Effects of Trimetazidine in Nonischemic Heart Failure: A Randomized Study

ObjectivesHeart failure (HF) is associated with changes in myocardial metabolism that lead to impairment of contractile function. Trimetazidine (TMZ) modulates cardiac energetic efficiency and improves outcomes in ischemic heart disease. We evaluated the effects of TMZ on left ventricular ejection fraction (LVEF), cardiac metabolism, exercise capacity, O₂ uptake, and quality of life in patients with nonischemic HF.Methods and ResultsSixty patients with stable nonischemic HF under optimal medical therapy were included in this randomized double-blind study. Patients were randomized to TMZ (35 mg orally twice a day) or placebo for 6 months. LVEF, 6-minute walk test (6MWT), maximum O₂ uptake in cardiopulmonary exercise test, different markers of metabolism, oxidative stress, and endothelial function, and quality of life were assessed at baseline and after TMZ treatment. Left ventricular peak glucose uptake was evaluated with the use of the maximum standardized uptake value (SUV) by 18-fluorodeoxyglucose positron emission tomography (¹⁸FDG-PET). Etiology was idiopathic in 85% and hypertensive in 15%. Both groups were similar in age, functional class, LVEF, and levels of N-terminal pro–B-type natriuretic peptide at baseline. After 6 months of TMZ treatment, no changes were observed in LVEF (31 ± 10% vs 34 ± 8%; P = .8), 6MWT (443 ± 25 m vs 506 ± 79 m; P = .03), maximum O₂ uptake (19.1 ± 5.0 mL kg⁻¹ min⁻¹ vs 23.0 ± 7.2 mL kg⁻¹ min⁻¹; P = .11), functional class (percentages of patients in functional classes I/II/III/IV 10/3753/0 vs 7/40/50/3; P = .14), or quality of life (32 ± 26 points vs 24 ± 18 points; P = .25) in TMZ versus placebo, respectively. In the subgroup of patients evaluated with ¹⁸FDG-PET, no significant differences were observed in SUV between both groups (7.0 ± 3.6 vs 8.2 ± 3.4 respectively; P = .47).ConclusionsIn patients with nonischemic HF, the addition of TMZ to optimal medical treatment does not result in significant changes of LVEF, exercise capacity, O₂ uptake, or quality of life.     

Evolution of Myocardial Dysfunction in Asymptomatic Patients at Risk of Heart Failure

ObjectivesThe determinants of changes in systolic and diastolic parameters in patients age >65 years, at risk of heart failure (HF), and with and without asymptomatic type 2 diabetes mellitus (T2DM) was assessed by echocardiography. The association between metformin and myocardial function was also assessed.BackgroundThe increasing prevalence of T2DM will likely further fuel the epidemic of HF. Understanding the development or progression of left ventricular (LV) dysfunction may inform effective measures for HF prevention.MethodsA total of 982 patients with at least one HF risk factor (hypertension, obesity, or T2DM) were recruited from 2 community-based populations and divided into 2 groups: T2DM (n = 431, age 71 ± 4 years) and non-T2DM (n = 551, age 71 ± 5 years). Associations of metformin therapy were evaluated in the T2DM group. All underwent a comprehensive echocardiogram, including global longitudinal strain (GLS) and diastolic function (transmitral flow [E], annular velocity [e’]) at baseline and follow-up (median 19 months [interquartile range: 17 to 26 months]). Comparisons were facilitated by propensity matching.ResultsA reduction in GLS was observed in the T2DM group (baseline ?17.8 ± 2.6% vs. follow-up ?17.4 ± 2.8%; p = 0.003), but not in the non-T2DM group (?18.7 ± 2.7% vs. ?18.6 ± 3.0%; p = 0.41). Estimated LV filling pressures increased in both the T2DM group (p = 0.001) and the non-T2DM group (p = 0.04). Metformin-treated patients with T2DM did not increase estimated LV filling pressure (E/e’ baseline 8.9 ± 2.7 vs. follow-up 9.1 ± 2.7; p = 0.485) or change e’ (7.6 ± 1.5 cm/s vs. 7.6 ± 1.8 cm/s; p = 0.88). After propensity matching, metformin was associated with a smaller change in e’ (β = 0.58 [95% CI: 0.13 to 1.03]; p = 0.013) and E/e’ (β = ?0.96 [95% CI: ?1.66 to ?0.26]; p = 0.007) but was not associated with a change in GLS (p = 0.46).ConclusionsOver 2 years, there is a worsening of GLS and LV filling pressures in asymptomatic diabetic patients with HF risk factors. Metformin use is associated with less deterioration of LV filling pressures and myocardial relaxation but had no association with systolic function.     

