Impact of Cardiac Magnetic Resonance Left Atrial Ejection Fraction in Advanced Ischemic Cardiomyopathy.

BACKGROUND: The prognostic significance of cardiac magnetic resonance (CMR)-based left atrial ejection fraction (LAEF) is not well defined in the ischemic cardiomyopathy (ICM) cohort. OBJECTIVES: The authors sought to assess the prognostic impact of LAEF, when adjusted for left ventricular remodeling, myocardial infarct size (MIS), left atrial volume index, and functional mitral regurgitation (FMR), on outcomes in patients with advanced ICM. METHODS: ICM patients who underwent CMR were retrospectively evaluated (April 2001-December 2019). LAEF, left atrial volume index, MIS, left ventricular remodeling, and FMR were derived from CMR. The primary clinical endpoint was a composite of all-cause mortality and cardiac transplant. A baseline multivariable Cox proportional hazards regression model was constructed to assess prognostic power of LAEF. RESULTS: There were 718 patients (416 primary events) evaluated, with a median duration of follow-up of 1,763 days (4.8 years) and a mean LAEF of 36% ± 15%. On multivariable analysis, higher LAEF was independently associated with reduced risk (HR: 0.24, 95% CI: 0.12-0.48, P < 0.001), even after adjusting for FMR and MIS. The highest adjusted risk was observed in patients with an LAEF <20% and an MIS of >30% (HR: 3.20, 95% CI: 1.73-5.93). The lowest risk was in patients within the comparator group with an LAEF of >50% and a MIS of <15% (HR: 1.07, 95% CI: 0.81-1.42). CONCLUSIONS: Reduced LAEF is independently associated with increased mortality in ICM. Risk associated with declining LAEF is continuous and incremental to other risk factors for adverse outcomes in patients with ICM even after adjusting for MIS and FMR severity.

Racial and Ethnic Disparities in the Management of Chronic Coronary Disease.

Chronic coronary disease (CCD) comprises a continuum of conditions that include obstructive and non-obstructive coronary artery disease with or without prior acute coronary syndrome. Racial and ethnic representation disparities are pervasive in CCD guideline-informing clinical trials and evidence-based management. These disparities manifest across the entire spectrum of CCD management, spanning from non-pharmacological lifestyle changes to guideline-directed medical therapy, and cardiac rehabilitation to invasive procedures. Recognizing and addressing the historical factors underlying these disparities is crucial for enhancing the quality and equity of CCD management within an increasingly diverse population.

Indole-3-Propionic Acid Protects Against Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a common but poorly understood form of heart failure, characterized by impaired diastolic function. It is highly heterogeneous with multiple comorbidities, including obesity and diabetes, making human studies difficult. METHODS: Metabolomic analyses in a mouse model of HFpEF showed that levels of indole-3-propionic acid (IPA), a metabolite produced by gut bacteria from tryptophan, were reduced in the plasma and heart tissue of HFpEF mice as compared with controls. We then examined the role of IPA in mouse models of HFpEF as well as 2 human HFpEF cohorts. RESULTS: The protective role and therapeutic effects of IPA were confirmed in mouse models of HFpEF using IPA dietary supplementation. IPA attenuated diastolic dysfunction, metabolic remodeling, oxidative stress, inflammation, gut microbiota dysbiosis, and intestinal epithelial barrier damage. In the heart, IPA suppressed the expression of NNMT (nicotinamide N-methyl transferase), restored nicotinamide, NAD+/NADH, and SIRT3 (sirtuin 3) levels. IPA mediates the protective effects on diastolic dysfunction, at least in part, by promoting the expression of SIRT3. SIRT3 regulation was mediated by IPA binding to the aryl hydrocarbon receptor, as Sirt3 knockdown diminished the effects of IPA on diastolic dysfunction in vivo. The role of the nicotinamide adenine dinucleotide circuit in HFpEF was further confirmed by nicotinamide supplementation, Nnmt knockdown, and Nnmt overexpression in vivo. IPA levels were significantly reduced in patients with HFpEF in 2 independent human cohorts, consistent with a protective function in humans, as well as mice. CONCLUSIONS: Our findings reveal that IPA protects against diastolic dysfunction in HFpEF by enhancing the nicotinamide adenine dinucleotide salvage pathway, suggesting the possibility of therapeutic management by either altering the gut microbiome composition or supplementing the diet with IPA.

