Traditional and novel non-statin lipid-lowering drugs.

Non-statin drugs find utility in the management of dyslipidaemia in mixed dyslipidaemia, patients with statin intolerance, and when guidelines directed low-density lipoprotein cholesterol (LDL-C) target cannot be achieved despite maximally tolerated statin. The most definite indication of fenofibrate monotherapy is fasting serum triglyceride >500 mg/dl to reduce the risk of acute pancreatitis It offers a modest reduction in cardiovascular events. The statin-ezetimibe combination is commonly used for lipid lowering particularly after ACS. Fish oils reduce serum triglycerides by about 25 %. EPA (and not DHA) seems to have cardioprotective effects. Despite cardiovascular outcome benefits, bile-exchange resins have limited use due to poor tolerance. Bempedoic acid added to maximally tolerated statin therapy is approved to lower LDL-C in adults with primary hypercholesterolemia or mixed dyslipidaemias, HeFH, in patients with ASCVD who require additional lowering of LDL-C, and in patients who are statin-intolerant. Inclisiran is a long-acting double-stranded small interfering RNA (siRNA) that inhibits the transcription of PCSK-9 leading to a decrease in PCSK9 generation in hepatocytes and an increase in LDL receptor expression in the liver cell membrane leading to about 50 % reduction in serum LDL-C levels. Lomitapide lowers plasma levels of all ApoB-containing lipoproteins, including VLDL, LDL, and chylomicrons by inhibiting the enzyme microsomal triglyceride transfer protein (MTP) and approved for the treatment of adult patients with homozygous familial hypercholesterolemia (HoFH). Close monitoring for hepatotoxicity is required. Mipomersen is a single-stranded synthetic antisense oligonucleotide (ASO) that affects the production and secretion of apoB-containing lipoproteins with demonstrated efficacy in both homozygous and heterozygous FH patients. It is approved for restricted use due to risk of hepatotoxicity. Pelacarsen is an antisense oligonucleotide that reduces the production of apo(a) in the liver.

Approaches in Managing Resistant Hypertension: A Review.

In India, around 234 million adults (one in three) suffer from hypertension (HTN). An average of 10% of these cases are likely to be resistant hypertension (RH). This load of 23 million patients is expected to expand further with revisions in diagnostic criteria. The treatment and control rates of hypertension in India average around 30% and 15%, respectively. Pharmacological management involves a stepwise approach starting with optimizing the A-C-D (angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs), and thiazide-like diuretics) triple-drug combination, followed by substitution with a thiazide-like diuretic and use of spironolactone as a next step (fourth drug). The subsequent steps are suggestions based on expert input and must be individualized. These include using a ß-blocker as the fifth drug and an α1-blocker or a peripheral vasodilator as a final option when target blood pressure (BP) values are not achieved. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are likely to be helpful in managing RH due to their renal and cardiovascular protection as well as mortality benefits. SGLT2i lowers BP independent of the dosage and concomitant anti-hypertensive medications. Patient education and tools to monitor BP and treatment compliance will improve outcomes with these medications. In addition to therapeutic intervention, a preventive approach for RH mandates a need to identify patients at risk and use appropriate preventive and optimal therapy to prevent uncontrolled hypertension in patients with cardiovascular disorders.

Management of Heart Failure in a Resource-Limited Setting: Expert Opinion from India.

Heart failure poses a global health challenge affecting millions of individuals, and access to guideline-directed medical therapy is often limited. This limitation is frequently attributed to factors such as drug availability, slow adoption, clinical inertia, and delayed diagnosis. Despite international recommendations promoting the use of guideline-directed medical therapy for heart failure management, personalized approaches are essential in settings with resource constraints. In India, crucial treatments like angiotensin II receptor blocker neprilysin inhibitors and sodium-glucose co-transporter 2 inhibitors are not fully utilized despite their established safety and efficacy. To address this issue, an expert consensus involving 150 specialists, including cardiologists, nephrologists, and endocrinologists, was convened. They deliberated on patient profiles, monitoring, and adverse side effects and provided tailored recommendations for guideline-directed medical therapy in heart failure management. Stressing the significance of early initiation of guideline-directed medical therapy in patients with heart failure, especially with sodium-glucose co-transporter 2 inhibitors, the consensus also explored innovative therapies like vericiguat. To improve heart failure outcomes in resource-limited settings, the experts proposed several measures, including enhanced patient education, cardiac rehabilitation, improved drug access, and reforms in healthcare policies.

