Diabetes mellitus does not alter mortality or hospitalisation risk in patients with newly diagnosed heart failure with preserved ejection fraction: Time to rethink pathophysiological models of disease progression.

INTRODUCTION: Type 2 diabetes is a common and adverse prognostic co-morbidity for patients with heart failure with reduced ejection fraction (HFrEF). The effect of diabetes on long-term outcomes for heart failure with preserved ejection fraction (HFpEF) is less established. METHODS: Prospective cohort study of patients referred to a regional HF clinic with newly diagnosed with HFrEF and HFpEF according to the 2016 European Society of Cardiology guidelines. The association between diabetes, all-cause mortality and hospitalisation was quantified using Kaplan-Meier or Cox regression analysis. RESULTS: Between 1st May 2012 and 1st May 2013, of 960 unselected consecutive patients referred with suspected HF, 464 and 314 patients met the criteria for HFpEF and HFrEF respectively. Within HFpEF and HFrEF groups, patients with diabetes were more frequently male and in both groups patients with diabetes were more likely to be treated with ß-adrenoceptor antagonists and angiotensin converting enzyme inhibitors. After adjustment for age, sex, medical therapy and co-morbidities, diabetes was associated with increased mortality in individuals with HFrEF (HR 1.46 95% CI: 1.05-2.02; p = .023), but not in those with HFpEF (HR 1.26 95% CI 0.92-1.72; p = .146). CONCLUSION: In unselected patients with newly diagnosed HF, diabetes is not an adverse prognostic marker in patients with HFpEF, but is in HFrEF.

Atrial secondary mitral regurgitation: prevalence, characteristics, management, and long-term outcomes.

BACKGROUND: The prevalence, clinical characteristics, management and long-term outcomes of patients with atrial secondary mitral regurgitation (ASMR) are not well described. METHODS: We performed a retrospective, observational study of consecutive patients with grade III/IV MR determined by transthoracic echocardiography. The aetiology of MR was grouped as being either primary (due to degenerative mitral valve disease), ventricular SMR (VSMR: due to left ventricular dilatation/dysfunction), ASMR (due to LA dilatation), or other. RESULTS: A total of 388 individuals were identified who had grade III/IV MR; of whom 37 (9.5%) had ASMR, 113 (29.1%) had VSMR, 193 had primary MR (49.7%), and 45 (11.6%) were classified as having other causes. Compared to MR of other subtypes, patients with ASMR were on average older (median age 82 [74-87] years, p < 0.001), were more likely to be female (67.6%, p = 0.004) and usually had atrial fibrillation (83.8%, p = 0.001). All-cause mortality was highest in patients with ASMR (p < 0.001), but similar to that in patients with VSMR once adjusted for age and sex (hazard ratio [HR] 0.81, 95% confidence interval [CI] 0.52-1.25). Hospitalisation for worsening heart failure was more commonly observed in those with ASMR or VSMR (p < 0.001) although was similar between these groups when age and sex were accounted for (HR 0.74, 95% CI 0.34-1.58). For patients with ASMR, the only variables associated with outcomes were age and co-morbidities. CONCLUSIONS: ASMR is a prevalent and distinct disease process associated with a poor prognosis, with much of this related to older age and co-morbidities.

Guideline-directed medical therapy is similarly effective in heart failure with mildly reduced ejection fraction.

AIMS: Current guidelines recommend that disease-modifying pharmacological therapies may be considered for patients who have heart failure with mildly reduced ejection fraction (HFmrEF). We aimed to describe the characteristics, outcomes, provision of pharmacological therapies and dose-related associations with mortality risk in HFmrEF. METHODS AND RESULTS: We explored data from two prospective observational studies, which permitted the examination of the effects of pharmacological therapies across a broad spectrum of left ventricular ejection fraction (LVEF). The combined dataset consisted of 2388 unique patients, with a mean age of 73.7 ± 13.2 years of whom 1525 (63.9%) were male. LVEF ranged from 5 to 71% (mean 37.2 ± 12.8%) and 1504 (63.0%) were categorised as having reduced ejection fraction (HFrEF), 421 (17.6%) as HFmrEF and 463 (19.4%) as preserved ejection fraction (HFpEF). Patients with HFmrEF more closely resembled HFrEF than HFpEF. Adjusted all-cause mortality risk was lower in HFmrEF (hazard ratio [HR] 0.86 (95% confidence interval [CI] 0.74-0.99); p = 0.040) and in HFpEF (HR 0.61 (95% CI 0.52-0.71); p < 0.001) compared to HFrEF. Adjusted all-cause mortality risk was lower in patients with HFrEF and HFmrEF who received the highest doses of beta-blockers or renin-angiotensin inhibitors. These associations were not evident in HFpEF. Once adjusted for relevant confounders, each mg equivalent of bisoprolol (HR 0.95 [95% CI 0.91-1.00]; p = 0.047) and ramipril (HR 0.95 [95%CI 0.90-1.00]; p = 0.044) was associated with incremental reductions in mortality risk in patients with HFmrEF. CONCLUSIONS: Pharmacological therapies were associated with lower mortality risk in HFmrEF, supporting guideline recommendations which extend the indications of these agents to all patients with LVEF < 50%. HFmrEF more closely resembles HFrEF in terms of clinical characteristics and outcomes. Pharmacological therapies are associated with lower mortality risk in HFmrEF and HFrEF, but not in HFpEF.