No inferioridad de la titulación de enfermera de insuficiencia cardiaca en comparación con la de cardiólogo de insuficiencia cardiaca. Ensayo aleatorizado multicéntrico ETIFIC

Introduction and objectivesBeta-blockers, angiotensin-converting enzyme inhibitors (ACE inhibitors), angiotensin-II-receptor-blockers (ARB), and mineralocorticoid-receptor antagonists decrease mortality and heart failure (HF) hospitalizations in HF patients with reduced left ventricular ejection fraction. The effect is dose-dependent. Careful titration is recommended. However, suboptimal doses are common in clinical practice. This study aimed to compare the safety and efficacy of dose titration of the aforementioned drugs by HF nurses vs HF cardiologists.MethodsETIFIC was a multicenter (n = 20) noninferiority randomized controlled open label trial. A total of 320 hospitalized patients with new-onset HF, reduced ejection fraction and New York Heart Association II-III, without beta-blocker contraindications were randomized 1:1 in blocks of 4 patients each stratified by hospital: 164 to HF nurse titration vs 156 to HF cardiologist titration (144 vs 145 analyzed). The primary endpoint was the beta-blocker mean relative dose (% of target dose) achieved at 4 months. Secondary endpoints included ACE inhibitors, ARB, and mineralocorticoid-receptor antagonists mean relative doses, associated variables, adverse events, and clinical outcomes at 6 months.ResultsThe mean ± standard deviation relative doses achieved by HF nurses vs HF cardiologists were as follows: beta-blockers 71.09% ± 31.49% vs 56.29% ± 31.32%, with a difference of 14.8% (95%CI, 7.5-22.1), P < .001; ACE inhibitors 72.61% ± 29.80% vs 56.13% ± 30.37%, P < .001; ARB 44.48% ± 33.47% vs 43.51% ± 33.69%, P = .93; and mineralocorticoid-receptor antagonists 71% ± 32.12% vs 70.47% ± 29.78%, P = .86; mean ± standard deviation visits were 6.41 ± 2.82 vs 2.81 ± 1.58, P < .001, while the number (%) of adverse events were 34 (23.6) vs 30 (20.7), P = .55; and at 6 months HF hospitalizations were 1 (0.69) vs 9 (5.51), P = .01.ConclusionsETIFIC is the first multicenter randomized trial to demonstrate the noninferiority of HF specialist-nurse titration vs HF cardiologist titration. Moreover, HF nurses achieved higher beta-blocker/ACE inhibitors doses, with more outpatient visits and fewer HF hospitalizations.Trial registry number: NCT02546856.     

Heart Rate Responses During Exercise by Dominant Ventricle in Pediatric and Young Adult Patients With a Fontan Circulation

BackgroundPatients with univentricular physiology palliated with the Fontan operation have multiple late cardiovascular and extracardiac complications, including autonomic dysfunction. Despite the observation, little is known about autonomic function driving exercise-related heart rate responses in Fontan patients and whether dominant ventricle subtype or underlying cardiac anatomy affects heart rate responses during exercise.MethodsWe performed a retrospective chart review of all single ventricle patients palliated with a Fontan operation who underwent a maximal effort cardiopulmonary exercise test at Cincinnati Children’s Hospital Medical Center from 2013 to 2018.ResultsOne hundred and three Fontan patients aged 16.7 ± 5.5 years were included in this study. Although both the systemic right (n = 38) and systemic left (n = 65) ventricle groups demonstrated chronotropic incompetence, there were no differences between the groups in maximal heart rate (167.5 ± 17.4 vs 169.6 ± 20.9 bpm, P = 0.59), heart rate reserve (87.3 ± 22.6 vs 96.8 ± 25.7, P = 0.06) nor chronotropic index (70 ± 13% vs 74 ± 20%, P = 0.19). In addition, there were no differences between the groups in heart rate recovery at 1, 3, 5, and 10 minutes. Interestingly, patients with hypoplastic left heart syndrome (n = 34) had lower heart rate reserve (84.76 ± 22.8 vs 96.38 ± 26.75, P = 0.04) and chronotropic index (70.5 ± 12.5% vs 76.3 ± 13.2%, P = 0.04) compared with patients with tricuspid atresia (n = 42).ConclusionsFontan patients commonly have chronotropic incompetence, diminished heart rate reserve but with preserved heart rate recovery. Although there is overall no difference in chronotropy in Fontan patients based on dominant systemic ventricle, there is a difference between patients with hypoplastic left heart syndrome and those with tricuspid atresia.     

