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Clinical research in cardiology 112(1), 111-122 (2023). doi:10.1007/s00392-022-02053-8 special issue: "Spotlight: Heart Failure", Published by Springer, Berlin

Aims \ud \ud In patients with chronic heart failure, QRS duration is a consistent predictor of poor outcomes. It has been suggested that for indicated patients, cardiac resynchronization therapy (CRT) could come sooner in the treatment algorithm, perhaps in parallel with the attainment of optimal guideline-directed medical therapy (GDMT). We aimed to investigate differences in left ventricular (LV) remodelling in those with narrow QRS (NQRS) compared with wide QRS (WQRS) in the absence of CRT, whether an early CRT strategy resulted in unnecessary implants and the effect of early CRT on outcomes.\ud \ud \ud \ud Methods \ud \ud Our cohort consisted of 214 consecutive patients with LV ejection fraction (LVEF) of 35% or less who underwent repeat echocardiography 1 year after enrolment. Of these, 116 patients had NQRS, and 98 had WQRS of whom 40 received CRT within 1 year and 58 did not.\ud \ud \ud \ud Results \ud \ud In the absence of CRT, patients with WQRS had less LV reverse remodelling compared with those with NQRS, with differences in ΔLVEF (+2 vs. +9%, P < 0.001) ΔLV end-diastolic diameter (−1 vs. −2 mm, P = 0.095), ΔLV end-systolic diameter (−2 vs. −4.5 mm, P = 0.038), LV end-systolic volume (−12.6 vs. −25.0 ml, P = 0.054) and LV end-diastolic volume (−7.3 vs. −12.2 ml, P = 0.071). LVEF was more likely to improve by at least 10% if patients had NQRS or received CRT (P = 0.08). Thirteen (24%) patients with WQRS achieved an LVEF greater than 35% in the absence of CRT; however, none achieved greater than 50%.\ud \ud \ud \ud Conclusion \ud \ud A strictly linear approach to heart failure therapy might lead to delays to optimal treatment in those patients with the most to gain from CRT and the least to gain from GDMT.

Aims An increasing proportion of patients with heart failure with reduced ejection fraction (HFrEF) have co‐morbidities. The effect of these co‐morbidities on modes of death and the effect of disease‐modifying agents in multi‐morbid patients is unknown. Methods and results We performed a prospective cohort study of ambulatory patients with HFrEF to assess predictors of outcomes. We identified four key co‐morbidities—ischaemic aetiology of heart failure, diabetes mellitus, chronic obstructive pulmonary disease (COPD), and chronic kidney disease (CKD)—that were highly prevalent and associated with an increased risk of all‐cause mortality. We used these data to explore modes of death and the utilization of disease‐modifying agents in patients with and without these co‐morbidities. The cohort included 1789 consecutively recruited patients who had an average age of 69.6 ± 12.5 years, and 1307 (73%) were male. Ischaemic aetiology of heart failure was the most common co‐morbidity, occurring in 1061 (59%) patients; 503 (28%) patients had diabetes mellitus, 283 (16%) had COPD, and 140 (8%) had CKD stage IV/V. During mean follow‐up of 3.8 ± 1.6 years, 737 (41.5%) patients died, classified as progressive heart failure (n = 227, 32%), sudden (n = 112, 16%), and non‐cardiovascular deaths (n = 314, 44%). Multi‐morbid patients were older (P 2.5‐fold and 1.5‐fold increased risk of sudden death, whilst higher doses of beta‐adrenoceptor antagonists were protective (hazard ratio per milligram 0.92, 95% confidence interval 0.86–0.98, P = 0.009). Each milligram of bisoprolol‐equivalent beta‐adrenoceptor antagonist was associated with 9% (P = 0.001) and 11% (P = 0.023) reduction of sudden deaths in patients with

