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The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has important implications for the safety of participants in clinical trials and the research staff caring for them and, consequently, for the trials themselves. Patients with heart failure may be at greater risk of infection with COVID-19 and the consequences might also be more serious, but they are also at risk of adverse outcomes if their clinical care is compromised. As physicians and clinical trialists, it is our responsibility to ensure safe and effective care is delivered to trial participants without affecting the integrity of the trial. The social contract with our patients demands no less. Many regulatory authorities from different world regions have issued guidance statements regarding the conduct of clinical trials during this COVID-19 crisis. However, international trials may benefit from expert guidance from a global panel of experts to supplement local advice and regulations, thereby enhancing the safety of participants and the integrity of the trial. Accordingly, the Heart Failure Association of the European Society of Cardiology on 21 and 22 March 2020 conducted web-based meetings with expert clinical trialists in Europe, North America, South America, Australia, and Asia. The main objectives of this Expert Position Paper are to highlight the challenges that this pandemic poses for the conduct of clinical trials in heart failure and to offer advice on how they might be overcome, with some practical examples. While this panel of experts are focused on heart failure clinical trials, these discussions and recommendations may apply to clinical trials in other therapeutic areas.

Aims Current guidelines recommend initiating family screening for hypertrophic cardiomyopathy (HCM) after age 10 or 12 years unless early screening criteria are met. The aim was to evaluate if current screening guidelines miss early onset disease. Methods and results Children who underwent family screening for HCM before age 18 years were analysed. Major cardiac events (MaCEs) were defined as death, sudden cardiac death (SCD), or need for major cardiac interventions (myectomy, implantable cardioverter-defibrillator insertion, transplantation). Of 524 children screened, 331 were under 10 years of age, 9.9% had echocardiographic evidence of HCM, and 1.1% were symptomatic at first screening. The median (interquartile range) age at HCM onset was 8.9 (4.7–13.4) years, and at MaCE was 10.9 (8.5–14.3) years with a median time to MaCE from HCM onset of 1.5 (0.5–4.1) years. About 52.5% phenotype-positive children and 41% with MaCEs were Conclusion A third of children not eligible for early screening by current guidelines had phenotype-positive HCM. MYH7 and MYBC3 mutation-positive patients were at highest risk for developing early HCM and experiencing an event or requiring a major intervention. Our findings suggest that younger family members should be considered for early clinical and genetic screening to identify the subset in need of closer monitoring and interventions.

Aims Circulating high-sensitivity cardiac troponin (hsTn) and soluble ST2 (sST2) reflect myocardial stress in patients with heart failure (HF). Production of cyclic guanosine 3′5′ monophosphate (cGMP) in response to activation of natriuretic peptide receptors reduces cardiac afterload and preload. We assessed the effects of sacubitril/valsartan on these biomarkers in patients with reduced ejection fraction and acute decompensated HF (ADHF). Methods and results PIONEER-HF was a randomized, double-blind trial of sacubitril/valsartan vs. enalapril in hospitalized patients with ADHF following haemodynamic stabilization. We measured circulating hsTnT, sST2, and urinary cGMP at baseline, 1, 2 (sST2, cGMP), 4, and 8 weeks (n = 694 with all baseline biomarkers). Ratios of geometric means (timepoint/baseline) were determined and compared as a ratio for sacubitril/valsartan vs. enalapril. Compared with enalapril, sacubitril/valsartan led to a significantly greater decline in hsTnT and sST2. This effect emerged as early as 1 week for sST2 and was significant for both at 4 weeks with a 16% greater reduction in hsTnT (P

