The Promise of Cilnidipine in Hypertension with Comorbidities: National Consensus Statement: National Consensus Group Comprises Cardiologists, Nephrologists, and Diabetologists from India in a National Meet at New Delhi held on 22nd May 2022.

The rapidly increasing burden of hypertension is responsible for premature deaths from cardiovascular disease (CVD), renal disease, and stroke, with a tremendous public health and financial burden. Hypertension detection, treatment, and control vary worldwide; it is still low, particularly in low- and middle-income countries (LMICs). High blood pressure (BP) and CVD risk have a strong, linear, and independent association. They contribute to alarming numbers of all-cause and CVD deaths. A major culprit for increased hypertension is sympathetic activity, and further complications of hypertension are heart failure, ischemic heart disease (IHD), stroke, and renal failure. Now, antihypertensive interventions have emerged as a global public health priority to reduce BP-related morbidity and mortality. Calcium channel blockers (CCB) are highly effective vasodilators. and the most common drugs used for managing hypertension and CVD. Cilnidipine, with both L- and N-type calcium channel blocking activity, is a promising 4th generation CCB. It causes vasodilation via L-type calcium channel blockade and inhibits the sympathetic nervous system (SNS) via N-type calcium channel blockade. Cilnidipine, which acts as a dual L/N-type CCB, is linked to a reduced occurrence of pedal edema compared to amlodipine, which solely blocks L-type calcium channels. The antihypertensive properties of cilnidipine are very substantial, with low BP variability and long-acting properties. It is beneficial for hypertensive patients to deal with morning hypertension and for patients with abnormal nocturnal BP due to exaggerated sympathetic nerve activation. Besides its BP-lowering effect, it also exhibits organ protection via sympathetic nerve inhibition and renin-angiotensin-aldosterone system inhibition; it controls heart rate and proteinuria. Reno-protective, neuroprotective, and cardioprotective effects of cilnidipine have been well-documented and demonstrated.

Effects of initial invasive vs. initial conservative treatment strategies on recurrent and total cardiovascular events in the ISCHEMIA trial.

AIMS: The International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial prespecified an analysis to determine whether accounting for recurrent cardiovascular events in addition to first events modified understanding of the treatment effects. METHODS AND RESULTS: Patients with stable coronary artery disease (CAD) and moderate or severe ischaemia on stress testing were randomized to either initial invasive (INV) or initial conservative (CON) management. The primary outcome was a composite of cardiovascular death, myocardial infarction (MI), and hospitalization for unstable angina, heart failure, or cardiac arrest. The Ghosh-Lin method was used to estimate mean cumulative incidence of total events with death as a competing risk. The 5179 ISCHEMIA patients experienced 670 index events (318 INV, 352 CON) and 203 recurrent events (102 INV, 101 CON). A single primary event was observed in 9.8% of INV and 10.8% of CON patients while ≥2 primary events were observed in 2.5% and 2.8%, respectively. Patients with recurrent events were older; had more frequent hypertension, diabetes, prior MI, or cerebrovascular disease; and had more multivessel CAD. The average number of primary endpoint events per 100 patients over 4 years was 18.2 in INV [95% confidence interval (CI) 15.8-20.9] and 19.7 in CON (95% CI 17.5-22.2), difference -1.5 (95% CI -5.0 to 2.0, P = 0.398). Comparable results were obtained when all-cause death was substituted for cardiovascular death and when stroke was added as an event. CONCLUSIONS: In stable CAD patients with moderate or severe myocardial ischaemia enrolled in ISCHEMIA, an initial INV treatment strategy did not prevent either net recurrent events or net total events more effectively than an initial CON strategy. CLINICAL TRIAL REGISTRATION: ISCHEMIA ClinicalTrials.gov number, NCT01471522, https://clinicaltrials.gov/ct2/show/NCT01471522.

Causes of cardiovascular and noncardiovascular death in the ISCHEMIA trial.