ObjectiveEstimating survival can aid care planning, but the use of absolute survival projections can be challenging for patients and clinicians to contextualise. We aimed to define how heart failure and its major comorbidities contribute to loss of actuarially predicted life expectancy.MethodsWe conducted an observational cohort study of 1794 adults with stable chronic heart failure and reduced left ventricular ejection fraction, recruited from cardiology outpatient departments of four UK hospitals. Data from an 11-year maximum (5-year median) follow-up period (999 deaths) were used to define how heart failure and its major comorbidities impact on survival, relative to an age–sex matched control UK population, using a relative survival framework.ResultsAfter 10 years, mortality in the reference control population was 29%. In people with heart failure, this increased by an additional 37% (95% CI 34% to 40%), equating to an additional 2.2 years of lost life or a 2.4-fold (2.2–2.5) excess loss of life. This excess was greater in men than women (2.4 years (2.2–2.7) vs 1.6 years (1.2–2.0); pConclusionsComorbidity accounts for the majority of lost life expectancy in people with heart failure. Women, but not men, without comorbidity experience survival close to reference controls.

BackgroundEstimating survival can aid care planning, but the use of absolute survival projections can be challenging for patients and clinicians to contextualize. We aimed to define how heart failure and its major comorbidities contribute to loss of actuarially predicted life expectancy.MethodsWe conducted an observational cohort study of 1794 adults with stable chronic heart failure and reduced left ventricular ejection fraction, recruited from cardiology outpatient departments of 4 United Kingdom (UK) hospitals. Data from an 11-year maximum (5-year median) follow-up period (999 deaths) was used to define how heart failure and its major comorbidities impact upon survival, relative to an age-sex matched control UK population, using a relative survival framework.ResultsAfter 10 years, mortality in the reference control population was 29%. In people with heart failure, this increased by an additional 37% (95% confidence interval 34-40%), equating to an additional 2.2-years of lost life, or a 2.4-fold (2.2-2.5) excess loss of life. This excess was greater in men than women (2.4 years [2.2-2.7] versus 1.6 years [1.2-2.0]; pConclusionsComorbidity accounts for the majority of lost life expectancy in people with heart failure. Women, but not men, without comorbidity experience survival close to reference controls.

Introduction . Heart failure (HF) with preserved ejection fraction (HFpEF) is a growing problem, but its diagnosis and management in routine clinical practice remains difficult. Recent European Society of Cardiology (ESC) guidelines sought to provide a diagnostic framework to identify patients with HFpEF. We aimed to assess the prevalence, characteristics and prognosis of HFpEF patients identified using these guidelines. Methods We characterised 960 consecutive patients referred from primary care with signs and symptoms of heart failure and elevated NT-proBNP, between 1st May 2012 and 1st May 2013, using the 2016 European Society of Cardiology (ESC) guidelines for the diagnosis and treatment of acute and chronic heart failure. Results . HFpEF (n=464, 48%) was more common than HF with reduced EF (HFrEF) (n=314, 33%) or neither HFrEF/HFpEF (n=182, 19%). Patients with HFpEF were older, (mean age 83.8 vs. 81.9 years; p Conclusion . ESC guided diagnosis of HFpEF can be an important adjunct to management of older patients presenting with symptoms and signs of HF and may be useful in developing new approaches to the treatment of HFpEF. Conflict of Interest nil