Targeting STAT3 in tumor-associated antigen-presenting cells as a strategy for kidney and bladder cancer immunotherapy.

Introduction: Immune checkpoint blockade (ICB) improved clinical outcomes in renal and bladder cancer patients, but the response rates remain limited especially in metastatic disease. While STAT3 transcription factor is well-known master regulator of tumor immune evasion, little is known about the role of STAT3 in the resistance of renal or bladder cancers to immunotherapy. Methods: To better understand immune alterations associated with ICB resistance, we assessed blood biomarkers in renal cancer patients classified as responders or non-responders to first line nivolumab/ipilimumab immunotherapy. Results: We observed that non-responders showed elevated levels of proinflammatory mediators, such as IL-1RA, IL-6, IL-8 and to lesser extent IL-10, which are associated with STAT3 activation and tumor immunosuppression. In addition, we found STAT3 activation primarily in circulating myeloid immune cells such as tolerogenic MDSCs. To assess whether STAT3 inhibition within these cell subsets can promote antitumor immune responses and/or enhance sensitivity to ICB in vivo, we used an original antisense oligonucleotide (ASO) strategy for myeloid-cell selective STAT3 knockdown (CpG-STAT3ASO). Our results in syngeneic models of renal and bladder cancers in mice demonstrated potent antitumor activity of CpG-STAT3ASO alone in contrast to PD1 blockade alone in both models. The CpG-STAT3ASO/anti-PD1 combination improved therapeutic efficacy especially against bladder tumors. Therapeutic efficacy correlated with activation of dendritic cells (DCs) and M1 macrophages in the tumor microenvironment, reduced percentages of regulatory T cells (Tregs) and the expansion of CD8 T cells in both tumor models. Discussion/Conclusion: Our study underscores the potential of using myeloid-cell targeted CpG-STAT3 inhibitors for genitourinary cancer therapy to disrupt tolerogenic signaling, restore immune cell activity and sensitivity to immune checkpoint inhibitors and/or T cell-based immunotherapies.

Serum sodium and eplerenone use in patients with a myocardial infarction and left ventricular dysfunction or heart failure: insights from the EPHESUS trial.

BACKGROUND: Sodium changes are common in myocardial infarction (MI) complicated with left ventricular systolic dysfunction (LVSD) and/or heart failure (HF). Sodium handling is fine-tuned in the distal nephron, were eplerenone exhibits some of its pleotropic effects. Little is known about the effect of eplerenone on serum sodium and the prognostic relevance of sodium alterations in patients with MI complicated with LVSD and/or HF. METHODS: The EPHESUS trial randomized 6632 patients to either eplerenone or placebo. Hyponatremia and hypernatremia were defined as sodium < 135 mmol/L or > 145 mmol/L, respectively. Linear mixed models and time updated Cox regression analysis were used to determine the effect of eplerenone on sodium changes and the prognostic importance of sodium changes, respectively. The primary outcomes were all-cause mortality and a composite of cardiovascular (CV) mortality and CV-hospitalization. RESULTS: A total of 6221 patients had a post-baseline sodium measurement, 797 patients developed hyponatremia (mean of 0.2 events/per patient) and 1476 developed hypernatremia (mean of 0.4 events/per patient). Patients assigned to eplerenone had a lower mean serum sodium over the follow-up (140 vs 141 mmol/L; p < 0.0001) and more often developed hyponatremia episodes (15 vs 11% p = 0.0001) and less often hypernatremia episodes (22 vs. 26% p = 0.0003). Hyponatremia, but not hypernatremia was associated with adverse outcome for all outcome endpoints in the placebo group but not in the eplerenone group (interaction p value < 0.05 for all). Baseline sodium values did not influence the treatment effect of eplerenone in reducing the various endpoints (interaction p value > 0.05 for all). Development of new-onset hyponatremia following eplerenone initiation did not diminish the beneficial eplerenone treatment effect. CONCLUSION: Eplerenone induces minor reductions in serum sodium. The beneficial effect of eplerenone was maintained regardless of the baseline serum sodium or the development of hyponatremia. Sodium alterations should not refrain clinicians from prescribing eplerenone to patients who had an MI complicated with LVSD and/or HF. TRAIL REGISTRY: ClinicalTrials.gov identifier: NCT00232180. Serum sodium and eplerenone use in patients with a myocardial infarction and left ventricular dysfunction or heart failure: insights from the EPHESUS trial.

