Matrix metalloproteinase-12 cleaved fragment of titin as a predictor of functional capacity in patients with heart failure and preserved ejection fraction.

OBJECTIVES: Serum levels of matrix metalloproteinase-12 cleaved fragment of titin (TIM), a novel circulatory biomarker specific for cardiac titin degradation, has emerged as a potential biomarker in cardiovascular diseases. In this work, we aimed to evaluate the association between TIM and maximal functional capacity assessed by the percentage of predicted peak exercise oxygen uptake (pp-peakVO2) in patients with heart failure and preserved ejection fraction (HFpEF). Design. In this post-hoc study, we included 46 stable symptomatic (New York Heart Association II-III) HFpEF patients enrolled in the TRAINING-HF study (NCT02638961). pp-peak-VO2 was calculated from baseline values. Baseline circulating levels of TIM were measured by competitive ELISA in serum from the TRAINING-HF patients. The independent association between TIM and pp-peakVO2 was evaluated by multivariate linear regression analysis. Results. The mean age of the sample was 73.8 ± 8.7 years, 56.5% were females, and 76.1% were on NYHA II. The medians of pp-peakVO2 and TIM were 60.9% (50.4-69.3), and 130.1 ng/mL (98.1-159.5), respectively. The median of NT-proBNP was 912 pg/mL (302-1826). pp-peakVO2 was significant and inversely correlated with TIM (r= -41, p = .005). In multivariate analysis, after adjusting for NYHA class, hypertension, body mass index, and glomerular filtration rate, higher TIM was significantly associated with lower pp-peak VO2 (p = .029). Conclusions. In this sample of stable and symptomatic HFpEF patients, higher serum levels of TIM identified patients with worse functional status.

Inspiratory Muscle Function and Exercise Capacity in Patients With Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome characterized by impaired exercise capacity resulting from dyspnea and fatigue. The pathophysiological mechanisms underlying the exercise intolerance in HFpEF are not well established. We sought to evaluate the effects of inspiratory muscle function on exercise tolerance in symptomatic patients with HFpEF. METHODS AND RESULTS: A total of 74 stable symptomatic patients with HFpEF and New York Heart Association class II-III underwent a cardiopulmonary exercise test between June 2012 and May 2016. Inspiratory muscle weakness was defined as maximum inspiratory pressure (MIP) <70% of normal predicted values. Pearson correlation coefficient and multivariate linear regression analysis were used to assess the association between percent of predicted MIP (pp-MIP) and maximal exercise capacity [measured by peak oxygen uptake (peak VO2) and percent of predicted peak VO2 (pp-peak VO2)]. Thirty-one patients (42%) displayed inspiratory muscle weakness. Mean (standard deviation) age was 72.5 ± 9.1 years, 53% were women, and 35.1% displayed New York Heart Association class III. Mean peak VO2 and pp-peak VO2 were 10 ± 2.8 mL•min•kg and 57.3 ± 13.8%, respectively. The median (interquartile range) of pp-MIP was 72% (58%-90%). pp-MIP was not correlated with peak VO2 (r = -0.047, P = .689) nor pp-peak VO2 (r = -0.078, P = .509). Furthermore, in multivariable analysis, pp-MIP showed no association with peak VO2 (ß coefficient = 0.01, 95% confidence interval -0.01 to 0.03, P = .241) and pp-peak VO2 (ß coefficient = -0.00, 95% confidence interval -0.10 to 0.10, P = .975). CONCLUSIONS: In symptomatic elderly patients with HFpEF, we found that pp-MIP was not associated with either peak VO2 or pp-peak VO2.

Effect of ß-Blocker Withdrawal on Functional Capacity in Heart Failure and Preserved Ejection Fraction.