BACKGROUND: The International Study of Comparative Health Effectiveness with Medical and Invasive Approaches trial demonstrated no overall difference in the composite primary endpoint and the secondary endpoints of cardiovascular (CV) death/myocardial infarction or all-cause mortality between an initial invasive or conservative strategy among participants with chronic coronary disease and moderate or severe myocardial ischemia. Detailed cause-specific death analyses have not been reported. METHODS: We compared overall and cause-specific death rates by treatment group using Cox models with adjustment for pre-specified baseline covariates. Cause of death was adjudicated by an independent Clinical Events Committee as CV, non-CV, and undetermined. We evaluated the association of risk factors and treatment strategy with cause of death. RESULTS: Four-year cumulative incidence rates for CV death were similar between invasive and conservative strategies (2.6% vs 3.0%; hazard ratio [HR] 0.98; 95% CI [0.70-1.38]), but non-CV death rates were higher in the invasive strategy (3.3% vs 2.1%; HR 1.45 [1.00-2.09]). Overall, 13% of deaths were attributed to undetermined causes (38/289). Fewer undetermined deaths (0.6% vs 1.3%; HR 0.48 [0.24-0.95]) and more malignancy deaths (2.0% vs 0.8%; HR 2.11 [1.23-3.60]) occurred in the invasive strategy than in the conservative strategy. CONCLUSIONS: In International Study of Comparative Health Effectiveness with Medical and Invasive Approaches, all-cause and CV death rates were similar between treatment strategies. The observation of fewer undetermined deaths and more malignancy deaths in the invasive strategy remains unexplained. These findings should be interpreted with caution in the context of prior studies and the overall trial results.

Prolapsing giant right atrial myxoma in a young male presenting as pulmonary embolism.

A 22-year male presented with complaints of dyspnea. Multimodality imaging revealed a polypoidal right atrial mass with submassive pulmonary embolism. The patient underwent urgent surgery. The pathological examination confirmed it as cardiac myxoma. Cardiac myxoma, a most common primary cardiac tumor, is commonly found in the left atrium. The right atrium is an uncommon site and the usual mode of presentation is the tumor or thrombus embolization to the pulmonary circulation.

Various Factors that are Causing Difference in Prevalence of Coronary Risk Factors among Siblings.

BACKGROUND AND AIM: Coronary artery disease (CAD) is one of the predominant types of cardiovascular disease (CVD). The aim of present study was to study various factors that are causing difference in prevalence of coronary risk factors among siblings. MATERIALS AND METHODS: This cross-sectional study was conducted in Dayanand Medical College and Hospital, among the healthy individuals (not known CAD) attending regular health care outpatient department (OPD) and their siblings over a period of 1½ years. All individuals coming for regular health checkup (not known CAD) of age more than 30 years or above and their siblings (with or without known CAD). RESULTS: This was a cross-sectional study, conducted among 100 pairs of healthy siblings (not known cases of CAD) who came for health checkup at health center of Dayanand Medical College and Hospital, a tertiary care hospital in North India. Prevalence of obesity was more in siblings living in urban area than their counter siblings living in rural area, but it was statistically insignificant. Six had impaired fasting blood sugar (FBS) and two were diabetic. Among their siblings living in urban area, 21 were nondiabetic, 10 had impaired FBS, and seven were diabetic. This correlation was statistically significant with p-value of 0.02. Among the CAD negative, out of 23 subjects, two subjects (9.0%) had heavy stress level, while remaining four subjects (17.0%) and 17 subjects (74.0%) had light and moderate stress levels, respectively. Among the CAD negative, out of 23 subjects, 10 subjects (43.0%) had high stress level, while remaining zero subject (0%) and 13 subjects (57.0%) had light and moderate stress levels, respectively. Significant results were obtained while comparing the CAD findings of subjects divided on the basis of stress level. CONCLUSION: In our study, among siblings (CAD positive and CAD negative), significant results were obtained for residence, socioeconomic class, physical activity, stress levels, smoking, waist-to-hip ratio (WHR), and diabetes, that is, all these factors have correlation in increasing CAD among siblings.