Background: Heart failure with reduced ejection fraction (HFrEF) is characterized by blunting of the positive relationship between heart rate and left ventricular (LV) contractility known as the force-frequency relationship (FFR). We have previously described that tailoring the rate-response programming of cardiac implantable electronic devices in patients with HFrEF on the basis of individual noninvasive FFR data acutely improves exercise capacity. We aimed to examine whether using FFR data to tailor heart rate response in patients with HFrEF with cardiac implantable electronic devices favorably influences exercise capacity and LV function 6 months later. Methods: We conducted a single-center, double-blind, randomized, parallel-group trial in patients with stable symptomatic HFrEF taking optimal guideline-directed medical therapy and with a cardiac implantable electronic device (cardiac resynchronization therapy or implantable cardioverter-defibrillator). Participants were randomized on a 1:1 basis between tailored rate-response programming on the basis of individual FFR data and conventional age-guided rate-response programming. The primary outcome measure was change in walk time on a treadmill walk test. Secondary outcomes included changes in LV systolic function, peak oxygen consumption, and quality of life. Results: We randomized 83 patients with a mean±SD age 74.6±8.7 years and LV ejection fraction 35.2±10.5. Mean change in exercise time at 6 months was 75.4 (95% CI, 23.4 to 127.5) seconds for FFR-guided rate-adaptive pacing and 3.1 (95% CI, −44.1 to 50.3) seconds for conventional settings (analysis of covariance; P =0.044 between groups) despite lower peak mean±SD heart rates (98.6±19.4 versus 112.0±20.3 beats per minute). FFR-guided heart rate settings had no adverse effect on LV structure or function, whereas conventional settings were associated with a reduction in LV ejection fraction. Conclusions: In this phase II study, FFR-guided rate-response programming determined using a reproducible, noninvasive method appears to improve exercise time and limit changes to LV function in people with HFrEF and cardiac implantable electronic devices. Work is ongoing to confirm our findings in a multicenter setting and on longer-term clinical outcomes. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02964650.

Background: Hospitalization is a common adverse event in people with heart failure and reduced ejection fraction, yet is often not primarily due to decompensated heart failure (HF). We investigated the long-term prognosis following infection-related hospitalization. Methods: We conducted a prospective observational cohort study of 711 people with heart failure and reduced ejection fraction recruited from 4 specialist HF clinics in the United Kingdom. All hospitalization episodes (n=1568) were recorded and categorized as primarily due to decompensated HF, other cardiovascular disease, infection-related, or other noncardiovascular disease. Survival was determined after the first hospitalization. Results: During 2900 patient-years of follow-up, there were a total of 14 686 hospital days. At least one hospitalization occurred in 467 people (66%); 25% of first hospitalizations were primarily due to infection and these were not associated with typical signs including tachycardia and pyrexia. Compared with other categories of hospitalization, infection-related was associated with older age, lower serum albumin, higher blood neutrophil counts, and greater prevalence of chronic obstructive pulmonary disease at recruitment. Median survival after first infection-related hospitalization was 18.6 months, comparable to that after first decompensated HF hospitalization, even after age-sex adjustment. The burden of all-cause rehospitalization was comparable irrespective of the category of first hospitalization, but infection more commonly caused re-hospitalization after index infection hospitalization. Conclusions: Infection is a common driver of hospitalization in heart failure and reduced ejection fraction and often presents without classical signs. It is associated with high mortality rates, comparable to decompensated HF, and a major burden of rehospitalization caused by recurrent episodes of infection.

Pacemakers are safe and effective for bradycardia. Studies suggest left ventricular systolic (LV) dysfunction and heart failure are common in this population. Personalised pacemaker programming in an observational cohort has successfully reduced pacing burden improving LV function. No trial has

Aims The UK National Institute for Health and Care Excellence (UK-NICE) and European Society of Cardiology (ESC) guidelines advise natriuretic peptide (NP) assessment in patients presenting to primary care with symptoms possibly due to chronic heart failure (HF), to determine need for specialist involvement. This prospective service evaluation aimed to describe the diagnostic and prognostic utility of these guidelines. Methods and results We prospectively collected clinical, echocardiography and outcomes data (minimum 5 years) from all patients referred to the Leeds HF Service for 12 months of following the initiation of the NP-guideline-directed pathway. Between 1 May 2012 and 1 August 2013, 1020 people with symptoms possibly due to HF attended either with a raised NT-pro-BNP or a previous myocardial infarction (MI) with an overall rate of left ventricular systolic dysfunction (LVSD) of 33%. Of these, 991 satisfied the ESC criteria (NT-pro-BNP ≥125 pg/mL) in whom the rate of LVSD was 32%, and 821 the UK-NICE criteria in whom the rate of LVSD was 49% in those with a previous MI, 25% in those with NT-pro-BNP concentration 400–2000 pg/mL, and 54% in those with NT-pro-BNP concentration of >2000 pg/mL. An NT-pro-BNP concentration 125–400 pg/mL had a 12% risk of LVSD. Specificity was poor in women >70 years, who made up the largest proportion of attendees. Elevated NT-pro-BNP levels were associated with lower survival even in the absence of LVSD. Conclusion In people referred through the ESC and UK-NICE guidelines, elevated NT-pro-BNP is a marker of increased mortality risk, but there is wide variation in specificity for LVSD. Age- and sex-adjusted criteria might improve performance.