BACKGROUND: Chronotropic incompetence has shown to be associated with a decrease in exercise capacity in heart failure with preserved ejection fraction (HFpEF), yet ß-blockers are commonly used in HFpEF despite the lack of robust evidence. OBJECTIVES: This study aimed to evaluate the effect of ß-blocker withdrawal on peak oxygen consumption (peak Vo2) in patients with HFpEF and chronotropic incompetence. METHODS: This is a multicenter, randomized, investigator-blinded, crossover clinical trial consisting of 2 treatment periods of 2 weeks separated by a washout period of 2 weeks. Patients with stable HFpEF, New York Heart Association functional classes II and III, previous treatment with ß-blockers, and chronotropic incompetence were first randomized to withdrawing from (arm A: n = 26) versus continuing (arm B: n = 26) ß-blocker treatment and were then crossed over to receive the opposite intervention. Changes in peak Vo2 and percentage of predicted peak Vo2 (peak Vo2%) measured at the end of the trial were the primary outcome measures. To account for the paired-data nature of this crossover trial, linear mixed regression analysis was used. RESULTS: The mean age was 72.6 ± 13.1 years, and most of the patients were women (59.6%) in New York Heart Association functional class II (66.7%). The mean peakVo2 and peak Vo2% were 12.4 ± 2.9 mL/kg/min, and 72.4 ± 17.8%, respectively. No significant baseline differences were found across treatment arms. Peak Vo2 and peak Vo2% increased significantly after ß-blocker withdrawal (14.3 vs 12.2 mL/kg/min [Δ +2.1 mL/kg/min]; P < 0.001 and 81.1 vs 69.4% [Δ +11.7%]; P < 0.001, respectively). CONCLUSIONS: ß-blocker withdrawal improved maximal functional capacity in patients with HFpEF and chronotropic incompetence. ß-blocker use in HFpEF deserves profound re-evaluation. (ß-blockers Withdrawal in Patients With HFpEF and Chronotropic Incompetence: Effect on Functional Capacity [PRESERVE-HR]; NCT03871803; 2017-005077-39).

Beta-blockers withdrawal in patients with heart failure with preserved ejection fraction and chronotropic incompetence: Effect on functional capacity rationale and study design of a prospective, randomized, controlled trial (The Preserve-HR trial).

BACKGROUND: The pathophysiology of heart failure with preserved ejection fraction (HFpEF) is complex and multifactorial. Chronotropic incompetence (ChI) has emerged as a crucial pathophysiological mechanism. Beta-blockers, drugs with negative chronotropic effects, are commonly used in HFpEF, although current evidence does not support its routine use in these patients. HYPOTHESIS: We postulate beta-blockers may have deleterious effects in HFpEF and ChI. This work aims to evaluate the short-term effect of beta-blockers withdrawal on functional capacity assessed by the maximal oxygen uptake (peakVO2) in patients with HFpEF and ChI. METHODS: This is a prospective, crossover, randomized (1:1) and multicenter study. After randomization, the clinical and cardiac rhythm will be continuously registered for 30 days. PeakVO2 is assessed by cardiopulmonary exercise testing (CPET) at 15 and 30 days in both groups. Secondary endpoints include quality of life, cognitive, and safety assessment. Patients with stable HFpEF, functional class New York Heart Association (NYHA) II-III, chronic treatment with beta-blockers, and ChI will be enrolled. A sample size estimation [alfa: 0.05, power: 90%, a 20% loss rate, and delta change of mean peakVO2: +1.2 mL/kg/min (SD ± 2.0)] of 52 patients is necessary to test our hypothesis. RESULTS: Patients started enrolling in October 2018. As January 14th, 2020, 28 patients have been enrolled. It is projected to enroll the last patient at the end of July 2020. CONCLUSIONS: Optimizing therapy that improves functional capacity remains an unmeet priority in HFpEF. Deprescribing beta-blockers in patients with HFpEF and ChI seems a plausible intervention to improve functional capacity. This trial is an attempt towards precision medicine in this complex syndrome. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03871803.

Home-based inspiratory muscle training for management of older patients with heart failure with preserved ejection fraction: does baseline inspiratory muscle pressure matter?

