Heart Failure with Preserved Left Ventricular Ejection Fraction: A Complex Conundrum Simply Not Limited to Diastolic Dysfunction.

Over the last two decades, the changing paradigm of heart failure with preserved ejection fraction (HFpEF) has transformed our understanding not only of the pathophysiology of this clinical entity but also the diagnostic and therapeutic approaches aimed at treating this complex patient population. No longer HFpEF should be seen as simply left ventricular diastolic dysfunction but as a group of that in addition of having small and thick left ventricles with abnormal diastolic filling patterns as their main pathophysiologic abnormality; they also have whole host of different abnormalities. In fact, this heterogeneous clinical entity embodies numerous mechanisms and is linked to multiorgan dysfunction, with hypertension and obesity playing a major role. Although we have gained an enormous amount of understanding not only on the causes but also the downstream effects of HFpEF, there is still much to be learned before we can fully comprehend this complex clinical entity. It is the main intention of this review to synthesize the most recent attributes, mechanism, diagnostic tools, and most useful therapeutic alternatives to be considered when evaluating patients either complaining of dyspnea on exertion as well as exercise intolerance or those recently admitted with HF symptoms but with normal LVEF in the absence of any other valvular abnormalities.

Growth Differentiation Factor 15 (GDF-15), a New Biomarker in Heart Failure Management.

The emergence of biomarkers across medicine's subspecialties continues to evolve. In essence, a biomarker is a biological observation that clearly substitutes a clinical endpoint or intermediate outcome not only are more difficult to observe but also, biomarkers are easier, less expensive and could be measured over shorter periods. In general, biomarkers are versatile and not only used for disease screening and diagnosis but, most importantly, for disease characterization, monitoring, and determination of prognosis as well as individualized therapeutic responses. Obviously, heart failure (HF) is no exception to the use of biomarkers. Currently, natriuretic peptides are the most used biomarkers for both diagnosis and prognostication, while their role in the monitoring of treatment is still debatable. Although several other new biomarkers are currently under investigation regarding diagnosis and determination of prognosis, none of them are specific for HF, and none are recommended for routine clinical use at present. However, among these emerging biomarkers, we would like to highlight the potential for growth differentiation factor (GDF)-15 as a plausible new biomarker that could be helpful in providing prognostic information regarding HF morbidity and mortality.

Epigenetic Regulation and its Effects on Aging and Cardiovascular Disease.

Cardiovascular disease (CVD), specifically coronary atherosclerosis, is regulated by an interplay between genetic and lifestyle factors. Most recently, a factor getting much attention is the role epigenetics play in atherosclerosis; particularly the development of coronary artery disease. Furthermore, it is important to understand the intricate interaction between the environment and each individual genetic material and how this interaction affects gene expression and consequently influences the development of atherosclerosis. Our main goal is to discuss epigenetic regulations; particularly, the factors contributing to coronary atherosclerosis and their role in aging and longevity. We reviewed the current literature and provided a simplified yet structured and reasonable appraisal of this topic. This role has also been recently linked to longevity and aging. Epigenetic regulations (modifications) whether through histone modifications or DNA or RNA methylation have been shown to be regulated by environmental factors such as social stress, smoking, chemical contaminants, and diet. These sensitive interactions are further aggravated by racial health disparities that ultimately impact cardiovascular disease outcomes through epigenetic interactions. Certainly, limiting our exposure to such causative events at younger ages seems our "golden opportunity" to tackle the incidence of coronary atherosclerosis and probably the answer to longevity.

Obstructive Sleep Apnea and Cardiovascular Diseases: Sad Realities and Untold Truths regarding Care of Patients in 2022.

Obstructive sleep apnea (OSA) is one of the most common and serious sleep-related breathing disorders with a high prevalence among patients with cardiovascular (CV) diseases. Despite its widespread presence, OSA remains severely undiagnosed and untreated. CV mortality and morbidity are significantly increased in the presence of OSA as it is associated with an increased risk of resistant hypertension, heart failure, arrhythmias, and coronary artery disease. Evaluation and treatment of OSA should focus on recognizing patients at risk of developing OSA. The use of screening questionnaires should be routine, but a formal polysomnography sleep study is fundamental in establishing and classifying OSA. Recognition of OSA patients will allow for the institution of appropriate therapy that should alleviate OSA-related symptoms with the intent of decreasing adverse CV risk. In this review, we focus on the impact OSA has on CV disease and evaluate contemporary OSA treatments. Our goal is to heighten awareness among CV practitioners.