A Bidirectional Mendelian Randomization Study to evaluate the causal role of reduced blood vitamin D levels with type 2 diabetes risk in South Asians and Europeans.

CONTEXT: Multiple observational studies have reported an inverse relationship between 25-hydroxyvitamin D concentrations (25(OH)D) and type 2 diabetes (T2D). However, the results of short- and long-term interventional trials concerning the relationship between 25(OH)D and T2D risk have been inconsistent. OBJECTIVES AND METHODS: To evaluate the causal role of reduced blood 25(OH)D in T2D, here we have performed a bidirectional Mendelian randomization study using 59,890 individuals (5,862 T2D cases and 54,028 controls) from European and Asian Indian ancestries. We used six known SNPs, including three T2D SNPs and three vitamin D pathway SNPs, as a genetic instrument to evaluate the causality and direction of the association between T2D and circulating 25(OH)D concentration. RESULTS: Results of the combined meta-analysis of eight participating studies showed that a composite score of three T2D SNPs would significantly increase T2D risk by an odds ratio (OR) of 1.24, p = 1.82 × 10-32; Z score 11.86, which, however, had no significant association with 25(OH)D status (Beta -0.02nmol/L ± SE 0.01nmol/L; p = 0.83; Z score -0.21). Likewise, the genetically instrumented composite score of 25(OH)D lowering alleles significantly decreased 25(OH)D concentrations (-2.1nmol/L ± SE 0.1nmol/L, p = 7.92 × 10-78; Z score -18.68) but was not associated with increased risk for T2D (OR 1.00, p = 0.12; Z score 1.54). However, using 25(OH)D synthesis SNP (DHCR7; rs12785878) as an individual genetic instrument, a per allele reduction of 25(OH)D concentration (-4.2nmol/L ± SE 0.3nmol/L) was predicted to increase T2D risk by 5%, p = 0.004; Z score 2.84. This effect, however, was not seen in other 25(OH)D SNPs (GC rs2282679, CYP2R1 rs12794714) when used as an individual instrument. CONCLUSION: Our new data on this bidirectional Mendelian randomization study suggests that genetically instrumented T2D risk does not cause changes in 25(OH)D levels. However, genetically regulated 25(OH)D deficiency due to vitamin D synthesis gene (DHCR7) may influence the risk of T2D.

APOC3 genetic variation, serum triglycerides, and risk of coronary artery disease in Asian Indians, Europeans, and other ethnic groups.

BACKGROUND: Hypertriglyceridemia has emerged as a critical coronary artery disease (CAD) risk factor. Rare loss-of-function (LoF) variants in apolipoprotein C-III have been reported to reduce triglycerides (TG) and are cardioprotective in American Indians and Europeans. However, there is a lack of data in other Europeans and non-Europeans. Also, whether genetically increased plasma TG due to ApoC-III is causally associated with increased CAD risk is still unclear and inconsistent. The objectives of this study were to verify the cardioprotective role of earlier reported six LoF variants of APOC3 in South Asians and other multi-ethnic cohorts and to evaluate the causal association of TG raising common variants for increasing CAD risk. METHODS: We performed gene-centric and Mendelian randomization analyses and evaluated the role of genetic variation encompassing APOC3 for affecting circulating TG and the risk for developing CAD. RESULTS: One rare LoF variant (rs138326449) with a 37% reduction in TG was associated with lowered risk for CAD in Europeans (p = 0.007), but we could not confirm this association in Asian Indians (p = 0.641). Our data could not validate the cardioprotective role of other five LoF variants analysed. A common variant rs5128 in the APOC3 was strongly associated with elevated TG levels showing a p-value 2.8 × 10- 424. Measures of plasma ApoC-III in a small subset of Sikhs revealed a 37% increase in ApoC-III concentrations among homozygous mutant carriers than the wild-type carriers of rs5128. A genetically instrumented per 1SD increment of plasma TG level of 15 mg/dL would cause a mild increase (3%) in the risk for CAD (p = 0.042). CONCLUSIONS: Our results highlight the challenges of inclusion of rare variant information in clinical risk assessment and the generalizability of implementation of ApoC-III inhibition for treating atherosclerotic disease. More studies would be needed to confirm whether genetically raised TG and ApoC-III concentrations would increase CAD risk.