BACKGROUND: Heart failure with preserved ejection fraction is a clinical syndrome characterised by reduced exercise capacity. Some evidence has shown that a simple and home-based programme of inspiratory muscle training offers promising results in terms of aerobic capacity improvement in patients with heart failure with preserved ejection fraction. This study aimed to investigate whether the baseline inspiratory muscle function predicts the changes in aerobic capacity (measured as peak oxygen uptake; peak VO2) after a 12-week home-based programme of inspiratory muscle training in patients with heart failure with preserved ejection fraction. METHODS: A total of 45 stable symptomatic patients with heart failure with preserved ejection fraction and New York Heart Association II-III received a 12-week home-based programme of inspiratory muscle training between June 2015 and December 2016. They underwent cardiopulmonary exercise testing and measurements of maximum inspiratory pressure pre and post-inspiratory muscle training. Maximum inspiratory pressure and peak VO2 were registered in both visits. Multivariate linear regression analysis was used to assess the association between changes in peak VO2 (Δ-peakVO2) and baseline predicted maximum inspiratory pressure (pp-MIP). RESULTS: The median (interquartile range) age was 73 (68-77) years, 47% were women and 35.6% displayed New York Heart Association III. The mean peak VO2 at baseline and Δ-peakVO2 post-training were 10.4±2.8 ml/min/kg and +2.2±1.3 ml/min/kg (+21.3%), respectively. The median (interquartile range) of pp-MIP and Δ-MIP were 71% (64-92) and 39.2 (26.7-80.4) cmH2O, respectively. After a multivariate analysis, baseline pp-MIP was not associated with Δ-peakVO2 (ß coefficient 0.005, 95% confidence interval -0.009-0.019, P=0.452). CONCLUSIONS: In symptomatic and deconditioned older patients with heart failure with preserved ejection fraction, a home-based inspiratory muscle training programme improves aerobic capacity regardless of the baseline maximum inspiratory pressure.

Inspiratory Muscle Training and Functional Electrical Stimulation for Treatment of Heart Failure With Preserved Ejection Fraction: The TRAINING-HF Trial.

INTRODUCTION AND OBJECTIVES: Despite the prevalence of heart failure with preserved ejection fraction (HFpEF), there is currently no evidence-based effective therapy for this disease. This study sought to evaluate whether inspiratory muscle training (IMT), functional electrical stimulation (FES), or a combination of both (IMT + FES) improves 12- and 24-week exercise capacity as well as left ventricular diastolic function, biomarker profile, and quality of life in HFpEF. METHODS: A total of 61 stable symptomatic patients (New York Heart Association II-III) with HFpEF were randomized (1:1:1:1) to receive a 12-week program of IMT, FES, or IMT + FES vs usual care. The primary endpoint of the study was to evaluate change in peak exercise oxygen uptake at 12 and 24 weeks. Secondary endpoints were changes in quality of life, echocardiogram parameters, and prognostic biomarkers. We used a mixed-effects model for repeated-measures to compare endpoints changes. RESULTS: Mean age and peak exercise oxygen uptake were 74 ± 9 years and 9.9 ± 2.5mL/min/kg, respectively. The proportion of women was 58%. At 12 weeks, the mean increase in peak exercise oxygen uptake (mL/kg/min) compared with usual care was 2.98, 2.93, and 2.47 for IMT, FES, and IMT + FES, respectively (P < .001) and this beneficial effect persisted after 6 months (1.95, 2.08, and 1.56; P < .001). Significant increases in quality of life scores were found at 12 weeks (P < .001). No other changes were found. CONCLUSIONS: In HFpEF patients with low aerobic capacity, IMT and FES were associated with a significant improvement in exercise capacity and quality of life. This trial was registered at ClinicalTrials.gov (Identifier: NCT02638961)..

Peak Exercise Oxygen Uptake Predicts Recurrent Admissions in Heart Failure With Preserved Ejection Fraction.