Non-pharmaceutical interventions and covid-19 burden in the United States: retrospective, observational cohort study.

Objective: To evaluate the adoption and discontinuation of four broadly used non-pharmaceutical interventions on shifts in the covid-19 burden among US states. Design: Retrospective, observational cohort study. Setting: US state data on covid-19 between 19 January 2020 and 7 March 2021. Participants: US population with a diagnosis of covid-19. Main outcome measures: Empirically derived breakpoints in case and mortality velocities (ie, rate of change) were used to identify periods of stable, decreasing, or increasing covid-19 burden. Associations between adoption of non-pharmaceutical interventions and subsequent decreases in case or death rates were estimated by use of generalised linear models accounting for weekly variability across US states. State level case and mortality counts per day were obtained from the Covid-19 Tracking Project. State level policies on non-pharmaceutical interventions included stay-at-home orders, indoor public gathering bans (mild >10 or severe ≤10 people), indoor restaurant dining bans, and public mask mandates. National policies were not included in statistical models. Results: 28 602 830 cases and 511 899 deaths were recorded during the study. Odds of a reduction in covid-19 case velocity increased for stay-at-home orders (odds ratio 2.02, 95% confidence interval 1.63 to 2.52), indoor dining bans (1.62, 1.25 to 2.10), public mask mandates (2.18, 1.47 to 3.23), and severe indoor public gathering bans (1.68, 1.31 to 2.16) in univariate analysis. In mutually adjusted models, odds remained elevated for orders to stay at home (adjusted odds ratio 1.47, 95% confidence interval 1.04 to 2.07) and public mask mandates (2.27, 1.51 to 3.41). Stay-at-home orders (odds ratio 2.00, 95% confidence interval 1.53 to 2.62; adjusted odds ratio 1.89, 95% confidence interval 1.25 to 2.87) was also associated with a greater likelihood of decrease in death velocity in unadjusted and adjusted models. Conclusions: State level non-pharmaceutical interventions used in the US during the covid-19 pandemic, in particular stay-at-home orders, were associated with a decreased covid-19 burden.

The Effects of Storytelling With or Without Social Contextual Information Regarding Eye Gaze and Visual Attention in Children with Autistic Spectrum Disorder and Typical Development: A Randomized, Controlled Eye-Tracking Study.

This study examined the effects of storytelling with or without contextual information on children with autism spectrum disorder (ASD) and typical development (TD) using eye-tracker. They were randomized into two groups-the stories included and did not include social contextual information respectively. Training was delivered in groups, with eight sessions across four weeks, 30 min/session. Participants' fixation duration, visit duration, and fixation count on human faces from 20 photos and a video were recorded. Our findings revealed that storytelling with social contextual information enhanced participants' eye gazes on eyes/ faces in static information (photos) for both children with ASD and TD, but the same advantage could not be seen for children with ASD in regard to dynamic information (videos).Clinical Trial Registration Number (URL: http://www.clinicaltrials.gov ): NCT04587557.

