Effects of exercise training in heart failure with preserved ejection fraction: an updated systematic literature review.

Physical activity is associated with a lower risk of adverse cardiovascular outcomes, including heart failure (HF). Exercise training is a class IA level recommendation in patients with stable HF, but its impact is less clear in heart failure with preserved ejection fraction (HFpEF). The aim of this study was to analyze the effects of the exercise training on cardiovascular outcomes in patients with HFpEF. A systematic literature search was conducted on the main electronic databases, proceedings of major meetings, and reference lists of the identified studies, using specific terms for only English language studies published between 2000 and 2018. We followed the PRISMA to perform our review. Quality of studies was also assessed. The systematic review identified 9 studies on 348 patients, of moderate (n = 2) to good (n = 7) quality. The training consisted of a combination of supervised in-hospital and home-based outpatient programs, including aerobic exercise, endurance and resistance training, walking, and treadmill and bicycle ergometer. Most of the protocols ranged 12-16 weeks, with a frequency of 2-3 sessions weekly, lasting 20-60 min per session. There were significant improvements in peak oxygen uptake, 6-min walking test distance, and ventilatory threshold, whereas quality of life and echocardiographic parameters improved only in some studies. Endothelial function/arterial stiffness remained unchanged. No adverse events were reported. Appropriate exercise programs are able to get a favorable cardiovascular outcome in patients with HFpEF. This could also benefit in terms of quality of life, even if more controversial. Further researches are necessary.

Pacemaker-detected severe sleep apnea predicts new-onset atrial fibrillation.

AIMS: Sleep apnea (SA) diagnosed on overnight polysomnography is a risk factor for atrial fibrillation (AF). Advanced pacemakers are now able to monitor intrathoracic impedance for automatic detection of SA events. METHODS AND RESULTS: We enrolled 160 consecutive recipients of a dual-chamber pacemaker endowed with the ApneaScan algorithm (Boston Scientific). If the pacemaker-measured Respiratory Disturbance Index was ≥30 episodes per hour for at least one night during the first week after implantation, SA was defined as severe. Patients were considered to have experienced AF episodes if the device detected a cumulative AF burden ≥6 h in a day. Sixteen patients in AF at the time of implantation were excluded from our analysis. During follow-up, AF burden ≥6 h/day was documented in 35 (24%) of the patients included in the analysis and in 12 (13%) of the 96 patients with no history of AF. Severe SA was detected in 89 patients during the first week after implantation; 58 of these had no history of AF. Severe SA at the baseline was associated with a higher risk of AF both in the whole population (log-rank test, hazard ratio: 2.38; 95% CI: 1.21-4.66; P = 0.025) and among patients with no previous history of AF (log-rank test, hazard ratio: 2.80; 95% CI: 1.10-7.10; P = 0.047). Moreover, severe SA at the time of follow-up device interrogation predicted AF occurrence within the next 3 months (log-rank test, hazard ration: 2.13; 95% CI: 1.11-4.08; P = 0.036). CONCLUSIONS: In pacemaker patients, device-diagnosed severe SA was independently associated with a higher risk of AF (≥6 h/day) and new-onset AF. In particular, severe SA on follow-up data review identified patients who were ∼2-fold more likely to experience an AF episode in the next 3 months.

Clinical significance and prognostic value of right bundle branch block in permanent pacemaker patients.

AIMS: In patients undergoing pacemaker implantation with no prior history of heart failure (HF), the presence of left bundle branch block (LBBB) has been identified as an independent predictor of HF-related death or hospitalization, while the prognostic significance of right bundle branch block (RBBB) remains uncertain. We aimed to assess the long-term risk of all-cause mortality in patients with a standard indication for permanent pacing and normal or moderately depressed left ventricular function when RBBB is detected at the time of implantation. METHODS: We retrospectively enrolled 1348 consecutive patients who had undergone single- or dual-chamber pacemaker implantation at the study center, from January 1990 to December 2022. Patients with a left ventricular ejection fraction ≤35% or a prior diagnosis of HF were excluded. RESULTS: The baseline 12-lead electrocardiogram revealed an RBBB in 241 (18%) and an LBBB in 98 (7%) patients. During a median follow-up of 65 [25th-75th percentile: 32-117] months, 704 (52%) patients died. The combined endpoint of cardiovascular death or HF hospitalization was reached by 173 (13%) patients. On multivariate analysis, RBBB was confirmed as an independent predictor of death [hazard ratio, 1.33; 95% confidence interval (CI), 1.09-1.63; P  = 0.005]. However, when considering the combined endpoint of cardiovascular death and HF hospitalization, this endpoint was independently associated with LBBB (hazard ratio, 2.13; 95% CI, 1.38-3.29; P  < 0.001), but not with RBBB. CONCLUSION: In patients with standard pacemaker indications and normal or moderately depressed left ventricular function, the presence of basal RBBB was an independent predictor of mortality. However, it was not associated with the combined endpoint of cardiovascular death and HF hospitalization.

