Physiological Pacing for the Prevention and Treatment of Heart Failure: a State-of-the-Art Review.

Permanent pacing from the right ventricular apex can reduce quality of life and increase the risk of heart failure and death. This review summarizes the milestones in the evolution of pacemakers toward physiological pacing with biventricular pacing systems and lead implantation into the cardiac conduction system to synchronize cardiac contraction and relaxation. Both approaches aim to reproduce normal cardiac activation and help to prevent and treat heart failure.

Atrial fibrillation and heart failure with preserved ejection fraction "twindemic"-Shared root causes and treatment targets.

Heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF) are comorbid conditions that are increasingly prevalent and have a high socioeconomic burden. This article discusses their shared pathophysiology, focusing on the triad of hypertension, obesity, and aging. We highlight the misperception that pharmacological heart rate lowering is beneficial, which has resulted in an overprescription of β-blockers in HFpEF and AF.

Left ventricular volume and maximal functional capacity in heart failure with preserved ejection fraction: Size matters.

Aims: Emerging evidence suggests that smaller left ventricular volumes may identify subjects with lower cardiorespiratory fitness. Whether left ventricular size predicts functional capacity in patients with heart failure with preserved ejection fraction (HFpEF) is unclear. This study aimed to explore the association between indexed left ventricular end-diastolic volume (iLVEDV) and maximal functional capacity, assessed by peak oxygen consumption (peakVO), in stable outpatients with HFpEF.

Impact of the COVID-19 pandemic on the rate of lower limb amputation in Veterans.

Background: The COVID-19 pandemic led to changes in health care, including postponement of nonurgent appointments. These changes, combined with overall decreased activity levels, may have placed individuals with vascular disease at increased risk for skin ulceration and amputation.

Objective: To determine the rates of lower limb amputation in Veterans due to complications of diabetes and/or vascular disease in the year following onset of the COVID-19 pandemic (March 2020-March 2021) compared to the previous 3 years (March 2017-March 2020).

β-Blocker Withdrawal and Functional Capacity Improvement in Patients With Heart Failure With Preserved Ejection Fraction.

Importance: Increasing the patient's heart rate (HR) has emerged as a therapeutic option in patients with heart failure with preserved ejection fraction (HFpEF). However, the evidence is conflicting, and the profile of patients who benefit most from this strategy remains unclear.

Objective: To assess the association of β-blocker treatment withdrawal with changes in the percentage of predicted peak oxygen consumption (VO2) across indexed left ventricular diastolic (iLVEDV) and indexed left ventricular systolic volumes (iLVESV), and left ventricular ejection fraction (LVEF) in patients with HFpEF and chronotropic incompetence.

Rationale and design of the PACE HFpEF trial: Physiologic accelerated pacing as a holistic treatment of heart failure with preserved ejection fraction.

Background: In heart failure with preserved ejection fraction (HFpEF), it has been assumed that pharmacologic heart rate suppression should provide clinical benefits through an increase in diastolic filling time. Contrary to this assumption, heart rate lowering in patients with preserved left ventricular ejection fraction and hypertension or coronary artery disease results in adverse outcomes and suggests that the opposite may be beneficial. Namely, shortening the diastolic filling time with a higher heart rate might normalize the elevated filling pressures that are the of HFpEF.

2-Deoxyglucose and hydroxychloroquine HPLC-MS-MS analytical methods and pharmacokinetic interactions after oral co-administration in male rats.

Our previous work has shown a synergistic tumoricidal efficacy of combining the hexokinase (HK) inhibitor 2-deoxyglucose (2-DG) and the autophagy inhibitor chloroquine (CQ) through intraperitoneal injections on HK2-addicted prostate cancers in animal models. The pharmacokinetic (PK) behaviors of these oral drugs after simultaneous oral administration have not been reported. We developed high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS-MS) analytical methods for 2-DG and the clinically favored drug hydroxychloroquine (HCQ) for sera samples.