Non-Pharmaceutical Interventions and COVID-19 Burden in the United States.

BACKGROUND: Non-pharmaceutical interventions (NPIs) are mitigation strategies used to reduce the spread of transmissible diseases. The relative effectiveness of specific NPIs remains uncertain. METHODS: We used state-level Coronavirus disease 2019 (COVID-19) case and mortality data between January 19, 2020 and March 7, 2021 to model NPI policy effectiveness. Empirically derived breakpoints in case and mortality velocities were used to identify periods of stable, decreasing, or increasing COVID-19 burden. The associations between NPI adoption and subsequent decreases in case or death velocities were estimated using generalized linear models accounting for weekly variability shared across states. State-level NPI policies included: stay at home order, indoor public gathering ban (mild >10 or severe ≤10), indoor restaurant dining ban, and public mask mandate. RESULTS: 28,602,830 cases and 511,899 deaths were recorded. The odds of a decrease in COVID-19 case velocity were significantly elevated for stay at home (OR 2.02, 95% CI 1.63-2.52), indoor dining ban (OR 1.62, 95% CI 1.25-2.10), public mask mandate (OR 2.18, 95% CI 1.47-3.23), and severe gathering ban (OR 1.68, 95% CI 1.31-2.16). In mutually adjusted models, odds remained elevated for stay at home (AOR 1.47, 95% CI 1.04-2.07) and public mask mandate (AOR = 2.27, 95% CI 1.51-3.41). Stay at home (OR 2.00, 95% CI 1.53-2.62; AOR 1.89, 95% CI 1.25-2.87) was also associated with greater likelihood of decrease in death velocity in unadjusted and adjusted models. CONCLUSIONS: NPIs employed in the U.S. during the COVID-19 pandemic, most significantly stay at home orders, were associated with decreased COVID-19 burden.

Burden and Unmet Needs with Portable Oxygen in Patients on Long-Term Oxygen Therapy.

Rationale: Over 1.5 million Americans receive long-term oxygen therapy (LTOT) for the treatment of chronic hypoxemia to optimize functional status and quality of life. However, current portable oxygen equipment, including portable gas tanks (GTs), portable liquid tanks (LTs), and portable oxygen concentrators (POCs), each have limitations that can hinder patient mobility and daily activities. Objectives: To examine patient experiences with portable oxygen to guide equipment innovation and thereby improve patient care on oxygen therapy. Methods: The burden and unmet needs with portable oxygen equipment were assessed in 836 LTOT patients with chronic lung disease (chronic obstructive pulmonary disease [COPD], interstitial lung disease, and pulmonary hypertension) through an online survey. The survey included a combination of multiple-choice, Likert-scale, short-answer, and open-ended questions. Distribution was achieved through patient support organizations, including the U.S. COPD Coalition, the Pulmonary Fibrosis Foundation, and the Pulmonary Hypertension Association. Results: Improvements in portability were ranked as the highest priority by patients across all equipment types, followed by increases in the duration of oxygen supply for GTs, accessibility for LTs, and flow capabilities for POCs. All device types were found to be burdensome, with the greatest burden among GT users, 51% of whom characterized GT use as "strenuous" or "extremely strenuous" (high burden). POCs ranked as the most common (61%) and least burdensome devices; however, 29% of POC users still reported a high associated burden. Forty-seven percent of POC respondents described using a POC despite it not meeting their oxygen needs to benefit from advantages over alternative equipment. Among non-POC users, limited oxygen flow rate capabilities and cost were the top reasons preventing POC use. Conclusions: Although improvements have been made to portable oxygen equipment, this study highlights the burden that remains and reveals a clear need for advances in technology to improve the functional status and quality of life of portable LTOT users.

Dynamic Assessment of Pulmonary Artery Pulsatility Index Provides Incremental Risk Assessment for Early Right Ventricular Failure After Left Ventricular Assist Device.