INTRODUCTION AND OBJECTIVES: Heart failure with preserved ejection fraction (HFpEF) is a highly prevalent syndrome with an elevated risk of morbidity and mortality. To date, there is scarce evidence on the role of peak exercise oxygen uptake (peak VO2) for predicting the morbidity burden in HFpEF. We sought to evaluate the association between peak VO2 and the risk of recurrent hospitalizations in patients with HFpEF. METHODS: A total of 74 stable symptomatic patients with HFpEF underwent a cardiopulmonary exercise test between June 2012 and May 2016. A negative binomial regression method was used to determine the association between the percentage of predicted peak VO2 (pp-peak VO2) and recurrent hospitalizations. Risk estimates are reported as incidence rate ratios. RESULTS: The mean age was 72.5 ± 9.1 years, 53% were women, and all patients were in New York Heart Association functional class II to III. Mean peak VO2 and median pp-peak VO2 were 10 ± 2.8mL/min/kg and 60% (range, 47-67), respectively. During a median follow-up of 276 days [interquartile range, 153-1231], 84 all-cause hospitalizations in 31 patients (41.9%) were registered. A total of 15 (20.3%) deaths were also recorded. On multivariate analysis, accounting for mortality as a terminal event, pp-peak VO2 was independently and linearly associated with the risk of recurrent admission. Thus, and modeled as continuous, a 10% decrease of pp-peak VO2 increased the risk of recurrent hospitalizations by 32% (IRR, 1.32; 95%CI, 1.03-1.68; P = .028). CONCLUSIONS: In symptomatic elderly patients with HFpEF, pp-peak VO2 predicts all-cause recurrent admission.

Early effects of empagliflozin on exercise tolerance in patients with heart failure: A pilot study.

BACKGROUND: Sodium-glucose linked transporter 2 inhibition recently emerged as a promising therapy for reducing the risk of heart failure (HF) in patients with type 2 diabetes mellitus (T2DM). However, there is a lack of data endorsing its role in symptomatic HF patients. We sought to evaluate the short-term effects of empagliflozin on maximal exercise capacity in these patients. HYPOTHESIS: We postulate tretament with empagliflozin may improve functional capacity in patients with T2DM and established HF. METHODS: Nineteen T2DM patients with symptomatic HF were prospectively included and underwent cardiopulmonary exercise testing before and 30 days after initiation of empagliflozin therapy. A mixed-effects model for repeated measures was used. RESULTS: Median patient age was 72 years (interquartile range, 60-79 years); 42.1% were in New York Heart Association class III. Baseline mean (± SD) peak oxygen consumption (peak VO2 ) was 10.9 ± 4.0 mL/min/kg. Peak VO2 increased significantly at 30 days (∆: +1.21 [0.66 to 1.76] mL/min/kg; P < 0.001). A significant improvement in ventilatory efficiency during exercise, 6-minute walking distance, and quality of life, and a reduction in antigen carbohydrate 125, were also found. Estimated glomerular filtration rate and natriuretic peptides did not significantly change. CONCLUSIONS: In this pilot study, empagliflozin was associated with 1-month improvement in exercise capacity in T2DM patients with symptomatic HF. This beneficial effect was also found for other surrogates of severity.

Heart rate response and functional capacity in patients with chronic heart failure with preserved ejection fraction.

AIMS: The mechanisms of exercise intolerance in heart failure with preserved ejection fraction (HFpEF) are not yet elucidated. Chronotropic incompetence has emerged as a potential mechanism. We aimed to evaluate whether heart rate (HR) response to exercise is associated to functional capacity in patients with symptomatic HFpEF. METHODS AND RESULTS: We prospectively studied 74 HFpEF patients [35.1% New York Heart Association Class III, 53% female, age (mean ± standard deviation) 72.5 ± 9.1 years, and 59.5% atrial fibrillation]. Functional performance was assessed by peak oxygen consumption (peak VO2 ). The mean (standard deviation) peak VO2 was 10 ± 2.8 mL/min/kg. The following chronotropic parameters were calculated: Delta-HR (HR at peak exercise - HR at rest), chronotropic index (CI) = (HR at peak exercise - resting HR)/[(220 - age) - resting HR], and CI according to the equation developed by Keteyian et al. (CIK) (HR at peak exercise - HR at rest)/[119 + (HR at rest/2) - (age/2) - 5 - HR at rest]. In a bivariate setting, peak VO2 was positively and significantly correlated with Delta-HR (r = 0.35, P = 0.003), CI (r = 0.27, P = 0.022), CIK (r = 0.28, P = 0.018), and borderline with HR at peak exercise (r = 0.22, P = 0.055). In a multivariable linear regression analysis that included clinical, analytical, echocardiographic, and functional capacity covariates, the chronotropic parameters were positively associated with peak VO2 . We found a linear relationship between Delta-HR and peak VO2 (ß coefficient of 0.03; 95% confidence interval: 0.004-0.05; P = 0.030); conversely, the association among CIs and peak VO2 was exponentially shaped. CONCLUSIONS: In patients with chronic HFpEF, the HR response to exercise was positively associated to patient's functional capacity.

