Left Atrial Reservoir Strain and Recurrence of Atrial Fibrillation Following De-Novo Pulmonary Vein Isolation　- Results of the ASTRA-AF Pilot Study.

BACKGROUND: Achieving early rhythm control and maintaining sinus rhythm are associated with improved outcomes in patients with atrial fibrillation (AF). Pulmonary vein isolation (PVI) is a validated alternative to medical rhythm control. This study determined associations between left atrial strain reservoir (LASR) and AF recurrence after PVI.Methods and Results: In all, 132 patients (88 with paroxysmal AF [PAF], 44 with persisting AF [PersAF]) who presented in sinus rhythm for de novo PVI of AF between December 2017 and January 2019 were included in the study. All patients underwent preprocedural echocardiography. After 12 months, all patients underwent 24-h Holter electrocardiogram monitoring to screen for AF recurrence. Kaplan-Meier curve analysis revealed an association between decreasing LASRand increased AF recurrence, with a cut-off at 31.4%. In univariable Cox regression analysis, LASRdemonstrated an association with AF recurrence, with hazard ratios (HR) of 0.83 (95% confidence interval [CI] 073-0.93; P=0.001) per 5% increase in univariable models and 0.83 (95% CI 073-0.95; P=0.005) in multivariable analysis. When clinical variables with age, sex and type of AF (PAF/PersAF) were included in the multivariable analysis, LASRremained relevant in a model with age (HR 0.86; 95% CI 073-1.00; P=0.046). CONCLUSIONS: In patients undergoing de novo PVI for AF, LASRcould be of use in risk stratification regarding AF recurrence.

Association of atrial mechanical dispersion with atrial fibrillation recurrence following catheter ablation: results of the ASTRA-AF pilot study.

AIMS: For patients with symptomatic drug-refractory atrial fibrillation (AF), catheter ablation to achieve rhythm control is an important therapeutic option. The atrial mechanical dispersion measured as standard deviation of the time to peak strain (SD-TPS) is associated with the risk of AF recurrence following catheter ablation. METHODS: The study cohort prospectively enrolled n = 132 consecutive patients with paroxysmal (n = 88) or persistent AF (n = 44) presenting for de novo pulmonary vein isolation (PVI) and followed for 1 year. We related left atrial (LA) volume, LA ejection fraction, SD-TPS, and global longitudinal strain of the left ventricle and clinical variables (sex, age, and type of AF) to AF recurrence. RESULTS: Kaplan-Meier curves showed higher AF recurrence rate with an increase of SD-TPS with the calculated cut-off of 38.6 ms. Uni- and multivariable Cox regression analysis could show that SD-TPS had the highest relevance regarding AF recurrence with a HR of 1.05 (95% CI, 1.01; 1.09, p = 0.01) and HR of 1.05 (95% CI, 1.01; 1.09, p = 0.02) per 10 ms increase. In the additional analyses for the model including the clinical variables age, sex, and type of AF with paroxysmal or persisting AF, SD-TPS did only show a trend and after adjusting for covariates, SD-TPS showed a HR of 1.04 (95% CI, 0.99; 1.09, p = 0.09) per 10 ms increase. CONCLUSION: Atrial mechanical dispersion was associated with recurrent AF.

Protocolized Natriuresis-Guided Decongestion Improves Diuretic Response: The Multicenter ENACT-HF Study.

BACKGROUND: The use of urinary sodium to guide diuretics in acute heart failure is recommended by experts and the most recent European Society of Cardiology guidelines. However, there are limited data to support this recommendation. The ENACT-HF study (Efficacy of a Standardized Diuretic Protocol in Acute Heart Failure) investigated the feasibility and efficacy of a standardized natriuresis-guided diuretic protocol in patients with acute heart failure and signs of volume overload. METHODS: ENACT-HF was an international, multicenter, open-label, pragmatic, 2-phase study, comparing the current standard of care of each center with a standardized diuretic protocol, including urinary sodium to guide therapy. The primary end point was natriuresis after 1 day. Secondary end points included cumulative natriuresis and diuresis after 2 days of treatment, length of stay, and in-hospital mortality. All end points were adjusted for baseline differences between both treatment arms. RESULTS: Four hundred one patients from 29 centers in 18 countries worldwide were included in the study. The natriuresis after 1 day was significantly higher in the protocol arm compared with the standard of care arm (282 versus 174 mmol; adjusted mean ratio, 1.64; P<0.001). After 2 days, the natriuresis remained higher in the protocol arm (538 versus 365 mmol; adjusted mean ratio, 1.52; P<0.001), with a significantly higher diuresis (5776 versus 4381 mL; adjusted mean ratio, 1.33; P<0.001). The protocol arm had a shorter length of stay (5.8 versus 7.0 days; adjusted mean ratio, 0.87; P=0.036). In-hospital mortality was low and did not significantly differ between the 2 arms (1.4% versus 2.0%; P=0.852). CONCLUSIONS: A standardized natriuresis-guided diuretic protocol to guide decongestion in acute heart failure was feasible, safe, and resulted in higher natriuresis and diuresis, as well as a shorter length of stay.