Increased Exhaled Nitric Oxide Levels After Exercise in Patients With Chronic Systolic Heart Failure With Pulmonary Venous Hypertension

BackgroundFractional exhaled nitric oxide (eNO) is recognized as a marker of pulmonary endothelial function. Oxidative stress is associated with systemic endothelial nitric oxide production, but its correlation with eNO in heart failure (HF) patients has not been described. Previous studies have reported increased eNO levels after exercise in symptomatic HF patients but decreased levels with pulmonary arterial hypertension. Our objective was to prospectively examine the potential myocardial and functional determinants of exercise-induced rise of eNO in HF.Methods and ResultsThirty-four consecutive ambulatory patients with chronic systolic HF (left ventricular ejection fraction [LVEF] ≤45%) underwent symptom-limited cardiopulmonary stress testing and echocardiography. eNO was determined immediately after exercise. Systemic endothelial dysfunction was assessed by asymmetric dimethylarginine (ADMA) and the L-arginine/ADMA ratio. In our study cohort (mean age 53 ± 13 years, 76% male, median LVEF 31%, interquartile range [IQR] 25%–40%), the mean eNO was 23 ± 9 ppb. eNO levels were higher in patients with diastolic dysfunction stages 2 or 3 than stage 1 or normal diastology (26.1 ± 9 vs 19.5 ± 7 ppb; P = .013). eNO had a positive correlation with estimated systolic pulmonary artery pressure (r = 0.57; P = .0009) and indexed left atrium volume (r = 0.43; P = .014), but it did not correlate with cardiopulmonary exercise test parameters, ADMA, or symptom score.ConclusionsIn contrast to earlier reports, the increase in postexercise eNO observed in stable chronic systolic HF patients may be attributed to the presence of underlying pulmonary venous hypertension probably secondary to advanced diastolic dysfunction.     

Age-Related Maximum Heart Rate Among Ischemic and Nonischemic Heart Failure Patients Receiving β-Blockade Therapy

BackgroundEquations to predict maximum heart rate (HR_max) in heart failure (HF) patients receiving β-adrenergic blocking (BB) agents do not consider the cause of HF. We determined equations to predict HR_max in patients with ischemic and nonischemic HF receiving BB therapy.Methods and ResultsUsing treadmill cardiopulmonary exercise testing, we studied HF patients receiving BB therapy being considered for transplantation from 1999 to 2010. Exclusions were pacemaker and/or implantable defibrillator, left ventricle ejection fraction (LVEF) >50%, peak respiratory exchange ratio (RER) <1.00, and Chagas disease. We used linear regression equations to predict HR_max based on age in ischemic and nonischemic patients. We analyzed 278 patients, aged 47 ± 10 years, with ischemic (n = 75) and nonischemic (n = 203) HF. LVEF was 30.8 ± 9.4% and 28.6 ± 8.2% (P = .04), peak VO₂ 16.9 ± 4.7 and 16.9 ± 5.2 mL kg^?1 min^?1 (P = NS), and the HR_max 130.8 ± 23.3 and 125.3 ± 25.3 beats/min (P = .051) in ischemic and nonischemic patients, respectively. We devised the equation HR_max = 168 ? 0.76 × age (R² = 0.095; P = .007) for ischemic HF patients, but there was no significant relationship between age and HR_max in nonischemic HF patients (R² = 0.006; P = NS).ConclusionsOur study suggests that equations to estimate HR_max should consider the cause of HF.     

A Possible Role for Systemic Hypoxia in the Reactive Component of Pulmonary Hypertension in Heart Failure

BackgroundThe mechanisms underlying the reactive component of pulmonary hypertension (PH) in heart failure (HF) are unclear. We examined whether resting systemic oxygen levels are related to pulmonary hemodynamics in HF.Methods and ResultsThirty-nine HF patients underwent right heart catheterization. Subsequently, patients were classified as having: 1) no PH (n = 12); 2) passive PH (n = 10); or 3) reactive PH (n = 17). Blood was drawn from the radial and pulmonary arteries for the determination of PaO₂, SaO₂, PvO₂, SvO₂, and vasoactive neurohormones. PaO₂ and PvO₂ were lower in reactive PH versus no PH and passive PH patients (65.3 ± 8.6 vs 78.3 ± 11.4 mm Hg and 74.5 ± 14.0 mm Hg; 29.2 ± 4.1 vs 36.2 ± 2.8 mm Hg and 33.4 ± 2.3 mm Hg; P < .05). SaO₂ and SvO₂ were lower in reactive PH versus no PH patients (93 ± 3% vs 96 ± 3%; 51 ± 11% vs 68 ± 4%; P < .05), but not different versus passive PH patients. The transpulmonary pressure gradient (TPG) was inversely related to PaO₂, PvO₂, SaO₂, and SvO₂ in the reactive PH patients only (r ≤ ?0.557; P < .05). Similarly, plasma endothelin-1 correlated with PaO₂, PvO₂, SvO₂ (r ≤ ?0.495), and TPG (r = 0.662; P < .05) in reactive PH patients only.ConclusionsSystemic hypoxia may play a role in the reactive component of PH in HF, potentially via a hypoxia-induced increase in endothelial release of the vasoconstrictor endothelin-1.     

