Significance of Pulmonary Hypertension in Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most prevalent hereditary cardiac disease characterized by the presence of left ventricular and/or septal hypertrophy in the absence of other underlying cardiac disorders. Patients of HCM have a broad range of clinical presentation from being asymptomatic to severely ill condition requires hospitalization and urgent management. Broadly, HCM is classified in two variants: obstructive and nonobstructive. The mainstay of diagnosis is through echocardiography. As HCM chiefly affect the left heart, pulmonary hypertension (PH) is an expected complication of this disease. Though the existence of PH in HCM is known for a long time, its clinical significance, underlying mechanism, and prognostic impact in HCM have been revealed by few recent studies. Specifically, studies have shown increased events of thromboembolism, atrial fibrillation, and heart failure in patients with HCM and PH. These studies elucidated the underlying mechanism of PH in HCM--a rise of pressure in the precapillary and postcapillary pulmonary vasculature. In addition to left ventricular involvement, studies have shown right ventricular involvement and the association of left and right ventricular dysfunction in these patients. Further, it has been shown that surgical intervention to reduce septal thickness improves survival in pharmacotherapy nonresponders and the presence of PH does not increase mortality in these patients. We present a comprehensive review exploring the prevalence, underlying mechanisms, and impact of PH on HCM.

Fish Oil and Cardiometabolic Diseases: Recent Updates and Controversies.

Fatty acids derived from fish oil are long-chain omega-3 (n-3) polyunsaturated fatty acids. The important polyunsaturated fatty acids of fish oil are eicosapentaenoic acid, and docosahexaenoic acid. For decades, there has been a debate about the use of omega-3 fatty acids and their benefits on cardiovascular health. The more recent trials including the JELIS, VITAL, STRENGTH, and ASCEND trials, addressed the paucity of data of omega-3 fatty acids on primary and secondary prevention of cardiovascular events and the risk-benefit balance of these supplements. Prior to these studies, many large randomized controlled trials have shown conflicting results on the effect of polyunsaturated fatty acids in patients with prior coronary artery disease, stroke, or major vascular events. These inconsistent results warrant a better understanding of the effects of omega-3 fatty acids on the subtypes of cardiovascular diseases, and their use in primary and secondary prevention. More recently, icosapent ethyl showed a significant reduction in cardiovascular mortality and ischemic events in patients with elevated triglyceride (TG) and established cardiovascular disease or diabetes. The REDUCE-IT trial paved the way to further reduce cardiovascular risk in patients with high TG despite being on a maximally tolerated statin. The aim of this review is to discuss these recent updates on the use of various forms of fish oil, including prescription form and supplement in cardiometabolic diseases, and their surrounding controversies.

Ranolazine: Multifaceted Role beyond Coronary Artery Disease, a Recent Perspective.

Ranolazine is a piperazine derivative approved as an antianginal. Primarily used as a second-line antianginal in stable coronary artery disease. Ranolazine blocks the late Na + current and prevents the rise of cytosolic calcium. It decreases myocardial wall tension and improves coronary blood flow. Ranolazine is effective in atrial fibrillation (AF) as an adjunct to electrical or pharmacological cardioversion. It can be used in combination with amiodarone or dronedarone. It has also been used in AF arising after coronary artery bypass grafting surgery. Role of ranolazine is also being evaluated in pulmonary arterial hypertension, diastolic dysfunction, and chemotherapy-induced cardiotoxicity. Ranolazine has some anti-glycemic effect and has shown a reduction of hemoglobin A1c in multiple trials. The antianginal effect of ranolazine has also been seen to be more in patients with diabetes compared to those without diabetes. Ranolazine is being evaluated in patients with the peripheral arterial disease with intermittent claudication and hypertrophic cardiomyopathy. Pilot studies have shown that ranolazine may be beneficial in neurological conditions with myotonia. The evidence-base on the use of ranolazine in various conditions is rapidly increasing with results of further trials eagerly awaited. Accumulating evidence may see ranolazine in routine clinical use for many conditions beyond its traditional role as an antianginal.

Role of Ranolazine in cardiovascular disease and diabetes: Exploring beyond angina.