Acute effects of withdrawal of cardiac resynchronization therapy on left and right ventricular function, dyssynchrony, and contractile function in patients with New York Heart Association functional class I/II heart failure: MADIT-CRT.

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.

Heart Rate Reduction and Outcomes in Heart Failure Outpatients.

Aim. Pharmacologic reduction in heart rate with beta-blockers (BB) or ivabradine is associated with improved survival in heart failure (HF) with sinus rhythm. We analyzed the association of different heart rate-reducing drug treatments on outcomes in HF outpatients. Methods. Consecutive patients with HF in sinus rhythm referred to a specialized tertiary service were prospectively enrolled from August 2015 until March 2018. Clinical characteristics were assessed at baseline. We performed Cox regression analyses to examine the effect of the resting heart rate and different heart rate-reducing drug regimens on all-cause mortality and a composite endpoint of "all-cause mortality or heart transplantation" over a mean follow-up of 3.1 years. Results. Of the 278 patients included, 213 (76.6%) were male, the median age was 57.0 years (IQR 49.0-66.1), and 185 (73.7%) had an ejection fraction <40%. Most patients received BB in submaximal [n = 118] or maximum dose [n = 136]. Patients on BB in maximum dose plus ivabradine [n = 24] were younger (53.0 vs. 58.0 years) and had a lower EF (25 vs. 31%). Higher resting heart rate was associated with an increased risk of death or transplantation (HR 1.03 [1.01, 1.06], p = 0.0072), even after adjusting for age and sex. There were no differences between the groups concerning all-cause mortality or the composite endpoint. Conclusion. Our prospective study confirms the association between low heart rate and survival in HF patients receiving various heart rate-reducing medications. We could not identify a specific effect of either regimen.

Relationship between improvement in left ventricular dyssynchrony and contractile function and clinical outcome with cardiac resynchronization therapy: the MADIT-CRT trial.

AIMS: 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. METHODS AND RESULTS: 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, P < 0.001) and contractile function (CRT-D: -1.4 ± 3.1% vs. ICD: -0.4 ± 2.5%, P < 0.001) 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 (P < 0.001). CONCLUSION: 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.

LMNA Mutation in a Family with a Strong History of Sudden Cardiac Death.

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.

Combining diastolic dysfunction and natriuretic peptides to risk stratify patients with heart failure with reduced ejection fraction.

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.

Non-Invasive Risk Prediction Based on Right Ventricular Function in Patients with Pulmonary Arterial Hypertension.

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.

Non-immune risk predictors of cardiac allograft vasculopathy: Results from the U.S. organ procurement and transplantation network.

BACKGROUND: 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. METHODS: 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). RESULTS: 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%) (p < 0.001). 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%. CONCLUSIONS: 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.

Gender differences in characteristics and outcomes in heart failure patients referred for end-stage treatment.

AIMS: Despite signals from clinical trials and mechanistic studies implying different resilience to heart failure (HF) depending on gender, the impact of gender on presentation and outcomes in patients with HF remains unclear. This study assessed the impact of gender on clinical presentation and outcomes in patients with HF referred to a specialised tertiary HF service. METHODS AND RESULTS: Consecutive patients with HF referred to a specialised tertiary HF service offering advanced therapy options including left ventricular assist devices (LVAD) and heart transplantation were prospectively enrolled from August 2015 until March 2018. We assessed clinical characteristics at baseline and performed survival analyses and age-adjusted Cox regression analyses in men vs. women for all-cause death and a combined disease-related endpoint comprising death, heart transplantation, and LVAD implantation. Analyses were performed for the overall study population and for patients with HF with reduced ejection fraction (HFrEF). Of 356 patients included, 283 (79.5%) were male. The median age was 58 years (interquartile range 50-67). Two hundred and fifty-one (74.5%) patients had HFrEF. HF aetiology, ejection fraction, functional status measures, and most of the cardiac and non-cardiac comorbidities did not differ between men and women. In a median follow-up of 3.2 years, 50 patients died (45 men, 5 women), 15 patients underwent LVAD implantation, and 8 patients heart transplantation. While all-cause death was not significantly different between both genders in the overall population [16.9 vs. 6.0%, P = 0.065, hazard ratio (HR) 2.29 (95% confidence interval 0.91-5.78), P = 0.078], in the HFrEF subgroup, a significant difference between men and women was observed [20.7% vs. 3.9%, P = 0.017, HR 3.67 (95% confidence interval 1.13-11.91), P = 0.031]. The combined endpoint was more often reached in men than in women in both the overall population [21.6% vs. 9.0%, P = 0.053, HR 2.51 (1.08-5.82), P = 0.032] and the HFrEF subgroup [27.1% vs. 7.7%, P = 0.015, HR 3.58 (1.29-9.94), P = 0.014]. CONCLUSIONS: Patients referred to a specialised tertiary HF service showed a similar clinical profile without relevant gender differences. In the mid-term follow-up, more male than female patients died or underwent heart transplantation and LVAD implantation. These findings call for independent validation and for further research into gender-specific drivers of HF progression.

