John Gierula

Effects of Vitamin D on Cardiac Function in Patients With Chronic HF: The VINDICATE Study

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. Objectives The VINDICATE (VitamIN D treatIng patients with Chronic heArT failurE) study was undertaken to establish safety and efficacy of high-dose 25 (OH) vitamin D3 (cholecalciferol) supplementation in patients with chronic HF due to LVSD. Methods We enrolled 229 patients (179 men) with chronic HF due to LVSD and vitamin D deficiency (cholecalciferol <50 nmol/l [<20 ng/ml]). Participants were allocated to 1 year of vitamin D3 supplementation (4,000 IU [100 μg] daily) or matching non−calcium-based placebo. The primary endpoint was change in 6-minute walk distance between baseline and 12 months. Secondary endpoints included change in LV ejection fraction at 1 year, and safety measures of renal function and serum calcium concentration assessed every 3 months. Results One year of high-dose vitamin D3 supplementation did not improve 6-min walk distance at 1 year, but was associated with a significant improvement in cardiac function (LV ejection fraction +6.07% [95% confidence interval (CI): 3.20 to 8.95; p < 0.0001]); and a reversal of LV remodeling (LV end diastolic diameter -2.49 mm [95% CI: -4.09 to -0.90; p = 0.002] and LV end systolic diameter -2.09 mm [95% CI: -4.11 to -0.06 p = 0.043]). Conclusions One year of 100 μg daily vitamin D3 supplementation does not improve 6-min walk distance but has beneficial effects on LV structure and function in patients on contemporary optimal medical therapy. Further studies are necessary to determine whether these translate to improvements in outcomes. (VitamIN D Treating patIents With Chronic heArT failurE [VINDICATE]; NCT01619891)

Cardiac resynchronization therapy in pacemaker-dependent patients with left ventricular dysfunction

AIMS Heart failure and left ventricular (LV) systolic dysfunction (LVSD) are common in patients with permanent pacemakers. The aim was to determine if cardiac resynchronization therapy (CRT) at the time of pulse generator replacement (PGR) is of benefit in patients with unavoidable RV pacing and LVSD. METHODS AND RESULTS Fifty patients with unavoidable RV pacing, LVSD, and mild or no symptoms of heart failure, listed for PGR were randomized 1 : 1 to either standard RV-PGR (comparator) or CRT. The primary endpoint was the difference in change in LV ejection fraction (LVEF) between RV-PGR and CRT groups from baseline to 6 months. Secondary endpoints included peak oxygen consumption, quality of life, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels. At 6 months there was a difference in change in median (interquartile range) LVEF [9 (6-12) vs. -1.5 (-4.5 to -0.8)%; P < 0.0001] between the CRT and RV-PGR arms. There were also improvements in exercise capacity (P = 0.007), quality of life (P = 0.03), and NT-proBNP (P = 0.007) in those randomized to CRT. After 809 (729-880) days, 17 patients had died or been hospitalized (6 in CRT group and 11 in the comparator RV-PGR group) and two patients in the RV-PGR arm had required CRT for deteriorating heart failure. Patients with standard RV-PGR had more days in hospital during follow-up than those in the CRT group [4 (2-7) vs. 11 (6-16) days; P = 0.047]. CONCLUSION Performing CRT in pacemaker patients with unavoidable RV pacing and LVSD but without severe symptoms of heart failure, at the time of PGR, improves cardiac function, exercise capacity, quality of life, and NT-pro-BNP levels.

Chronotropic Incompetence Does Not Limit Exercise Capacity in Chronic Heart Failure.

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).

Ambulatory heart rate range predicts mode-specific mortality and hospitalisation in chronic heart failure

Objective We aimed to define the prognostic value of the heart rate range during a 24 h period in patients with chronic heart failure (CHF). Methods Prospective observational cohort study of 791 patients with CHF associated with left ventricular systolic dysfunction. Mode-specific mortality and hospitalisation were linked with ambulatory heart rate range (AHRR; calculated as maximum minus minimum heart rate using 24 h Holter monitor data, including paced and non-sinus complexes) in univariate and multivariate analyses. Findings were then corroborated in a validation cohort of 408 patients with CHF with preserved or reduced left ventricular ejection fraction. Results After a mean 4.1 years of follow-up, increasing AHRR was associated with reduced risk of all-cause, sudden, non-cardiovascular and progressive heart failure death in univariate analyses. After accounting for characteristics that differed between groups above and below median AHRR using multivariate analysis, AHRR remained strongly associated with all-cause mortality (HR 0.991/bpm increase in AHRR (95% CI 0.999 to 0.982); p=0.046). AHRR was not associated with the risk of any non-elective hospitalisation, but was associated with heart-failure-related hospitalisation. AHRR was modestly associated with the SD of normal-to-normal beats (R2=0.2; p<0.001) and with peak exercise-test heart rate (R2=0.33; p<0.001). Analysis of the validation cohort revealed AHRR to be associated with all-cause and mode-specific death as described in the derivation cohort. Conclusions AHRR is a novel and readily available prognosticator in patients with CHF, which may reflect autonomic tone and exercise capacity.

