State of the art on angiotensin-neprilysin inhibitors.

Angiotensin receptor neprilysin inhibitor (ARNI) decreases renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous systems (SNS) activity promoting vasodilation, decreasing myocardial hypertrophy and fibrosis. Beyond the SNS, RAAS and natriuretic peptide systems, ARNI results in increased circulatory and myocardial nitric oxide levels activating cGMP and protein kinase G, which reduces oxidative stress, myocyte hypertrophy, cell death and has anti-thrombotic effects. ARNIs have a class I indication by heart failure (HF) guidelines in HFrEF patients with NYHA class II to III symptoms. Beyond HFrEF, the use of ARNIs has also been expanded to other clinical settings including HF with preserved ejection fraction (EF, HFpEF), acute HF, advanced HF, hypertension, arrhythmias and chronic kidney disease. This paper reviews the clinical benefits of ARNIs in both HF and the aforementioned cardiovascular conditions. We also discuss the combined use of ARNI with SGLT2i and their potential synergistic benefits on cardiovascular outcomes.

Coronavirus Disease-2019 and Implications on the Liver.

The coronavirus disease-2019 (COVID-19) pandemic has had a large impact on patients with chronic liver disease (CLD) and liver transplantation (LT) recipients. Patients with advanced CLD are at a significantly increased risk of poor outcomes in the setting of severe acute respiratory syndrome coronavirus 2 infection. The pandemic has also considerably altered the management and care that is provided to patients with CLD, pre-LT patients, and LT recipients. Vaccination against COVID-19 protects patients with CLD and LT recipients from adverse outcomes and is safe in these patients; however, vaccine efficacy may be reduced in LT recipients and other immunosuppressed patients.

Triple Antithrombotic Therapy in Patients With Left Ventricular Assist Devices.

Data on the efficacy and safety of the combination of warfarin and dual-antiplatelet therapy compared with warfarin and mono-antiplatelet therapy (MAPT) in patients with left ventricular assist devices (LVAD) remains scarce. Single-center study of 130 consecutive patients with durable LVAD. Baseline demographics, antithrombotic and antiplatelet regimen, and outcomes were compared between patients receiving warfarin plus dual-antiplatelet therapy (Group 1) and warfarin plus MAPT (Group 2). Antiplatelet therapy was assessed at hospital discharge post-LVAD implant and included aspirin, clopidogrel and dipyridamole. Outcomes at 1-year were assessed in each group. All patients were on aspirin and warfarin. No significant differences with regards to age, gender or ethnicity were noted at baseline between the two groups. Group 1 was more likely to have higher lactate dehydrogenase LDH levels at discharge and a history of stroke. No significant differences in international normalized ratio INR, hemoglobin or hematocrit were noted at discharge. During the study period, 48 patients had gastrointestinal bleeding events: 28 of 68 (41.2%) in Group 1 vs 20 of 62 (32.2%) in Group 2 (P = 0.293). At 1year, no statistically significant differences were noted in gastrointestinal bleeding (Group 1=27.90% vs Group 2 = 25.80, P = 0.784), ischemic stroke (Group 1 = 8.8% vs group 2 = 6.5%, P = 0.612), hemorrhagic stroke (Group 1 = 4.4% vs group 2 = 3.2%, P = 0.725) or mortality (Group 1 = 5.9% vs Group 2 = 1.6%, P = 0.206). Rates of pump thrombosis however were lower in Group 1 (Group 1 = 0% vs Group 2 = 6.5%, P = 0.033). Our study showed a high prevalence of triple-therapy antithrombotic use in LVAD patients with no significant differences in bleeding, stroke or survival. However, the risk for pump thrombosis was lower at 1-year when compared to patient receiving MAPT.

Comanagement With Nephrologist Care Is Associated With Fewer Cardiovascular Events Among Liver Transplant Recipients With Chronic Kidney Disease.

