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Introduction: Conflicting data exist on the prognostic significance of permanent pacemaker (PPM) implantation after transcatheter aortic valve replacement (TAVR)., Objective: The purpose of this study was to evaluate whether PPM implantation after TAVR is associated with adverse outcomes., Methods: A retrospective analysis of a cohort comprised patients enrolled in a prospective registry between 2008 and 2019. Participants were allocated into 3 groups: patients without a prior pacemaker (n = 930 [75%]), those with previous pacemaker implantation (n = 118 [10%]), and those with pacemaker implantation after TAVR (n = 191 [15%]). The primary outcome included death and heart failure hospitalizations at 1 year. Secondary outcomes included death and heart failure hospitalizations stratified by pacing burden., Results: A total of 1239 patients underwent TAVR with a median follow-up period of 2.3 years (interquartile range 1-4 years). Patients with previous and new pacemaker implantation were older (84 [80-88], 84 [80-88], and 82 [78-86] years; P = .009) and had lower baseline left ventricular ejection fraction (50% ± 15%, 55% ± 12%, and 56% ± 12%; P < .001). Patients who underwent new pacemaker implantation had higher combined outcome of death and heart failure hospitalizations (21%,12%, and 14%; P = .01). New pacemaker implantation was associated with almost twice the risk of 1-year mortality (odds ratio 1.85; 95% confidence interval 1.13-3.02; P = .014). Pacing burden, however, was not associated with the primary outcome. Furthermore, no significant difference was observed at long-term follow-up (cumulative probability to develop the primary end point at 3 years was 57% ± 2% [without PPM], 57% ± 6% [prior PPM], 54% ± 4% [new PPM]; P = .52)., Conclusion: Pacemaker implantation after TAVR is associated with higher 1-year adverse outcome, but this attenuates over time, suggesting that competing factors may play a role. Interestingly, pacing burden is not associated with adverse clinical course., (Copyright © 2022 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: The association between proton pump inhibitor (PPI) use and increased risk of dementia is controversial., Aim: Investigating this issue in a large population of community-dwelling elders., Methods: Our database was retrospectively searched for all community-dwelling patients aged ≥65 years who newly diagnosed with dementia/cognitive decline (DCD) between January 2002 - December 2012. Receiving ≥11 prescriptions of PPIs/year was categorized as PPI users. Clinical data were collected from the medical files. Risk of DCD in PPI users was analyzed by Cox regression models., Results: Included 48,632 elders of whom 8,848 were diagnosed with DCD (18.2%). PPI use was documented in 10,507, of whom 1,959 were subsequently diagnosed with DCD (18.6%). Among 38,125 non-PPI users, 6,889 (18.1%) were diagnosed with DCD. The hazard ratio for occurrence of DCD in PPI users compared to non-users was 0.85 (95% CI: 0.81-0.89, P <0.001) in an un-adjusted Cox regression model and 0.83 in a Cox regression model adjusted for age and sex (95% CI: 0.79-0.87, P <0.001). Multivariate Cox regression accounting for background diseases, marital status, and socioeconomic state yielded a hazard ratio of 0.77 (95% CI: 0.73-0.81, P <0.001)., Conclusion: PPI use wasn't associated with DCD development in chronic PPI users., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Endothelial function is a marker for cardiovascular risk. Thus, abnormal endothelial function may be associated with adverse 1-year outcome in patients presenting to the emergency department chest pain unit (CPU)., Methods: Following endothelial function testing, using EndoPAT 2000 in 300 consecutive subjects with chest pain and no history of coronary artery disease (CAD) presenting to CPU, patients underwent coronary computerized tomographic angiography (CCTA) or single-photon emission computed tomography according to availability., Results: Mean 10-year Framingham risk score (FRS) was 6.6±5.9%, median reactive hyperemia index (RHI) as a measure of endothelial function 2.08 and mean was 2.0±0.4. During a 1-year follow-up, the 20 (6.6%) patients who developed major adverse cardiovascular end-points (MACE), including all-cause mortality, non-fatal myocardial infarction, hospitalization for heart failure or angina pectoris, stroke, coronary artery bypass grafting and percutaneous coronary interventions, had higher 10-year FRS (10.5±8.2% vs 6.3±5.7%; p<0.001), lower baseline RHI (1.43±0.41 vs 2.10±0.44; p<0.001) and a greater extent of coronary atherosclerosis lesions (70% vs 3.9%, p<0.001) in the CPU CCTA, compared to those without MACE. RHI≤the median was associated with higher 1-year MACE (13% vs 0.7%, p<0.001) compared to RHI>the median. Multivariate analysis demonstrated that RHI≤the median is an independent predictor of coronary atherosclerosis lesions in the CPU CCTA (OR 5.98, 95% CI 03.29-10.88; p<0.001) and 1-year MACE (OR 15.207, 95% CI 2.00-115.33; p<0.01)., Conclusions: Our findings suggest that non-invasive endothelial function testing may have clinical utility in triaging patients in the CPU and in predicting 1-year