Maternal and Fetal Hemodynamic Adaptations to Pregnancy and Clinical Outcomes in Maternal Cardiac Disease

BackgroundAlthough insufficient maternal cardiac output (CO) has been implicated in poor outcomes in mothers with heart disease (HD), maternal-fetal interactions remain incompletely understood. We sought to quantify maternal-fetal hemodynamics with the use of magnetic resonance imaging (MRI) and explore their relationship with adverse events.MethodsPregnant women with moderate or severe HD (n = 22; mean age 32 ± 5 years) were compared with healthy control women (n = 21; 34 ± 3 years). An MRI was performed during the third trimester at peak output (maternal-fetal) and 6 months postpartum with return of maternal hemodynamics to baseline (reference). Phase-contrast MRI was used for flow quantification and was combined with T1/T2 relaxometry for derivation of fetal oxygen delivery/consumption.ResultsThird-trimester CO and cardiac index (CI) measurements were similar in HD and control groups (CO 7.2 ± 1.5 vs 7.3 ± 1.6 L/min, P = 0.79; CI 4.0 ± 0.7 vs 4.3 ± 0.7 L/min/m,² P = 0.28). However, the magnitude of CO/CI increase (Δ, peak pregnancy − reference) in the HD group exceeded that in the control group (CO 46 ± 24% vs 27 ± 16% [P = 0.007]; CI 51 ± 28% vs 28 ± 17% [P = 0.005]). Fetal growth and oxygen delivery/consumption were similar between groups. Adverse cardiovascular outcomes (nonmutually exclusive) in 6 HD women included arrhythmia (n = 4), heart failure (n = 2), and hypertensive disorder of pregnancy (n = 1); premature delivery was observed in 2 of these women. The odds of a maternal cardiovascular event were inversely associated with peak CI (odds ratio 0.10, 95% confidence interval 0.001-0.86; P = 0.04) and Δ,CI (0.02, 0.001-0.71; P = 0.03).ConclusionsMaternal-fetal hemodynamics can be well characterised in pregnancy with the use of MRI. Impaired adaptation to pregnancy in women with HD appears to be associated with development of adverse outcomes of pregnancy.     

The Relationship Between Leptin and Ventilatory Control in Heart Failure

BackgroundIncreased serum leptin concentration has been linked to increased ventilation in patients with mild heart failure (HF). However, in animal models the absence of leptin has also been associated with increased ventilation. This study evaluated the relationship of circulating leptin concentration with exercise ventilation in HF patients.Methods and ResultsFifty-eight consecutive ambulatory HF patients were stratified by quintiles of leptin concentration, with a lowest quintile of mean leptin concentration of 1.8 ± 8.9 ng/mL and a highest of 33.3 ± 30.3 ng/mL. Peak exercise ventilatory efficiency (VE/VCO₂) was significantly elevated in the lowest (46 ± 6 vs 34 ± 4; P < .01) as well as in the highest (38 ± 8 vs 34 ± 4; P < .05) leptin concentration quintiles compared with the reference middle quintile. Multiple regression analysis adjusted for confounders such as age, sex, and body mass index showed leptin concentration to be independently inversely correlated to VE/VCO₂ in the low-to-normal quintiles (β = ?0.64; P < .01), positively in the normal-to-high quintiles (β = 0.52; P = .02), and positively correlated to P_ETCO₂ in the low-to-normal quintiles (β = 0.59; P = .01) and inversely in the normal-to-high quintiles (β = ?0.53; P = .02).ConclusionsIn HF patients, both high and low leptin concentrations are associated with increased VE/VCO₂ and decreased P_ETCO₂ with a nonlinear U-shaped relationship, suggesting that either leptin deficiency or leptin resistance may modulate ventilatory control in HF patients.     