Obesity and Altered Aspirin Pharmacology.

Obesity is an independent risk factor for cardiovascular morbidity and mortality due to atherothrombotic events and represents a group of patients who are in need of optimized antithrombotic therapy. Central to the obesity-related risk of atherothrombosis is a pro-thrombotic state characterized by increased levels of coagulation factors, impaired fibrinolysis, and platelet hyper-reactivity, which results from the interaction among the features clustering in obesity: insulin resistance, inflammation, oxidative stress, and endothelial dysfunction. Aspirin is a cornerstone antiplatelet drug that has substantial interpatient variability in pharmacodynamic response and a number of reports have demonstrated that obesity is a risk factor for a reduced aspirin pharmacodynamic response. The inflammatory state associated with obesity, particularly a metabolic endotoxemia, may set in motion a number of mechanisms that increase platelet reactivity and platelet turnover and decrease aspirin bioavailability, all contributing to a poor aspirin response. A greater understanding of the mechanisms underlying obesity-related high on-aspirin platelet reactivity will help in optimization of antithrombotic therapy in this patient population.

Aspirin responsiveness changes in obese patients following bariatric surgery.

AIMS: Bariatric surgery has emerged as a promising treatment option for weight loss and to counter the metabolic consequences of obesity. Obesity has been linked to a hyperaggregable state, as well as a blunted response to aspirin. This pilot study assessed the hypothesis that bariatric surgery would lead to an improvement in aspirin-induced platelet inhibition and a reduction in platelet aggregability. METHODS: Fifteen patients scheduled to undergo bariatric surgery were administered two 7-day courses of aspirin 81 mg: the first course administered before surgery and the second was 3 months following surgery. Platelet aggregation was measured before and after each aspirin course using VerifyNow-Aspirin. The primary endpoint was the change in on-treatment aspirin reactive units (ARU) pre- and postsurgery. Data from bariatric surgery study patients were compared to data of normal weighted subjects gathered in a previous study. RESULTS: Roux-en-Y gastric bypass was performed in 80%, and 20% underwent sleeve gastrectomy. The mean starting body mass index (BMI) was 46.9 kg/m2 . Patients lost on average 24.5 kg, resulting in a postsurgical BMI of 38.5 kg/m2 . Postbariatric surgery, off-treatment ARU was significantly reduced from presurgery levels (602±59 vs 531±78; P=.035). On-aspirin platelet reactivity was also significantly reduced following surgery (469±60 vs 432±143, P=.03). There was a significant correlation between the extent of weight loss and the degree of improvement in on-aspirin platelet reactivity (r2 =.49, P=.024). Presurgery on-aspirin platelet reactivity was significantly higher in obese patients compared to normal weighted subjects (469±60 vs 419±52; P=.016) and reduced to the baseline after the surgery (432±63 vs 419±52; P=.54). CONCLUSION: Aspirin-induced platelet inhibition may be more potent following bariatric surgery. The mechanisms behind this improvement require further investigation.

Obesity and Inflammation and Altered Clopidogrel Pharmacokinetics and Pharmacodynamics.

BACKGROUND: Clopidogrel is a key antiplatelet drug that has substantial interpatient variability in pharmacodynamic response. Patients with lesser degrees of platelet inhibition in response to clopidogrel appear to be at increased risk of cardiovascular events. Obesity is an independent risk factor for cardiovascular morbidity and mortality due to atherothrombotic events and represents a group of patients who are in need of optimized antithrombotic therapy. Central to the obesity-related risk of atherothrombosis is a pro-thrombotic state characterized by increased levels of coagulation factors, impaired fibrinolysis and platelet hyper-reactivity, which results from the interaction among the features clustering in obesity: insulin resistance, inflammation, oxidative stress, and endothelial dysfunction. RESULTS: A number of reports have demonstrated that obesity is a risk factor for a reduced clopidogrel pharmacodynamic response. The inflammatory state associated with obesity, particularly a metabolic endotoxemia, may set in motion, a number of mechanisms that increase platelet reactivity, suppress cytochrome P450 enzyme activity, and increase platelet turnover, all contributing to a poor clopidogrel response. CONCLUSION: Comprehensive understanding of the mechanisms underlying obesity-related high onclopidogrel platelet reactivity will help in the optimization of antithrombotic therapy in this patient population.