Aims Lamin A/C (LMNA) mutations cause familial dilated cardiomyopathy (DCM) with frequent conduction blocks and arrhythmias. We explored the prevalence, cardiac penetrance, and expressivity of LMNA mutations among familial DCM in Norway. Furthermore, we explored the risk factors and the outcomes in LMNA patients. Methods and results During 2003–15, genetic testing was performed in patients referred for familial DCM. LMNA genotype-positive subjects were examined by electrocardiography, Holter monitoring, cardiac magnetic resonance imaging, and echocardiography. A positive cardiac phenotype was defined as the presence of atrioventricular (AV) block, atrial fibrillation/flutter (AF), ventricular tachycardia (VT), and/or echocardiographic DCM. Heart transplantation was recorded and compared with non-ischaemic DCM of other origin. Of 561 unrelated familial DCM probands, 35 (6.2%) had an LMNA mutation. Family screening diagnosed an additional 93 LMNA genotype-positive family members. We clinically followed up 79 LMNA genotype-positive [age 42 ± 16 years, ejection fraction (EF) 45 ± 13%], including 44 (56%) with VT. Asymptomatic LMNA genotype-positive family members (age 31 ± 15 years) had a 9% annual incidence of a newly documented cardiac phenotype and 61% (19/31) of cardiac penetrance during 4.4 ± 2.9 years of follow-up. Ten (32%) had AV block, 7 (23%) AF, and 12 (39%) non-sustained VT. Heart transplantation was performed in 15 of 79 (19%) LMNA patients during 7.8 ± 6.3 years of follow-up. Conclusion LMNA mutation prevalence was 6.2% of familial DCM in Norway. Cardiac penetrance was high in young asymptomatic LMNA genotype-positive family members with frequent AV block and VT, highlighting the importance of early family screening and cardiological follow-up. Nearly 20% of the LMNA patients required heart transplantation.

We examined whether an additive treatment with an angiotensin receptor blocker, olmesartan, reduces the mortality and morbidity in hypertensive patients with chronic heart failure (CHF) treated with angiotensin-converting enzyme (ACE) inhibitors, β-blockers, or both. In this prospective, randomized, open-label, blinded endpoint study, a total of 1147 hypertensive patients with symptomatic CHF (mean age 66 years, 75% male) were randomized to the addition of olmesartan (n = 578) to baseline therapy vs. control (n = 569). The primary endpoint was a composite of all-cause death, non-fatal acute myocardial infarction, non-fatal stroke, and hospitalization for worsening heart failure. During a median follow-up of 4.4 years, the primary endpoint occurred in 192 patients (33.2%) in the olmesartan group and in 166 patients (29.2%) in the control group [hazard ratio (HR) 1.18; 95% confidence interval (CI), 0.96–1.46, P = 0.112], while renal dysfunction developed more frequently in the olmesartan group (16.8 vs. 10.7%, HR 1.64; 95% CI 1.19–2.26, P = 0.003). Subgroup analysis revealed that addition of olmesartan to combination of ACE inhibitors and β-blockers was associated with increased incidence of the primary endpoint (38.1 vs. 28.2%, HR 1.47; 95% CI 1.11–1.95, P = 0.006), all-cause death (19.4 vs. 13.5%, HR 1.50; 95% CI 1.01–2.23, P = 0.046), and renal dysfunction (21.1 vs. 12.5%, HR 1.85; 95% CI 1.24–2.76, P = 0.003). Additive use of olmesartan did not improve clinical outcomes but worsened renal function in hypertensive CHF patients treated with evidence-based medications. Particularly, the triple combination therapy with olmesartan, ACE inhibitors and β-blockers was associated with increased adverse cardiac events. This study is registered at clinicaltrials.gov-NCT00417222.

Purpose The prognostic implications of blood glucose on a wide range of outcomes including early mortality, hospitalizations, and incident diabetes diagnoses have not been fully elucidated in acute heart failure syndromes (AHFS). Methods In a population-based cohort of 16 524 AHFS patients presenting to the emergency department (ED) in Ontario, Canada between 2004 and 2007, we performed a competing risk analysis for 30-day mortality, new diabetes diagnoses, and hospitalization outcomes. Presentation blood glucose concentrations were categorized as follows: 3.9–6.1 [referent], >6.1–7.8, >7.8–9.4, >9.4–11.1, and >11.1 mmol/L. Results Among AHFS patients without diabetes presenting to the ED ( n = 9275), blood glucose >6.1 mmol/L ( n = 5252, 56.6%) was associated with increased risks of all-cause death [hazard ratio (HR) range: 1.26 (95% CI 1.05–1.50) to 1.50 (95% CI 1.11–2.02)], and cardiovascular death [HR range: 1.28 (95% CI 1.03–1.59) to 1.64 (95% CI 1.16–2.33)]. Among AHFS patients with diabetes ( n = 7249), presenting blood glucose >11.1 mmol/L ( n = 2286, 31.5%) was associated with increased risks of all-cause death (HR 1.48, 95% CI 1.10–2.00) and diabetes-related hospitalizations (HR 1.39, 95% CI; 1.20–1.61). Presentation blood glucose >9.4 mmol/L was associated with increased risks of hospitalization for HF or cardiovascular causes [HR range: 1.09 (95% CI 1.02–1.17) to 1.15 (95% CI 1.07–1.24)] in all patients. With higher presentation blood glucose, the risk of incident diabetes diagnosis increased, with adjusted HRs of 1.61 (>6.1–7.8 mmol/L) to 3.61 (>11.1 mmol/L) among those without the condition at baseline (all P < 0.001). Conclusions Mildly elevated presentation blood glucose was associated with early death, future diabetes, and hospitalizations for diabetes, HF, and cardiovascular causes among patients with AHFS.