Cavernous sinus syndrome: a series of 126 patients.

The etiology of cavernous sinus syndrome (CSS) remains difficult to determine in spite of the development of neuroimaging techniques. We conducted the current study to identify clinical and imaging features that allow a reliable approach to the etiologic diagnosis of patients with CSS. We studied a consecutive series of 126 patients with CSS, defined as involvement of 2 or more of the third, fourth, fifth (V1, V2), or sixth cranial nerves, or involvement of only 1 of them in combination with a neuroimaging-confirmed lesion in the cavernous sinus. Tumors were the most common cause of CSS (80 patients). All patients with optic nerve involvement had a tumor. No patient with a normal MRI had a tumor. The lack of pain during the course of the disease (odds ratio [OR], 0.58; 95% confidence intervals [CI], 0.06-0.40), V2 involvement (OR, 12.17; 95% CI, 2.98-49.71), and male sex (OR, 3.2; 95% CI, 1.31-8.14) were independently associated with the presence of a tumor. Pain at the onset of disease (OR, 12.09; 95% CI, 3.14-46.50) and third cranial nerve involvement (OR, 4.9; 95% CI, 1.01-24.60) were independently associated with Tolosa-Hunt syndrome.

Inspiratory Muscle Training and Functional Electrical Stimulation for Treatment of Heart Failure With Preserved Ejection Fraction: Rationale and Study Design of a Prospective Randomized Controlled Trial.

Heart failure with preserved ejection fraction (HFpEF) has become the most prevalent form of heart failure in developed countries. Regrettably, there is no evidence-based effective therapy for HFpEF. We seek to evaluate whether inspiratory muscle training, functional electrical stimulation, or a combination of both can improve exercise capacity as well as left ventricular diastolic function, biomarker profile, quality of life (QoL), and prognosis in patients with HFpEF. A total of 60 stable symptomatic patients with HFpEF (New York Heart Association class II-III/IV) will be randomized (1:1:1:1) to receive a 12-week program of inspiratory muscle training, functional electrical stimulation, a combination of both, or standard care alone. The primary endpoint of the study is change in peak exercise oxygen uptake; secondary endpoints are changes in QoL, echocardiogram parameters, and prognostic biomarkers. As of March 21, 2016, thirty patients have been enrolled. Searching for novel therapies that improve QoL and autonomy in the elderly with HFpEF has become a health care priority. We believe that this study will add important knowledge about the potential utility of 2 simple and feasible physical interventions for the treatment of advanced HFpEF.

The evolution of dental health in dental students at the University of Barcelona.

The aim of this research was to study the evolution of dental health of dental students during their academic training and to assess the extent to which the knowledge acquired was reflected in their own dental care. A sample of 107 students at the schools of dentistry and medicine (the latter as a comparison group) of the University of Barcelona, Spain, underwent an oral examination and completed a questionnaire during their training in the third and fifth academic years. The oral examinations were limited to the status of teeth. Bitewing radiographs were used for both posterior sectors, and these were interpreted using the criteria proposed by Pitts (1984). The data were analyzed using the SPSS package. At the end of the study, medical students had more teeth present than dental students (29.80 vs. 28.94 [p = 0.022]) and a lower DMFT index of 4.33 vs. 5.91 (p=0.038), with an FT component of 2.44 and 5.23 (p = 0.011), respectively. All dental students underwent more treatment of all types than medical students, and dental health habits and knowledge were superior in dental students. The third year was the key year for decision making with regard to the student's dental health. We conclude that dental students are highly motivated about maintaining their dental health and their dental education experiences appear to have had a clear influence on this behavior.