Chronic kidney disease (CKD) is associated with cardiovascular (CV) events, a leading complication in liver transplant recipients (LTRs). Timely subspecialty care is associated with improved clinical outcomes in patients with CKD. This study sought to assess associations between nephrology comanagement and CV events among LTRs at risk for or with CKD. METHODS: LTRs with CKD plus those at risk were identified in an inception cohort at a single tertiary care network between 2010 and 2016, using electronic health record data and manual chart review. CKD was defined as estimated glomerular filtration rate <60 mL/min/1.73 m2 or International Classification of Diseases 9th or 10th revision code for CKD and at-risk CKD as estimated glomerular filtration rate 60-89 mL/min/1.73 m2. Cox proportional hazard models assessed the association between nephrology comanagement and CV events among LTRs with or at risk for CKD. RESULTS: Among 602 LTRs followed for up to 6 y posttransplant, prevalence of CKD plus those at risk increased yearly (71% in year 1, 86% in year 6) (P < 0.0001). Rates of nephrology comanagement decreased yearly posttransplant (35% in year 1, 28% in year 6). In multivariable models, nephrology comanagement was associated with lower CV events (adjusted hazard ratio, 0.57; 95% confidence interval, 0.33-0.99). CONCLUSIONS: Among LTRs with CKD, nephrology comanagement may be associated with lower CV events. A prospective study is needed to identify the reasons for improved outcomes and barriers to nephrology referral.

Hypertension in cardiac transplant recipients: tackling a new face of an old foe.

PURPOSE OF REVIEW: Systemic hypertension (HTN) is a common complication arising in the heart transplant recipient. This article aims to review the most current literature and update readers on the epidemiology, pathophysiology and management of HTN in heart transplant patients. RECENT FINDINGS: In contrast to the general nontransplant hypertensive patient population, traditional risk factors, including family history of HTN, obesity and diabetes, play a minor role in the genesis of posttransplant HTN. Dysregulation in sodium and water balance, vascular stiffness, endothelial dysfunction, abnormal cardiorenal neural reflexes resulting from immunosuppression and cardiac denervation seem to be the predominant factors leading to postheart transplant HTN. Calcineurin inhibitors induced nephrotoxicity and steroid use further contributes to posttransplant HTN. SUMMARY: Owing to the paucity of data, particularly randomized controlled trials to guide the evaluation and management of HTN in the cardiac transplant patients, much of the available data come from the renal transplant population. The choice of antihypertensive should be based on timing related to transplantation and patient's comorbidities. Although calcium channel blockers and loop diuretics are the preferred agents in the early postheart transplant period, angiotensin-converting-enzyme inhibitors and angiotensin receptor blockers may be beneficial in the late postheart transplant period especially in the setting of diabetes and in the presence of proteinuria.

Association between plasminogen activator inhibitor-1 in young adulthood and nonalcoholic fatty liver disease in midlife: CARDIA.

BACKGROUND: Prior studies have demonstrated a cross-sectional association between elevated plasminogen activator inhibitor-1 (PAI-1) levels and nonalcoholic fatty liver disease (NAFLD). However, there are no prospective longitudinal assessments of the association between PAI-1 and NAFLD. We aimed to describe the association between PAI-1 levels in early adulthood with NAFLD in midlife. METHODS: Among the 5115 participants in the coronary artery risk development in young adults (CARDIA) study, participants were randomly selected from a subset that was free of obesity, diabetes and hypertension at the 1992-1993 exam and attended the 2005-2006 exam (n = 996). A subset of participants (n = 896) also had CT liver fat measured (2010-2011). Participants with secondary causes of steatosis were excluded (n = 87). NAFLD was defined as liver attenuation ≤51 Hounsfield units. Logistic regression models assessed the association between PAI-1 and NAFLD. RESULTS: Of 809 participants, 53% were female, 37% black with a mean age of 32 years. Median PAI-1 level at 1st assessment (1992-1993) was 23.4 ng/mL among participants with NAFLD vs 11.9 ng/mL among those without NAFLD (P < .0001). Median PAI-1 level at 2nd assessment (2005-2006) was 55.6 ng/mL among participants with NAFLD vs 19.5 ng/mL among those without NAFLD (P < .0001). Higher PAI-1 levels were independently associated with NAFLD (1st assessment adjusted OR [AOR] 2.16 per 1 standard deviation higher log(PAI-1) level (95% confidence interval [CI] 1.63-2.85); 2nd assessment AOR 2.71 (95% CI 2.03-3.61)). CONCLUSIONS: Plasma PAI-1 levels in young adulthood were independently associated with NAFLD in midlife. Further studies may indicate whether PAI-1 plays a role in NAFLD pathophysiology.