Aims To study the relation between body mass index (BMI) in young men and risk of early hospitalization with heart failure. Methods and results In a prospective cohort study, men from the Swedish Conscript Registry investigated 1968–2005 (n = 1 610 437; mean age, 18.6 years were followed 5–42 years (median, 23.0 years; interquartile range, 15.0–32.0), 5492 first hospitalizations for heart failure occurred (mean age at diagnosis, 46.6 (SD 8.0) years). Compared with men with a body mass index (BMI) of 18.5–20.0 kg/m2, men with a BMI 20.0–22.5 kg/m2 had an hazard ratio (HR) of 1.22 (95% CI, 1.10–1.35), after adjustment for age, year of conscription, comorbidities at baseline, parental education, blood pressure, IQ, muscle strength, and fitness. The risk rose incrementally with increasing BMI such that men with a BMI of 30–35 kg/m2 had an adjusted HR of 6.47 (95% CI, 5.39–7.77) and those with a BMI of ≥35 kg/m2 had an HR of 9.21 (95% CI, 6.57–12.92). The multiple-adjusted risk of heart failure per 1 unit increase in BMI ranged from 1.06 (95% CI, 1.02–1.11) in heart failure associated with valvular disease to 1.20 (95% CI, 1.18–1.22) for cases associated with coronary heart disease, diabetes, or hypertension. Conclusion We found a steeply rising risk of early heart failure detectable already at a normal body weight, increasing nearly 10-fold in the highest weight category. Given the current obesity epidemic, heart failure in the young may increase substantially in the future and physicians need to be aware of this.

Aims The globalization of clinical trials has highlighted geographic variations in patient characteristics, event rates, and treatment effects. We investigated these further in PARADIGM-HF, the largest and most globally representative trial in heart failure (HF) to date. Methods and results We looked at five regions: North America (NA) 602 (8%), Western Europe (WE) 1680 (20%), Central/Eastern Europe/Russia (CEER) 2762 (33%), Latin America (LA) 1433 (17%), and Asia-Pacific (AP) 1487 (18%). Notable differences included: WE patients (mean age 68 years) and NA (65 years) were older than AP (58 years) and LA (63 years) and had more coronary disease; NA and CEER patients had the worst signs, symptoms, and functional status. North American patients were the most likely to have a defibrillating-device (54 vs. 2% AP) and least likely prescribed a mineralocorticoid receptor antagonist (36 vs. 65% LA). Other evidence-based therapies were used most frequently in NA and WE. Rates of the primary composite outcome of cardiovascular (CV) death or HF hospitalization (per 100 patient-years) varied among regions: NA 13.6 (95% CI 11.7–15.7) WE 9.6 (8.6–10.6), CEER 12.3 (11.4–13.2), LA 11.2 (10.0–12.5), and AP 12.5 (11.3–13.8). After adjustment for prognostic variables, relative to NA, the risk of CV death was higher in LA and AP and the risk of HF hospitalization lower in WE. The benefit of sacubitril/valsartan was consistent across regions. Conclusion There were many regional differences in PARADIGM-HF, including in age, symptoms, comorbidity, background therapy, and event-rates, although these did not modify the benefit of sacubitril/valsartan. Clinical trial registration URL http://www.clinicaltrials.gov. Unique identifier: NCT01035255.

