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AIMS: Although acute heart failure (AHF) with volume overload is treated with loop diuretics, their dosing and type of administration are mainly based upon expert opinion. A recent position paper from the Heart Failure Association (HFA) proposed a step-wise pharmacologic diuretic strategy to increase the diuretic response and to achieve rapid decongestion. However, no study has evaluated this protocol prospectively. METHODS AND RESULTS: The Efficacy of a Standardized Diuretic Protocol in Acute Heart Failure (ENACT-HF) study is an international, multicentre, non-randomized, open-label, pragmatic study in AHF patients on chronic loop diuretic therapy, admitted to the hospital for intravenous loop diuretic therapy, aiming to enrol 500 patients. Inclusion criteria are as follows: at least one sign of volume overload (oedema, ascites, or pleural effusion), use=40mg of furosemide or equivalent for >1month, and a BNP>250ng/L or an N-terminal pro-B-type natriuretic peptide>1000pg/L. The study is designed in two sequential phases. During Phase 1, all centres will treat consecutive patients according to the local standard of care. In the Phase 2 of the study, all centres will implement a standardized diuretic protocol in the next cohort of consecutive patients. The protocol is based upon the recently published HFA algorithm on diuretic use and starts with intravenous administration of two times the oral home dose. It includes early assessment of diuretic response with a spot urinary sodium measurement after 2h and urine output after 6h. Diuretics will be tailored further based upon these measurements. The study is powered for its primary endpoint of natriuresis after 1day and will be able to detect a 15% difference with 80% power. Secondary endpoints are natriuresis and diuresis after 2days, change in congestion score, change in weight, in-hospital mortality, and length of hospitalization. CONCLUSIONS: The ENACT-HF study will investigate whether a step-wise diuretic approach, based upon early assessment of urinary sodium and urine output as proposed by the HFA, is feasible and able to improve decongestion in AHF with volume overload.

Objectives Palliative care (PC) has gained rising attention in a holistic treatment approach to chronic heart failure (HF). It is unclear whether there is a need for PC in left ventricular assist device (LVAD) patients or heart transplant recipients. Methods In a cross-sectional explorative pilot study, outpatients after heart transplantation (HTx, n = 69) or LVAD implantation (n = 21) underwent screening for palliative care (PC) need and evaluation of symptom burden and psychological distress using tools that emanated from palliative cancer care. Results The ‘Palliative Care Screening Tool for Heart Failure Patients’ revealed scores of 4.3 ± 2.2 in HTx and 6.0 ± 2.1 in LVAD patients (max. 12 points, P = 0.003), indicating the need for PC (≥5 points) in 32% of HTx and 67% of LVAD patients. Symptom burden, as assessed by MIDOS (‘Minimal Documentation System for Palliative Care’) scores was substantial in both groups (4.9 ± 4.7 in HTx vs 6.6 ± 5.3 in LVAD, max. 30 points, P = 0.181). ‘Fatigue’, ‘weakness’ and ‘pain’ were the most frequent symptoms. Using the ‘Distress-Thermometer’, ‘clinically relevant’ distress was detected in 57% of HTx and 47% of LVAD patients (P = 0.445). In the PHQ-4 (‘4-Item Patient Health Questionnaire’), 45% of LVAD patients, compared to only 10% of HTx patients, reported mild symptoms of anxiety and depression. Conclusions Findings reveal substantial need for PC in LVAD patients and, to a lesser extent, in heart transplant recipients, suggesting that multi-disciplinary PC should be introduced into routine aftercare.

ZusammenfassungDer echokardiografische Befund der linksventrikulären Hypertrophie impliziert im klinischen Alltag mehrere wichtige Differenzialdiagnosen. Häufig wird die linksventrikuläre Hypertrophie als Befund in einer sogenannten Routine-Echokardiografie erhoben. Für den Kliniker ist jedoch die zugrunde liegende Ursache für die linksventrikuläre Wandverdickung von entscheidender Bedeutung, um die weitere Diagnostik oder Behandlung zu planen. Der folgende Übersichtsartikel legt den Fokus auf physiologische und pathophysiologische Ursachen der linksventrikulären Wandverdickung. Eine physiologische Hypertrophie wird vor allem bei Sportlern beobachtet und als Sportlerherz charakterisiert, eine pathologische linksventrikuläre Wandverdickung liegt z. B. bei der hypertrophen Kardiomyopathie und bei der Amyloidose oder einer Ödembildung vor.