CSI clinical practice guidelines for dyslipidemia management: Executive summary.

Dyslipidemias are the most important coronary artery disease (CAD) risk factor. Proper management of dyslipidemia is crucial to control the epidemic of premature CAD in India. Cardiological Society of India strived to develop consensus-based guidelines for better lipid management for CAD prevention and treatment. The executive summary provides a bird's eye-view of the 'CSI: Clinical Practice Guidelines for Dyslipidemia Management' published in this issue of the Indian Heart Journal. The summary is focused on the busy clinician and encourages evidence-based management of patients and high-risk individuals. The summary has serialized various aspects of lipid management including epidemiology and categorization of CAD risk. The focus is on management of specific dyslipidemias relevant to India-raised low density lipoprotein (LDL) cholesterol, non-high density lipoprotein cholesterol (non-HDL-C), apolipoproteins, triglycerides and lipoprotein(a). Drug therapies for lipid lowering (statins, non-statin drugs and other pharmaceutical agents) and lifestyle management (dietary interventions, physical activity and yoga) are summarized. Management of dyslipidemias in oft-neglected patient phenotypes-the elderly, young and children, and patients with comorbidities-stroke, peripheral arterial disease, kidney failure, posttransplant, HIV (Human immunodeficiency virus), Covid-19 and familial hypercholesterolemia is also presented. This consensus statement is based on major international guidelines (mainly European) and expert opinion of lipid management leaders from India with focus on the dictum: earlier the better, lower the better, longer the better and together the better. These consensus guidelines cannot replace the individual clinician judgement who remains the sole arbiter in management of the patient.

Sensitive and rapid quantitation of dexamethasone in human plasma using liquid chromatography coupled with triple quadrupole mass spectrometer.

The aim of this paper was to develop, validate, and utilize a sensitive liquid chromatography-tandem mass spectrometry bioanalytical method for bioequivalence/clinical trial studies conducted in human plasma. To accomplish the target, a stable labeled internal standard, that is, dexamethasone D4 was used as an internal standard to track and compensate the parent compound during processing, and extraction from plasma. The method involves a rapid liquid-liquid phase extraction from plasma, followed by reverse phase chromatography, and mass spectrometry detection, with a total run time of 3.5 min. The method was developed and validated from 2 to 600 ng/ml for dexamethasone. The mean recovery for dexamethasone was found to be 81.0%. The validated method enabled the analysis of dexamethasone in samples from clinical pharmacokinetic studies. The peak concentration of dexamethasone ranged between 253 to 281 ng/ml and 319 to 343 ng/ml, respectively, in fasted and fed conditions. The terminal half-life values for dexamethasone ranged between 3.5 to 8.2 h and 3.0 to 7.5 h, respectively.

Genomic Analyses of a Fungemia Outbreak Caused by Lodderomyces elongisporus in a Neonatal Intensive Care Unit in Delhi, India.

Lodderomyces elongisporus is a recently emerging yeast pathogen predominantly reported in adult patients who had immunosuppression and/or intravenous access devices. Here, we report a fungemia outbreak caused by L. elongisporus in a neonatal intensive care unit (NICU) in Delhi, India, from September 2021 to February 2022. All 10 neonates had low birthweight, and nine of the patients survived after amphotericin B treatment. Whole-genome sequence analyses of the patient isolates as well as those from other sources in India grouped them into two clusters: one cluster consists of isolates exclusively from stored apples and the other cluster includes isolates from patients, clinical environments, and stored apples. All outbreak strains from patients were closely related to each other and showed highly similar heterozygosity patterns across all 11 major scaffolds. While overall very similar, strains from the inanimate environment of the same neonatal intensive care unit showed loss of heterozygosity at scaffold 2 (NW_001813676) compared to the patient strains. Interestingly, evidence for recombination was found in all samples. All clinical strains were susceptible to 10 tested antifungal drugs, and comparisons with strains with high fluconazole MICs derived from the surface of stored apples revealed significant genome divergence between the clinical and apple surface strains, including 119 nonsynonymous single nucleotide polymorphisms (SNPs) in 24 triazole resistance-related genes previously found in other Candida spp. Together, our results indicate significant diversity, recombination, and persistence in the hospital setting and a high rate of evolution in this emerging yeast pathogen. IMPORTANCE Lodderomyces elongisporus was initially considered a teleomorph of Candida parapsilosis. However, DNA sequence analyses revealed it as a distinctive species. Invasive infections due to L. elongisporus have been reported globally. We report an outbreak of fungemia due to L. elongisporus in a NICU affecting 10 preterm, low-birthweight neonates during a period of 6 months. The outbreak investigation identified two environmental sites, the railing and the temperature panel of the neonate open care warmer, harboring L. elongisporus. Whole-genome sequencing confirmed that the neonate isolates were closely related to each other whereas strains from the inanimate clinical environment were related to clinical strains but showed a marked loss of heterozygosity. Further, L. elongisporus strains recovered previously from the surface of stored apples showed high fluconazole MICs and alterations in triazole resistance-related genes. Genome-wide SNP comparisons revealed recombination as an important source for genomic diversity during adaptation of L. elongisporus to different environments.