154 Patients receiving standard pacemaker generator replacements frequently have impaired left ventricular function and exercise intolerance, related to the percentage of right ventricular pacing

Background Right ventricular (RV) pacing is an accepted treatment for symptomatic bradycardia. However, long-term RV pacing is increasingly recognised to be detrimental to left ventricular (LV) systolic function. We wanted to establish the prevalence, associated features and predictors of LV systolic dysfunction (LVSD) and outcome in a contemporary group of patients with long–term RV pacemakers. Methods We prospectively recruited consecutive patients listed for PGR between 2008 and 2010 at Leeds General Infirmary. We performed echocardiography, exercise testing and recorded indications for pacing, pacing variables and duration of pacing, co-morbidities, current medication and renal function. Results Of 399 PGR procedures 342 subjects (86%), 184 men, attended. Non-attendees had similar pacing variables and were of similar age as attendees. Mean age (SE) was 76 (1), and mean duration of pacing was 10 (0.3) years. Comorbidites were common: diabetes mellitus in 11%, previous myocardial infarction in 15%, previous cardiac surgery in 26% and atrial fibrillation (AF) in 26%. Medical therapy included β-blockers in 60% and ACE inhibitors in 70%. Dual chamber devices were implanted in 77% (45% of all patients had rate responsive (RR) pacing programmed). Mean percentage of ventricular pacing (%VP) was 61 (2)%. Mean left ventricular ejection fraction (LVEF) was 49 (1)%, (44% had an LVEF <50%). Mean peak oxygen uptake (pVo2) (in 107 subjects) was 17 (1) ml/kg/min and mean creatinine was 108 (3) μmol/l. There was an inverse relationship between LVEF and %VP (0.42; p<0.0001), and years since first implanted (p=0.09) but there was no effect on LVEF of age, the presence of AF and the pacing mode. In single chamber devices, RR pacing was associated with higher %VP (p=0.01), and a trend to worse LVEF (p=0.09). These differences were not seen in RR programmed dual chamber devices. There was a negative relationship between pVo2 and %VP (r=0.21; p<0.03). Even with a short follow-up period of 16 (0.5) months, 23 (7%) patients are dead. Patients dead at the censor date were older at the time of the assessment (p<0.005), had a higher %VP (p<0.03) and worse renal function (p<0.001), but did not have significantly worse LVEF or pVo2. The presence of a single chamber device was associated with a poorer outcome (p<0.002) despite patients with a single chamber device being of similar age as those with a dual chamber device. Conclusions Patients receiving standard pacemaker generator replacements frequently have cardiovascular comorbidities, left ventricular dysfunction and impaired pVo2 and suffer a high mortality rate. In an unselected population of patients with pacemakers, we have established that the amount of RV pacing is related not only to important surrogate measures of outcome such as exercise tolerance and LVEF but also mortality. Whether an aggressive policy of limiting RV pacing in patients at risk reduces mortality is unknown.

Patients with long-term permanent pacemakers have a high prevalence of left ventricular dysfunction.

Introduction Patients with right ventricular pacemakers are at increased risk of left ventricular systolic dysfunction (LVSD). We aimed to establish the prevalence, degree and associations of LVSD in patients with long-term right ventricular pacemakers listed for pulse generator replacement (PGR). Methods All patients listed for PGR at Leeds General Infirmary were invited to attend for an assessment during which we recorded medical history, symptomatic status, medical therapy, date and indication of first implantation, the percentage of right ventricular pacing (% RVP) and an echocardiogram. Results We collected data on 491 patients. A left ventricular ejection fraction less than 50% was observed in 40% of our cohort, however, this was much higher (59%) in those with more than 80% RVP than in those with less than 80% RVP (22%) (P < 0.0001). Multivariable analysis revealed % RVP, (but not complete heart block at baseline), serum creatinine and previous myocardial infarction to be independently related to the presence of LVSD. A model combining % RVP and previous myocardial infarction has a c-statistic of 0.74 for predicting LVSD. After a mean follow-up time of 668 days, 56 patients (12%) were dead or had been hospitalized for heart failure. In multivariable analysis, previous myocardial infarction and high % RVP were independently associated with a worse survival. Conclusion Patients with right ventricular pacemakers have a high prevalence of LVSD, and this is greater in those exposed to more RVP. Those with LVSD and high amounts of RVP are at higher risk of hospitalization or death. Simple variables can identify those patients who might benefit from a more comprehensive review.

Mortality Reduction Associated With β-Adrenoceptor Inhibition in Chronic Heart Failure Is Greater in Patients With Diabetes

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.