Background: Diastolic dysfunction (DD) might help to risk stratify patients with heart failure (HF) with reduced ejection fraction (HFrEF). Nonetheless, HF guidelines/risk scores don't consider DD. We aimed to show the independent prognostic value of DD for nonfatal HF/death in patients with HFrEF on top of natriuretic peptides (NP). Methods: We analyzed 1155 baseline echocardiograms of the MADIT-CRT study (LVEF≤30%, QRS ≥ 130 ms, NYHA class I/II), classifying DD according to 2016 ASE/EACVI classification. Results: Patients were 64 ± 11 years-old, 24% females, LVEF was 24 ± 5%, 58% had abnormal BNP (≥100 pg/ml). While 45% had impaired relaxation, 33% had pseudonormal filling, 12% restrictive pattern, 6% indeterminate diastolic function, 4% were not classifiable due to missing data. During a follow-up of 2.1 ± 1.0 years, there were 233 HF/death. Compared to patients without pseudonormal/restrictive filling and with normal NP (23%), patients with pseudonormal/restrictive filling, alone (15%) or combined to elevated NP (30%), were at higher risk of events (respectively padj = 0.025 and padj < 0.001), as opposed to those with abnormal NP alone (22%; padj = 0.55). Adding DD to conventional markers of risk and NP improved prediction (C-statistic 0.733 versus 0.708, p = 0.024). DD was the first parameter to be considered to risk stratify MADIT-CRT population, according to Classification-And-Regression-Tree analysis. Conclusions: Among HFrEF patients with mild symptoms, pseudonormal/restrictive filling, either alone or combined with elevated NP, was associated with high risk of events, as opposed to isolated elevation of NP. DD provided incremental risk prediction for death/HF beyond commonly used markers. These data might suggest to integrate DD into HF guidelines/risk scores.

Background The aim of the present study was to compare clinical characteristics and cardiac structure and function in competitive triathletes with and without myocardial fibrosis. Methods Cardiac fibrosis in 61 healthy male competitive triathletes (>10 hrs of training per week, age 45±10 yrs) was quantified using LGE-sequences in CMR (1.5 tesla scanner). Transthoracic echocardiography, physical examination, past medical history and routine lab diagnosis for exclusion of other conditions were performed. Baseline characteristics like blood pressure at rest (BP), bodymass-index (BMI), and systolic and diastolic echocardiographic parameters (left atrial volume index (LAVI), e', E, A, right ventricular pressure gradient) as well as global longitudinal strain, were analysed by two independent observers blinded to the CMR measurements. Triathletes were sub-divided into LGE-positives (LGE+) vs. LGE-negatives (LGE-). Results All individuals appeared healthy with no drug history. Focal non-ischaemic LGE was detected in 19 triathletes. Compared to LGE-negative triathletes, LGE-positives showed significantly higher systolic BP (142 vs. 128 mmHg, p=0.004). Logistic regression showed, that per 10 mmHg enhanced blood pressure the chance for LGE rises by 89%. Triathletes with and without LGE demonstrated no difference in conventional echocardiographic measurements such as left ventricular ejection fraction and volumes and no difference in diastolic parameters. But the presence of MF did mediate global longitudinal strain (GLS). Global longitudinal strain was significantly reduced in LGE positive athletes (LGE+: −19.8±3.4; LGE-: −21.7±2.4, p=0.04) Conclusions Reduced global longitudinal strain mediated as an early echocardiographic marker for subclinical changes in asymptomatic competitive triathletes with myocardial fibrosis compared to triathletes without LGE. Novel echocardiographic parameter such as longitudinal strain might serve as an easy tool to identify high endurance athletes at higher risk for cardiovascular events and that individuals with enhanced blood pressure should undergo cardiac consultation before starting endurance-training in competitive disciplines. Funding Acknowledgement Type of funding source: None

Cardiac allograft vasculopathy (CAV) remains a major long-term complication in heart transplant (HT) recipients related to increased mortality. We aimed to identify non-immune recipient- and donor-related risk factors for the development of CAV in HT patients.40,647 recipients, prospectively enrolled from April 1995 to January 2019 in the Organ Procurement and Transplantation Network (OPTN), were analyzed after exclusion of pediatric patients, those with missing information on CAV, and re-transplantation. Multivariable-adjusted Cox regression analyses were performed to identify recipient- and donor-related risk factors for CAV. 5-year population attributable risk for classical cardiovascular risk factors was calculated to estimate the recipients' CAV risk. Analyses were based on OPTN data (June 30, 2019).Of 40,647 post-transplant patients, 14,698 (36.2%) developed CAV with a higher incidence in males (37.3%) than in females (32.6%) (p0.001). The mean follow-up time was 68.2 months. In recipients, male sex, African American and Asian ethnicity, ischemic cardiomyopathy, body mass index and smoking were associated with CAV occurrence. In donors, older age, male sex, smoking, diabetes and arterial hypertension were related to CAV. Results remained fairly stable after analysis of different time periods. 5-year attributable CAV risk for classical cardiovascular risk factors was 9.1%.In this large registry with known limitations concerning data completeness, CAV incidence was higher in males than in females. Next to male sex and donor age, the classical cardiovascular risk factors were related to incident CAV. Classical cardiovascular risk factors played only a minor role for the 5-year attributable CAV risk.

