Elevated Lp(a): Guidance for Identifying and Managing Patients.

Lipoprotein(a) (Lp(a)) is a unique low-density lipoprotein-like lipoprotein that is considered an independent and causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve stenosis. The Lp(a) molecule also contains apolipoprotein A and apolipoprotein B, which collectively promote atherosclerosis, thrombosis, and inflammation. Lp(a) is highly genetic and minimally responsive to nonpharmacological measures. Lp(a) serum levels ≥125 nmol/L are associated with increased ASCVD risk, but this threshold has not been accepted universally. Elevated Lp(a) is the most common genetic dyslipidemia affecting approximately 20% of the general population. Certain currently available lipid-lowering drugs, including the proprotein convertase subtilisin/kexin type 9 therapies, produce moderate reductions in Lp(a); however, none are indicated for the treatment of elevated Lp(a). There are currently four investigational RNA-based therapeutic agents that reduce Lp(a) by 70% to 100%. Two of these agents are being evaluated for ASCVD risk reduction in adequately powered outcomes trials, with results expected in 2 to 3 years. Until such therapies become available and demonstrate favorable clinical outcomes, strategies for elevated Lp(a) primarily involve early and intensive ASCVD risk factor management.

Effects of Ubiquinol and/or D-ribose in Patients With Heart Failure With Preserved Ejection Fraction.

Patients with heart failure with preserved ejection fraction (HFpEF) have few pharmacologic therapies, and it is not known if supplementing with ubiquinol and/or d-ribose could improve outcomes. The overall objective of this study was to determine if ubiquinol and/or d-ribose would reduce the symptoms and improve cardiac performance in patients with HFpEF. This was a phase 2 randomized, double-blind, placebo-controlled trial of 216 patients with HFpEF who were ≥ 50 years old with a left ventricular ejection fraction (EF) ≥ 50%. A total of 4 study groups received various supplements over 12 weeks: Group 1 received placebo ubiquinol capsules and d-ribose powder, Group 2 received ubiquinol capsules (600 mg/d) and placebo d-ribose powder, Group 3 received placebo ubiquinol capsules with d-ribose powder (15 g/d), and Group 4 received ubiquinol capsules and d-ribose powder. There were 7 outcome measures for this study: Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score, level of vigor using a subscale from the Profile of Mood States, EF, the ratio of mitral peak velocity of early filling to early diastolic mitral annular velocity (septal E/e' ratio), B-type natriuretic peptides, lactate/adenosine triphosphate ratio, and the 6-minute walk test. Treatment with ubiquinol and/or d-ribose significantly improved the KCCQ clinical summary score (17.30 to 25.82 points), vigor score (7.65 to 8.15 points), and EF (7.08% to 8.03%) and reduced B-type natriuretic peptides (-72.02 to -47.51) and lactate/adenosine triphosphate ratio (-4.32 to -3.35 × 10-4). There were no significant increases in the septal E/e' or the 6-minute walk test. In conclusion, ubiquinol and d-ribose reduced the symptoms of HFpEF and increased the EF. These findings support the use of these supplements in addition to standard therapeutic treatments for patients with HFpEF.

Mitochondrial bioenergetics and D-ribose in HFpEF: a brief narrative review.

OBJECTIVE: In this review article, we briefly describe the status of treatment options for HFpEF and the role of mitochondrial dysfunction in the pathogenesis of HFpEF as an alternative therapeutic target. We also examine the mechanisms of D-ribose in cellular energy production and discuss the potential disadvantages and benefits of supplemental use of D-ribose in patients with HFpEF. BACKGROUND: Heart failure is a major cardiovascular disease that impacts over 6 million Americans and is one of the leading causes for morbidity and mortality. Patients with heart failure often experience shortness of breath and fatigue along with impaired physical capacity, all leading to poor quality of life. As a subtype of heart failure, heart failure with preserved ejection fraction (HFpEF) is characterized with impaired diastolic function. Currently, there are no effective treatments specifically for HFpEF, thus clinicians and researchers are searching for therapies to improve cardiac function. Emerging evidence indicate that mitochondrial dysfunction and impaired cardiac bioenergetics are among the underlying mechanisms for HFpEF. There is increased interest in investigating the use of supplements such as D-ribose to enhance mitochondrial function and improve production of adenosine triphosphate (ATP). METHODS: For this narrative review, more than 100 relevant scientific articles were considered from various databases (e.g., PubMed, Web of Science, CINAHL, and Google Scholar) using the keywords "Heart Failure", "HFpEF", "D-ribose", "ATP", "Mitochondria", Bioenergetics", and "Cellular Respiration". CONCLUSIONS: It is essential to find potential targeted therapeutic treatments for HFpEF. Since there is evidence that the HFpEF is related to impaired myocardial bioenergetics, enhancing mitochondrial function could augment cardiac function. Using a supplement such as D-ribose could improve mitochondrial function by increasing ATP and enhancing cardiac performance for patients with HFpEF. There is a recently completed clinical trial with HFpEF patients that indicates D-ribose increases ATP production and improves cardiac ejection fraction.