Aims To evaluate oral doses of the non-steroidal mineralocorticoid receptor antagonist finerenone given for 90 days in patients with worsening heart failure and reduced ejection fraction and chronic kidney disease and/or diabetes mellitus. Methods and results Miner Alocorticoid Receptor antagonist Tolerability Study-Heart Failure (ARTS-HF) was a randomized, double-blind, phase 2b multicentre study (ClinicalTrials.gov: NCT01807221). Of 1286 screened patients, 1066 were randomized. Patients received oral, once-daily finerenone (2.5, 5, 7.5, 10, or 15 mg, uptitrated to 5, 10, 15, 20, or 20 mg, respectively, on Day 30) or eplerenone (25 mg every other day, increased to 25 mg once daily on Day 30, and to 50 mg once daily on Day 60) for 90 days. The primary endpoint was the percentage of individuals with a decrease of >30% in plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) from baseline to Day 90. A key exploratory endpoint was a composite clinical endpoint of death from any cause, cardiovascular hospitalizations, or emergency presentation for worsening HF until Day 90. Mean age ranged from 69.2 to 72.5 years in different treatment groups (standard deviation 9.7–10.6 years). Decreases in NT-proBNP of >30% from baseline occurred in 37.2% of patients in the eplerenone group and 30.9, 32.5, 37.3, 38.8, and 34.2% in the 2.5→5, 5→10, 7.5→15, 10→20, and 15→20 mg finerenone groups, respectively (P = 0.42–0.88). Except for the 2.5→5 mg finerenone group, the composite clinical endpoint occurred numerically less frequently in finerenone-treated patients compared with eplerenone; this difference reached nominal statistical significance in the 10→20 mg group (hazard ratio 0.56, 95% confidence interval, CI, 0.35; 0.90; nominal P = 0.02), despite the fact that this phase 2 study was not designed to detect statistical significant differences. A potassium level increase to ≥5.6 mmol/L at any time point occurred in 4.3% of patients, with a balanced distribution among all treatment groups. Conclusion Finerenone was well tolerated and induced a 30% or greater decrease in NT-proBNP levels in a similar proportion of patients to eplerenone. The finding of reduced clinical events in the finerenone 10→20 mg group should be further explored in a large outcomes trial.

Aims: Remote management of heart failure using implantable electronic devices (REM-HF) aimed to assess the clinical and cost-effectiveness of remote monitoring (RM) of heart failure in patients with cardiac implanted electronic devices (CIEDs).Methods and results: Between 29 September 2011 and 31 March 2014, we randomly assigned 1650 patients with heart failure and a CIED to active RM or usual care (UC). The active RM pathway included formalized remote follow-up protocols, and UC was standard practice in nine recruiting centres in England. The primary endpoint in the time to event analysis was the 1st event of death from any cause or unplanned hospitalization for cardiovascular reasons. Secondary endpoints included death from any cause, death from cardiovascular reasons, death from cardiovascular reasons and unplanned cardiovascular hospitalization, unplanned cardiovascular hospitalization, and unplanned hospitalization. REM-HF is registered with ISRCTN (96536028). The mean age of the population was 70 years (range 23–98); 86% were male. Patients were followed for a median of 2.8 years (range 0–4.3 years) completing on 31 January 2016. Patient adherence was high with a drop out of 4.3% over the course of the study. The incidence of the primary endpoint did not differ significantly between active RM and UC groups, which occurred in 42.4 and 40.8% of patients, respectively [hazard ratio 1.01; 95% confidence interval (CI) 0.87–1.18; P = 0.87]. There were no significant differences between the two groups with respect to any of the secondary endpoints or the time to the primary endpoint components.Conclusion: Among patients with heart failure and a CIED, RM using weekly downloads and a formalized follow up approach does not improve outcomes.