BACKGROUND: The therapeutic success in patients with congenital heart disease (CHD) leads to a growing number of adults with CHD (adult CHD [ACHD]) who develop end-stage heart failure. We aimed to determine patient characteristics and outcomes of ACHD listed for heart transplantation. METHODS: Using data from all the patients with ACHD in 20 transplant centers in the Eurotransplant region from 1999 to 2015, we analyzed patient characteristics, waiting list, and post-transplantation outcomes. RESULTS: A total of 204 patients with ACHD were listed during the study period. The median age was 38 years, and 62.3% of the patients were listed in high urgency (HU), and 37.7% of the patients were in transplantable (T)-listing status. A total of 23.5% of the patients died or were delisted owing to clinical worsening, and 75% of the patients underwent transplantation. Median waiting time for patients with HU-listing status was 4.18 months and with T-listing status 9.07 months. There was no difference in crude mortality or delisting between patients who were HU status listed and T status listed (p = 0.65). In multivariable regression analysis, markers for respiratory failure (mechanical ventilation, hazard ratio [HR]: 1.41, 95% CI: 1.11-1.81, p = 0.006) and arrhythmias (anti-arrhythmic medication, HR: 1.42, 95% CI: 1.01-2.01, p = 0.044) were associated with a higher risk of death or delisting. In the overall cohort, post-transplantation mortality was 26.8% after 1 year and 33.4% after 5 years. CONCLUSIONS: Listed patients are at high risk of death without differences in the urgency of listing. Respiratory failure requiring invasive ventilation and possibly arrhythmias requiring anti-arrhythmic medication indicate worse outcomes on waiting list. (C) 2020 International Society for Heart and Lung Transplantation. All rights reserved.

We report a family with heterozygous deletion of exons 3–6 of the LMNA gene. The main presentation of affected family members was characterized by ventricular and supraventricular arrhythmias, atrioventricular (AV) block and sudden cardiac death (SCD) but also by severe dilative cardiomyopathy (DCM). We report on two siblings, a 36-year-old female and her 40-year-old brother, who suffer from heart failure with mildly reduced ejection fraction, AV conduction delays and premature ventricular complexes. Their 65-year-old mother underwent heart transplantation at the age of 55 due to advanced heart failure. Originally, the LMNA mutation was detected in one of the uncles. This index patient and three of his brothers died of SCD as well as their father and aunt. The two siblings were treated with implanted defibrillators in our specialized tertiary heart failure center. This case report places this specific genetic variant in the context of LMNA-associated familial DCM.

Despite the increasing use of ventricular assist devices (VADs), gender differences in indications, hemodynamics, and outcome are not well understood. We examined gender differences and gender-specific predictors for perioperative outcome in patients on ventricular support.Multicenter data of 966 patients (median age 55 years, 151 women) from the European Registry for Patients with Mechanical Circulatory Support (EUROMACS) were analyzed. Median follow-up was 1.26 years.At the time of VAD implantation, women were more often in an unstable condition (Interagency Registry for Mechanically Assisted Circulatory Support [INTERMACS] profile 1 and 2) (51.7% vs 41.6% in men), experiencing significantly more often major bleeding (p = 0.0012), arrhythmias (p = 0.022), and right ventricular (RV) failure (p0.001) with need for additional RV support. The survival of women on isolated LVAD support was significantly worse (1-year survival 75.5% vs 83.2% in men). Age-adjusted Cox regression analyses showed significant associations with mortality for preoperative inotropic therapy, percutaneous mechanical support, INTERMACS profile 1 and 2, RV dysfunction, major bleeding, cerebral bleeding, ischemic stroke, and RV failure. In women, pump thrombosis was more strongly related with mortality compared to men, while the direction of the association of renal dysfunction with mortality was different for women and men (p-value interaction 0.028 and 0.023, respectively).Women and men differ in perioperative hemodynamics, adverse events, and mortality after VAD implantation. A gender-dependent association of pump thrombosis with mortality was seen. The impact on treatment practice needs to be shown.