MACE., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Atrial fibrillation (AF) is a major risk factor of ischemic stroke. We tested whether the adoption of the CHADS(2) score in clinical guidelines has impacted treatment strategies for stroke prevention, and examined how AF affects stroke outcome., Methods: In the setting of two national surveys [National Acute Stroke Israeli Surveys; all patients hospitalized for stroke in Israel during February-March 2004, and March-April 2007] data of patients with and without AF were analyzed with respect to patient characteristics, use of anticoagulation, stroke severity, clinical course, and long-term outcome., Results: Of 3040 patients with acute ischemic stroke, 586 patients (19%) had a history of AF. Severe strokes on admission were significantly more frequent in patients with AF, as was the proportion of total anterior circulation strokes. Ischemic stroke associated with AF predicted poor outcome at discharge (adjusted OR 1.56; 95%CI 1.24-1.96) and higher mortality rates throughout follow-up. Among patients with a CHADS(2) score ≥ 2 prior to the index stroke and without known contraindications, 41% received anticoagulation. This proportion increased to only 62% after the index stroke, even after excluding patients with severe disability and no significant increase between 2004 and 2007 was detectable. Increasing age, in-hospital infectious complications, and unfavorable functional status at discharge were independently associated with decreased likelihood of receiving anticoagulation., Conclusions: In deviation from current recommendations and in spite of the introduction of CHADS(2) criteria, anticoagulation for stroke prevention remains underutilized, despite the particularly poor outcome of strokes associated with AF., (Copyright © 2011. Published by Elsevier Ireland Ltd.)

Background: Adverse cardiovascular events (CVE) tend to peak during early morning post-waking hours. Our objective was to explore a possible correlation between early and late morning hours and flow-mediated dilation (FMD), and whether early morning FMD reduction contributes to a circadian pattern of cardiac and vascular vulnerability., Methods: Brachial FMD was prospectively assessed in 268 consecutive healthy subjects, 169 (63%) men, mean age 53 ± 11 years, without any concomitant medications. Following an overnight fast, FMD and endothelium-independent nitroglycerin-mediated vasodilation were assessed using high-resolution ultrasound. All subjects were followed up by phone every 6 months for combined CVE, which included all-cause mortality, myocardial infarction, hospitalization for heart failure or angina pectoris, stroke, coronary artery bypass grafting and percutaneous coronary interventions., Results: The cohort was divided into Group A with FMD performed immediately post-waking, between 6:00 and 10:00 am [n=151 (56%) subjects], and Group B after 10:00 am [n=117 (46%) subjects]. Although both groups were comparable regarding baseline brachial artery diameter and the prevalence of risk factors, FMD was significantly lower in Group A compared with Group B subjects (10.4 ± 3.4% vs. 13.5 ± 3.5%, p=0.007, respectively). In a mean follow-up of 45 ± 21 months, the composite CVEs were significantly more common in subjects with ≤(n=128) vs. >(n=140) the median FMD of 11.3% [18/128 (14.1%) vs. 1/140 (0.7%), p=0.007, respectively]. Furthermore, FMD independently predicted long-term adverse CVE., Conclusions: FMD is blunted in early compared to late morning post-waking hours, and independently predicts long-term adverse CVE in healthy subjects with no apparent heart disease., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: A number of reports controversially describe the influence of cholesterol level and lipid-lowering treatment (LLT) on the progression of coronary calcium (CC). We tested the hypothesis that long-term changes in serum cholesterol (CL) would affect the progression of CC., Methods: The study population comprised 510 patients with stable angina pectoris, mean age of 63 ± 9 years. At baseline 372 patients received statin and/or fibrate (LLT group) while 138 patients did not (No-LLT at baseline group). Spiral CT every 24 months was used to track the progression of CC over a median 5.6 year follow-up., Results: CL decreased during follow-up in both groups, but more pronouncedly in patients with LLT. The changes in total calcium score (TCS) were similar in both groups (p=0.3). Changes in CL during follow-up were not associated with CC: TCS increased by 501 ± 63 from baseline in the 1st (upper) quartile, and by 350 ± 44, 403 ± 41 and 480 ± 56 in the 2nd, 3rd, and 4th quartiles of CL longitudinal changes (p = 0.2), respectively. Baseline TCS and its changes were not correlated with baseline CL and its changes. New calcified lesions were diagnosed in 132 (28.2%) out of the 467 patients available for this analysis, without significant difference between groups (p=0.4). Multivariate analysis demonstrated that only baseline TCS (p < 0.001), body mass index (p = 0.007) and age (p = 0.006) were independent predictors for the TCS changes., Conclusions: Longitudinal CL changes do not seem to have a measurable effect on the rate of progression of CC., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: Endothelial dysfunction is considered an important prognostic factor in atherosclerosis. The aim of this study was to detect the long-term association of peripheral vascular endothelial function and clinical outcome in healthy subjects without apparent coronary artery disease (CAD)., Methods: We prospectively assessed brachial flow-mediated dilation (FMD) in 435 consecutive healthy subjects: 281 (65%) men, mean age 54+/-12 years and body mass index 28+/-4 kg/m(2). After overnight fasting and discontinuation of all medications for > or =12 h, FMD and endothelium-independent nitroglycerin-mediated vasodilation were assessed using high resolution linear array ultrasound., Results: Subjects were divided into 2 groups: below (n=221) and above (n=214) the median FMD of 10.7%, and were comparable regarding CAD risk factors, lipoproteins, fasting glucose, C-reactive protein, and concomitant medications, with a mean clinical follow-up of 32+/-2 months. Composite cardiovascular endpoints (all-cause mortality, non-fatal myocardial infarction, heart failure or angina pectoris hospitalization, stroke, coronary artery bypass grafting and percutaneous coronary interventions) were significantly more common in subjects with below median FMD of 10.7%, than above (11.8% vs 4.7%, p=0.007, respectively). Univariate analysis demonstrated that median FMD significantly predicted cardiovascular events [odds ratio (OR) of 2.78 and 95% CI 1.35 to 5.71 (p=0.003)]. After multivariate analysis including conventional CAD risk factors, median FMD was the best independent predictor of long-term cardiovascular adverse events [OR of 2.70 and 95% CI 1.16 to 6.32 (p=0.011)]., Conclusions: Brachial artery median FMD independently predicts long-term adverse cardiovascular events in healthy subjects in addition to traditional risk factor assessment.

Background and Purpose: The role of blood lipids and lipoprotein-related variables in the prediction of ischemic stroke is less clear than that for coronary heart disease. Apolipoprotein B (Apo B), which reflects the concentration of potentially atherogenic lipoprotein particles, and apolipoprotein AI (Apo A-I), which reflects the corresponding concentration of the anti-atherogenic HDL, represent additional lipoprotein-related variables that may indicate vascular risk. We examined the association between serum concentrations of Apo B, Apo A-I, and the Apo A-I/Apo B ratio and the risk of incident ischemic cerebrovascular events in patients with pre-existing atherothrombotic disease., Methods: Patients with documented chronic coronary heart disease and measured Apo B and Apo A-I concentration, screened for but not included in a clinical trial of lipid modification were followed over 4.8 to 8.1 years for hospitalized incident cerebrovascular events., Results: Among 3,434 patients 266 (7.7%) developed an incident ischemic cerebrovascular event. Adjusting for potential confounders, the hazard ratios (HR) for incident ischemic cerebrovascular events associated with the top versus bottom quartile of Apo B was 1.68 (95%CI, 1.18-2.40), of Apo A-I 0.71 (95%CI, 0.50-1.00), and of Apo A-I/Apo B ratio 0.51 (95%CI, 0.35-0.74)., Conclusions: These findings support the hypothesis that Apo B, Apo A-I and the Apo A-I/Apo B ratio predict incident ischemic stroke among patients with preexisting atherothrombotic disease. The potential clinical role of measuring these apolipoproteins for ischemic stroke prediction warrants further study.

Background: Exercise training can improve aerobic capacity and symptoms in congestive heart failure (CHF) patients., Aims: To test the feasibility of exercise training in advanced CHF patients, and examine the potential benefit from peripheral vascular and muscular conditioning as well as improved central hemodynamic and neurohumoral status., Methods and Results: Thirty NYHA functional class III, CHF patients (mean age 61+/-13 yr, ejection fraction 27+/-4%, VO2max 11.3+/-3.9 ml/kg/min) were enrolled. Exercise capacity, cardiovascular parameters and serum levels of brain natriuretic peptide (NT-proBNP) were determined at baseline and after 18 weeks of moderate intensity exercise training. Twenty eight (93%) patients, who completed the exercise program, experienced marked improvements in the 6 min walk (+39%) and exercise duration on the modified Bruce protocol (+66%). Smaller improvements were recorded in the cardiac index (a 15% increase), in the maximal oxygen consumption (a 13% increase in VO2max), in the left ventricular ejection fraction (an 11% increase) and in the systemic vascular resistance and pulmonary artery pressure (an 11% decrease). NT-proBNP levels were not significantly affected. They correlated with exercise capacity and VO2max on baseline measurement, but these correlations were not found after training., Conclusion: Rehabilitation is feasible, even in advanced CHF, and leads to markedly improved exercise performance, but does not affect the level of the principal neurohumoral marker of prognosis - NT-proBNP. Resting cardiovascular performance and maximal oxygen consumption improve less than functional capacity, suggesting that an important benefit is derived from muscle conditioning and improved peripheral vascular response to exercise.