Atrial fibrillation and risk of progressive heart failure in patients with preserved ejection fraction heart failure.

AIMS: Understanding of the pathophysiology of progressive heart failure (HF) in patients with heart failure with preserved ejection fraction (HFpEF) is incomplete. We sought to identify factors differentially associated with risk of progressive HF death and hospitalization in patients with HFpEF compared with patients with HF and reduced ejection fraction (HFrEF). METHODS AND RESULTS: Prospective cohort study of patients newly referred to secondary care with suspicion of HF, based on symptoms and signs of HF and elevated natriuretic peptides (NP), followed up for a minimum of 6 years. HFpEF and HFrEF were diagnosed according to the 2016 European Society of Cardiology guidelines. Of 960 patients referred, 467 had HFpEF (49%), 311 had HFrEF (32%), and 182 (19%) had neither. Atrial fibrillation (AF) was found in 37% of patients with HFpEF and 34% with HFrEF. During 6 years follow-up, 19% of HFrEF and 14% of HFpEF patients were hospitalized or died due to progressive HF, hazard ratio (HR) 0.67 (95% CI: 0.47-0.96; P = 0.028). AF was the only marker that was differentially associated with progressive HF death or hospitalization in patients with HFpEF HR 2.58 (95% CI: 1.59-4.21; P < 0.001) versus HFrEF HR 1.11 (95% CI: 0.65-1.89; P = 0.7). CONCLUSIONS: De novo patients diagnosed with HFrEF have greater risk of death or hospitalization due to progressive HF than patients with HFpEF. AF is associated with increased risk of progressive HF death or hospitalization in HFpEF but not HFrEF, raising the intriguing possibility that this may be a novel therapeutic target in this growing population.

Personalised reprogramming to prevent progressive pacemaker-related left ventricular dysfunction: A phase II randomised, controlled clinical trial.

BACKGROUND: Pacemakers are widely utilised to treat bradycardia, but right ventricular (RV) pacing is associated with heightened risk of left ventricular (LV) systolic dysfunction and heart failure. We aimed to compare personalised pacemaker reprogramming to avoid RV pacing with usual care on echocardiographic and patient-orientated outcomes. METHODS: A prospective phase II randomised, double-blind, parallel-group trial in 100 patients with a pacemaker implanted for indications other than third degree heart block for ≥2 years. Personalised pacemaker reprogramming was guided by a published protocol. Primary outcome was change in LV ejection fraction on echocardiography after 6 months. Secondary outcomes included LV remodeling, quality of life, and battery longevity. RESULTS: Clinical and pacemaker variables were similar between groups. The mean age (SD) of participants was 76 (+/-9) years and 71% were male. Nine patients withdrew due to concurrent illness, leaving 91 patients in the intention-to-treat analysis. At 6 months, personalised programming compared to usual care, reduced RV pacing (-6.5±1.8% versus -0.21±1.7%; p<0.01), improved LV function (LV ejection fraction +3.09% [95% confidence interval (CI) 0.48 to 5.70%; p = 0.02]) and LV dimensions (LV end systolic volume indexed to body surface area -2.99mL/m2 [95% CI -5.69 to -0.29; p = 0.03]). Intervention also preserved battery longevity by approximately 5 months (+0.38 years [95% CI 0.14 to 0.62; p<0.01)) with no evidence of an effect on quality of life (+0.19, [95% CI -0.25 to 0.62; p = 0.402]). CONCLUSIONS: Personalised programming in patients with pacemakers for bradycardia can improve LV function and size, extend battery longevity, and is safe and acceptable to patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03627585.

Long-term performance of left ventricular leads in cardiac resynchronisation therapy.

BACKGROUND: Cardiac resynchronisation therapy (CRT) confers symptomatic and survival benefits in chronic heart failure with reduced ejection fraction (HFrEF). There remains a paucity of data on long-term performance of left ventricular (LV) leads, particularly with newer quadripolar lead designs. METHODS: This single-centre study utilised an electronic, outpatient HFrEF database to identify CRT recipients (2008-2014). The primary endpoint was temporal trend in LV pacing thresholds during follow-up. Secondary outcomes were complications relating to acute or chronic lead failure and device-related infections. RESULTS: Two hundred eighty patients were included, with mean (±SD) age of 74.2 years (±9.0) and median follow-up of 7.6 years (interquartile range 4-9). Mean LV threshold was 1.37 V (±0.73) at implant and remained stable over the study period. No differences were observed based upon lead manufacturer. Compared to non-quadripolar leads (n = 216), those of quadripolar designs (n = 64) had a lower threshold at 6 months (1.20 vs 1.37 V; P = .04) and at the end of the study period (1.32 vs 1.46 V; P = .04). Patients with HFrEF of ischaemic aetiology had higher thresholds at implant (1.46 vs 1.34 V; P = .05), and this persisted until the end of follow-up (1.49 vs 1.34 V; P = .03). There was low incidence of acute (0.71%; 2/280) and chronic lead failure (1.79%; 5/280), with four cases (1.43%) of device infection. CONCLUSIONS: LV leads in the context of CRT have excellent chronic stability and low rates of adverse events. Those with newer quadripolar lead designs have lower thresholds at initial follow-up and in the longer term.

Personalized Rate-Response Programming Improves Exercise Tolerance After 6 Months in People With Cardiac Implantable Electronic Devices and Heart Failure: A Phase II Study.

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.