Background: Right ventricular dysfunction is a major determinant of outcome in pulmonary arterial hypertension (PAH). We aimed to identify echocardiographic right heart parameters associated with adverse outcome and to develop a non-invasive, echocardiography-based risk score for PAH patients. Methods and Results: In 254 PAH patients we analyzed functional status, laboratory results, and echocardiographic parameters. We included these parameters to estimate all-cause death or lung transplantation using Cox regression models. The analyses included a conventional model using guideline-recommended variables and an extended echocardiographic model. Based on the final model a 12-point risk score was derived, indicating the association with the primary outcome within five years. During a median follow-up time of 4.2 years 74 patients died or underwent lung transplantation. The conventional model resulted in a C-Index of 0.539, whereas the extended echocardiographic model improved the discrimination (C-index 0.639, p-value 0.017). Ultimately, the newly developed risk score included WHO functional class, 6-min walking distance, N-terminal brain natriuretic peptide concentrations, pericardial effusion, right atrial area, tricuspid annular plane systolic excursion, and fractional area change. Conclusion: Integrating right heart function assessed by echocardiography improves prediction of death or lung transplantation in PAH patients. Independent validation of this finding is warranted.

Background Myocardial fibrosis is an occasional finding in asymptomatic athletes. Purpose Evaluation of clinical conditions with possible impact on cardiac fibrosis in competitive triathletes. Methods Cardiac fibrosis in 61 male competitive triathletes (>10 hrs of training per week, mean 45 yrs) and 19 controls (mean 38 yrs), was quantified using late gadolinium enhancement (LGE) in cardiac magnet-resonance imaging (CMR). Physical examination, past medical history, and routine lab diagnosis were performed and baseline characteristics like blood pressure at rest (BP), body mass index (BMI), and echocardiographic parameters were measured. Triathletes were sub-divided into LGE positives vs. negatives. Results All individuals appeared healthy with no drug history of note and a normal cardiac function according to echocardiography. Focal non-ischaemic LGE was detected in 18 triathletes (5.2±4.5 g; 3.5±2.8 g/m2) and none of the controls. Compared to LGE negative triathletes, LGE positives showed significantly higher systolic BP and BMI (see Table). 67% of the LGE positives and only 14% of the LGE negative athletes showed first degree arterial hypertension and 56% of the LGE positives vs. 21% of the LGE negatives were formally overweight (BMI≥25 kg/m2). Controls had smaller left atrial volume indices than the triathletes, in line with characteristics of the athlete's heart. The triathletes were older than the controls (see Table below), but had a normal diastolic function. 38% of the controls and 31% of all triathletes were overweight. Equally to the LGE negatives, 14% of the controls were hypertensive. Clinical parameters Athletes LGE+ LGE− Controls p-value (athletes vs. controls) p-value (LGE+ vs. LGE−) p-value (LGE− vs. controls) n 61 18 43 19 Age (yrs) 44.6±9.80 48.2±9.04 42.2±9.96 38.4±11.12 0.0371* 0.1222 0.0016* BMI (kg/m2) 24.1±2.57 25.3±2.75 23.8±2.4 24.5±2.74 0.2564 0.0315* 0.1228 Sys. BP (mmHg) 132±15.80 144±17.52 128±12.99 124±15.93 0.0145* 0.0020* 0.2426 LAVI (ml/m2) 29.13±6.79 31.45±8.02 26.68±6.26 24.25±5.48 0.0014* 0.4389 0.0053* All values shown as mean values with standard deviation, if not otherwise indicated, BMI = body mass index, LAVI = left atrial volume index, athletes = all triathletes; LGE+ = triathletes with cardiac LGE visualised by CMR, LGE− = triathletes without LGE in CMR. *Significant p-value, vs. = versus, Sys. BP = systolic blood pressure. Conclusion In competitive triathletes, there is a significant correlation between cardiac fibrosis and arterial hypertension at rest as well as overweight. We therefore recommend, that individuals with these characteristics should undergo cardiac consultation before starting endurance-training in competitive disciplines.

AIMS: We tested the hypothesis that a machine learning (ML) algorithm utilizing both complex echocardiographic data and clinical parameters could be used to phenogroup a heart failure (HF) cohort and identify patients with beneficial response to cardiac resynchronization therapy (CRT). METHODS AND RESULTS: We studied 1106 HF patients from the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) (left ventricular ejection fraction ≤ 30%, QRS ≥ 130 ms, New York Heart Association class ≤ II) randomized to CRT with a defibrillator (CRT-D, n = 677) or an implantable cardioverter defibrillator (ICD, n = 429). An unsupervised ML algorithm (Multiple Kernel Learning and K-means clustering) was used to categorize subjects by similarities in clinical parameters, and left ventricular volume and deformation traces at baseline into mutually exclusive groups. The treatment effect of CRT-D on the primary outcome (all-cause death or HF event) and on volume response was compared among these groups. Our analysis identified four phenogroups, significantly different in the majority of baseline clinical characteristics, biomarker values, measures of left and right ventricular structure and function and the primary outcome occurrence. Two phenogroups included a higher proportion of known clinical characteristics predictive of CRT response, and were associated with a substantially better treatment effect of CRT-D on the primary outcome [hazard ratio (HR) 0.35; 95% confidence interval (CI) 0.19-0.64; P = 0.0005 and HR 0.36; 95% CI 0.19-0.68; P = 0.001] than observed in the other groups (interaction P = 0.02). CONCLUSIONS: Our results serve as a proof-of-concept that, by integrating clinical parameters and full heart cycle imaging data, unsupervised ML can provide a clinically meaningful classification of a phenotypically heterogeneous HF cohort and might aid in optimizing the rate of responders to specific therapies.

