel group, open label, multi-centric cluster randomised controlled trial.

Background: Heart failure (HF) is a debilitating condition associated with enormous public health burden. Management of HF is complex as it requires care-coordination with different cadres of health care providers. We propose to develop a team based collaborative care model (CCM), facilitated by trained nurses, for management of HF with the support of mHealth and evaluate its acceptability and effectiveness in Indian setting. Methods: The proposed study will use mixed-methods research. Formative qualitative research will identify barriers and facilitators for implementing CCM for the management of HF. Subsequently, a cluster randomised controlled trial (RCT) involving 22 centres (tertiary-care hospitals) and more than 1500 HF patients will be conducted to assess the efficacy of the CCM in improving the overall survival as well as days alive and out of hospital (DAOH) at two-years (CTRI/2021/11/037797). The DAOH will be calculated by subtracting days in hospital and days from death until end of study follow-up from the total follow-up time. Poisson regression with a robust variance estimate and an offset term to account for clustering will be employed in the analyses of DAOH. A rate ratio and its 95% confidence interval (CI) will be estimated. The scalability of the proposed intervention model will be assessed through economic analyses (cost-effectiveness) and the acceptability of the intervention at both the provider and patient level will be understood through both qualitative and quantitative process evaluation methods. Potential Impact: The TIME-HF trial will provide evidence on whether a CCM with mHealth support is effective in improving the clinical outcomes of HF with reduced ejection fraction in India. The findings may change the practice of management of HF in low and middle-income countries.

Comparative study on safety, efficacy, and midterm results of balloon mitral valvotomy performed with triple lumen and double lumen mitral valvotomy catheters.

BACKGROUND: The triple lumen Inoue balloon is routinely used for balloon mitral valvotomy (BMV) in India. Its major limitation is the high cost. The double lumen Accura balloon is less expensive, making it an attractive alternative in the developing countries. The study was meant to assess the safety, efficacy and midterm results of Accura balloon with respect to the Inoue balloon. PATIENTS AND METHODS: 816 consecutive patients, who underwent elective BMV in this Institute from 1997 to 2003, were included in the study. The data of 487 patients who underwent BMV with Accura balloon was compared with 329 patients who underwent BMV with Inoue balloon. The clinical, echocardiographic, and hemodynamic data of these patients were analyzed retrospectively to assess the safety and efficacy of Accura balloon with respect to the Inoue balloon. RESULTS: Immediate procedural success (93.9% in Inoue group and 91.6% in Accura group p. NS) and complications (6.6% in Inoue group and 5.6% in Accura group p. NS) were comparable between the study groups. The two study population had similar restenosis rate and events at 1 year after BMV. Both balloons could be reused multiple times without compromising on the safety and effectiveness. Accura balloons were less costly than Inoue balloon. The reusability with Accura was slightly more and found to be more cost-effective. CONCLUSIONS: Both Accura and Inoue balloon mitral valvotomy balloons are effective in providing relief from hemodynamically significant mitral stenosis in terms of gain in valve area and reduction in trans mitral gradient. Both groups have similar procedural success and complication rates, restenosis, and follow-up events at 1 year. Both balloons could be reused multiple times and Accura balloon is found to be more cost effective.

A multicentric, 2 × 2 factorial, randomised, open-label trial to evaluate the clinical effectiveness of structured physical activity training and cognitive behavioural therapy versus usual care in heart failure patients: a protocol for the PACT-HF trial.

Background: Heart failure (HF) is a multi-morbid chronic condition, which adversely affects the quality of life of the affected individual. Engaging the patient and their caregivers in self-care is known to reduce mortality, rehospitalisation and improve quality of life among HF patients. The PACT-HF trial will answer whether clinical benefits in terms of mortality and hospitalisation outcomes can be demonstrated by using a pragmatic design to explore the specific effects of physical activity, and cognitive behavioural therapy in HF patients in India. Methods: We will conduct a 2 × 2 factorial, randomized, open-label trial, which aims to see if rehabilitation strategies of structured physical activity training and cognitive behavioural therapy for depression and self-management reduce the risk of repeat hospitalisation and deaths in HF patients in India. Patients will be randomised to (1) physical activity + usual care (2) cognitive behaviour therapy + usual care, (3) physical activity + cognitive behaviour therapy + usual care, and (4) usual care at 1:1:1:1 ratio. Time to mortality will be the primary outcome. A composite of mortality and hospitalisation for HF will be the main secondary outcome. Additional secondary outcomes will include 'days alive and out of hospital', cumulative hospitalisation, quality of life, Minnesota Living with Heart Failure questionnaire score, depression score, six minutes walking distance, handgrip strength, and adherence to medicines and lifestyle.  The effects of intervention on the primary outcome will be estimated from Cox proportional hazard models. For the continuous secondary outcome variables, differences between randomised groups will be estimated from linear mixed models or generalised estimating equations (GEE) as appropriate. Discussion: PACT-HF is designed to provide reliable evidence about the balance of benefits and risks conferred by physical activity and cognitive behavioural therapy-based cardiac rehabilitation for those with HF, irrespective of their initial disease severity.