Towards Precision in HF Pharmacotherapy.

PURPOSE OF REVIEW: Heart failure (HF) is a disease state with great heterogeneity, which complicates the therapeutic process. Identifying more precise HF phenotypes will allow for the development of more targeted therapies and improvement in patient outcomes. This review explores the future for precision medicine in HF treatment. RECENT FINDINGS: Rather than a continuous disease spectrum with a uniform pathogenesis, HF has phenotypes with different underlying pathophysiologic features. The challenge is to establish clinical phenotypic characterizations to direct therapy. Phenomapping, a process of using machine learning algorithms applied to clinical data sets, has been used to identify phenotypically distinct and clinically meaningful HF groups. As powerful technologies extend our knowledge, future analyses may be able to compile more comprehensive phenotypic profiles using genetic, epigenetic, proteomic, and metabolomic measurements. Identifying clinical characterizations of particular HF patients that would be uniquely or disproportionately responsive to a specific treatment would allow for more direct selection of optimal therapy, reduce trial-and-error prescribing, and help avoid adverse drug reactions.

The Importance of Research and Scholarly Activity in Pharmacy Training.

Regardless of practice setting, it is imperative that pharmacists be able to either participate in generating new knowledge or use the ever-expanding body of literature to guide patient care. However, competing priorities in Pharm.D. curricula and residency training programs have resulted in limited emphasis on acquiring research and scholarly skills. Factors likely contributing to this reduced focus include the lack of curricular and postgraduate training standards emphasizing the development of research skills, time to commit to scholarly activity, and accessibility to experienced mentors. Strategies for increasing scholarly activity for pharmacy students and residents should therefore continue to be a focus of professional degree and residency training programs. Several resources are available for academic planners, program directors, and institutions to augment scholarly experience for pharmacy trainees and clinicians. This commentary highlights the importance of providing research opportunities for students and residents, describes the potential barriers to these activities, and provides recommendations on how to increase the instruction and mentoring of trainees to generate and use research.

Oral Administration of Sustained Release Niacin Inhibits Platelet Aggregation.

BACKGROUND: Previous studies have suggested that niacin may have antiplatelet properties, however the effects of niacin on the platelet activity are not well defined. OBJECTIVE: The purpose of this trial was to investigate whether the oral administration of niacin inhibits platelet aggregation. METHOD: This study was run in three segments measuring the inhibitory effect of niacin: 1) 3 mmol/L niacin in vitro, 2) one hour after 1-gram sustained-release (SR) niacin administration, 3) twelve hours after 2-gram SR niacin administration. Platelet aggregation was measured using the VerifyNow-Aspirin and whole blood impedance aggregometry. RESULTS: Preincubation with niacin resulted in a significant inhibition of platelet aggregation. Significant inhibition of platelet aggregation was found one hour following the oral administration of 1 gram of SR niacin while the oral administration of a 2 gram dose of SR niacin did not produce significant platelet inhibition when platelet aggregation was measured 12 hours after the dose. CONCLUSION: Niacin has a small, direct effect on platelet aggregation. Niacin platelet inhibition is transient and may dissipate as it is converted into metabolites. The clinical significance is unknown.

Sequential Evolution of Vancomycin-Intermediate Resistance Alters Virulence in Staphylococcus aureus: Pharmacokinetic/Pharmacodynamic Targets for Vancomycin Exposure.