We tested the hypothesis that a machine learning (ML) algorithm utilizing both complex echocardiographic data and clinical parameters could be used to phenogroup a heart failure (HF) cohort and identify patients with beneficial response to cardiac resynchronization therapy (CRT).We studied 1106 HF patients from the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) (left ventricular ejection fraction ≤ 30%, QRS ≥ 130 ms, New York Heart Association class ≤ II) randomized to CRT with a defibrillator (CRT-D, n = 677) or an implantable cardioverter defibrillator (ICD, n = 429). An unsupervised ML algorithm (Multiple Kernel Learning and K-means clustering) was used to categorize subjects by similarities in clinical parameters, and left ventricular volume and deformation traces at baseline into mutually exclusive groups. The treatment effect of CRT-D on the primary outcome (all-cause death or HF event) and on volume response was compared among these groups. Our analysis identified four phenogroups, significantly different in the majority of baseline clinical characteristics, biomarker values, measures of left and right ventricular structure and function and the primary outcome occurrence. Two phenogroups included a higher proportion of known clinical characteristics predictive of CRT response, and were associated with a substantially better treatment effect of CRT-D on the primary outcome [hazard ratio (HR) 0.35; 95% confidence interval (CI) 0.19-0.64; P = 0.0005 and HR 0.36; 95% CI 0.19-0.68; P = 0.001] than observed in the other groups (interaction P = 0.02).Our results serve as a proof-of-concept that, by integrating clinical parameters and full heart cycle imaging data, unsupervised ML can provide a clinically meaningful classification of a phenotypically heterogeneous HF cohort and might aid in optimizing the rate of responders to specific therapies.

Background— There are limited data regarding factors associated with spontaneous left ventricular reverse remodeling (S-LVRR) among mildly symptomatic heart failure (HF) patients and its prognostic implications on clinical outcomes. Methods and Results— Best subsets logistic regression analysis was used to identify factors associated with S-LVRR (defined as ≥15% reduction in left ventricular end-systolic volume at 1-year of follow-up) among 612 patients treated with internal cardioverter defibrillator–only therapy in Multicenter Automatic Defibrillator Implantation Trial–Cardiac Resynchronization Therapy (MADIT-CRT) and to create a score for the prediction of S-LVRR. Cox proportional hazards regression modeling was used to assess the clinical outcome of all internal cardioverter defibrillator–only patients (n=714) with a high S-LVRR score. S-LVRR occurred in 25% of internal cardioverter defibrillator–only patients. Predictors of S-LVRR included systolic blood pressure≥140 mm Hg, serum creatinineP =0.019) reduction in the risk of HF or death. Treatment with cardiac resynchronization therapy was associated with a significant reduction in the risk of HF or death only among internal cardioverter defibrillator–treated patients with a low (Q1–3) S-LVRR score (hazard ratio=0.55; P P =0.72). Conclusions— Our data suggest that approximately one quarter of mild HF patients eligible for biventricular pacing experience S-LVRR. Combined assessment of clinical factors associated with S-LVRR can be used to identify mild HF patients with a low risk for clinical events without cardiac resynchronization therapy intervention. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00180271.

The effect of cardiac resynchronization therapy (CRT) on left ventricular wall thickness and left ventricular mass (LVM) is unknown.To evaluate the effects of CRT on septal and posterior wall thickness (SWT and PWT) and LVM in patients with left bundle branch block (LBBB) and non-LBBB vs implantable cardioverter-defibrillator patients and to assess the relationship between CRT-induced changes and cardiac events.We investigated 843 patients with LBBB and 366 patients with non-LBBB enrolled in the Multicenter Automatic Defibrillator Implantation Trial - Cardiac Resynchronization Therapy (MADIT-CRT) trial to analyze changes in SWT, PWT, and LVM at 12 months and subsequent outcome. The primary end point was heart failure or death; secondary end points included ventricular tachycardia, ventricular fibrillation, or death.In LBBB patients, reduction in SWT, PWT, and LVM was more pronounced in CRT defibrillator (CRT-D) than in implantable cardioverter-defibrillator (SWT:-6.7% ± 4.4% vs-1.0% ± 1.9%; PWT:-6.4% ± 4.3% vs-0.8% ± 1.9%; LVM:-23.6% ± 9.9% vs-5.1% ± 5.1%; P.001 for all). In CRT-D patients with non-LBBB, LVM reduction was less pronounced; however, changes in SWT and PWT were comparable. Changes in LVM correlated with changes in left ventricular end-diastolic volume. In CRT-D patients with LBBB, reduction in SWT and LVM was associated with reduction in heart failure/death (SWT: hazard ratio 0.94; 95% confidence interval 0.89-0.99 per percent change; P = .03) and ventricular tachycardia/ventricular fibrillation/death (SWT: hazard ratio 0.95; 95% confidence interval 0.91-1.00; P = .04). CRT-D patients with non-LBBB did not show favorable reduction in clinical or arrhythmic end points related to changes in SWT, PWT, or LVM.CRT-D was associated with significant reduction in SWT, PWT, and LVM in patients with LBBB along with left ventricular volume changes and associated favorable clinical and arrhythmia outcomes.