Incremental benefit of three-dimensional transthoracic echocardiography in the assessment of left atrial appendage aneurysm leading to severe extrinsic compression of a coronary artery.

Left atrial appendage aneurysm (LAA AN) is a rare disease entity, which can be congenital or acquired in nature. We report an adult patient with LAA AN presenting with anginal chest pain in whom live/real time three-dimensional transthoracic echocardiography (3DTTE) provided incremental value over the two-dimensional (2D) technique in providing a more comprehensive assessment of the lesion. A literature review of the salient features of LAA AN is also provided in a tabular form.

Knowledge about Informed Consent among Doctors of Various Specialities: A Pilot Survey.

BACKGROUND: Informed consent is an integral part of clinical practice. Improper informed consent can lead to mistrust between doctors and patients as well as medico-legal issues. Awareness and knowledge of various aspects of consent is essential in present day medical practice. METHODS: A paper and web-based survey was undertaken to evaluate knowledge about informed consent among doctors. A law and a medical student generated a list of questions based upon available case laws and legislations which were further validated by experts. 500 doctors undertook the survey and of these 457 completed the survey of 18 questions. Both univariate and multivariate models were used to analyze responses. RESULTS: 413 complete questionnaires were included in the analysis. The proportion of respondents furnishing correct responses varied between 49.6% and 93.7%. There were 9 questions for which, over 25% respondents provided inappropriate responses. The questions included those enquiring whether initial consent for diagnostic or therapeutic procedures could apply to extended procedures or surgery and who was capable of giving consent for different procedures. There were significant differences of knowledge between residents and consultants for few questions. The physicians fared worse than surgeons and anesthetists although the difference was not statistically significant. CONCLUSION: Significant knowledge gaps were identified. There were deficiencies in providing correct response particularly in practical scenarios. There is a need to include knowledge about different aspects of informed consent in the medical curriculum.

Rosuvastatin: Role in Secondary Prevention of Cardiovascular Disease.

Cardiovascular (CV) diseases are a major cause of premature death and disability. Non-communicable diseases (NCD) are responsible for 52% of mortality amongst Indians, of these CV diseases are responsible for 66% of NCD mortality in India. We not only need widespread primary preventive strategy but also need effective secondary prevention protocols to reduce this. Secondary prevention in patients who already had myocardial infarction (MI) or revascularization is of utmost importance to reduce mortality, cardiac events and improve quality of life. Lifestyle changes and medical therapy have a very important role in secondary prevention of CVD. Optimal control of hypertension, diabetes mellitus and dyslipidemia plays a critical role in secondary prevention. Statins are one of the most commonly used drugs in secondary prevention as a part of medical therapy. Effective LDL reduction, more patients achieving LDL goals, reduction in intima thickness, improvement in endothelial dysfunction, reduction in inflammatory markers are considered to be surrogate markers of reduced risk with statins. Rosuvastatin is one of the two most commonly used statins. It is a potent, effective and safe HMG-COA reductase inhibitor. Data related to secondary prevention is limited with rosuvastatin. Most of the clinical evidences with rosuvastatin have shown more effective LDL reduction than other statins. More number of patients achieve LDL goals and reduction in intima thickness. This article attempts to explore data on role of rosuvastatin for secondary prevention.

Lipid management in India: a nationwide, cross-sectional physician survey.