Performance of 2014 NICE defibrillator implantation guidelines in heart failure risk stratification

Objective Define the real-world performance of recently updated National Institute for Health and Care Excellence guidelines (TA314) on implantable cardioverter-defibrillator (ICD) use in people with chronic heart failure. Methods Multicentre prospective cohort study of 1026 patients with stable chronic heart failure, associated with left ventricular ejection fraction (LVEF) ≤45% recruited in cardiology outpatient departments of four UK hospitals. We assessed the capacity of TA314 to identify patients at increased risk of sudden cardiac death (SCD) or appropriate ICD shock. Results The overall risk of SCD or appropriate ICD shock was 2.1 events per 100 patient-years (95% CI 1.7 to 2.6). Patients meeting TA314 ICD criteria (31.1%) were 2.5-fold (95% CI 1.6 to 3.9) more likely to suffer SCD or appropriate ICD shock; they were also 1.5-fold (95% CI 1.1 to 2.2) more likely to die from non-cardiovascular causes and 1.6-fold (95% CI 1.1 to 2.3) more likely to die from progressive heart failure. Patients with diabetes not meeting TA314 criteria experienced comparable absolute risk of SCD or appropriate ICD shock to patients without diabetes who met TA314 criteria. Patients with ischaemic cardiomyopathy not meeting TA314 criteria experienced comparable absolute risk of SCD or appropriate ICD shock to patients with non-ischaemic cardiomyopathy who met TA314 criteria. Conclusions TA314 can identify patients with reduced LVEF who are at increased relative risk of sudden death. Clinicians should also consider clinical context and the absolute risk of SCD when advising patients about the potential risks and benefits of ICD therapy.

Pacing-associated left ventricular dysfunction? Think reprogramming first!

Objective Heart failure and left ventricular systolic dysfunction (LVSD) are common in patients with permanent pacemakers, but whether right ventricular (RV) pacing is contributory or merely a bystander in patients with more severe cardiac disease is controversial. The aim of the present study was to determine whether reprogramming of existing pacemakers to reduce RV pacing is safe and leads to improvements in cardiac function. Methods This was a prospective service evaluation of the effects of optimising pacemaker programming to avoid RV pacing in 66 consecutive attendees of a teaching hospital pacemaker clinic without complete heart block. The main outcome measures were left ventricular ejection fraction (LVEF), N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) levels, quality of life and cardiopulmonary exercise testing at baseline and after 6 months. Results At 6 months, the protocol reduced absolute RV pacing by a mean of 49% (95% CI 41% to 57%) (p<0.0001 from baseline) and resulted in a mean absolute improvement in LVEF of 6% (4% to 8%) (p<0.0001 from baseline) but no reduction in exercise capacity, NT-pro-BNP or quality of life. There was a relationship between the magnitude of change in EF and the reduction in RV pacing (p=0.04) and changes in NT-pro-BNP seemed to relate to change in RV pacing (p=0.07). Conclusions Programming standard pacemakers to avoid RV pacing is safe, does not adversely affect patients’ symptoms or quality of life and is associated with improved LV function, related to the reductions in RV pacing percentage.

Response to (resynchronization) therapy in chronic heart failure: time for a different approach

Although chronic heart failure (CHF) remains an incurable syndrome of exercise intolerance, cardiac dysfunction and reduced longevity, the last two decades have seen an unprecedented improvement in the quality and quantity of life for patients diagnosed with CHF caused by left ventricular systolic dysfunction (LVSD). One of the major advances has been cardiac resynchronization therapy (CRT), which can improve symptoms and prognosis in CHF patients with LVSD and conduction delay.1 Guidelines describing the criteria for selection of CHF patients for CRT are based upon large randomized, placebo-controlled studies demonstrating reduced hospitalization and mortality (over a finite time).3,4 In addition to these studies, there are hundreds of smaller, mostly observational, studies using multiple imaging techniques and various measures of response to try to identify subgroups of patients more or less likely to benefit from CRT. Thankfully, none of the proposed pre-assessment deselection techniques have been adopted into international guidelines, and the indications remain resolutely a broad QRS, left ventricular systolic dysfunction, and sinus rhythm. The data presented by Versteeg et al.2 contribute to the increasing recognition of the pointlessness of trying to predict response to CRT from baseline variables, with the only predictor of symptomatic response being a broad QRS complex. Furthermore their data show that changes in echocardiographic variables are unrelated to changes in symptoms following CRT. These unique data should not only stimulate discussion about the use of contemporary measures of response (often based upon arbitrary percentages of change from baseline) and other surrogate outcomes in chronic disease, but also question the use of cohort studies to deselect subgroups of patients previously included in prospective randomized placebo-controlled trials. The response of any individual to any intervention for a chronic disease is variable and CHF is no different. Cardiac resynchronization therapy is associated with a greater symptomatic response than medical therapy,5 yet many patients experience no improvement. Versteeg et al.2 show us that improvements in symptoms and improvements in cardiac function tend not to occur together (only 30% have a response in both, although 80% have a response in