Inherited disorders of hemostasis are natural models for investigating mechanisms of thrombosis and development of antithrombotic therapy. Because mice with total factor XI deficiency are protected against ischemic stroke and do not manifest excessive bleeding, we investigated the incidence of ischemic stroke in patients with severe inherited factor XI deficiency. Incidence of ischemic stroke in 115 patients aged 45 years or more with severe factor XI deficiency (activity less than 15 U/dL) was compared with incidence in the Israeli population as estimated from a stroke survey of 1528 patients. Adjustment for major risk factors of stroke (hypertension, diabetes mellitus, hypercholesterolemia, current smoking) was based on comparison of their prevalence in the stroke survey to an Israeli health survey of 9509 subjects. Incidence of myocardial infarction in the factor XI cohort was also recorded. After adjustment for the 4 major risk factors of ischemic stroke, the expected incidence of ischemic stroke was 8.56 compared with one observed (P = .003). The reduced 1:115 incidence of ischemic stroke contrasted with a 19:115 incidence of myocardial infarction, similar to the expected incidence. Thus, severe factor XI deficiency probably is protective against ischemic stroke but not against acute myocardial infarction.

Aim: To date there have been no studies exploring the effects of long-term versus intermediate-term and short-term supervised exercise training program in patients with severe chronic heart failure (CHF) on optimal medical therapy. We assessed exercise tolerance and mortality in CHF patients undergoing long- versus intermediate-term exercise training (ET)., Methods: Forty-two consecutive severe CHF patients (New York Heart Association functional class III) were referred for a supervised exercise and cardiac rehabilitation program and were followed-up for 3 years: 20/42 (48%) patients discontinued ET after intermediate-term period of 1.6+/-0.8 years (Group A, intermediate-term ET), and 22/42 (52%) remained on the ET program for 3.0+/-0.3 years (Group B, long-term ET). Exercise duration, 6-min walked distance and metabolic equivalents (METs) assessed by modified Bruce protocol were recorded before, 4.5 months after, and 3 years after initiation of ET., Results: Both groups were comparable regarding age, gender, prevalence of ischemic etiology, mean ejection fraction and medications. Risk factors for ischemic heart disease were similar, except for the prevalence of diabetes, which was higher in Group A compared to Group B (11/20 versus 5/22, p=0.03). Significantly more Group A patients died after ET discontinuation (4/20 versus 0/22, p=0.01). At the end of follow-up a significant improvement could be seen in Group B patients compared to A in exercise duration, 6-min walked distance and metabolic equivalents (p<0.01 for all)., Conclusions: Higher survival rate was observed in severe CHF patients undergoing long-term versus intermediate-term exercise training. Long-term supervised exercise training is safe and improves exercise tolerance in these patients.

Background: Malnutrition is prevalent in elderly populations. Recommended methods of nutritional screening are often too complicated and time-consuming for routine application in frail, very old, hospitalized patients., Objective: Our aims were to identify risk factors for development of malnutrition in very old hospitalized patients and to evaluate the total Mini Nutritional Assessment (MNA) score and MNA subscores as predictors of in-hospital and long-term mortality., Design: A prospective cohort study of patients aged > or =75 y was conducted in a geriatric hospital. Assessment included demographic, clinical, and laboratory data and cognitive, functional, and nutritional status. Follow-up was conducted for < or =2.7 y., Results: Of the 414 patients studied, only 73 (17.6%) were well-nourished. Low serum albumin and phosphorus concentrations, dementia, and cerebrovascular accident (CVA) were significant risk factors for malnutrition. Survival was significantly lower in malnourished patients and patients at risk of malnutrition than in well-nourished patients (P < 0.0001). Low MNA-3 subscores (dietary habits) were significantly correlated with laboratory indexes of malnutrition and were significantly lower in patients with infections, malignancy, pressure ulcers, dementia, recent orthopedic surgery, and CVA. Multivariate analysis showed that a low MNA-3 score was an independent predictor of mortality; scores <7.5 increased the risk of death 2.05-fold., Conclusions: The prevalence of malnutrition was high in elderly hospitalized patients. Dietary habits were significant predictors of poor hospitalization outcome. A questionnaire on dietary habits can serve as a useful tool in assessing nutritional status and prognosis in elderly patients.