Background— Left ventricular dysfunction is a known predictor of ventricular arrhythmias. We hypothesized that measures of regional longitudinal deformation by speckle-tracking echocardiography predict ventricular tachyarrhythmias and provide incremental prognostic information over clinical and conventional echocardiographic characteristics. Methods and Results— We studied 1064 patients enrolled in the MADIT-CRT trial (Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy) with speckle-tracking data available. Peak longitudinal strain was obtained for the septal, lateral, anterior, and inferior myocardial walls at baseline. The end point was the first event of ventricular tachycardia (VT) or fibrillation (VF). During the median follow-up of 2.9 years, 254 (24%) patients developed VT/VF. Patients with VT/VF had significantly lower left ventricular ejection fraction (28.3% versus 29.5%; P P P =0.022; inferior-strain, −8.3% versus −9.9%; P P P =0.001; inferior: hazard ratio, 1.08 [1.04–1.12]; P P =0.039). Only strain obtained from the inferior myocardial wall provided incremental prognostic information for VT/VF over clinical and echocardiographic parameters (C statistic 0.71 versus 0.69; P =0.005). Conclusions— Assessment of regional longitudinal myocardial deformation in the inferior region provided incremental prognostic information over clinical and echocardiographic risk factors in predicting ventricular tachyarrhythmias. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00180271.

Background— Despite benefits of cardiac resynchronization therapy (CRT) in patients with severe but less symptomatic heart failure, approximately 30% of patients do not fully respond to treatment. We hypothesized that a combined assessment of left ventricular (LV) dyssynchrony and contractile function by strain-based imaging would identify patients who would most benefit from CRT. Methods and Results— We studied 1077 patients with New York Heart Association class I/II, LV ejection fraction ≤30% and QRS width ≥130 ms enrolled in the Multicenter Automatic Defibrillator Implantation Trial–Cardiac Resynchronization Therapy trial with sufficient echocardiographic image quality for cardiac deformation analysis (implantable cardioverter-defibrillator [ICD], n=416; CRT, n=661). Patients were assigned to CRT plus an ICD or to ICD alone in 3:2 random assignment. We assessed the degree to which baseline echocardiographic assessments of dyssynchrony, measured as the standard deviation of time-to-peak transverse strain over 12 segments, contractile function, measured as global longitudinal strain, or both predicted the effect of treatment on the primary outcome of death or heart failure. With 213 primary events occurring over a mean of 2.4 years, the benefit of CRT plus an ICD relative to ICD alone was greatest in patients with mild to moderate dyssynchrony (time-to-peak transverse strain standard deviation, 142 to 230 ms) and greater baseline contractile function (global longitudinal strain ≤−8.7%). Overall, those patients with mild to moderate dyssynchrony and those with best contractile function at baseline demonstrated the greatest benefit from CRT (adjusted hazards ratio, 0.20; 95% confidence interval, 0.09 to 0.44). Dyssynchrony and global longitudinal strain predicted response to CRT independent of each other, QRS width, LV ejection fraction, and presence versus absence of left bundle-branch block, although the observed benefit remained greatest in patients with left bundle-branch block. Conclusions— Both mechanical dyssynchrony and contractile function are important independent correlates of benefit from CRT. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00180271.

