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.

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.

Future of personalized pharmacotherapy in chronic heart failure patients.

There is a significant amount of diversity among heart failure (HF) patients. Contemporary HF regimens often do not take into consideration many of the factors that might influence an individual's response to treatment. Clinical recommendations based on trial data derived from mainly younger Caucasian male study populations have, in most cases, been applied equally to women and African-Americans. Subgroup analyses of randomized HF trials and results of retrospective cohort studies have been used for customizing HF regimens in women and African-Americans. Pharmacogenetics is an emerging strategy for personalizing HF therapy. Genetic biomarkers may play an important role in predicting a patient's response to treatment and in predicting those at risk of toxicity. HF pharmacotherapy has improved over the last two decades; however, substantial work remains in order to personalize HF management and maximize the benefit of pharmacologic interventions, while limiting adverse events.

Rhabdomyolysis in a patient receiving high-dose simvastatin after the induction of therapeutic hypothermia.

OBJECTIVE: To report a case of rhabdomyolysis in a patient receiving high-dose simvastatin after the induction of therapeutic hypothermia. CASE SUMMARY: A 45-year-old African American male was brought to the emergency department for a witnessed cardiac arrest. He was placed on a therapeutic hypothermia protocol and his simvastatin dose was increased from 40 to 80 mg at bedtime. Target core temperature (34 °C) was reached within 8 hours and was maintained for 24 hours. His admission creatine kinase was 965 units/L, which decreased to 153 units/L by day 4. On day 5, the patient voided a large quantity of orange-brown urine and had a dramatically increased creatine kinase (8523 unit/L) level and myoglobinuria. Statin therapy was subsequently discontinued. Creatine kinase remained elevated for 2 days, then gradually declined toward normal levels over the following week. DISCUSSION: Simvastatin undergoes extensive first-pass metabolism mediated by CYP3A4, making it susceptible to significant drug interactions. Therapeutic hypothermia has been shown to significantly reduce the clearance of CYP3A4 substrates. We attribute this patient's rhabdomyolysis to a therapy-drug interaction between the therapeutic hypothermia and the administration of high-dose simvastatin. We believe that the induced hypothermia caused a reduction in simvastatin clearance, leading to toxic plasma concentrations. According to the Naranjo probability scale, it was probable that the rhabdomyolysis was related to simvastatin use. The Horn Drug Interaction Probability Scale likewise classified the probability of a causal relationship between the potential therapy-drug interaction and the event as probable. CONCLUSIONS: Clinicians must be aware of the pharmacokinetic effects of therapeutic hypothermia to prevent potential drug-therapy interactions. It may be prudent to avoid the use of CYP3A4 substrates that are not essential treatments in patients undergoing therapeutic hypothermia until more information is known about their safety in this patient population.

The in vitro effects of niacin on platelet biomarkers in human volunteers.

Niacin is a natural pyridine derivative, proven to favorably modulate the blood lipid profile by increasing levels of high-density lipoprotein (HDL) cholesterol, and by reducing total cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, and Lp (a) lipoprotein concentrations. Considering that platelet activity is important in predicting vascular outcomes, and that HDL heavily constitutes platelet cellular membranes, we sought to evaluate the effect of niacin on human platelet activity indices. The blood obtained from 30 aspirin-naïve volunteers was preincubated with escalating concentrations of niacin in vitro. Platelet tests included whole blood and plasma aggregometry, rapid cartridge-based analyser, expression of major surface receptors by flow cytometry, and plasma prostaglandins by ELISA. Preincubation of blood with niacin at 0.3, 1.0 and 3.0 mM resulted in significant inhibition of maximal adenosine diphosphate (ADP)- (p=0.03), and collagen-induced platelet aggregation (p=0.01), and reduced activity by VerifyNow (p=0.007) bedside analyser. Surface platelet PAR-1 (MoAb WEDE-15; p=0.04), and vitronectin (CD51/CD61; p=0.02) receptors were up-regulated. Niacin was associated with a two- to three-fold increase of thromboxane B2, prostaglandins D2, and E2. Formation of platelet-monocyte microparticles (CD14+CD151), and expression of PECAM-1 (CD31), thrombospondin (CD36), GP IIb/IIIa (CD41a) antigen, and activity with MoAb PAC-1, GPIb (CD42b), P-selectin (CD62p), LAMP-3 (CD63), LAMP-1 (CD107a), CD40-ligand (CD154), GP37 (CD165), were not affected by niacin, suggesting no effect on prostacyclin release. In conclusion, niacin in vitro affects platelet activity by mildly inhibiting aggregation, and stimulating significant prostaglandin release, with mostly intact major platelet receptor expression. The effect of niacin is unique, differs from other known antiplatelet agents, and suggests potential opportunities for therapeutic combination, particularly in patients with low levels of HDL-C. These preliminary data, while intriguing, require confirmation in subjects receiving orally dosed extended-release niacin in order to determine whether these findings are clinically relevant.