Mitral regurgitation is a common finding in patients with chronic heart failure and is associated with a progressive worsening of symptoms, reduced survival and increased cost of care. However, the use of mitral valve surgery for these patients remains controversial and has not been shown to improve survival. Consequently, research has been increasingly directed towards the nonsurgical management of this important co-morbidity of heart failure.The present review will describe the relevance of mitral regurgitation in people with chronic heart failure, the current options for percutaneous treatment and the evidence base for each of these.Although at present there are few solid data to guide heart teams in deciding what degree of mitral regurgitation to treat, in which patients, and with what, this situation is likely to change over the next two years with the release of the first large randomised trials of percutaneous interventions.

IntroductionPermanent artificial pacemaker implantation is a safe and effective treatment for bradycardia and is associated with extended longevity and improved quality of life. However, the most common long-term complication of standard pacemaker therapy is pacemaker-associated heart failure. Pacemaker follow-up is potentially an opportunity to screen for heart failure to assess and optimise patient devices and medical therapy.Methods and analysisThe study is a multicentre, phase-3 randomised trial. The 1200 participants will be people who have a permanent pacemaker for bradycardia for at least 12 months, randomly assigned to undergo a transthoracic echocardiogram with their pacemaker check, thereby tailoring their management directed by left ventricular function or the pacemaker check alone, continuing with routine follow-up. The primary outcome measure is time to all-cause mortality or heart failure hospitalisation. Secondary outcomes include external validation of our risk stratification model to predict onset of heart failure and quality of life assessment.Ethics and DisseminationThe trial design and protocol have received national ethical approval (12/YH/0487). The results of this randomised trial will be published in international peer-reviewed journals, communicated to healthcare professionals and patient involvement groups and highlighted using social media campaigns.Trial registration numberNCT01819662.

Background Patients with chronic heart failure (HF) secondary to left ventricular systolic dysfunction (LVSD) are frequently deficient in vitamin D. Low vitamin D levels are associated with a worse prognosis.

Introduction: We aimed to evaluate the relationship between temporal changes in renal function and long-term mortality in patients with heart failure with reduced ejection fraction (HFrEF) and identify correlates of deteriorating renal function. Methods: A total of 381 patients with HFrEF enrolled in a prospective cohort study between 2006–2014 had eGFR measured at initial visit and at 1 year. Baseline characteristics were used in a multivariate analysis to establish variables that predict deterioration in eGFR. Follow-up data were used to assess whether declining eGFR was related to outcomes. Results: Patients were grouped into tertiles based on percentage change in eGFR. In a multivariate logistic regression analysis, male sex was associated with a 1.77-fold ([95% CI 1.01–2.89]; p = 0.045) and diabetes a 1.66-fold ([95% CI 1.02–2.70]; p = 0.041) greater risk of a decline in eGFR compared to those with stable/improving eGFR. Declining eGFR was associated with a 1.4-fold greater risk of death over 10 years ([95% CI 1.08–1.86]; p = 0.01) and a 3.12-fold ([1.44–6.75]; p = 0.004) greater risk of death at 1 year from second eGFR measurement. Conclusions: In patients with HFrEF diabetes and male sex are independent predictors of a decline in eGFR at 1 year. A decline eGFR over 1 year is associated with higher long-term all-cause mortality.