Effects of inspiratory muscle training in patients with heart failure with preserved ejection fraction.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is remarkably common in elderly people with highly prevalent comorbid conditions. Despite its increasing in prevalence, there is no evidence-based effective therapy for HFpEF. We sought to evaluate whether inspiratory muscle training (IMT) improves exercise capacity, as well as left ventricular diastolic function, biomarker profile and quality of life (QoL) in patients with advanced HFpEF and nonreduced maximal inspiratory pressure (MIP). DESIGN AND METHODS: A total of 26 patients with HFpEF (median (interquartile range) age, peak exercise oxygen uptake (peak VO2) and left ventricular ejection fraction of 73 years (66-76), 10 ml/min/kg (7.6-10.5) and 72% (65-77), respectively) were randomized to receive a 12-week programme of IMT plus standard care vs. standard care alone. The primary endpoint of the study was evaluated by positive changes in cardiopulmonary exercise parameters and distance walked in 6 minutes (6MWT). Secondary endpoints were changes in QoL, echocardiogram parameters of diastolic function, and prognostic biomarkers. RESULTS: The IMT group improved significantly their MIP (p < 0.001), peak VO2 (p < 0.001), exercise oxygen uptake at anaerobic threshold (p = 0.001), ventilatory efficiency (p = 0.007), metabolic equivalents (p < 0,001), 6MWT (p < 0.001), and QoL (p = 0.037) as compared to the control group. No changes on diastolic function parameters or biomarkers levels were observed between both groups. CONCLUSIONS: In HFpEF patients with low aerobic capacity and non-reduced MIP, IMT was associated with marked improvement in exercise capacity and QoL.

Effects of smoking on periodontal tissues.

BACKGROUND/AIMS: Most studies about the association between tobacco and periodontal disease have shown that tobacco negatively affects periodontal tissues, although some authors have failed to demonstrate such association. Very few studies have tried to find out whether the effect of tobacco on periodontal tissues was similar for women and men. The aims of this investigation were to confirm the possible relationship between tobacco consumption and periodontitis, to study the correlation between intensity of smoking and disease severity, and to investigate any differences between genders related to the effects of tobacco consumption in periodontal health. MATERIAL AND METHODS: In this case-control study, 240 dental patients were selected according to previously defined criteria and were divided in two groups according to their periodontal status. Patients with established periodontitis constituted the case group. The remaining patients constituted the control group. Smoking status, probing depth, gingival recession, clinical attachment level, tooth mobility, periodontal bleeding index and plaque index were determined for each participant. Generated data were processed for statistical analysis using multiple comparisons, covariance analysis and logistic regression analysis. RESULTS: Logistic regression analysis showed that smokers had 2.7 times and former smokers 2.3 times greater probabilities to have established periodontal disease than non-smokers, independent of age, sex and plaque index. Among cases, probing depth, gingival recession and clinical attachment level were greater in smokers than in former smokers or non-smokers, whereas plaque index did not show differences. Bleeding on probing was less evident in smokers than in non-smokers. There was a dose-effect relationship between cigarette consumption and the probability of having advanced periodontal disease. The association between tobacco smoking and periodontal disease was more evident after 10 years of smoking, independent of age, gender and plaque index. Finally, it was observed that tobacco affected periodontal tissues more severely in men than in women. CONCLUSIONS: Smoking is a risk factor strongly associated with periodontitis. The effects of smoking on periodontal tissues depend on the number of cigarettes smoked daily and the duration of the habit. The effect of tobacco on periodontal tissues seems to be more pronounced in men than in women.