Staphylococcus aureus possesses exceptional virulence and a remarkable ability to adapt in the face of antibiotic therapy. We examined the in vitro evolution of S. aureus in response to escalating vancomycin exposure by evaluating bacterial killing and the progression of resistance. A hollow-fiber infection model was utilized to simulate human doses of vancomycin increasing from 0.5 to 4 g every 12 h (q12h) versus a high inoculum (10(8) CFU/ml) of methicillin-resistant S. aureus (MRSA) USA300 and USA400. Host-pathogen interactions using Galleria mellonella and accessory gene regulator (agr) expression were studied in serially obtained isolates. In both USA300 and USA400 MRSA isolates, vancomycin exposure up to 2 g q12h resulted in persistence and regrowth, whereas 4 g administered q12h achieved sustained killing against both strains. As vancomycin exposure increased from 0.5 to 2 g q12h, the bacterial population shifted toward vancomycin-intermediate resistance, and collateral increases in the MICs of daptomycin and televancin were observed over 10 days. Guideline-recommended exposure of a ratio of the area under the concentration-time curve for the free, unbound fraction of the drug to the MIC (fAUC/MIC ratio) of 200 displayed a 0.344-log bacterial reduction in area, whereas fAUC/MICs of 371 and 554 were needed to achieve 1.00- and 2.00-log reductions in area, respectively. The stepwise increase in resistance paralleled a decrease in G. mellonella mortality (P = 0.021) and a gradual decline of RNAIII expression over 10 days. Currently recommended doses of vancomycin resulted in amplification of resistance and collateral damage to other antibiotics. Decreases in agr expression and virulence during therapy may be an adaptive mechanism of S. aureus persistence.

P2Y12 antagonists in non-ST-segment elevation acute coronary syndromes: latest evidence and optimal use.

Dual antiplatelet therapy (DAPT), which includes the combination of aspirin and a P2Y12 platelet receptor inhibitor, is a well-established antiplatelet regimen in the treatment of patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS). Three P2Y12 inhibitor options (clopidogrel, prasugrel and ticagrelor) are currently available, all having different efficacy and safety profiles along with contrasting contraindications, special warnings and precautions for use. This review compares and contrasts the unique P2Y12 antagonists in the NSTE-ACS setting, covering the latest evidence and their optimal use.

Optimal aspirin dose in acute coronary syndromes: an emerging consensus.

Numerous clinical trials testing the efficacy of aspirin for the secondary prevention of cardiovascular disease have been published. We reviewed the literature pertaining to aspirin dose in acute coronary syndrome patients. Clinical trials assessing the comparative efficacy of different doses of aspirin are scarce. This complex antiplatelet therapy landscape makes it difficult to identify the best aspirin dose for optimizing efficacy and minimizing risk of adverse events, while complying with the various guidelines and recommendations. Despite this fact, current evidence suggests that aspirin doses of 75-100 mg/day may offer the optimal benefit:risk ratio in acute coronary syndrome patients.

Clopidogrel, prasugrel, or ticagrelor? a practical guide to use of antiplatelet agents in patients with acute coronary syndromes.

Aspirin is a cornerstone of therapy in the treatment of patients with acute coronary syndromes (ACS). However, dual antiplatelet therapy reduces the risk of stent thrombosis and cardiovascular events compared with aspirin alone in the treatment of patients with ACS. Recently, there has been debate as to which antiplatelet agent should be added to aspirin in the ACS treatment regimen. This review summarizes the pharmacologic and clinical data comparing clopidogrel, prasugrel, and ticagrelor, and provides a practical guide to clinicians for determining which antiplatelet to use for patients with ACS.

Novel anticoagulants in atrial fibrillation stroke prevention.

This review article evaluates novel oral anticoagulants in comparison with warfarin for thromboembolism prophylaxis in patients with atrial fibrillation (AF). AF is the most frequently diagnosed arrhythmia in the United States. The most serious side effect of AF is stroke. Warfarin has several decades of proven efficacy in AF-related stroke prevention but the drug's numerous drawbacks make its implementation difficult for practitioners and patients. The difficulties of warfarin have prompted the development of alternative anticoagulants for AF-related stroke prevention with better efficacy, safety, and convenience. The oral direct thrombin inhibitor, dabigatran, and the oral factor Xa inhibitors, rivaroxaban and apixaban, have been evaluated in a large phase III trial. Dabigatran, rivaroxaban and apixaban were shown to be noninferior compared with warfarin in the prevention of stroke. Dabigatran and apixaban were found to be statistically superior to warfarin. All three may also have a better safety profile than warfarin. In conclusion, novel anticoagulants have a different pharmacologic profile compared with warfarin that may eliminate many of the treatment inconveniences. Practitioners must also be aware of the disadvantages these new drugs possess when choosing a management strategy for their patients. Drug selection may become clearer as these new drugs are used more extensively.