Background Noncardiovascular death is increasingly common in people with chronic heart failure ( CHF ), yet its causes remain poorly characterized. We aimed to define the prevalence of sepsis death in people with CHF and to ascertain its risk marker profile. Methods and Results We conducted a prospective cohort study of 1802 patients with CHF and left ventricular ejection fraction ≤45% attending CHF clinics in 4 United Kingdom hospitals between 2006 and 2014. Mode of death was defined over a 10.3‐year follow‐up period (mean 4 years). Competing risk regression defined mode‐specific hazard ratios for sepsis, other noncardiovascular, progressive heart failure, and sudden cardiac death in relation to established heart failure prognostic markers. Of 737 deaths, 173 (23.5%) were due to sepsis; respiratory tract infections accounted for 69.9% (n=121) of these events. Those who died from sepsis were older, had higher platelet counts, and had a higher prevalence of chronic obstructive pulmonary disease than those who died from other causes. Sepsis death was independently associated with older age (hazard ratio=1.05; 95% confidence interval 1.03‐1.07), greater prevalence of chronic obstructive pulmonary disease (2.43; 1.74‐3.40), male sex (1.73; 1.16‐2.60), lower log serum vitamin D (0.68; 0.49‐0.95), and higher platelet count (1.002; 1.000‐1.005) than nonsepsis death. Established heart failure prognostic markers exhibited different patterns of association with sepsis death, other noncardiovascular death, progressive heart failure death, and sudden cardiac death. Conclusions Sepsis is a major contributor to death in people with CHF and has a different risk marker profile from other modes of death, suggesting that it may be amenable to targeted preventative strategies.

Background The CASTLE ‐ AF (Catheter Ablation versus Standard Conventional Therapy in Patients With Left Ventricular Dysfunction and Atrial Fibrillation) trial recently reported that catheter ablation of atrial fibrillation ( AF ) improves survival in heart failure (HF) with reduced ejection fraction ( HF r EF ). However, established AF was not associated with mortality in trials of contemporary HF r EF pharmacotherapies. We investigated whether HF r EF pathogenesis may influence the conclusions of studies evaluating the prognostic impact of AF . Methods and Results Using a prospective cohort study of 791 patients with HFr EF , with AF determined using 24‐hour ambulatory ECG monitoring, univariable and multivariable Cox regression analyses were used to define the association between AF and mode‐specific mortality (mean follow‐up of 5.4 years). One‐year HF‐related hospitalization was assessed with binary logistic regression analysis. One‐year cardiac remodeling was assessed in a subgroup (n=378) using echocardiography. AF was present in 28.2% of patients, with 9.4% of these being paroxysmal. While AF was associated with increased risk of all‐cause mortality (hazard ratio, 1.27; 95% confidence interval 1.03–1.57), with diverging survival curves after 1 year of follow‐up, this association was lost in age‐sex–adjusted analyses. However, AF was associated with increased risk of age‐sex–adjusted all‐cause mortality in people with ischemic pathogenesis, with a statistically significant interaction between pathogenesis and AF. This was predominantly attributed to progressive HF deaths. After 1 year, HF hospitalization and cardiac remodeling were not associated with AF , even in people with ischemic pathogenesis. Conclusions AF is associated with increased risk of death in HF r EF of ischemic pathogenesis, predominantly due to progressive HF deaths during long‐term follow‐up. HF r EF pathogenesis should be considered in trial design and interpretation.