In 2006, the Task Force of the European Society of Cardiology published its consensus document on the use of autologous cell therapy for repair of the heart.1 Since then, there have been numerous clinical trials and analyses performed to establish the role of autologous cell therapy in the treatment of both acute and chronic cardiac disease. The majority of these studies have been Phase II clinical trials. Phase III clinical trials of autologous cell therapy have been launched (e.g. BAMI), which marks the successful progression of clinical investigation of autologous cell therapy in heart disease. The Task Force has reviewed its 2006 recommendations and the developments in this area of research and proposes updated recommendations for the future of autologous cell therapy in the heart. This article does not duplicate the many reviews on stem cells and the heart but gives considered recommendations based on the experience from the last 10 years (Table 1)., published version, peerReviewed

Aims Anecdotal observations suggest that sub-clinical electrophysiological manifestations of arrhythmogenic right ventricular cardiomyopathy (ARVC) develop before detectable structural changes ensue on cardiac imaging. To test this hypothesis, we investigated a murine model with conditional cardiac genetic deletion of one desmoplakin allele (DSP ±) and compared the findings to patients with non-diagnostic features of ARVC who carried mutations in desmoplakin. Methods and results Murine: the DSP (±) mice underwent electrophysiological, echocardiographic, and immunohistochemical studies. They had normal echocardiograms but delayed conduction and inducible ventricular tachycardia associated with mislocalization and reduced intercalated disc expression of Cx43. Sodium current density and myocardial histology were normal at 2 months of age. Human: ten patients with heterozygous mutations in DSP without overt structural heart disease (DSP+) and 12 controls with supraventricular tachycardia were studied by high-density electrophysiological mapping of the right ventricle. Using a standard S1–S2 protocol, restitution curves of local conduction and repolarization parameters were constructed. Significantly greater mean increases in delay were identified particularly in the outflow tract vs. controls (P< 0.01) coupled with more uniform wavefront progression. The odds of a segment with a maximal activation–repolarization interval restitution slope >1 was 99% higher (95% CI: 13%; 351%, P= 0.017) in DSP+ vs. controls. Immunostaining revealed Cx43 mislocalization and variable Na channel distribution. Conclusion Desmoplakin disease causes connexin mislocalization in the mouse and man preceding any overt histological abnormalities resulting in significant alterations in conduction–repolarization kinetics prior to morphological changes detectable on conventional cardiac imaging. Haploinsufficiency of desmoplakin is sufficient to cause significant Cx43 mislocalization. Changes in sodium current density and histological abnormalities may contribute to a worsening phenotype or disease but are not necessary to generate an arrhythmogenic substrate. This has important implications for the earlier diagnosis of ARVC and risk stratification.

AIMS: Thiazolidinediones are insulin sensitizers, and are associated with fluid retention and increased risk of heart failure (HF) in people with type 2 diabetes. We assessed fatal and non-fatal HF events and their outcome, and identified HF predictors in the RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycaemia in Diabetes) trial population. METHODS AND RESULTS: In a multicentre, open-label study, we randomized 4447 people with type 2 diabetes on metformin or sulfonylurea monotherapy with a mean HbA(1c) of 7.9% to add-on rosiglitazone (n = 2220) or to a combination of metformin and sulfonylurea (n = 2227) and followed them over 5.5 years on average. Heart failure hospitalizations and deaths were adjudicated by a Clinical Endpoint Committee using pre-specified criteria. Independent predictors of HF events were identified out of a group of 30 pre-specified clinical, demographic, and biological variables. In the rosiglitazone group, the risk of HF death or hospitalization was doubled: HR = 2.10 (95% CI, 1.35-3.27): the excess HF event rate was 2.6 (1.1-4.1) per 1000 person-years. An excess in HF deaths was observed (10 vs. two), including four HF deaths as first HF events. By contrast, there was no increase in cardiovascular mortality or hospitalization (HR = 0.99, 95% CI, 0.85-1.16) or in cardiovascular deaths (60 vs. 71). Independent predictors of HF were rosiglitazone assignment, age, urinary albumin : creatinine ratio, body mass index, and systolic blood pressure at baseline. A history of previous cardiovascular disease was not predictive of HF. Duration of HF hospitalization and rate of HF re-hospitalization were similar in the two groups. CONCLUSION: These findings confirm the increased risk of HF events in people treated with rosiglitazone and support the recommendation that this agent should not continue to be used in people developing symptomatic HF while using the medication. Close follow-up for the risk of HF should be offered to elderly people, people with markedly increased body mass index, people with microalbuminuria/proteinuria, and people with increased systolic blood pressure.