BACKGROUND: Current international guidelines on dyslipidemia are not concordant on various aspects of management. Also, there are no uniformly accepted Indian guidelines. We, therefore, performed a physician survey to understand lipid management practices in India. METHODS: An anonymous survey questionnaire was administered to gauge physicians' self-reported behavior regarding lipid management aspects. Results were expressed in terms of percentages based on the number of responses obtained. RESULTS: A total of 404 physicians participated in the survey. Eighty-eight percent respondents ordered a lipid profile before starting statin therapy, and 80% preferred to set lipid targets, though the tools used for calculating cardiovascular risk varied. Atorvastatin was preferred over rosuvastatin in primary prevention (72.9 vs. 32.4%), secondary prevention (54.6 vs. 46.7%), diabetic patients (56.3 vs. 40.3%) and post-ACS (78.3 vs. 34%). High-intensity statins were preferred by 73.7% of respondents in post-ACS cases. Fifty percent doctors chose not to use a statin in diabetic patients, irrespective of their LDL-C levels. The most preferred drug option for managing atherogenic dyslipidemia and moderate hypertriglyceridemia was statin-fibrate combination (55.1%) and fibrates (35.4%), respectively. Sixty-three percent doctors preferred to prescribe statins in patients with moderately high LDL-C and normal triglycerides, without CHD or CHD risk equivalents. Around 28% of doctors preferred not to use pharmacotherapy for managing isolated low HDL. Of the participants, 73% used fibrates in ≤20% of their dyslipidemic patients, with fenofibrate being the most preferred (90.5%). Ezetimibe was mainly used in patients with uncontrolled LDL-C despite statin therapy (52.4% respondents). Most preferred approaches to manage statin intolerance included reducing statin dose (39%) and stopping and restarting statins at a lower dose (34.5%). Fifty-two percent of doctors chose not to alter pre-existing therapy in patients who had LDL-C levels at goal but elevated non-HDL-C levels. CONCLUSION: This is the first survey in India that provides useful insights into Indian physicians' self-reported perspectives on managing dyslipidemia in routine clinical practice. Despite concordance with the currently available guidelines in certain aspects, there is incongruence in managing specific dyslipidemia problems. Further continuing medical education and the development of evidence-based, India-specific lipid guidelines can help reduce some of these differences.

Unilateral Pulmonary Artery Agenesis in an Elderly Female.

Unilateral pulmonary artery agenesis (UPAA) is a rare congenital anomaly due to a malformation of the sixth aortic arch of the affected side during embryogenesis. It can occur in isolation or may be associated with other congenital cardiovascular malformations. The diagnosis is usually set at adolescence, however it can remain asymptomatic and late diagnosis is possible. Recurrent pulmonary infections, decreased exercise tolerance, and shortness of breath on exertion are the most common symptoms.

Polygenic Risk Score Assessment for Coronary Artery Disease in Asian Indians.

We evaluated the performance of various polygenic risk score (PRS) models derived from European (EU), South Asian (SA), and Punjabi Asian Indians (AI) studies on 13,974 subjects from AI ancestry. While all models successfully predicted Coronary artery disease (CAD) risk, the AI, SA, and EU + AI were superior predictors and more transportable than the EU model; the predictive performance in training and test sets was 18% and 22% higher in AI and EU + AI models, respectively than in EU. Comparing individuals with extreme PRS quartiles, the AI and EU + AI captured individuals with high CAD risk showed 2.6 to 4.6 times higher efficiency than the EU. Interestingly, including the clinical risk score did not significantly change the performance of any genetic model. The enrichment of diversity variants in EU PRS improves risk prediction and transportability. Establishing population-specific normative and risk factors and inclusion into genetic models would refine the risk stratification and improve the clinical utility of CAD PRS.

Comparison of the efficacy, safety, and tolerability of the FDC of telmisartan + bisoprolol with telmisartan + metoprolol succinate ER combination therapy for stage 1 and stage 2 hypertension: A double-blind, multicentric, phase-III clinical study.