Incidence and predictors of heart failure hospitalization and death in permanent pacemaker patients: a single-centre experience over medium-term follow-up.

AIM: The aim of this study was to assess the incidence and clinical predictors of the development of new-onset heart failure (HF) over medium-term follow-up, in patients treated with permanent pacing in daily clinical practice. METHODS AND RESULTS: We retrospectively enrolled all consecutive patients who underwent single- or dual-chamber pacemaker implantation at the study centre. Patients with a left ventricular ejection fraction (LVEF) ≤35% or a prior diagnosis of HF were excluded. Ventricular leads were routinely implanted in the right apex. Pacemakers were implanted in 490 patients with a standard pacemaker indication and LVEF >35%. Left bundle-branch block (LBBB) was reported in 30 (8%) patients, and an LVEF <50% in 64 (13%) patients. During a follow-up of 27 ± 21 months, 32 (7%) patients reached the combined endpoint of HF death or hospitalization. On multivariate analysis, LBBB (HR, 3.50; 95% CI, 1.1-11.1; P = 0.033) and LVEF <50% (HR, 5.1; 95% CI, 1.9-14.2; P = 0.002) were confirmed as independent predictors of HF death or hospitalization. Patients with LVEF <50% and/or LBBB displayed significantly higher rates of HF death or hospitalization (log-rank test, all P<0.001). CONCLUSION: The majority of patients with a standard indication for permanent pacing and normal LV function remained in a clinically stable condition after pacemaker implantation. However, ∼7% of patients developed new-onset HF over a period of follow-up of 27 months, and the presence of LBBB and LVEF <50% at the baseline predicted HF death or hospitalization.

Association Between Device-Detected Sleep-Disordered Breathing and Implantable Defibrillator Therapy in Patients With Heart Failure.

BACKGROUND: Sleep-disordered breathing is highly prevalent in heart failure (HF) and has been suggested as a risk factor for malignant ventricular arrhythmias. The Respiratory Disturbance Index (RDI) computed by an implantable cardioverter-defibrillator (ICD) algorithm accurately identifies severe sleep apnea. OBJECTIVES: In the present analysis, the authors evaluated the association between ICD-detected sleep apnea and the incidence of appropriate ICD therapies in patients with HF. METHODS: We enrolled 411 HF patients who had received an ICD endowed with an algorithm that calculates the RDI each night. In this analysis, the weekly mean RDI value was considered. The endpoint was the first appropriate ICD shock. RESULTS: The median follow-up was 26 months (25th to 75th percentile: 16-35 months). During follow-up, 1 or more ICD shocks were documented in 58 (14%) patients. Patients with shocks were younger (age 66 ± 13 years vs 70 ± 10 years; P = 0.038), and had more frequently undergone implantation for secondary prevention (21% vs 10%; P = 0.026). The maximum RDI value calculated during the entire follow-up period did not differ between patients with and without shocks (55 ± 15 episodes/h vs 54 ± 14 episodes/h; P = 0.539). However, the ICD-detected RDI showed considerable variability during follow-up. The overall median of the weekly RDI was 33 episodes/h (25th to 75th percentile: 24-45 episodes/h). A time-dependent Cox regression model revealed that a continuously measured weekly mean RDI of ≥45 episodes/h was independently associated with shock occurrence (HR: 4.63; 95% CI: 2.54-8.43; P < 0.001), after correction for baseline confounders (age, secondary prevention). CONCLUSIONS: In HF patients, appropriate ICD shocks were more likely to be delivered during periods when patients exhibited more sleep-disordered breathing. (Arrhythmias Detection in a Real World Population [RHYTHM DETECT]; NCT02275637).

Continuous monitoring of sleep-disordered breathing with pacemakers: Indexes for risk stratification of atrial fibrillation and risk of stroke.