The traditional and modifiable risk factors of coronary artery disease - a community-based cross-sectional study among 2 populations.

ABSTRACT: A community-based cross-sectional study was undertaken by the Cardiology Society of India (Kerala Chapter) to determine the prevalence of coronary artery disease (CAD) and its risk factors. The periodontal health status of the rural and urban participants in the Thiruvananthapuram district of Kerala was evaluated to document any association between periodontal disease (PD) and CAD and to describe any shared risk factors.The participants were selected using a multistage cluster random sampling method. Socio-demographic data and personal histories were collected using a structured interview schedule and validated tools. Body mass index, blood pressure, electrocardiogram, and biochemical investigations were recorded and analyzed using standard protocols. A modification of the Ramfjord periodontal disease index was used to assess periodontal health.PD was more frequent among rural (61.4%) than in the urban population (35.5%). The frequencies of CAD associated with PD in the rural and urban populations were 82.6% and 40.5%, respectively. PD was not found to be a significant risk factor for CAD in the univariate regression analysis of urban populations. In the rural population, the odds of PD as a risk factor for CAD were found to be 3.08 (95% CI [1.38-8.38]) and significant (P = .043) in univariate regression analysis and 1.54 (95% CI: 0.44-5.4) and non-significant (P = .503) in the multivariate regression analysis.In rural areas, male sex and dyslipidemia demonstrated borderline significance as risk factors for CAD. PD was not found to be an independent risk factor after adjusting for age, sex, tobacco use, hypertension, sedentary lifestyle, and dyslipidemia. Male sex and dyslipidemia were identified as shared risk factors between PD and CAD, which could have confounded the significant association between the latter. In urban areas, age, male sex, and dyslipidemia demonstrated an independent association with CAD. This study could not establish an independent association between PD and CAD in either community. Future epidemiological studies should identify and recruit novel environmental factors to understand the interrelationships between PD and CAD and focus on the role of effect modifiers that may have a protective role against PD colluding with CAD.

Efficacy of a family-based cardiovascular risk reduction intervention in individuals with a family history of premature coronary heart disease in India (PROLIFIC): an open-label, single-centre, cluster randomised controlled trial.

BACKGROUND: Coronary heart disease, a leading cause of death globally, is amenable to lifestyle interventions. The family environment can affect the ability or willingness of individuals to make lifestyle changes. We aimed to investigate the efficacy of a targeted family-based intervention for reduction of total cardiovascular risk in individuals with a family history of premature coronary heart disease. METHODS: We did an open-label, cluster randomised controlled trial (PROLIFIC) in the families (first-degree relatives and spouses, older than age 18 years) of individuals with coronary heart disease who had been diagnosed before age 55 years. Patients with coronary heart disease diagnosed within the past year were selected from a tertiary care speciality hospital that provides care for patients from Kerala, India. Family members of selected patients who were bedridden or terminally ill, and individuals with a history of established cardiovascular heart disease and stroke were excluded, as were families with fewer than two eligible family members. Simple randomisation with computer-generated random numbers was used to randomly assign families to intervention and usual care groups (1:1). Participants in the intervention group received a comprehensive package of interventions facilitated by non-physician health workers, consisting of: screening for cardiovascular risk factors; structured lifestyle interventions; linkage to a primary health-care facility for individuals with established chronic disease risk factors or conditions; and active follow-up for adherence. The usual care group received one-time counselling and annual screening for risk factors. We obtained data on lifestyle, clinical, and biochemical characteristics at baseline and annually during the 2-year follow-up. The primary outcome was achievement or maintenance of any three of the following: blood pressure lower than 140/90 mm Hg, fasting plasma glucose lower than 110 mg/dL, low-density lipoprotein cholesterol lower than 100 mg/dL, and abstinence from tobacco. The primary outcome was analysed in all participants available for follow-up at the relevant timepoint. This trial is registered with Clinicaltrials.gov, NCT02771873. FINDINGS: From Jan 1, 2015, to April 30, 2017, 980 patients with coronary heart disease were assessed for eligibility and 230 were excluded primarily due to lack of evidence of coronary artery disease (n=199), or a diagnosis of coronary heart disease more than 1 year previously (n=29). Of the 750 remaining families, 368 (with 825 participants) were assigned to the intervention group and 382 (with 846 participants) were assigned to the usual care group. At the 2-year follow-up, data from 803 (97%) of 825 participants in the intervention group and 819 (97%) of 846 participants in the usual care group were available. Of the 1671 participants, 1111 (66·5%) were women, and 560 (33·5%) were men. The mean age of the study population was 40·8 years (SD 14·2). At the 2-year follow-up, the primary outcome was achieved by 514 (64%) of 803 participants in the intervention group and 379 (46%) of 819 in the usual care group. After adjustment for clustering and baseline risk factors, the odds of achieving the primary outcome at the 2-year timepoint was two times higher in the intervention group than in the usual care group (odds ratio 2·2, 95% CI 1·7-2·7; p<0·0001). INTERPRETATION: The reduction of total cardiovascular risk observed after the intervention could have a substantial public health impact by preventing future cardiovascular events. FUNDING: The Wellcome Trust and Department of Biotechnology, Government of India, and India Alliance.