Effect of aerobic exercise on amyloid accumulation in preclinical Alzheimer's: A 1-year randomized controlled trial.

BACKGROUND: Our goal was to investigate the role of physical exercise to protect brain health as we age, including the potential to mitigate Alzheimer's-related pathology. We assessed the effect of 52 weeks of a supervised aerobic exercise program on amyloid accumulation, cognitive performance, and brain volume in cognitively normal older adults with elevated and sub-threshold levels of cerebral amyloid as measured by amyloid PET imaging. METHODS AND FINDINGS: This 52-week randomized controlled trial compared the effects of 150 minutes per week of aerobic exercise vs. education control intervention. A total of 117 underactive older adults (mean age 72.9 [7.7]) without evidence of cognitive impairment, with elevated (n = 79) or subthreshold (n = 38) levels of cerebral amyloid were randomized, and 110 participants completed the study. Exercise was conducted with supervision and monitoring by trained exercise specialists. We conducted 18F-AV45 PET imaging of cerebral amyloid and anatomical MRI for whole brain and hippocampal volume at baseline and Week 52 follow-up to index brain health. Neuropsychological tests were conducted at baseline, Week 26, and Week 52 to assess executive function, verbal memory, and visuospatial cognitive domains. Cardiorespiratory fitness testing was performed at baseline and Week 52 to assess response to exercise. The aerobic exercise group significantly improved cardiorespiratory fitness (11% vs. 1% in the control group) but there were no differences in change measures of amyloid, brain volume, or cognitive performance compared to control. CONCLUSIONS: Aerobic exercise was not associated with reduced amyloid accumulation in cognitively normal older adults with cerebral amyloid. In spite of strong systemic cardiorespiratory effects of the intervention, the observed lack of cognitive or brain structure benefits suggests brain benefits of exercise reported in other studies are likely to be related to non-amyloid effects. TRIAL REGISTRATION: NCT02000583; ClinicalTrials.gov.

Potential use of ubiquinol and d-ribose in patients with heart failure with preserved ejection fraction.

•Manuscript Highlights.•HFpEF is associated with reduced ATP production in the myocardium.•Ubiquinol and d-ribose both contribute to the generation of myocardial ATP.•Both ubiquinol and d-ribose are being studied as supplemental treatments for patients with HFpEF.

Use of speckle tracking to assess heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) currently represents approximately 50% of heart failure (HF) cases in the USA and is increasingly recognized as a leading cause of morbidity and mortality. Recent data suggest that the prevalence of HFpEF relative to HF with reduced ejection fraction (HFrEF) is increasing at a rate of 1% per year. With an aging population and increasing risk factors such as hypertension, obesity, and diabetes mellitus, HFpEF will soon be the most prevalent HF phenotype. Two-dimensional speckle-tracking echocardiography (STE) has been used to diagnose HFpEF specifically by focusing on the longitudinal systolic function of the left ventricle (LV). Yet there are many patients with HFpEF in whom there are no differences in LV global longitudinal systolic strain, but there are changes in left atrial function and structure. There are several proposed pathophysiological mechanisms for HFpEF such as endothelial dysfunction, interactions among proteins, signaling pathways, and myocardial bioenergetics. Yet only one specific therapy, mineralocorticoid receptor antagonist, spironolactone, is recommended as a treatment for patients with HFpEF. However, spironolactone does not address many of the pathophysiologic changes that occur in HFpEF, thus new novel therapeutic agents are needed. With the limited available therapies, clinicians should use STE to assess for the presence of this syndrome in their patients to provide effective diagnosis and management.

Understanding D-Ribose and Mitochondrial Function.