Rationale and Design of the Efficacy of a Standardized Diuretic Protocol in Acute Heart Failure Study.

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 ≥ 40 mg of furosemide or equivalent for >1 month, and a BNP > 250 ng/L or an N-terminal pro-B-type natriuretic peptide > 1000 pg/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 2 h and urine output after 6 h. Diuretics will be tailored further based upon these measurements. The study is powered for its primary endpoint of natriuresis after 1 day and will be able to detect a 15% difference with 80% power. Secondary endpoints are natriuresis and diuresis after 2 days, 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.

Study design and rationale of the pAtients pResenTing with cOngenital heaRt dIseAse Register (ARTORIA-R).

AIM: Due to improved therapy in childhood, many patients with congenital heart disease reach adulthood and are termed adults with congenital heart disease (ACHD). ACHD often develop heart failure (HF) as a consequence of initial palliative surgery or complex anatomy and subsequently require advanced HF therapy. ACHD are usually excluded from trials evaluating heart failure therapies, and in this context, more data about heart failure trajectories in ACHD are needed to guide the management of ACHD suffering from HF. METHODS AND RESULTS: The pAtients pResenTing with cOngenital heaRt dIseAse Register (ARTORIA-R) will collect data from ACHD evaluated or listed for heart or heart-combined organ transplantation from 16 countries in Europe and the Asia/Pacific region. We plan retrospective collection of data from 1989-2020 and will include patients prospectively. Additional organizations and hospitals in charge of transplantation of ACHD will be asked in the future to contribute data to the register. The primary outcome is the combined endpoint of delisting due to clinical worsening or death on the waiting list. The secondary outcome is delisting due to clinical improvement while on the waiting list. All-cause mortality following transplantation will also be assessed. The data will be entered into an electronic database with access to the investigators participating in the register. All variables of the register reflect key components important for listing of the patients or assessing current HF treatment. CONCLUSION: The ARTORIA-R will provide robust information on current management and outcomes of adults with congenital heart disease suffering from advanced heart failure.

Assessing palliative care need in left ventricular assist device patients and heart transplant recipients.

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.

Clinical characteristics and outcomes of patients with adult congenital heart disease listed for heart and heart‒lung transplantation in the Eurotransplant region.

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.

Machine learning-based phenogrouping in heart failure to identify responders to cardiac resynchronization therapy.

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.

Gender differences and outcomes in left ventricular assist device support: The European Registry for Patients with Mechanical Circulatory Support.

BACKGROUND: 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. METHODS: 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. RESULTS: 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 (p < 0.001) 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). CONCLUSIONS: 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.

Endothelin-1 in humans is increased by oxygen-derived radicals ex vivo and in vivo.

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.

Regional Longitudinal Deformation Improves Prediction of Ventricular Tachyarrhythmias in Patients With Heart Failure With Reduced Ejection Fraction: A MADIT-CRT Substudy (Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy).

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<0.001) and longitudinal strain in all myocardial walls compared with patients without VT/VF (anterior-strain, -7.7% versus -8.8%; P<0.001; lateral-strain, -7.3% versus -7.9%; P=0.022; inferior-strain, -8.3% versus -9.9%; P<0.001; septal-strain, -9.1% versus -10.0%; P<0.001). After multivariate adjustment, only anterior and inferior longitudinal strain remained independent predictors of VT/VF (anterior: hazard ratio, 1.08 [1.03-1.13]; P=0.001; inferior: hazard ratio, 1.08 [1.04-1.12]; P<0.001; per 1% absolute decrease for both). When including B-type natriuretic peptide in the model, only a decreasing myocardial function in the inferior myocardial wall predicted VT/VF (hazard ratio, 1.05 [1.00-1.11]; 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.

Predictors of spontaneous reverse remodeling in mild heart failure patients with left ventricular dysfunction.

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 creatinine<1.0 mg/dL, QRS 130 to 160 ms, and nonischemic cardiomyopathy. Multivariate analysis showed that each 1-point increment in S-LVRR score (range, 0-7) was associated with an 11% (P=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<0.001), but not among those with a higher (Q4) score (hazard ratio=1.06; 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.