Ranolazine was FDA approved for chronic angina in 2006. Since then, there has been extensive research involving this drug. The mechanism of action, debatable at the time of approval, has been demonstrated. Ranolazine acts via inhibition of late sodium channel current in the myocardium. This acts by lowering abnormally high cytosolic calcium levels. Other possible clinical applications of Ranolazine have also been explored. Out of many lines of investigation, its effects in atrial fibrillation, especially post-CABG and recurrent atrial fibrillation show promise. It has also shown definite HbA1c lowering effects when used in diabetics with coronary artery disease. Other possible indications for the drug include pulmonary arterial hypertension, diastolic dysfunction and chemotherapy-induced cardiotoxicity. This review aims to summarize major research regarding Ranolazine in potential applications beyond chronic angina. There are few dedicated large, randomized, phase III trials exploring the newer effects of Ranolazine. There are a few such trials underway, but more are needed.

Serelaxin in acute heart failure: Most recent update on clinical and preclinical evidence.

Heart failure continues to be a widely prevalent disease across the world, affecting millions of Americans annually. Acute heart failure (AHF) has a substantial effect on rising healthcare costs and is one of the major causes of morbidity and mortality. The search for new drugs for symptom relief and to improve long-term outcomes in heart failure has led to development of serelaxin, a recombinant human relaxin-2 hormone. Relaxin was discovered in pregnancy, but eventually found to have a number of other physiological actions, not only in pregnancy, but also in nonpregnant women and men. The actions of serelaxin are primarily via nitric oxide, leading to the observed vasodilatory effects, and increase in renal plasma flow. It has also been found to increase expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP)-2 and MMP-9. The antifibrotic and antiinflammatory effects of the drug also play a role in heart failure. In Phase II studies, serelaxin has shown reduction in pulmonary arterial pressure, pulmonary capillary wedge pressure, and NT-proBNP. The recently published results of the RELAX-AHF, a phase III clinical trial on serelaxin, has opened new avenues into our understanding of its effects in heart failure. The trial showed improvement in short-term dyspnea scores and 180-day mortality, but, interestingly, failed to show any improvement of the secondary endpoints of death or readmission at 60 days. Ongoing Phase III trials like RELAX-AHF-2 and RELAX-AHF-ASIA would explain these data better and improve understanding of the use of serelaxin in clinical practice. This article summarizes the most updated published preclinical and clinical study data on serelaxin, including pharmacokinetic, pharmacodynamic, safety studies in hepatic, renal impaired patients, Phase II and Phase III trials.

Specific antidotes against direct oral anticoagulants: A comprehensive review of clinical trials data.

The Vitamin K antagonist warfarin was the only oral anticoagulant available for decades for the treatment of thrombosis and prevention of thromboembolism until Direct Oral Anticoagulants (DOACs); a group of new oral anticoagulants got approved in the last few years. Direct thrombin inhibitor: dabigatran and factor Xa inhibitors: apixaban, rivaroxaban, and edoxaban directly inhibit the coagulation cascade. DOACs have many advantages over warfarin. However, the biggest drawback of DOACs has been the lack of specific antidotes to reverse the anticoagulant effect in emergency situations. Activated charcoal, hemodialysis, and activated Prothrombin Complex Concentrate (PCC) were amongst the nonspecific agents used in a DOAC associated bleeding but with limited success. Idarucizumab, the first novel antidote against direct thrombin inhibitor dabigatran was approved by US FDA in October 2015. It comprehensively reversed dabigatran-induced anticoagulation in a phase I study. A phase III trial on Idarucizumab also complete reversal of anticoagulant effect of dabigatran. Andexanet alfa (PRT064445), a specific reversal agent against factor Xa inhibitors, showed a complete reversal of anticoagulant activity of apixaban and rivaroxaban within minutes after administration without adverse effects in two recently completed parallel phase III trials ANNEXA-A and ANNEXA-R respectively. It is currently being studied in ANNEXA-4, a phase IV study. Aripazine (PER-977), the third reversal agent, has shown promising activity against dabigatran, apixaban, rivaroxaban, as well as subcutaneous fondaparinux and LMWH. This review article summarizes pharmacological characteristics of these novel antidotes, coagulation's tests affected, available clinical and preclinical data, and the need for phase III and IV studies.