Effects of Continuous Accelerated Pacing on Cardiac Structure and Function in Patients With Heart Failure With Preserved Ejection Fraction: Insights From the myPACE Randomized Clinical Trial.

Background: Heart failure with preserved ejection fraction ≥50% is prevalent with few evidence-based therapies. In a trial of patients with heart failure with preserved ejection fraction with specialized pacemakers, treatment with accelerated personalized pacing averaging 75 bpm (myPACE) markedly improved quality of life, NT-proBNP (N-terminal pro-brain natriuretic peptide), physical activity, and atrial fibrillation burden compared with the standard lower rate setting of 60 bpm (usual care).

Methods And Results: In this exploratory study, provider-initiated echocardiographic studies obtained before and after the trial were assessed for changes in left ventricular (LV) structure and function among participants who continued their pacing assignment.

Effect of paced heart rate on quality of life and natriuretic peptides for stage B or C heart failure with preserved ejection fraction: A secondary analysis of the myPACE trial.

Aim: Emerging evidence suggests a beneficial effect of higher heart rates in some patients with heart failure with preserved ejection fraction (HFpEF). This study aimed to evaluate the impact of higher backup pacing rates in HFpEF patients with preexisting pacemaker systems that limit pacemaker-mediated dyssynchrony across left ventricular (LV) volumes and LV ejection fraction (LVEF).

Methods And Results: This is a post-hoc analysis of the myPACE clinical trial that evaluated the effects of personalized accelerated pacing setting (myPACE) versus standard of care on changes in Minnesota Living with Heart Failure Questionnaire (MLHFQ) score, N-terminal pro-brain natriuretic peptide (NT-proBNP), pacemaker-detected activity levels, and atrial fibrillation (AF) burden in patients with HFpEF with preexisting pacemakers.

Personalized accelerated physiologic pacing.

Heart failure with preserved ejection fraction (HFpEF) is increasingly prevalent with a high socioeconomic burden. Pharmacological heart rate lowering was recommended to improve ventricular filling in HFpEF. This article discusses the misperceptions that have resulted in an overprescription of beta-blockers, which in all likelihood have untoward effects on patients with HFpEF, even if they have atrial fibrillation or coronary artery disease as a comorbidity.

Association of Nondihydropyridine Calcium Channel Blockers Versus β-Adrenergic Receptor Blockers With Risk of Heart Failure Hospitalization.

Heart failure (HF) with preserved ejection fraction (HFpEF) and atrial fibrillation (AF) are interrelated and often coexisting conditions in older adults. Although equally recommended, nondihydropyridine calcium channel blockers (non-DHP CCBs), such as diltiazem and verapamil, are less often used than β blockers. Because recent studies suggested that β-blocker use in both HFpEF and AF may increase the risk for HF, we tested whether non-DHP CCBs were associated with lower HF hospitalization risk than β blockers.

Beta-Blocker Use and Heart Failure Outcomes in Mildly Reduced and Preserved Ejection Fraction.

Background: Although studies consistently show that beta-blockers reduce morbidity and mortality in patients with reduced ejection fraction (EF), data are inconsistent in patients with heart failure with mildly reduced ejection fraction (HFmrEF) and suggest potential negative effects in heart failure with preserved ejection fraction (HFpEF).

Objectives: The purpose of this study was to examine the association of beta-blockers with heart failure (HF) hospitalization and death in patients with HF and EF ≥40% METHODS: Beta-blocker use was assessed at first encounter in outpatients ≥65 years of age with HFmrEF and HFpEF in the U.S.

Effect of Personalized Accelerated Pacing on Quality of Life, Physical Activity, and Atrial Fibrillation in Patients With Preclinical and Overt Heart Failure With Preserved Ejection Fraction: The myPACE Randomized Clinical Trial.

Importance: Patients with heart failure with preserved ejection fraction (HFpEF) with a pacemaker may benefit from a higher, more physiologic backup heart rate than the nominal 60 beats per minute (bpm) setting.