Symptomatic sustained ventricular tachycardia is a life threatening arrhythmia requiring prompt treatment. However, the risk associated with asymptomatic nonsustained ventricular tachycardia (NSVT) detected on routine permanent pacemaker (PPM) interrogation in patients with known cardiac conduction disease is unknown. Our aim is to determine if asymptomatic NSVT detected on PPM interrogation is associated with increased mortality. As part of a prospective observational cohort study, 582 patients with long-term pacemakers were recruited at a tertiary cardiac centre, and followed for 4 ± 1.96 years (mean ± standard deviation). At each subsequent pacemaker check, any symptoms and ventricular high-rate episodes were recorded. We excluded 17 patients due to incomplete data. In the remaining 565 patients (57% male, age 74.5 ± 19.2 years, left ventricular ejection fraction 50.0 ± 11.3%), NSVT was found in 125 (22.1%) patients with a higher prevalence in males (65% vs 54%; p = 0.033). Those with NSVT were more likely to have had coronary artery disease (p = 0) or previous myocardial infarction (p = 0.015). After correction for baseline variables, NSVT had no impact on survival (n = 52 [42%] vs n = 162 [37%]; log-rank p = 0.331, hazard ratio: 0.927, 95% confidence interval: 0.678 to 1.268, p = 0.697). In conclusion, asymptomatic NSVT identified on PPM interrogation does not appear to be associated with increased mortality, thus whether treatment to suppress this arrhythmia is of benefit remains unproven.

Purpose Low 25-hydroxyvitamin D (25[OH]D) concentrations have been associated with adverse outcomes in selected populations with established chronic heart failure (CHF). However, it remains unclear whether 25[OH]D deficiency is associated with mortality and hospitalisation in unselected patients receiving contemporary medical and device therapy for CHF. Methods We prospectively examined the prevalence and correlates of 25[OH]D deficiency in 1802 ambulatory patients with CHF due to left ventricular systolic dysfunction (left ventricular ejection fraction ≤ 45%) attending heart failure clinics in the north of England. Results 73% of patients were deficient in 25[OH]D (

Aims Cardiac resynchronization therapy (CRT) for chronic heart failure with left ventricular systolic dysfunction (LVSD) consistently improves survival against optimal medical therapy alone. Limited data exist comparing the outcomes between CRT with pacemaker (CRT-P) and with defibrillator (CRT-D). We aimed to investigate the long-term prognosis of patients who received CRT-P or CRT-D. Methods and results Data were prospectively collected from consecutive patients with standard indications for CRT, who were implanted at a single large tertiary centre between 2008 and 2012. All-cause mortality was compared between those patients who received either CRT-P or CRT-D. A subgroup analysis was performed in patients with ischaemic cardiomyopathy. During the period in question, 795 patients received CRT devices: 544 (68.4%) CRT-P and 251 (31.6%) CRT-D. The mean follow-up was 1072 ± (SD 556) days. Overall, there was no survival benefit in those patients implanted with a CRT-D compared with CRT-P (hazard ratio 1.09, 95% confidence interval 0.84-1.41, P = 0.51). In patients with ischaemic chronic heart failure [n = 530 (66.7%)], there was a trend for improved survival with CRT-D; however, this was not significant after adjustment. In a subgroup analysis, there were no differences in mode-specific mortality in those patients implanted with CRT-D compared with CRT-P. Conclusion In this large consecutive patient cohort, we did not find a survival benefit of CRT-D compared with CRT-P. Patients indicated for CRT devices may not reliably benefit from the addition of a defibrillator.

OBJECTIVE Diabetes increases mortality in patients with chronic heart failure (CHF) and reduced left ventricular ejection fraction. Studies have questioned the safety of β-adrenoceptor blockers (β-blockers) in some patients with diabetes and reduced left ventricular ejection fraction. We examined whether β-blockers and ACE inhibitors (ACEIs) are associated with differential effects on mortality in CHF patients with and without diabetes. RESEARCH DESIGN AND METHODS We conducted a prospective cohort study of 1,797 patients with CHF recruited between 2006 and 2014, with mean follow-up of 4 years. β-Blocker dose was expressed as the equivalent dose of bisoprolol (mg/day) and ACEI dose as the equivalent dose of ramipril (mg/day). Cox regression analysis was used to examine the interaction between diabetes and drug dose on all-cause mortality. RESULTS Patients with diabetes were prescribed larger doses of β-blockers and ACEIs than were patients without diabetes. Increasing β-blocker dose was associated with lower mortality in patients with diabetes (8.9% per mg/day; 95% CI 5–12.6) and without diabetes (3.5% per mg/day; 95% CI 0.7–6.3), although the effect was larger in people with diabetes (interaction P = 0.027). Increasing ACEI dose was associated with lower mortality in patients with diabetes (5.9% per mg/day; 95% CI 2.5–9.2) and without diabetes (5.1% per mg/day; 95% CI 2.6–7.6), with similar effect size in these groups (interaction P = 0.76). CONCLUSIONS Increasing β-blocker dose is associated with a greater prognostic advantage in CHF patients with diabetes than in CHF patients without diabetes.