BACKGROUND: The pulmonary artery pulsatility index (PAPi) has been studied to predict right ventricular failure (RVF) after left ventricular assist device (LVAD) implantation, but only as a single time point before LVAD implantation. Multiple clinical factors and therapies impact RV function in pre-LVAD patients. Thus, we hypothesized that serial PAPi measurements during cardiac intensive care unit (CICU) optimization before LVAD implantation would provide incremental risk stratification for early RVF after LVAD implantation. METHODS AND RESULTS: Consecutive patients who underwent sequential pulmonary artery catherization with cardiac intensive care optimization before durable LVAD implantation were included. Serial hemodynamics were reviewed retrospectively across the optimization period. The optimal PAPi was defined by the initial PAPi + the PAPi at optimized hemodynamics. RVF was defined as need for a right ventricular assist device or prolonged inotrope use (>14 days postoperatively). Patients with early RVF had significantly lower mean optimal PAPi (3.5 vs 7.5, P < .001) compared with those who did not develop RVF. After adjusting for established risk factors of early RVF after LVAD implantation, the optimal PAPi was independently and incrementally associated with early RVF after LVAD implantation (odds ratio 0.64, 95% confidence interval 0.532-0.765, P < .0001). CONCLUSIONS: Optimal PAPi achieved during medical optimization before LVAD implantation provides independent and incremental risk stratification for early RVF, likely identifying dynamic RV reserve.

Coronary artery disease in the young in the US population-based cohort.

BACKGROUND: Although most prevalent in the elderly, coronary artery disease (CAD) also affects younger adults. However, CAD in young adults is not as well characterized. OBJECTIVE: To explore factors associated with CAD in young patients. METHODS: We investigated the prevalence and baseline characteristics of young patients with CAD using the National Health and Nutrition Examination Survey (NHANES) survey between 1999 and 2016. The primary outcome was a reported history of CAD at age <55 years old, defined based on the subject's response to survey questions 'Have you ever been told by a physician that you had coronary artery disease?' and 'How old were you when were told you had coronary heart disease?'. Multivariable logistic regression models were used to assess factors associated with CAD in young patients. RESULTS: Of 42,038 NHANES participants, 707 (1.7%) reported CAD at young age. Young patients with CAD were more likely to be male, non-whites, cigarette smokers, recreational drug users, had a family history of CAD, compared to young patients without CAD (all p-values <0.05). In multivariable logistic regression models, diabetes (OR: 3.94; 95% CI: 1.32-11.8; P=0.01), cigarette smoking (OR: 2.86; 95% CI: 1.52-5.53; P=0.001), alcohol consumption (OR: 1.17; 95% CI: 1.04-1.35; P=0.01) and cocaine use (OR: 4.48; 95% CI: 1.33-15.1; P=0.01) were independently associated with CAD in young patients. CONCLUSION: CAD in young patients may be influenced by lifestyle factors such as alcohol consumption or cocaine use, as well as conventional risk factors such as smoking or diabetes.

Predictors of In-Hospital Mortality after Transcatheter Aortic Valve Implantation.

The development of aortic valve stenosis is strongly associated with older adults. Patients who undergo transcatheter aortic valve implantation (TAVI) for severe aortic stenosis frequently have heart failure (HF). We investigated the predictors of mortality after TAVI according to the presence of HF, and specifically HF with preserved ejection fraction (HFpEF) versus HF with reduced ejection fraction (HFrEF). Patients were identified from the Nationwide Inpatient Sample registry from January 2011 to September 2015 using the ICD-9 codes. Patients with HF who underwent TAVI were classified according to whether they were diagnosed with HFrEF or HFpEF. The principal outcome of interest was in-hospital mortality. Multivariable analysis was used to adjust for potential baseline confounders. Among 11,609 patients undergoing TAVI, 6,368 (54.9%) had baseline HF, including 4,290 (67.4%) with HFpEF and 2,078 (32.6%) with HFrEF. In TAVI patients with HF, in-hospital mortality was also not significantly different in those with HFrEF compared with HFpEF (3.66% vs 3.17%, respectively; adjusted odds ratio 1.14, 95% confidence interval 0.84 to 1.53; p = 0.38). Polyvalvular heart disease was an additional independent predictor of in-hospital mortality in HFrEF, whereas age, liver disease, and the absence of depression and anemia were additional independent predictors of mortality in HFpEF. In conclusion, baseline HF in patients undergoing TAVI is prevalent and is more commonly due to HFpEF than HFrEF. Mortality is similar in those with HFrEF and HFpEF. Knowledge of the specific predictors of mortality after TAVI in HF patients may be useful for patient selection and prognostic guidance.