BACKGROUND: Sleep apnea (SA) is a risk factor for atrial fibrillation (AF). Advanced pacemakers are now able to calculate indexes of SA severity. HYPOTHESIS: We investigated the changes in pacemaker-measured indexes of SA, we assessed their predictive value for AF occurrence and the associated risk of stroke and death at long-term. METHODS: We enrolled 439 recipients of a pacemaker endowed with an algorithm for the calculation of a Respiratory Disturbance Index (RDI). The RDI variability was measured over the first 12 months after implantation, as well as its potential association with the occurrence of AF, defined as device-detected cumulative AF burden ≥6 hoursours in a day. RESULTS: The individual RDI mean was 30 ± 18 episodes/h, and the RDI maximum was 59 ± 21 episodes/h. RDI ≥30 episodes/h was detected in 351 (80%) patients during at least one night. The proportion of nights with RDI ≥30 episodes/h was 14% (2%-36%). AF ≥6 hours was detected in 129 (29%) patients during the first 12 months. The risk of AF was higher in patients with RDI maximum ≥63 episodes/h (HR:1.74; 95%CI: 1.22-2.48; P = .001) and with RDI mean ≥ 46 episodes/h (HR:1.63; 95%CI: 1.03-2.57; P = .014). The risk of all-cause death or stroke was higher in patients with AF burden ≥6 hours (HR:1.75; 95%CI: 1.06-2.86; P = .016). Moreover, among patients with no previous history of AF the risk was higher in those with RDI maximum ≥63 episodes/h (HR:1.96; 95%CI: 1.06-3.63; P = .031). CONCLUSIONS: Pacemaker-detected SA showed a considerable variability during follow-up. We confirmed the association between RDI and higher risk of AF, and we observed an association between higher RDI maximum and all-cause death or stroke among patients with no previous history of AF.

Occurrence of atrial fibrillation in pacemaker patients and its association with sleep apnea and heart rate variability.

AIMS: Sleep apnea (SA) is a risk factor for atrial fibrillation (AF) occurrence. Sympathovagal imbalance is a mechanism that predisposes to the development of AF and that occurs in SA. Some pacemakers can detect SA events and continuously measure a time domain measure of heart rate variability (HRV), i.e. the standard deviation of 5-min median atrial-atrial sensed intervals (SDANN). We evaluated the association between the occurrence of AF and device-detected SA and SDANN in patients who received pacemakers. METHODS: We enrolled 150 consecutive patients undergoing implantation of a dual-chamber pacemaker, capable of SA and SDANN estimation. The SA was defined as severe if the Respiratory Disturbance Index was ≥30 episodes/h for at least one night during the first week after implantation. RESULTS: Sixteen patients in permanent AF were excluded from our analysis. During follow-up, AF (cumulative device-detected AF duration > 6 h/day) occurred in 24(18%) patients out of the remaining 134 patients. Severe SA was detected in 84 patients. SDANN values were available in 74 patients and the median value was 76 ms [25°-75°percentile:58-77]. The risk of AF was higher in patients with severe SA (log-rank test; p = .033). The presence of either or both conditions (severe SA and SDANN < 76 ms) was associated with shorter time to AF event (p = .042) and was an independent predictor of AF (hazard ratio: 2.37; 95%CI:1.08 to 5.21; p = .033). CONCLUSION: In pacemaker patients, device-diagnosed severe SA and reduced SDANN are associated with a higher risk of AF.

Fixed and Low-Dose Combinations of Blood Pressure-Lowering Agents: For the Many or the Few?

Despite the widespread availability of several effective classes of drugs, systemic arterial hypertension remains poorly controlled in the majority of patients worldwide. In this article, we discuss the different modalities and effects of combination therapy and possible future research questions. Treatment with a single antihypertensive agent can effectively reduce blood pressure in only a limited number of patients, while most require therapy with two or more agents to achieve target levels. As initial therapy, American and European guidelines suggest a combination of two antihypertensive drugs and the use of a third antihypertensive drug when hypertension is still uncontrolled. Initial combination therapy is recommended in high-risk patients for an immediate blood pressure response, improved tolerability and possibly increased patient adherence. In addition to the potential benefits of combining different drug classes with synergistic pharmacological and physiological actions, this approach is useful for increasing the patient compliance with treatment, in particular if provided at fixed doses in a single pill. The minimisation of side effects is critical for the long-term treatment of a largely asymptomatic condition such as systemic hypertension. Low-dose combinations of different drugs from classes with complementary actions may provide the best ratio of lower side effects and improved tolerability with a significant blood pressure reduction, particularly in high-risk patients. This approach could be aided by a multidisciplinary lifestyle intervention on risk factors.

Antithrombotic Therapy After Percutaneous Coronary Intervention in Atrial Fibrillation: The Triple Trouble.