Objectives This study sought to examine whether the heart rate (HR) at which the force-frequency relationship (FFR) slope peaks (critical HR) could be used to tailor HR response in chronic heart failure (CHF) patients with cardiac pacemakers and whether this favorably influences exercise capacity. Background CHF secondary to left ventricular (LV) systolic dysfunction is characterized by blunting of the positive relationship between HR and LV contractility known as the FFR. Methods This observational study was carried out in patients with CHF and healthy subjects with pacemaker devices. The study assessed the 3 important features of the FFR (critical HR, peak contractility, and the FFR slope), and their reproducibility was measured noninvasively using echocardiography. The investigators then undertook a double-blind, randomized, controlled crossover study comparing the effects of tailored pacemaker rate-response programming on the basis of the FFR with conventional rate-response programming on exercise time and maximal oxygen consumption. Results The study enrolled 90 patients with CHF into the observational cohort study: mean age, 73.6 ± 8.9 years; mean left ventricular ejection fraction (LVEF), 33.5 ± 10.9%. The study investigated 15 control subjects with normal LV function (LVEF, 55.6 ± 5.3%). The critical HR (103 ± 22 beats/min vs. 126 ± 15 beats/min; p = 0.0002), peak contractility (3.8 ± 3.7 SBP/LVESVI vs. 9.8 ± 4.1 SBP/LVESVI; p = 0.0001), and the slope of the FFR (p Conclusions A personalized approach to rate-response programming, determined using a reproducible noninvasive method for assessing the FFR, improves exercise time in patients with CHF and pacemaker devices. (Bowditch Revisited: Defining the Optimum Heart Rate Range in Chronic Heart Failure; NCT02563873)

Background Limited heart rate (HR) rise (HRR) during exercise, known as chronotropic incompetence (CI), is commonly observed in chronic heart failure (CHF). HRR is closely related to workload, the limitation of which is characteristic of CHF. Whether CI is a causal factor for exercise intolerance, or simply an associated feature remains unknown. Objectives This study sought to clarify the role of the HR on exercise capacity in CHF. Methods This series of investigations consisted of a retrospective cohort study and 2 interventional randomized crossover studies to assess: 1) the relationship between HRR and exercise capacity in CHF; and 2) the effect of increasing and lowering HR on exercise capacity in CHF as assessed by symptom-limited treadmill exercise testing and measurement of peak oxygen consumption in patients with CHF due to left ventricular systolic dysfunction. Results The 3 key findings were: 1) the association of exercise capacity and HRR is much weaker in severe CHF compared to normal left ventricular function; 2) increasing HRR using rate-adaptive pacing (versus fixed-rate pacing) in unselected patients with CHF does not improve peak exercise capacity; and 3) acutely lowering baseline and peak HR by adjusting pacemaker variables in conjunction with a single dose of ivabradine does not adversely affect exercise capacity in unselected CHF patients. Conclusions The data refute the contention that CI contributes to impaired exercise capacity in CHF. This finding has widespread implications for pacemaker programming and the use of heart-rate lowering agents. (The Influence of Heart Rate Limitation on Exercise Tolerance in Pacemaker Patients [TREPPE]; NCT02247245 )