Advances in MRI Applications to Diagnose and Manage Cardiomyopathies.

PURPOSE OF REVIEW: The prevalence of heart failure continues to rise, and imaging characterization of the cardiomyopathic process is important for identifying myocardial disease, initiating appropriate treatment, and improving outcomes. We aimed to summarize recent advances in cardiac magnetic resonance imaging (CMR) applications for the diagnosis, characterization, and implications on management of various cardiomyopathies. RECENT FINDINGS: Parametric mapping by CMR has emerged as an important advancement in quantification of myocardial fibrosis, increased extracellular space, and myocardial edema. In addition, improved assessment of myocardial function with myocardial strain assessment may provide early identification of patients at risk and determining responsiveness to therapeutic interventions. Novel MRI techniques and the advent of artificial intelligence may help to uncover important mechanistic insights into the cardiomyopathic process. Innovative CMR techniques continue to evolve, and it will be of interest to determine how these advances can be incorporated into clinical practice to improve diagnosis, treatment, and management of patients with cardiomyopathies.

Is Time of the Essence? The Impact of Time of Hospital Presentation in Acute Heart Failure: Insights From ASCEND-HF Trial.

OBJECTIVES: As the largest acute heart failure (AHF) trial conducted to date, the global ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) trial database presented an opportunity to systematically describe the relationship among time of hospital presentation, clinical profile, inpatient management, and outcomes among patients admitted with AHF. BACKGROUND: Time of hospital presentation has been shown to impact outcomes among patients hospitalized with many conditions. However, the association among time of presentation and patient characteristics, management, and clinical outcomes among patients hospitalized with AHF has not been well characterized. METHODS: A post hoc analysis of the ASCEND-HF trial was performed, which enrolled 7,141 patients hospitalized for AHF. Patients were divided based on when they presented to the hospital; regular hours were defined as 9 am to 5 pm, Monday through Friday, and off hours were defined as 5 pm to 9 am, Monday through Friday and weekends. Clinical characteristics and outcomes were compared by time of presentation. RESULTS: Overall, 3,298 patients (46%) presented during off hours. Off-hour patients were more likely to have orthopnea (80% vs. 74%, respectively) and rales (56% vs. 49%, respectively) than regular-hour patients. Off-hour patients were more likely to receive intravenous (IV) nitroglycerin (18% vs. 11%, respectively) and IV loop diuretics (92% vs. 86%, respectively) as initial therapy and reported greater relief from dyspnea at 24 h (odds ratio [OR]: 1.14; 95% confidence interval [CI]: 1.04 to 1.24; p = 0.01) than regular-hour patients. After adjustment, off-hour presentation was associated with significantly lower 30-day mortality (OR: 0.74; 95% CI: 0.57 to 0.96; p = 0.03) and 180-day mortality (hazard ratio [HR]: 0.82; 95% CI: 0.72 to 0.94; p = 0.01) but similar 30-day rehospitalization rates (p = 0.40). CONCLUSIONS: In this AHF trial, patients admitted during off hours exhibited a distinct clinical profile, experienced greater dyspnea relief, and had lower post-discharge mortality than regular-hour patients. These findings have implications for future AHF trials.