Objective: To assess the effects of a moderately accelerated personalized backup heart rate compared with 60 bpm (usual care) in patients with preexisting pacemaker systems that limit pacemaker-mediated dyssynchrony.

Design, Setting, And Participants: This blinded randomized clinical trial enrolled patients with stage B and C HFpEF from the University of Vermont Medical Center pacemaker clinic between June 2019 and November 2020.

Heart rate changes and myocardial sodium.

Historic studies with sodium ion (Na ) micropipettes and first-generation fluorescent probes suggested that an increase in heart rate results in higher intracellular Na -levels. Using a dual fluorescence indicator approach, we simultaneously assessed the dynamic changes in intracellular Na and calcium (Ca ) with measures of force development in isolated excitable myocardial strip preparations from rat and human left ventricular myocardium at different stimulation rates and modeled the Na -effects on the sodium-calcium exchanger (NCX). To gain further insight into the effects of heart rate on intracellular Na -regulation and sodium/potassium ATPase (NKA) function, Na , and potassium ion (K ) levels were assessed in the coronary effluent (CE) of paced human subjects.

Ubiquitin Carboxyl-Terminal Hydrolase L1 of Cardiomyocytes Promotes Macroautophagy and Proteostasis and Protects Against Post-myocardial Infarction Cardiac Remodeling and Heart Failure.

Ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) is a deubiquitinase known to play essential roles in the nervous tissue. Myocardial upregulation of UCHL1 was observed in human dilated cardiomyopathy and several animal models of heart disease, but the (patho)physiological significance of UCHL1 in cardiomyocytes remains undefined. Hence, we conducted this study to fill this critical gap.

Beta-Blocker Use in Hypertension and Heart Failure (A Secondary Analysis of the Systolic Blood Pressure Intervention Trial).

Given the concern that beta-blocker use may be associated with an increased risk for heart failure (HF) in populations with normal left ventricular systolic function, we evaluated the association between beta-blocker use and incident HF events, as well as loop diuretic initiation in the Systolic Blood Pressure Intervention Trial (SPRINT). SPRINT demonstrated that a blood pressure target of <120 mm Hg reduced cardiovascular outcomes compared with <140 mm Hg in adults with at least one cardiovascular risk factor and without HF. The lower rate of the composite primary outcome in the 120 mm Hg group was primarily driven by a reduction in HF events.

SERCA2a-phospholamban interaction monitored by an interposed circularly permutated green fluorescent protein.

The interaction of phospholamban (PLB) and the sarcoplasmic reticulum Ca-ATPase (SERCA2a) is a key regulator of cardiac contractility and a therapeutic target in heart failure (HF). PLB-mediated increases in SERCA2a activity improve cardiac function and HF. Clinically, this mechanism can only be exploited by a general activation of the proteinkinase A (PKA), which is associated with side effects and adverse clinical outcomes.

Heart Rate-Induced Myocardial Ca Retention and Left Ventricular Volume Loss in Patients With Heart Failure With Preserved Ejection Fraction.

Background Increases in heart rate are thought to result in incomplete left ventricular (LV) relaxation and elevated filling pressures in patients with heart failure with preserved ejection fraction (HFpEF). Experimental studies in isolated human myocardium have suggested that incomplete relaxation is a result of cellular Ca overload caused by increased myocardial Na levels. We tested these heart rate paradigms in patients with HFpEF and referent controls without hypertension.

Genome-wide association studies of smooth pursuit and antisaccade eye movements in psychotic disorders: findings from the B-SNIP study.

Eye movement deviations, particularly deficits of initial sensorimotor processing and sustained pursuit maintenance, and antisaccade inhibition errors, are established intermediate phenotypes for psychotic disorders. We here studied eye movement measures of 849 participants from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study (schizophrenia N=230, schizoaffective disorder N=155, psychotic bipolar disorder N=206 and healthy controls N=258) as quantitative phenotypes in relation to genetic data, while controlling for genetically derived ancestry measures, age and sex. A mixed-modeling genome-wide association studies approach was used including ~4.