The role of clinic blood pressure for the diagnosis of hypertension.

PURPOSE OF REVIEW: Recent data from randomized clinical trials and updates to hypertension guidelines warrant a review of the literature for the diagnosis and management of hypertension in the clinic setting. Although there have been significant advances in ambulatory blood pressure (BP) monitoring and home BP monitoring, office BP (OBP) measurements remains the primary means of diagnosis and treatment. RECENT FINDINGS: The current review focuses on updated guidelines, proper technique, device selection, and the recent controversy regarding unattended BP measurements. We review the data on cardiovascular outcomes, the comparison of OBP with ambulatory BP monitoring and home BP monitoring and some of the pitfalls of OBP measurements. SUMMARY: The current review highlights the need for constant review of BP goals to minimize cardiovascular risk and some of the ongoing controversies regarding OBP measurements.

CDK4/6 dual inhibitor abemaciclib demonstrates compelling preclinical activity against esophageal adenocarcinoma: a novel therapeutic option for a deadly disease.

Esophageal adenocarcinoma (EAC) is a deadly disease with limited therapeutic options. In the present study, we determined the preclinical efficacy of CDK4/6 inhibitor abemaciclib for treatment of EAC. In vitro, apoptosis, proliferation, and pathway regulation were evaluated in OE19, OE33, and FLO1 EAC cell lines. In vivo, esophagojejunostomy was performed on rats to induce EAC. At 36 weeks post-surgery, MRI and endoscopic biopsy established baseline tumor volume and molecular correlates, respectively. Next, the study animals were randomized to 26mg/kg intraperitoneal abemaciclib treatment or vehicle control for 28 days. Pre and post treatment MRIs, histopathology, and qRT-PCR were utilized to determine response. Our results demonstrated treatment with abemaciclib lead to increased apoptosis, and decreased proliferation in OE19 (p=0.185), OE33 (p=0.048), and FLO1 (p=0.043) with anticipated downstream molecular inhibition. In vivo, 78.9% of treatment animals demonstrated >20% tumor volume decrease (placebo 0%). Mean tumor volume changed in the treatment arm by -65.5% (placebo +133.5%) (p<0.01), and prevalence changed by -37.5% (placebo +16.7%) (p<0.01). Pre vs post treatment qRT-PCR demonstrated significant inhibition of all downstream molecular correlates. Overall our findings suggest potent antitumor efficacy of abemaciclib against EAC with evident molecular pathway inhibition and reasonable safety, establishing the rationale for future clinical development.

Utility of ambulatory blood pressure monitoring for the management of hypertension.

PURPOSE OF REVIEW: Hypertension is a leading cause of cardiovascular morbidity and mortality, affecting nearly 80 million individuals in the United States alone. Accurate measurement of blood pressure (BP) is the crucial first step to reduce the associated cardiovascular risk of hypertension. For decades, clinicians have relied on office BP measurements for the diagnosis and subsequent management of hypertension. However, it has been clearly demonstrated that ambulatory BP measurements are a better predictor of cardiovascular risk and can provide clinicians with important additional information to improve BP control and reduce cardiovascular risk. This article reviews the available data and provides clinical insights into the use of ambulatory BP monitoring for the management of hypertension. RECENT FINDINGS: Ambulatory BP monitoring is uniquely capable of identifying patients with white-coat hypertension (WCH), masked hypertension and abnormal nocturnal BP profiles. Recently, ambulatory BP data have demonstrated the negative impact of WCH on right ventricular function, a greater prevalence of masked hypertension than previously recognized and the detrimental impact of nocturnal hypertension even in controlled hypertension. SUMMARY: Ambulatory BP monitoring provides clinicians with the most comprehensive evaluation of hypertension and the ability to define individual BP phenotypes. Hence, these out-of-office measurements can be utilized to improve hypertension control, translating into a reduction of cardiovascular events.