AIM: The present study compared the safety, efficacy, and tolerability of the new fixed-dose combination (FDC) of telmisartan 40 mg + bisoprolol 5 mg (TBP) tablets with the existing comparator FDC telmisartan 40 mg + metoprolol succinate ER 50 mg (TMS) tablets in patients with stage 1 and stage 2 hypertension. METHODOLOGY: The multicentric, double-blind, parallel-group, comparative, prospective, phase-III clinical study involved 264 subjects with stage 1 and stage 2 hypertension from 10 centres across India. The selected subjects were randomized into two groups: group A received the TMS and group B received the new FDC TBP. The primary endpoint was the mean change in seated systolic blood pressure (SeSBP) and seated diastolic blood pressure (SeDBP) from baseline to week 12 in both the control and study arms. The secondary endpoint was achieving the target of SeSBP <140 mmHg and SeDBP <90 mmHg from baseline to week 12 in both groups. Safety and tolerability parameters were evaluated in both groups based on adverse effects (AEs) reported by the patients and the physician. RESULTS: Both treatment groups exhibited a reduction in BP after 2 weeks of treatment, which was sustained until 12 weeks. The mean change in SeSBP and SeDBP at weeks 2, 6, and 12 compared to the previous visit showed statistical significance (p < 0.001) in all cases for both groups A and B. The mean changes in SeSBP and SeDBP from baseline to study end were numerically higher in group B than in group A. The mean difference in SeSBP from baseline to study end was significantly higher in group B compared to group A (p = 0.029). By week 12, 88.28 % and 89.84 % of subjects in group B achieved SeSBP <140 mmHg and SeDBP <90 mmHg respectively, while 86.71 % and 91.40 % of subjects in group A achieved the same targets. Reported AEs were mostly mild to moderate in both treatment groups, and no serious AEs or deaths were reported. Tolerability was rated as 'excellent' by 93.75 % of subjects in group B and 91.40 % of subjects in group A. CONCLUSION: Both the new FDC TBP and the existing comparator TMS combination therapy have comparable efficacy, tolerability, and safety for the management of stage 1 and stage 2 hypertension. TRIAL REGISTRY NAME: Clinical Trials Registry of India (CTRI) TRIAL REGISTRATION NO: CTRI/2021/11/037,926 PROTOCOL NO: MLBTL/05/2021 PROTOCOL URL: https://ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=62069&EncHid=&userName=bisoprolol.

Assessing the prediction of type 2 diabetes risk using polygenic and clinical risk scores in South Asian study populations.

Background: Genome-wide polygenic risk scores (PRS) have shown high specificity and sensitivity in predicting type 2 diabetes (T2D) risk in Europeans. However, the PRS-driven information and its clinical significance in non-Europeans are underrepresented. We examined the predictive efficacy and transferability of PRS models using variant information derived from genome-wide studies of Asian Indians (AIs) (PRSAI) and Europeans (PRSEU) using 13,974 AI individuals. Methods: Weighted PRS models were constructed and analyzed on 4602 individuals from the Asian Indian Diabetes Heart Study/Sikh Diabetes Study (AIDHS/SDS) as discovery/training and test/validation datasets. The results were further replicated in 9372 South Asian individuals from UK Biobank (UKBB). We also assessed the performance of each PRS model by combining data of the clinical risk score (CRS). Results: Both genetic models (PRSAI and PRSEU) successfully predicted the T2D risk. However, the PRSAI revealed 13.2% odds ratio (OR) 1.80 [95% confidence interval (CI) 1.63-1.97; p = 1.6 × 10-152] and 12.2% OR 1.38 (95% CI 1.30-1.46; p = 7.1 × 10-237) superior performance in AIDHS/SDS and UKBB validation sets, respectively. Comparing individuals of extreme PRS (ninth decile) with the average PRS (fifth decile), PRSAI showed about two-fold OR 20.73 (95% CI 10.27-41.83; p = 2.7 × 10-17) and 1.4-fold OR 3.19 (95% CI 2.51-4.06; p = 4.8 × 10-21) higher predictability to identify subgroups with higher genetic risk than the PRSEU. Combining PRS and CRS improved the area under the curve from 0.74 to 0.79 in PRSAI and 0.72 to 0.75 in PRSEU. Conclusion: Our data suggest the need for extending genetic and clinical studies in varied ethnic groups to exploit the full clinical potential of PRS as a risk prediction tool in diverse study populations.