One of the most common conundrums in all cardiovascular medicine pertains to the care of patients with atrial fibrillation after percutaneous coronary intervention, because of both dual antiplatelet therapy and oral anticoagulant therapy would seem to be necessary to reduce risks of stent thrombosis and thromboembolism, respectively, but also with an inevitable trade-off of more bleeding. Patients who require triple therapy are at high risk of both ischaemia and bleeding; therefore, defining a personalised secondary prevention strategy aimed at achieving the best net clinical benefit is essential. The good news is that we have entered an era of increased perceived and tangible safety that applies to both non-vitamin K-antagonist oral anticoagulants and newer drug-eluting stents. Even if the consistency across the major trials and the significantly lower risk of bleeding with dual therapy make it hard to argue that triple therapy should be used routinely, the aggregate evidence suggests that the net clinical benefit of dual therapy should give cardiologists confidence to drop aspirin when they are using a contemporary percutaneous coronary intervention strategy with drug-eluting stents. Waiting for more randomised trials and meta-analyses, for the time being, in patients not in clinical trials, full-dose oral triple therapy with dual antiplatelet agents and full-dose anticoagulation should be avoided as a routine practice, and the choice of the proper, that is, safer, oral anticoagulant, namely a non-vitamin K-antagonist oral anticoagulant, may be regarded by now as an additional bleeding avoiding strategy in patients with atrial fibrillation undergoing percutaneous coronary intervention.

Pulmonary hypertension and exercise training: a synopsis on the more recent evidences.

The benefits of exercise training in virtually all humans, including those with a clinically stable chronic disease are numerous. The potential value lies in the fact that functional capacity is oftentimes significantly compromised. Exercise training not only play a role in reversing some of the pathophysiologic processes associated with chronic diseases but also improves clinical trajectory. Given the significant pathologic consequences associated with pulmonary hypertension and its implications for deteriorating right ventricular function as well as the perceived potential for a precipitous and possibly critical drop in cardiac output during periods of physical exertion, exercise training was historically not recommended for these patients. More recently, a promising body of literature demonstrating the safety and efficacy of exercise training (with benefit on exercise capacity, peak oxygen consumption and quality of life) in pulmonary hypertension patients has emerged, but the conclusion about the effects of exercise training were non-exhaustive and therefore there is still a lack of knowledge regarding exercise training for these patients. Thus, we aim to ascertain the current effectiveness of exercise rehabilitation for pulmonary hypertension by performing a brief overview on the latest currently available evidences in such an "at a glance" synopsis addressed to summarize/quantify the more recent existing body of literature. KEY MESSAGES Exercise training was historically not recommended in pulmonary hypertension. Recently, exercise training safety-efficacy in pulmonary hypertension has emerged. Exercise training should be recommended in addition to optimal medical therapy.

Prevalence and clinical significance of left bundle branch block according to classical or strict definition criteria in permanent pacemaker patients.

BACKGROUND: Previous studies have shown that the presence of left bundle branch block (LBBB) is associated with an increased risk of cardiac mortality and heart failure (HF). Recently, new criteria to define strict LBBB have been proposed: QRS duration ≥140 ms for men and ≥130 ms for women, along with mid-QRS notching or slurring in ≥2 contiguous leads. HYPOTHESIS: We assessed the prevalence and prognostic significance of LBBB according to classical (QRS duration ≥120ms) and strict criteria in permanent pacemaker patients. METHODS: We retrospectively enrolled 723 consecutive patients who had undergone single- or dual-chamber pacemaker implantation at the study center from July 2002 to December 2014. Patients with a left ventricular ejection fraction ≤35% or a prior diagnosis of HF were excluded. RESULTS: LBBB was reported in 54 (7%) patients, and strict-LBBB in 15 (2%) patients. During a median follow-up of 48 months (range, 18-92 months), 147 (20%) patients reached the combined endpoint of death or HF hospitalization. Patients with LBBB and those with strict-LBBB displayed significantly higher rates of death or HF hospitalization (log-rank test, all P < 0.0001). In particular, strict-LBBB was associated with the worst outcome. The presence of LBBB according to classical definition criteria (hazard ratio [HR] = 1.98, confidence interval [CI]: 1.23-3.19, P = 0.005) and to strict criteria (HR = 2.20; CI: 1.04-4.65; P = 0.039) were both confirmed as independent predictors of death or HF hospitalization after adjustment for relevant clinical covariates. CONCLUSIONS: Among patients who had undergone standard pacemaker implantation, the prevalence of LBBB was 7% according to classical definition criteria and 2% according to strict criteria. The presence of LBBB, and particularly of strict-LBBB, at the baseline predicted a poor outcome in terms of death or HF hospitalization.