Aims Clinical parameters are weak predictors of outcome in patients with idiopathic dilated cardiomyopathy (IDC). We assessed the prognostic value of cardiac magnetic resonance (CMR) parameters in addition to conventional clinical and electrocardiographic characteristics. Methods and results One hundred and forty-one IDC patients were studied. QRS and QTc intervals were measured in 12-lead surface electrocardiogram. Patients were followed for median 1339 days, including 483 patient-years. The primary endpoint—cardiac death or sudden death—occurred in 25 (18%) patients, including 16 patients with cardiac death, 3 patients with sudden cardiac death (SCD), and 6 patients with ICD shock. Late gadolinium enhancement (LGE) was detected in 36 patients (26%). Kaplan–Meier survival analysis displayed QRS >110 ms (P = 0.010), the presence of LGE (P = 0.037), and diabetes mellitus (P < 0.001) as significant parameters for a worse outcome. Multivariable analysis revealed cardiac index (P < 0.001), right ventricular end-diastolic volume index (RVEDVI) (P = 0.006) derived from CMR imaging, the presence of diabetes mellitus (P = 0.006), and QRS >110 ms (P = 0.045) as significant predictors for the primary endpoint. Conclusion Cardiac index and RVEDVI derived from CMR imaging in addition to QRS duration >110 ms from conventional surface ECG and diabetes mellitus provide prognostic impact for cardiac death and SCD in patients with IDC.

Aims To investigate whether genetic variants of the histidine-rich calcium (HRC)-binding protein are associated with idiopathic dilated cardiomyopathy (DCM) and its progression. Methods and results We screened 123 idiopathic DCM patients and 96 healthy individuals by single-strand conformation polymorphism analysis and direct sequencing for genetic variants in HRC. Six polymorphisms were detected: Leu35Leu (A/G), Ser43Asn (G/A), Ser96Ala (T/G), Glu202_Glu203insGlu (−/GAG), Asp261del (GAT/−), and an in-frame insertion of 51 amino acids at His321. The analysis of their frequencies did not reveal any significant correlation with DCM development. However, the Ser96Ala polymorphism exhibited a statistically significant correlation with the occurrence of life-threatening ventricular arrhythmias. During a follow-up of 4.02 ± 2.4 years, the risk for ventricular arrhythmias was higher (HR, 9.620; 95% CI, 2.183–42.394; P = 0.003) in the Ala/Ala patients, compared with Ser/Ser homozygous patients. On multivariable Cox regression analysis, the Ser96Ala polymorphism was the only significant genetic arrythmogenesis predictor in DCM patients (HR, 4.191; 95% CI, 0.838–20.967; P = 0.018). Conclusion The Ser96Ala genetic variant of HRC is associated with life-threatening ventricular arrhythmias in idiopathic DCM and may serve as an independent predictor of susceptibility to arrhythmogenesis in the setting of DCM.

Aims:\ud The incidence and predictors of stroke in patients with heart failure and preserved ejection fraction (HF-PEF), but without atrial fibrillation (AF), are unknown. We described the incidence of stroke in HF-PEF patients with and without AF and predictors of stroke in those without AF.\ud Methods and results:\ud We pooled data from the CHARM-Preserved and I-Preserve trials. Using Cox regression, we derived a model for stroke in patients without AF in this cohort and compared its performance with a published model in heart failure patients with reduced ejection fraction (HF-REF)—predictive variables: age, body mass index, New York Heart Association class, history of stroke, and insulin-treated diabetes. The two stroke models were compared and Kaplan–Meier curves for stroke estimated. The risk model was validated in a third HF-PEF trial. Of the 6701 patients, 4676 did not have AF. Stroke occurred in 124 (6.1%) with AF and in 171 (3.7%) without AF (rates 1.80 and 1.00 per 100 patient-years, respectively). There was no difference in performance of the stroke model derived in the HF-PEF cohort and the published HF-REF model (c-index 0.71, 95% confidence interval 0.57–0.84 vs. 0.73, 0.59–0.85, respectively) as the predictive variables overlapped. The model performed well in the validation cohort (0.86, 0.62–0.99). The rate of stroke in patients in the upper third of risk approximated to that in patients with AF (1.60 and 1.80 per 100 patient-years, respectively).\ud Conclusions:\ud A small number of clinical variables identify a subset of patients with HF-PEF, but without AF, at elevated risk of stroke.