Bempedoic Acid for Lipid Management in the Indian Population: An Expert Opinion.

Lipid-lowering is a central theme in the management of patients with atherosclerotic cardiovascular disease (ASCVD) and heterozygous familial hypercholesterolemia (HeFH), with statins being currently used as the first-line lipid-lowering agent (LLAs). Bempedoic acid (BA) has been recently approved for lipid management in ASCVD/HeFH patients. This expert opinion paper brings out the essential concept to assess the current place of BA in the Indian population. Here we highlight that the majority of the patients with clinical ASCVD may not be receiving the optimal dose of statin, thereby failing to achieve their lipid targets. The addition of BA to statin results in a significant reduction in low-density lipoprotein cholesterol (LDL-C) along with substantial reductions in non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), and high-sensitivity C-reactive protein (hsCRP) levels. For patients who do not achieve LDL-C targets, BA can be an effective add-on alternative to choose among non-statin LLAs. BA is a good choice for statin-intolerant cases, especially in combination with ezetimibe. Given the lack of effect of worsening hyperglycemia or any increase in the occurrence of new-onset diabetes, BA can be used without hesitation in patients with diabetes. The small risk of hyperuricemia could be mitigated with appropriate patient selection and monitoring of serum uric acid levels in patients at high risk of hyperuricemia. We believe BA is an excellent non-statin therapy that is efficacious, well-tolerated, and cost-effective for lipid management in ASCVD, HeFH, and statin-intolerant patients in India.

Management of acute coronary syndrome in chronic kidney disease.

Few trials have addressed the management of acute coronary syndromes (ACS) in chronic kidney disease (CKD). Hence guidelines for the management of coronary heart disease (CHD) in CKD are based on meta-analysis, subgroup analyses, small prospective studies or retrospective analyses of controlled trials and registry data. The short-term as well as long-term prognosis of ACS patients with poor renal function is worse than those with normal renal function. The risk of cardiovascular (CV) events and mortality is inversely proportional to the estimated glomerular filtration rate (eGFR). Nevertheless, CV event rates increase even in early CKD. Contrast induced nephropathy (CIN) occurs in 15% of patients following diagnostic or therapeutic invasive procedures; less than 1% of these require dialysis. While treatment of CIN is not so effective, it is predictable and can be largely prevented. Despite a higher risk of adverse outcomes, patients with moderate-severe CKD are often treated less aggressively than patients with normal renal function due to safety concerns. Patients with CKD are less likely to receive aspirin, clopidogrel, or beta blockers and are less likely to undergo reperfusion or revascularization. Conservative treatment of ACS may partially account for worse outcome in CKD. Large registry data suggests that in-hospital revascularization is associated with improved survival, irrespective of eGFR. It is not clear whether coronary artery bypass grafting (CABG) surgery or percutaneous coronary intervention (PCI) leads to better outcomes in patients suitable for either procedure. While short-term risk of CABG in CKD is high, its long-term results have been better than medical treatment or PCI in registry data. Recent data suggest no differentials in outcomes with CABG or PCI. Randomized controlled trials involving patients with renal dysfunction are needed to confirm whether aggressive treatment of ACS will improve clinical outcomes.

A case-control study of risk factors for coronary heart disease in urban Indian middle-aged males.