Next-generation mapping: a novel approach for detection of pathogenic structural variants with a potential utility in clinical diagnosis.

BACKGROUND: Massively parallel DNA sequencing, such as exome sequencing, has become a routine clinical procedure to identify pathogenic variants responsible for a patient's phenotype. Exome sequencing has the capability of reliably identifying inherited and de novo single-nucleotide variants, small insertions, and deletions. However, due to the use of 100-300-bp fragment reads, this platform is not well powered to sensitively identify moderate to large structural variants (SV), such as insertions, deletions, inversions, and translocations. METHODS: To overcome these limitations, we used next-generation mapping (NGM) to image high molecular weight double-stranded DNA molecules (megabase size) with fluorescent tags in nanochannel arrays for de novo genome assembly. We investigated the capacity of this NGM platform to identify pathogenic SV in a series of patients diagnosed with Duchenne muscular dystrophy (DMD), due to large deletions, insertion, and inversion involving the DMD gene. RESULTS: We identified deletion, duplication, and inversion breakpoints within DMD. The sizes of deletions were in the range of 45-250 Kbp, whereas the one identified insertion was approximately 13 Kbp in size. This method refined the location of the break points within introns for cases with deletions compared to current polymerase chain reaction (PCR)-based clinical techniques. Heterozygous SV were detected in the known carrier mothers of the DMD patients, demonstrating the ability of the method to ascertain carrier status for large SV. The method was also able to identify a 5.1-Mbp inversion involving the DMD gene, previously identified by RNA sequencing. CONCLUSIONS: We showed the ability of NGM technology to detect pathogenic structural variants otherwise missed by PCR-based techniques or chromosomal microarrays. NGM is poised to become a new tool in the clinical genetic diagnostic strategy and research due to its ability to sensitively identify large genomic variations.

Incremental benefit of cardiac resynchronisation therapy with versus without a defibrillator.

OBJECTIVE: To determine the incremental value of implantable cardioverter defibrillators (ICD) in contemporary optimally treated patients with heart failure (HF) undergoing cardiac resynchronisation therapy (CRT). METHODS: Consecutive patients with HF undergoing CRT-pacemaker (CRT-P) or CRT-defibrillator (CRT-D) implantation in a single tertiary care centre between October 2008 and August 2015 were retrospectively evaluated. For patients with a primary prevention indication of the CRT-D, no benefit of the ICD was defined as absence of appropriate therapy (device analysis) or lethal ventricular tachyarrhythmias (mode of death analysis) during follow-up. RESULTS: 687 patients (CRT-P/CRT-D; n=361/326) were followed for 38±22 months. CRT-P recipients were older (75.7±9.1 vs 71.8±9.3 years; p<0.001) and had a higher comorbidity burden. Five patients with CRT-P (1%) experienced episodes of sustained ventricular-tachycardia vs 64 (20%) patients with CRT-D (p<0.001). Remote tele-monitoring detected the episodes of sustained ventricular tachycardia in four patients with CRT-P, allowing for elective upgrade to CRT-D. All-cause mortality was higher in patients with CRT-P versus CRT-D (21% vs 12%, p=0.003), even after adjusting for baseline characteristics (HR 2.5; 95% CI 1.36 to 4.60; p=0.003). However, mode of death analysis revealed a predominant non-cardiac mode of death in CRT-P recipients (n=47 (71%) vs n=13 (38%) in CRT-D, p=0.002). Multivariate analysis revealed that age >80 years, New York Heart Association class IV, intolerance to beta-blockers and underlying non-ischaemic cardiomyopathy were independently associated with little incremental value of a primary prevention ICD on top of CRT. CONCLUSIONS: The majority of patients with contemporary HF as currently selected for CRT-P exhibit mainly non-cardiac-driven mortality. Weighing risk of ventricular-tachyarrhythmic death versus risk of all-cause mortality helps to address the incremental value of an ICD to CRT-P.