Mitochondria are important organelles referred to as cellular powerhouses for their unique properties of cellular energy production. With many pathologic conditions and aging, mitochondrial function declines, and there is a reduction in the production of adenosine triphosphate. The energy carrying molecule generated by cellular respiration and by pentose phosphate pathway, an alternative pathway of glucose metabolism. D-ribose is a naturally occurring monosaccharide found in the cells and particularly in the mitochondria is essential in energy production. Without sufficient energy, cells cannot maintain integrity and function. Supplemental D-ribose has been shown to improve cellular processes when there is mitochondrial dysfunction. When individuals take supplemental D-ribose, it can bypass part of the pentose pathway to produce D-ribose-5-phosphate for the production of energy. In this article, we review how energy is produced by cellular respiration, the pentose pathway, and the use of supplemental D-ribose.

Effect of Long-term Nicotine Replacement Therapy vs Standard Smoking Cessation for Smokers With Chronic Lung Disease: A Randomized Clinical Trial.

Importance: Smokers with chronic obstructive pulmonary disease (COPD) have particular difficulty quitting. Long-term nicotine replacement therapy (LT-NRT) might offer a strategy for reducing harm from cigarettes and provide a pathway for later cessation. Objective: To compare the effect of LT-NRT vs standard smoking cessation (SSC) on exposure to cigarette smoke, harm related to smoking, and cessation among smokers with COPD. Design, Setting, and Participants: This unblinded, randomized clinical trial recruited smokers who self-reported a diagnosis of COPD at any level of readiness to quit from May 23, 2014, through November 30, 2015. The 12-month follow-up was completed December 6, 2016. Patients were recruited at a clinical research unit of an academic medical center. Analysis was based on intention to treat and performed from March 8 through November 30, 2017. Interventions: Standard smoking cessation treatment included 10 weeks of NRT and 4 follow-up counseling sessions for those willing to make a quit attempt. Long-term NRT included 12 months of NRT and 6 follow-up counseling sessions regardless of initial willingness to quit. Overall, 198 patients were randomized to SSC, and 197 were included in the primary analysis; 200 patients were randomized to LT-NRT, and 197 were included in the primary analysis. Main Outcomes and Measures: The primary outcome was 7-day abstinence verified by carbon monoxide (CO) levels at 12 months. Secondary outcomes included cigarettes smoked per day (CPD), exposure to CO, urinary excretion of 4-methylnitrosamino-1-3-pyridyl-1-butanol (NNAL) (a smoking-related carcinogen), and adverse events. Results: Among 398 patients who were randomized (59.8% female; mean [SD] age, 56.0 [9.3] years), the mean (SD) CPD was 23.1 (12.3). Twelve-month follow-up was completed by 373 participants (93.7%), and 394 (99.0%) were included in the primary analysis. At 12 months, CO-verified abstinence occurred in 23 of 197 participants (11.7%) in the SSC arm and 24 of 197 (12.2%) in the LT-NRT arm (risk difference, 0.5%; 95% CI, -5.9% to 6.9%). Continuing smokers in the SSC and LT-NRT arms had similar, significantly reduced harms caused by smoking, including cigarette consumption by 12.4 and 14.5 CPD, respectively, exhaled CO level by 5.5 and 7.8 ppm, respectively, and mean urinary NNAL excretion by 21.7% and 23.0%, respectively. In multivariate analyses, continuing smokers with greater adherence to NRT experienced less reduction in NNAL exposure. The frequency of major adverse cardiac events was similar in both groups. Conclusions and Relevance: Similar rates of cessation and similar reductions in exposure to tobacco smoke resulted with LT-NRT and SSC. Among continuing smokers, ongoing use of NRT was not associated with reductions in smoke exposure. Trial Registration: ClinicalTrials.gov Identifier: NCT02148445.

Impact of Radiofrequency Ablation of Atrial Fibrillation on Pulmonary Vein Cross Sectional Area: Implications for the Diagnosis of Pulmonary Vein Stenosis.