Endothelin-1, angiotensin II, and oxygen-derived radicals are pivotal factors in the development and progression of atherosclerosis. In vitro studies suggest that generation of oxygen-derived radicals by angiotensin II is an important mechanism increasing endothelin-1 synthesis, which consecutively may trigger effects such as cell proliferation and hypertrophy. The aim of this study was to confirm our previous data in an ex vivo and an in vivo setting. Explanted segments of internal mammary arteries were analyzed for big endothelin-1 expression following incubation with xanthine oxidase, angiotensin II, superoxide dismutase, and catalase to stimulate or to specifically inactivate oxygen-derived radicals. Endothelin-1 concentrations were determined by immunostaining and enzyme-linked immunosorbent assay. Further, oxypurinol was given to patients undergoing coronary angioplasty, a procedure known to increase plasma endothelin-1 concentrations. Angiotensin II and xanthine oxidase dose-dependently increased big endothelin-1 concentrations ( p < .01 and p < .0001); the effects could be inhibited by coincubation with superoxide dismutase and catalase as determined by both semiquantitative immunofluorescence and enzyme-linked immunosorbent assay ( p < .01). Patients undergoing coronary angioplasty exhibited significantly elevated big endothelin-1 concentrations 60 minutes after angioplasty ( p = .03); in patients also receiving oxypurinol immediately after angioplasty, big endothelin-1 concentrations decreased ( p = .001). Our results may explain the association between elevated angiotensin II levels, increased oxidative stress, and increased endothelin-1 concentrations in atherosclerosis. The data therefore support the concept that oxygen-derived free radicals stimulate the release of endothelin-1, which subsequently induces effects such as proliferation and enhanced agonist-induced vasoconstriction, previously attributed directly to angiotensin II.

Background: Abnormalities of regional function are known predictors of ventricular arrhythmia. We assessed whether measures of regional longitudinal deformation by speckle tracking echocardiography improve prediction of ventricular tachyarrhythmias over clinical, echocardiography parameters, or biomarkers. Methods: We studied 1064 patients enrolled in MADIT-CRT with speckle-tracking data available. Peak longitudinal strain was obtained for the septal, lateral, anterior and inferior myocardial walls. The endpoint was the first event of ventricular tachycardia (VT) or fibrillation (VF). Results: During the median follow-up of 2.9 years, 254 (24%) patients developed VT/VF. Patients with VT/VF had significantly lower LVEF (28.3% vs 29.5%, p Conclusion: In MADIT-CRT, assessment of regional longitudinal myocardial deformation in the inferior myocardial wall provided incremental prognostic information over clinical, conventional echocardiographic risk factors, or biomarkers in predicting ventricular tachyarrhythmias.

Background: Left ventricular and left atrial remodeling (defined as a reduction in left ventricular end-systolic volume [LVESV] and left atrial volume [LAV] respectively) have both been shown to be associated with better clinical outcome in patients with cardiac resynchronization therapy (CRT). However, a portion of CRT patients exhibit discordant remodeling (e.g. improvement in LVESV but not in LAV or vice versa). Whether combined assessment of LA and LV remodeling predicts clinical outcome is unknown. Objectives: We aimed to evaluate the predictive value of a combined assessment of LAV and LVESV change in CRT patients with left bundle branch block (LBBB) enrolled in MADIT-CRT. We hypothesized that combined assessment better predicts outcome than LAV or LVESV reduction alone. Methods: The study population comprised 533 CRT-D LBBB patients assigned to lesser remodeling (below median LAV and LVESV change), discordant remodeling (above median change in only LAV or LVESV), or complete left-sided remodeling (above median change in both LAV and LVESV). The end point was heart failure (HF) during follow-up. Results: At 1-year follow-up, 206 patients had lesser remodeling, 115 had discordant remodeling and 212 had complete left-sided remodeling. Patients with complete left-sided remodeling had less HF than those with discordant remodeling or lesser remodeling (Figure, p=0.002). Multivariate analysis confirmed that complete left-sided remodeling is associated with lower risk of HF than discordant remodeling and discordant remodeling is better than lesser remodeling (HR=0.62 per each group, 95% CI: 0.44-0.86, p = 0.004). Conclusions: A combined assessment of LAV and LVESV reduction predicts HF in CRT patients with LBBB. Patients with complete left-sided remodeling had a significantly lower risk of HF during long-term follow-up.

BACKGROUND: Cardiac resynchronization therapy (CRT) improves left ventricular (LV) function, size, mitral regurgitation, and clinical outcomes. Whether these improvements are due to the short-term effects of improvement in synchrony or contractile performance, or to long-term improvement in ventricular structure and function remains insufficiently elucidated. METHODS AND RESULTS: We used echocardiographic data from 63 patients enrolled in the MADIT-CRT trial who, after 1 year of CRT therapy, underwent echocardiographic evaluation with CRT turned both on and off within minutes. LV volumes, LV ejection fraction, left atrial (LA) volumes, and right ventricular function were assessed at baseline and in the on and off modes within a 5-minute time-frame at 12 months. Speckle-tracking strain analysis was used to assess LV dyssynchrony and contractile function. Interruption of long-term CRT resulted in acute deterioration of LV and RV function and acute increase in LV and LA volumes, although not to baseline. Acute withdrawal was also associated with increased dyssynchrony (SD time to peak transverse strain 178 ± 68 ms vs 195 ± 62 ms; P = .16; and SD time to peak longitudinal strain 108 ± 46 ms vs 125 ± 55 ms; P = .046). However, there was no deterioration in contractile function (global longitudinal strain), which had improved with CRT (-9.8 ± 4.3% vs -10.0 ± 3.7%; P = .93). CONCLUSIONS: Despite substantial LV reverse remodeling with CRT, interruption of long-term CRT after 12 months resulted in an acute worsening of LV size and function, LA volumes, and right ventricular function, with concomitant worsening of ventricular synchrony despite minimal change to the observed improvement in LV strain measures of contractile function. These findings suggest that the beneficial reverse remodeling associated with CRT may be mostly dependent on active pacing, although intrinsic improvements in contractile function may persist beyond termination of pacing.