Cardiovascular outcomes of sodium-glucose cotransporter 2 inhibitors: A comprehensive review of clinical and preclinical studies.

Diabetes is a leading cause of morbidity and mortality worldwide. Management of diabetes is changing at a rapid pace. Three new classes of antidiabetic drugs including GLP-1 (Glucagon-like peptide 1), DPP-IV (Dipeptidyl peptidase IV) and SGLT2 (Sodium glucose cotransporter 2) inhibitors have been approved in the last few years. Treating diabetes with the antidiabetic drug does not always reduce the cardiovascular complications of diabetes. On the contrary, there was a huge controversy regarding the effect of rosiglitazone on cardiovascular risk reduction a few years ago. Since then, submission of postmarketing cardiovascular outcome study data has been mandated by US FDA and other drug regulatory agencies for newer antidiabetic medications. This is to avoid further premature claims regarding cardiovascular harm or safety of the newer classes. We already have some cardiovascular safety data available on DPP-IV and GLP-1 groups of medications. Dapagliflozin, canagliflozin, and empagliflozin are currently approved SGLT2 inhibitors. We do not have sufficient cardiovascular outcome data available for this novel class. However, this group of drugs, which act by increasing renal glucose excretion, have also shown some non-glycemic benefits including weight reduction, blood pressure control, diuretic action, renal protection, decrease in arterial stiffness and uric acid reduction. Empagliflozin, a new member of SGLT2 class, showed significant cardiovascular morbidity and mortality benefit in recently published EMPA-REG OUTCOME trial. The authors summarize all the published clinical and preclinical cardiovascular outcome data of SGLT2 inhibitors, including recently completed and ongoing major clinical trials in this comprehensive review.

Perception, attitude and usage of complementary and alternative medicine among doctors and patients in a tertiary care hospital in India.

AIM: Complementary and alternative medicine (CAM) has been practiced in India for thousands of years. The aim of this study was to determine the extent of use, perception and attitude of doctors and patients utilizing the same healthcare facility. METHODS: This study was conducted among 200 doctors working at a tertiary care teaching Hospital, India and 403 patients attending the same, to determine the extent of usage, attitude and perception toward CAM. RESULTS: The use of CAM was more among doctors (58%) when compared with the patients (28%). Among doctors, those who had utilized CAM themselves, recommended CAM as a therapy to their patients (52%) and enquired about its use from patients (37%) to a greater extent. CAM was used concomitantly with allopathic medicine by 60% patients. Very few patients (7%) were asked by their doctors about CAM use, and only 19% patients voluntarily informed their doctors about the CAM they were using. Most patients who used CAM felt it to be more effective, safer, less costly and easily available in comparison to allopathic medicines. CONCLUSION: CAM is used commonly by both doctors and patients. There is a lack of communication between doctors and patients regarding CAM, which may be improved by sensitization of doctors and inclusion of CAM in the medical curriculum.

Effect of addition of either sitagliptin or pioglitazone in patients with uncontrolled type 2 diabetes mellitus on metformin: A randomized controlled trial.

OBJECTIVE: To compare and study the dipeptidy1 peptidase-4 (DPP-4) inhibitors in combination with metformin against established combination therapies. MATERIALS AND METHODS: This 16-week study was designed to compare sitagliptin versus pioglitazone as add-on therapy in patients of type 2 diabetes mellitus inadequately controlled with metformin alone. Fifty-two patients were randomized into two groups to receive either sitagliptin 100 mg (group 1) or pioglitazone 30 mg (group 2) in addition to metformin. The primary efficacy end point was change in HbA1c. Secondary end points included change in fasting plasma glucose (FPG), body weight and lipid profile. Treatment satisfaction was assessed using the Diabetes Treatment Satisfaction Questionnaire. Both the groups had a significant decrease in HbA1c. RESULTS: There was no significant difference between mean reductions in FPG in both the groups. There was a significant decrease in the mean body weight and body mass index in group 1 in contrast to the significant increase in the same in group 2. Both the treatment groups reported a significant decrease in High-density lipoprotein (HDL-C) and Triglyceride. CONCLUSION: Sitagliptin was well tolerated without any incidence of hypoglycemia. It was concluded that sitagliptin as an add-on to metformin is as effective and well tolerated as pioglitazone.