Management of Patients Admitted with Acute Decompensated Heart Failure.

BACKGROUND: Hospital admission for the treatment of acute decompensated heart failure is an unfortunate certainty in the vast majority of patients with heart failure. Regardless of the etiology, inpatient treatment for acute decompensated heart failure portends a worsening prognosis. METHODS: This review identifies patients with heart failure who need inpatient therapy and provides an overview of recommended therapies and management of these patients in the hospital setting. RESULTS: Inpatient therapy for patients with acute decompensated heart failure should be directed at decongestion and symptom improvement. Clinicians should also treat possible precipitating events, identify comorbid conditions that may exacerbate heart failure, evaluate and update current guideline-directed medical therapy, and perform risk stratification for all patients. Finally, efforts should be made to educate patients about the importance of restricting salt and fluid, monitoring daily weights, and adhering to a graded exercise program. CONCLUSION: Early discharge follow-up and continued optimization of guideline-directed medical therapy are key to preventing future heart failure readmissions.

Clinical characteristics, treatment patterns and outcomes of Hispanic hypertensive patients.

Hispanics are the largest and fastest-growing minority population in the United States, currently comprising about 16.3% (52 million) of the total population. With an increased prevalence of metabolic risk factors in this population, the rate of uncontrolled hypertension (HTN) in Hispanics significantly exceeds the rates observed among non-Hispanic blacks and whites. Unfortunately, data on HTN in Hispanics remains limited due to the under-representation of Hispanics in clinical trials; with most of the data primarily restricted to observational and retrospective subgroup analyses. This article aims to review the available data on prevalence, awareness and control of HTN, risk factors and some of the challenges unique to the Hispanics population. We also discuss treatment strategies derived from large HTN trials that included Hispanics.

Diuretic dosing in acute decompensated heart failure: lessons from DOSE.

The mainstay of treatment for acute decompensated heart failure (ADHF) is intravenous (IV) diuretic therapy either as a bolus or via continuous infusion. Despite being available for decades, few randomized trials exist to guide dosing and administration of these drugs. In 2011, the Diuretic Optimization Strategies Evaluation (DOSE) trial used a prospective, randomized design to compare bolus versus continuous infusion of IV furosemide, as well as high-dose versus low-dose therapy. The study found no difference in the primary end point for continuous versus bolus infusion. High-dose diuretics were more effective than low dose without clinically important negative effects on renal function. Although limited by patient selection criteria and protocol design, the study challenges long-held beliefs that continuous infusion is more effective than bolus dosing. The study also challenges the notion that high-dose diuretics carry clinically important renal toxicity risks for patients.

Utility of daily diuretic orders for identifying acute decompensated heart failure patients for quality improvement.

INTRODUCTION: Many studies have demonstrated gaps in adherence to American College of Cardiology (ACC)/American Heart Association (AHA) guidelines among patients with acute decompensated heart failure (ADHF). Quality improvement initiatives can improve compliance with guideline-recommended therapy yet a major challenge to such programs is identifying heart failure patients across the many wards and services of the complex hospital environment. METHODS AND RESULTS: Using our hospital's electronic order-entry system, we generated a daily list of all hospitalized patients receiving a loop diuretic. Over a 3-month period, each patient on this list was screened through chart review for a diagnosis of ADHF. For those patients with ADHF, a clinical reminder about ACC/AHA recommended therapies was placed in the chart. Patient outcomes were followed using the Get With The Guidelines heart failure database.During the study period, 98.6% of patients with ADHF were identified by the diuretics list. The diuretics list had a sensitivity of 98.6% and specificity of 92.2%. The diuretic list captured more ADHF patients than alternative methods such as chest x-ray and brain natriuretic peptide level. Use of the daily diuretic list and targeted reminders to clinicians was associated with an improvement in recommended therapies including smoking-cessation education and heart failure teaching. CONCLUSIONS: A daily list of inpatients receiving diuretics allowed real-time identification of most hospitalized heart failure patients at our institution. Targeted reminders to clinicians regarding ACC/AHA-recommended therapies for heart failure were associated with improvements in guideline adherence.