To assess long-term effects of cardiac resynchronization therapy (CRT) on left ventricular (LV) dyssynchrony and contractile function, by two-dimensional speckle-tracking echocardiography, compared with implantable cardioverter defibrillator (ICD) only in MADIT-CRT.We studied 761 patients in New York Heart Association I/II, ejection fraction ≤30%, and QRS ≥130 ms [n = 434, CRT-defibrillator (CRT-D), n = 327, ICD] with echocardiographic studies available at baseline and 12 months. Dyssynchrony was determined as the standard deviation of time to peak transverse strain between 12 segments of apical four- and two-chamber views, and contractile function as global longitudinal strain (GLS) by averaging longitudinal strain over these 12 segments. We compared changes in LV dyssynchrony and contractile function between treatment groups and assessed relationships between these changes over the first year and subsequent outcomes (median post 1-year follow-up = 14.9 months). Mean changes in LV dyssynchrony and contractile function measured by GLS in the overall population were, respectively, -29 ± 83 ms and -1 ± 2.9%. However, both LV dyssynchrony (CRT-D: -47 ± 83 ms vs. ICD: -6 ± 76 ms, P0.001) and contractile function (CRT-D: -1.4 ± 3.1% vs. ICD: -0.4 ± 2.5%, P0.001) improved to a greater extent in the CRT-D group compared with the ICD-only group. A greater improvement in dyssynchrony and contractile function at 1 year was associated with lower rates of the subsequent primary outcome of death or heart failure, adjusting for baseline dyssynchrony and contractile function, treatment arm, ischaemic status, and change in LV end-systolic volume. Each 20 ms decrease in LV dyssynchrony was associated with a 7% reduction in the primary outcome (P = 0.047); each 1% improvement in GLS over the 12-month period was associated with a 24% reduction in the primary outcome (P0.001).Cardiac resynchronization therapy resulted in a significant improvement in both LV dyssynchrony and contractile function measured by GLS compared with ICD only and these improvements were associated with better subsequent outcomes.

ObjectivesThe aim of our study was to evaluate the relationship between left ventricular (LV) dyssynchrony and the risk of ventricular tachycardia (VT) or ventricular fibrillation (VF) in patients enrolled in the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial—Cardiac Resynchronization Therapy) trial.BackgroundIntraventricular mechanical dyssynchrony might be an important factor in ventricular arrhythmogenesis by enhancing electrical heterogeneity in heart failure patients. The effects of dyssynchrony have not yet been evaluated in a large cohort of implantable cardioverter-defibrillator (ICD) and cardiac resynchronization therapy with defibrillator (CRT-D) patients.MethodsLV dyssynchrony was measured at baseline and at 12-months by speckle-tracking echocardiography, defined as the standard deviation of time to peak systolic strain in 12 LV myocardial segments. The endpoint was the first VT/VF/death or VT/VF. LV dyssynchrony was evaluated in 764 left bundle branch block (LBBB) patients and in 312 non-LBBB patients.ResultsBaseline LV dyssynchrony was not predictive of VT/VF/death or VT/VF in LBBB or non-LBBB patients in either treatment arm. In CRT-D patients with LBBB, improvement in LV dyssynchrony over a year was associated with significantly lower incidence of VT/VF/death (p < 0.001) and VT/VF (p < 0.001) compared to ICD patients and to CRT-D patients with unchanged or worsening dyssynchrony. Among LBBB patients, 15% decrease in LV dyssynchrony was associated with lower risk of VT/VF/death (hazard ratio: 0.49, 95% confidence interval: 0.24 to 0.99, p = 0.049) and VT/VF (hazard ratio: 0.30, 95% confidence interval: 0.12 to 0.77, p = 0.009) as compared to ICD patients. Patients without LBBB receiving CRT-D did not show reduction in VT/VF/death or in VT/VF in relation to improving dyssynchrony when evaluating cumulative event rates or risk of events.ConclusionsBaseline LV dyssynchrony did not predict VT/VF/death or VT/VF in mild heart failure patients with or without LBBB. CRT-induced improvement of LV dyssynchrony was associated with significant reduction of ventricular arrhythmias in patients with LBBB. (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy [MADIT-CRT]; NCT00180271)