Current status of CETP inhibitors in the treatment of hyperlipidemia: an update.

INTRODUCTION: The inverse relationship between HDL-C and cardiovascular disease risk suggests that increasing HDL-C could potentially reduce the disease risk. Reverse cholesterol transport is considered to be the primary mechanism by which HDL-C exerts its anti-atherogenic effects. A key regulator of RCT is cholesteryl ester transfer protein (CETP). AREAS COVERED: Inhibition of CETP has been identified as a possible strategy for substantially increasing HDL-C levels and CETP inhibitors have demonstrated clinical efficacy in preliminary clinical trials. The development of this novel class suffered a major setback when the major phase 3 trial of torcetrapib, the first CETP inhibitior was prematurely terminated due to an increase in cardiovascular and noncardiovascular mortality. Subsequent animal and clinical studies have shown that the increase in cardiovascular mortality reported with torcetrapib was molecule specific and independent of its CETP inhibition effect. The other two CETP inhibitors i.e. dalcetrapib and anacetrapib were well tolerated in phase I and II clinical trials and unlike torcetrapib, did not affect blood pressure and aldosterone levels. In this review article the authors have discussed the lessons learned from torcetrapib failure and important preclinical and clinical developments of CETP inhibitors and their role in management of hyperlipidemia and cardiovascular risk reduction.

SGLT2 inhibitors: a new emerging therapeutic class in the treatment of type 2 diabetes mellitus.

The incidence of type 2 diabetes mellitus is increasing worldwide. The existing therapeutic classes of antidiabetic drugs are not adequately effective in maintaining long-term glycemic control in most patients, even when used in combination. One emerging novel therapeutic class of antidiabetic drugs is sodium glucose cotransporter 2 (SGLT2) inhibitors. SGLT2 accounts for 90% of the glucose reabsorption in the kidney. The SGLT2 inhibitors increase urinary excretion of glucose and lower plasma glucose levels in an insulin-independent manner. Dapagliflozin, the most prominent molecule in this class, is currently in a phase III clinical trial. Other members of this class (eg, sergliflozin, remogliflozin) are also in different phases of clinical trials. This class of novel agents can effectively control blood sugar level without producing weight gain or hypoglycemia. Results of ongoing phase III clinical trials are crucial to determine whether the risk-benefit ratio will allow approval of this new class of drugs for the management of type 2 diabetes mellitus.

Recent advances in antiretroviral drugs.

IMPORTANCE OF THE FIELD: Acquired immunodeficiency syndrome (AIDS) is one of the leading causes of death worldwide. Although the combination therapies of highly active antiretroviral therapy (HAART) have significantly contributed to virological suppression, improved immune function and quality of life, issues such as tolerability, drug-drug interactions and cross-resistance amongst members of a particular drug class still pose a significant barrier to long-term successful treatment. There is a constant need for newer anti HIV drugs with increased potency and improved pharmacokinetic properties either in the existing classes or drugs from new classes that target several new steps in HIV replication cycle. AREAS COVERED IN THIS REVIEW: The authors have discussed newer antiretroviral drugs belonging to second-generation nucleoside analog reverse transcriptase inhibitors (amdoxovir, elvucitabine, apricitabine, racivir), non-nucleoside analog reverse transcriptase inhibitors (etravirine, rilpivirine), protease inhibitors (darunavir, tipranavir) as well as emerging new classes, i.e., fusion inhibitors (enfuvirtide, sifuvirtide), CCR5 inhibitors (maraviroc, vicriviroc, PRO 140, PRO 542), CD4-receptor inhibitors (ibalizumab), integrase inhibitors (raltegravir, elvitegravir, GSK-1349572), maturation inhibitors (bevirimat), cobicistat (pharmacoenhancer), lens epithelium-derived growth factor inhibitors and capsid assembly inhibitors. WHAT THE READER WILL GAIN: The reader will gain an understanding of the mechanism of action, mechanism of resistance, stages of development and important clinical trials related to the newer antiretroviral drugs and future potential of these drugs. TAKE HOME MESSAGE: The initial clinical trial data of these newer drugs are very encouraging for the long-term successful control of HIV in both treatment-naïve and treatment-experienced patients.