INTRODUCTION: Restoration of normal sinus rhythm by radiofrequency ablation (RFA) in atrial fibrillation (AF) patients can result in a reduction of left atrial (LA) volume and pulmonary vein (PV) dimensions. It is not clear if this PV size reduction represents a secondary effect of overall LA volume reduction or true PV stenosis. We assessed the relationship between LA volume reduction and PV orifice area pre- and post-RFA. METHODS: A retrospective cohort study was conducted at a tertiary care academic hospital. Pre- and post-RFA cardiac computed tomography (CT) studies of 100 consecutive AF patients were reviewed. Studies identifying obvious segmental PV narrowing were excluded. Left atrial volumes and PV orifice cross-sectional areas (PVOCA) were measured using proprietary software from the CT scanner vendor (GE Healthcare, Waukesha, WI). RESULTS: The cohort had a mean age of 60 ± 8 years, 73% were male, and 90% were Caucasian. Non-paroxysmal AF was present in 76% of patients with a mean duration from diagnosis to RFA of 55 ± 54 months. Mean procedural time was 244 ± 70 min. AF recurred in 27% at 3 month follow-up. Pre-RFA LA volumes were 132 ± 60 ml and mean PVOCA was 2.89 ± 2.32 cm2. In patients with successful ablation, mean LA volume decreased by 10% and PVOCA decreased by 21%. PVOCA was significantly reduced in patients with successful RFA compared to those who had recurrence (2.18 ± 1.12 vs. 2.8 ± 1.9 cm2, p = 0.04) but reduction in LA volume between groups was not significant (118 ± 42 vs. 133 ± 54 ml, p=0.15). CONCLUSIONS: The study demonstrates that both PV orifice dimensions and LA volume are reduced after successful AF ablation. These data warrant a reassessment of criteria for diagnosing PV stenosis based on changes in PV caliber alone, ideally incorporating LA volume changes.

Practice variation in the re-initiation of dofetilide: An observational study.

BACKGROUND: Dofetilide is a class III antiarrhythmic drug that has been reported to be safe and efficacious in the treatment of atrial dysrhythmias with a known initial risk of QT prolongation and torsades de pointes (TdP). As a result, the Federal Drug Administration (FDA) mandated in-hospital dofetilide initiation and adherence to a common dosing protocol. However, there is a lack of clarity on how to manage dofetilide re-initiation. METHODS: An observational survey was performed including 347 cardiologists in the United States and worldwide to evaluate the deviations from approved manufacturer's protocol during dofetilide initiation and re-initiation among practicing cardiologists. RESULTS: Most practicing cardiologists were cautious about outpatient dofetilide use and adhered to the manufacturer's in-patient dofetilide protocol during de-novo initiation and reported low incidence of TdP in clinical practice. There were substantial differences among practicing cardiologists with deviation from the manufacturer's protocol during re-initiation of dofetilide. About 21% cardiologists always admitted patients to the hospital while 37% admitted patients <10% of the time for dofetilide re-initiation. Only 4% reported major adverse events with outpatient dofetilide re-initiation. There was also wide variation regarding monitoring of electrolytes and QT interval as an outpatient with dofetilide. CONCLUSION: There is significant practice pattern variation in the use of dofetilide for the management of AF. This degree of variation noted is concerning and is a reflection of the current lack of substantial clinical evidence in the re-initiation dofetilide protocol to help direct the provider.

Management of Stroke risk in atrial fibrillation patients with bleeding on Oral Anticoagulation Therapy-Role of Left Atrial Appendage Closure, Octreotide and more.

BACKGROUND: Bleeding complications especially gastrointestinal bleeding remains a major challenge associated with oral anticoagulation therapy (OAT) and often leads clinicians to withdraw oral anticoagulation therapy (OAT) . This exposes patients to risk of stroke and systemic thromboembolism (STE). Novel oral anticoagulants (NOACs) have proved no better when it comes to bleeding events and in fact studies have shown that overall NOACs are associated with higher incidence of gastrointestinal (GI) bleeding compared to warfarin . OBJECTIVES: In this review, we describe the difficulties encountered in managing OAT in patients with bleeding and strategies to maneuver around these bleeding complications particularly gastrointestinal bleeding secondary to arteriovenous malformations (AVM) and other vascular abnormalities. FINDINGS: Left atrial appendage closure (LAAC) has emerged as a very elegant and promising tool for stroke prevention in non-valvular atrial fibrillation (AF) patients who are intolerant to OAT. But the need for OAT post procedure for a brief period is becoming a major hurdle for clinicians to pursue in this direction in patients with recurrent gastrointestinal bleeds. And in majority of cases, recurrent or refractory gastrointestinal bleeds are usually secondary to arteriovenous malformations/angiodysplasias (AVM/AD). We suggest that the problem has to be approached by decreasing or eliminating the acute bleeding risk and closing the LAA in the long term, to enable the patients to come off of OAT and minimize the risk of recurrent bleeding.

Left Atrial Appendage Closure for Stroke Prevention: Devices, Techniques, and Efficacy.