OBJECTIVE: There are few case-control studies on native Indians to explore the reasons for the growing prevalence of coronary heart disease (CHD) in Indians. The present study was undertaken to identify the conventional coronary risk factors in angiographically proven CHD cases by comparing their prevalence in age-and gender-matched healthy controls. METHODOLOGY: A hospital-based case-control study was performed on 197 middle-aged urban males (age 40-64 years) with angiographically proven CHD and 197 age (32 years) and gender-matched healthy controls in a tertiary cardiac care center of New Delhi. Prevalence of coronary risk factors with special emphasis on diet was determined by administration of a pre-tested questionnaire, physical examination, and biochemical estimation of blood lipids and glucose. Odds ratios (OR) and their 95% confidence intervals (CI) for the association of risk factors with CHD and their population attributable risks (PAR) were calculated. RESULTS: Logistic regression analysis showed that history of diabetes mellitus (OR 4.934, 95% CI 2.320-10.494), low education (OR 2.410, 95% CI 1.261-4.608), full cream milk consumption (OR 2.113 95% CI 1.176-3.798), and family history of premature cardiovascular disease (CVD) (OR 1.810, 95% CI 1.064-3.079) were independent risk factors for CHD. High HDL-C (OR 1.055 95% CI 1.025-1.086) and fruit intake (OR 1.473, 95% CI 1.020-2.128) emerged as anti-risk factors. 44.1% of PAR was attributable to low HDL-C (.3%), low education status (6.6%), history of diabetes mellitus (6.0%), family history of premature CVD (4.4%), low fruit consumption (4.3%), tobacco abuse (4.2%), full cream milk consumption (3.6%) or milk intake (3.4%), high fasting blood glucose (2.3%), and history of hypertension (2.07 percent;). CONCLUSIONS: Conventional risk factors are not enough to explain the high prevalence of CHD among native Indians. While efforts must go on to reduce the risk attributable to them, the role of emerging risk factors should be investigated.

Adaptation of 2016 European Society of Cardiology/European Atherosclerosis Society guideline for lipid management to Indian patients - A consensus document.

In the year 2016, European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines provided recommendations on dyslipidemia management. The recommendation from these guidelines are restricted to European subcontinent. To adapt the updated recommendations for Indian subset of dyslipidemia, a panel of experts in management of dyslipidemia provided their expert opinions. This document provides expert consensus on adapting 2016 ESC dyslipidemia guidelines recommendations in Indian setting. The document also discussed India-specific relevant literature to support the consensus opinions provided in management of dyslipidemia.

Recent landmark trials in cardiology.

A few recent clinical trials in the areas of acute myocardial infraction/acute coronary syndrome, implantable cardiovertordefibrillator, heart failure, and percutaneous coronary intervention vs. coronary artery bypass graft for multivessel coronary artery disease are presented here.

Recent landmark trials in cardiology.

This section outlines various recent ongoing /completed trials on use of amiodarone, beta blockers, clopidogrel antiplatelet agents, cardiac resynchronization therapy and drug-eluting stents in management of cardiac complications and morbidity.

Effect of sodium citrate ingestion on oxygen debt & exercise endurance during supramaximal exercise.

BACKGROUND & OBJECTIVES: Administration of alkalinizing agents has been shown to improve performance in high intensity exercise. The present investigation was undertaken to determine whether sodium citrate ingestion enhances supramaximal endurance performance on a cycle ergometer and to assess its effect on oxygen debt incurred for the same supramaximal energy output. METHODS: Ten untrained, healthy, males performed acute intense bicycle ergometry exercise in two sessions viz., without (control) and with sodium citrate ingestion (experimental) in a dose of 0.5 g/kg body weight. Pre-exercise O2 consumption, pulse rate (PR) and respiratory rate (RR)/minute were recorded before both sessions. Exhaustion time (ET) was noted and work done calculated in the control session. Post-exercise PR and RR/min were also recorded in both sessions of study. Venous blood samples were drawn post-exercise and analysed for pH and lactate. O2 debt incurred was calculated in both sessions. RESULTS: Work output in supramaximal exercise averaged 69.40 +/- 15.31 Watts in the control session. None of the subjects in the experimental session complained of fatigue even when the exhaustion time noted in the control session was reached. Post-exercise tachycardia and tachypnoea were both significantly less (P<0.05 and P<0.001 respectively) in subjects after the experimental session as compared to the control. O2 debt incurred and lowering of blood pH were also significantly less (P<0.001) in the post-citrate phase. However, serum lactate increased significantly (P<0.05) in subjects after the experimental session. INTERPRETATION & CONCLUSION: Ingestion of sodium citrate prior to supramaximal exercise resulted in a reduction in post exercise O2 debt incurred. Blood pH was almost normal despite a higher serum lactate concentration. This probably led to an enhancement in exercise performance.