Hypertensive response to exercise and exercise training in hypertension: odd couple no more.

The diagnostic and prognostic implication of exaggerated blood pressure response to exercise has been controversial, with opinions ranging from a benign process to a harbinger of potential cardiovascular morbidity. Nonetheless, lowering of blood pressure and prevention of hypertension is in first instance preferable by lifestyle changes, and many studies have shown the inverse association between physical activity level and the incidence of cardiovascular diseases suggesting low aerobic fitness as a strong predictor for future cardiovascular disease and all-cause mortality in both healthy and cardiovascular disease patients, including those with hypertension. Endothelial function, large artery stiffness and neurohormonal response are surely implicated both in the development of exaggerated blood pressure response to exercise and in the positive effect of physical exercise in the prevention and management of hypertension and cardiovascular disease in general. In their interesting and well documented review published in this issue Kim and Ha broadly described the possible pathophysiologic mechanisms of exaggerated blood pressure response to exercise and its clinical implications: in this regard, a very interesting issue could be represented by the role of exercise training. In fact, there is an the ample evidence in the literature that physical activity could positively affect endothelial function, arterial stiffness, neurohormonal response and finally blood pressure levels both in healthy men and in hypertensive patients and so should be considered a very important element in the prevention and management of cardiovascular disease.

The relationship between obesity and hypertension: an updated comprehensive overview on vicious twins.

Obesity is a growing global health concern, with a rapid increase being observed in morbid obesity. Obesity is associated with an increased cardiovascular risk and earlier onset of cardiovascular morbidity. The growing obesity epidemic is a major source of unsustainable health costs and morbidity and mortality because of hypertension, type 2 diabetes mellitus, dyslipidemia, certain cancers and major cardiovascular diseases. Similar to obesity, hypertension is a key unfavorable health metric that has disastrous health implications: currently, hypertension is the leading contributor to global disease burden, and the direct and indirect costs of treating hypertension are exponentially higher. Poor lifestyle characteristics and health metrics often cluster together to create complex and difficult-to-treat phenotypes: excess body mass is such an example, facilitating a cascade of pathophysiological sequelae that create such as a direct obesity-hypertension link, which consequently increases cardiovascular risk. Although some significant issues regarding assessment/management of obesity remain to be addressed and the underlying mechanisms governing these disparate effects of obesity on cardiovascular disease are complex and not completely understood, a variety of factors could have a critical role. Consequently, a comprehensive and exhaustive investigation of this relationship should analyze the pathogenetic factors and pathophysiological mechanisms linking obesity to hypertension as they provide the basis for a rational therapeutic strategy in the aim to fully describe and understand the obesity-hypertension link and discuss strategies to address the potential negative consequences from the perspective of both primordial prevention and treatment for those already impacted by this condition.

Effects of exercise training on systo-diastolic ventricular dysfunction in patients with hypertension: an echocardiographic study with tissue velocity and strain imaging evaluation.

There is a lack of detailed data regarding the effect of exercise training in pharmacologically treated hypertensive patients. Therefore, the aim of this study was to evaluate the effects of exercise training on left and right ventricular morphologic and functional parameters by means of conventional echocardiography and sensitive new echocardiographic techniques including tissue Doppler velocity and strain imaging, that were performed in pharmacologically treated hypertensive patients at baseline and at the end of a specific exercise training protocol for primary prevention of cardiovascular disease. We selected 116 pharmacologically treated hypertensive patients who completed the exercise training protocol. All patients underwent a clinical history and examination; transthoracic echocardiography and exercise testing were performed at baseline and at the end of the exercise training protocol. Conventional echocardiography revealed a mild degree of diastolic dysfunction without significant differences or variations from baseline to the end of the exercise training protocol. In contrast, tissue Doppler velocity and strain imaging measurements demonstrated and highlighted the positive influence of exercise training: for both left and right ventricle myocardial early peak diastolic velocities (Em), the ratio of myocardial early-late peak diastolic velocity (Em/Am), myocardial peak systolic velocities (Sm) and peak strain and strain rate values significantly increased at the end of the exercise training protocol, suggesting a relationship between exercise capacity and both left and right ventricular systo-diastolic function. Our study, by means of newer more sensitive echocardiographic techniques, clearly demonstrated the positive impact of exercise training on both left and right ventricular systo-diastolic function, in terms of adjunctive subclinical improvement, in pharmacologically treated hypertensive patients.