Left atrial appendage closure can be performed either surgically or percutaneously. Surgical approaches include direct suture, excision and suture, stapling, and clipping. Percutaneous approaches include endocardial, epicardial, and hybrid endocardial-epicardial techniques. Left atrial appendage anatomy is highly variable and complex; therefore, preprocedural imaging is crucial to determine device selection and sizing, which contribute to procedural success and reduction of complications. Currently, the WATCHMAN is the only device that is approved for left atrial appendage closure in the United States.

Caregiver coaching program effect: Reducing heart failure patient rehospitalizations and improving caregiver outcomes among African Americans.

OBJECTIVES: (1) Test whether FamHFcare intervention could reduce patients' heart failure (HF)-related rehospitalizations and improve family caregiver outcomes; (2) calculate effect size on caregiver outcomes; and (3) evaluate the FamHFcare. BACKGROUND: Few interventions target family caregivers for HF home care. METHODS: This study was a mixed method design with stratification and random assignment of 20 African American HF patient/caregiver dyads. Descriptive, univariate parametric/non-parametric, and post-hoc analyses were used. RESULTS: At 6 months, compared to standard care, the intervention group had significantly fewer HF rehospitalizations (M-W z = -1.8, p = 0.03), while caregiver confidence (M-W z = 2.8, p = 0.003) and social support scores (M-W z = 2.4, p = 0.01) were significantly higher, and caregiver depression (M-W z = -2.4, p = 0.01) were significantly lower. Caregivers rated the FamHFcare as helpful (M = 46.8 ± 4.1). CONCLUSIONS: The FamHFcare intervention was associated with fewer HF patient rehospitalizations and improved caregiver outcomes.

Disparities in lipid control and statin drug use among diabetics with noncoronary atherosclerotic vascular disease vs those with coronary artery disease.

BACKGROUND: Diabetes mellitus (DM), coronary artery disease (CAD), and noncoronary atherosclerotic vascular diseases (NCVDs) have similar risks of cardiovascular events and similar recommendations for lipid control. There are limited data regarding lipid control in diabetic patients with NCVD in current clinical practice. OBJECTIVE: To assess current day practice of lipid control in patients with DM with NCVD vs those with CAD. METHODS: We retrospectively identified 3336 patients with DM and known atherosclerotic vascular disease between January 2009 and March 2012. We compared demographic variables, lipid levels, and statin use in diabetics with CAD alone vs diabetics without CAD but with one or more NCVD. RESULTS: There were 234 patients in DM with NCVD group and 3102 patients in DM with CAD group. The DM with NCVD group had a higher mean total cholesterol (152 ± 40 vs 146 ± 42 mg/dL; P = .019) and mean low-density lipoprotein (LDL; 86 ± 35 vs 80 ± 34 mg/dL; P = .04) with only 70% of patients achieving LDL of <100 mg/dL (compared with 80% in the DM with CAD group; P < .001). Statin use was 100% in CAD vs 75% in NCVD group (P < .001). In addition to limited use of more potent statins in the NCVD group, there was also a significantly lower dose of statins used overall. CONCLUSION: Our study demonstrates lower use and less aggressive application of statins among diabetics with NCVD compared with diabetics with CAD, resulting in higher mean LDL and total cholesterol in the NCVD group.

Under-Utilization of Implantable Cardioverter Defibrillators in Patients with Heart Failure - The Current State of Sudden Cardiac Death Prophylaxis.

BACKGROUND: Despite ACC/AHA guidelines indicating implantable cardioverter defibrillator (ICD) as class I therapy for primary prevention of sudden cardiac death in patients with EF≤35%, ICD utilization rates in real world practice have been low. OBJECTIVE: To determine the rate of ICD implantation at a tertiary care academic center and to assess the reasons for under-utilization of the same. METHODS: Review of a prospectively collected database which included all patients diagnosed with an EF≤35% was performed to assess the rate of ICD implantation and mortality. Reasons for non-implantation of ICD were then assessed from detailed chart review. RESULTS: A total of 707 patients (age 69.4 ± 14.1 years) with mean EF of 26±7% were analyzed. Only 28% (200/707) of patients had ICDs implanted. Mortality was lower in the group with ICD (25% vs 37%, p=0.004). When patients who either died or were lost to follow-up prior to 2005 were excluded, ICD utilization rate was still low at 37.6%. The most common reason for non-implantation of ICD was physicians not discussing this option with their patients. Patient refusal was the second most common reason. CONCLUSIONS: ICD Implantation rates for primary prevention of SCD in patients with EF≤35% is low. Physician and patient education should be addressed to improve the utilization rates.