Brain Injury in Autonomic,Emotional, and Cognitive Regulatory Areas in Patients With Heart Failure

BackgroundHeart failure (HF) is accompanied by autonomic, emotional, and cognitive deficits, indicating brain alterations. Reduced gray matter volume and isolated white matter infarcts occur in HF, but the extent of damage is unclear. Using magnetic resonance T2 relaxometry, we evaluated the extent of injury across the entire brain in HF.Methods and ResultsProton-density and T2-weighted images were acquired from 13 HF (age 54.6 ± 8.3 years; 69% male, left ventricular ejection fraction 0.28 ± 0.07) and 49 controls (50.6 ± 7.3 years, 59% male). Whole brain maps of T2 relaxation times were compared at each voxel between groups using analysis of covariance (covariates: age and gender). Higher T2 relaxation values, indicating injured brain areas (P < .005), emerged in sites that control autonomic, analgesic, emotional, and cognitive functions (hypothalamus, raphé magnus, cerebellar cortex, deep nuclei and vermis; temporal, parietal, prefrontal, occipital, insular, cingulate, and ventral frontal cortices; corpus callosum; anterior thalamus; caudate nuclei; anterior fornix and hippocampus). No brain areas showed higher T2 values in control vs. HF subjects.ConclusionsBrain structural injury emerged in areas involved in autonomic, pain, mood, language, and cognitive function in HF patients. Comorbid conditions accompanying HF may result from neural injury associated with the syndrome.     

Endothelial Dysfunction is a Marker of Systemic Response to the Cardiac Resynchronization Therapy in Heart Failure

BackgroundCardiac resynchronization therapy (CRT) induces a significant improvement in patients with heart failure (HF), who are often characterized by the presence of endothelial dysfunction (ED) with impaired flow-mediated vasodilation (FMD). We aimed to study the ED in patients with HF candidates to CRT with defibrillator (CRT-D).Methods and ResultsWe studied 57 consecutive patients affected by HF and undergoing CRT-D. At the baseline we recorded a high prevalence of ED (64.9%) with impaired FMD (4.1 ± 3.8%). After 12 months of CRT, we reported a marked increase of the mean FMD (8.8 ± 4.8% vs 4.1 ± 3.8%; P < .05) along with significant improvement of left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV), New York Heart Association (NYHA) functional class, and 6-minute walk test (6MWT); 42 patients (73.7%) were classified as responders according to standard criteria. FMD was related to LVEF (r = 0.169; P < .05), LVESV (r = ?0.169; P < .05), NYHA functional class (r = ?0.27; P < .051), and 6MWT (r = 0.360; P < .01).ConclusionsED is not an independent predictor of CRT response, but it is able to intercept the systemic effects of CRT and is an affordable marker of response to CRT, especially in patients unable to perform the 6MWT.     

Quality of Life Assessment for Acute Heart Failure Patients From Emergency Department Presentation Through 30 Days After Discharge: A Pilot Study With the Kansas City Cardiomyopathy Questionnaire

BackgroundThere are no well validated patient-reported disease status instruments for acute heart failure (HF). We assessed the feasibility of using the Kansas City Cardiomyopathy Questionnaire (KCCQ) during acute heart failure hospitalization, and the association of acute changes with 30-day readmission.Methods and ResultsA convenience sample of acute HF patients were administered the KCCQ on presentation, discharge, and 30 days after discharge. We examined mean differences in KCCQ scores over time, and we stratified by readmission status to examine differences in hospital-based changes with the use of t test and logistic regression. Among 52 patients (mean age 63 ± 35 years, 56.9% male, 46.2% white), discharge and 30-day assessments were each completed by 90%. Scores were lowest at presentation, improved during hospitalization, and were highest at 30 days. The mean change was +11.9 ± 97.0 (P = .007) between presentation and discharge and +19.8 ± 87.8 (P < .001) between discharge and 30 days. Within the 30-day follow-up, 10 patients were readmitted, and there were no significant differences in score changes during hospitalization between patients with and without readmission (readmitted patients: +4.8 ± 81.5 vs no readmission +16.2 ± 27.4; P = .32).ConclusionsIn this pilot study, the KCCQ is feasible to use during acute HF hospitalizations and demonstrates sensitivity to acute changes, but score changes during hospitalization did not predict 30-day readmission.     

Fate of Hypoplastic Pulmonary Arteries After Arterial Duct Stenting in Congenital Heart Disease With Duct-Dependent Pulmonary Circulation

ObjectivesThis study sought to evaluate the impact of arterial duct (AD) stenting in promoting catch-up growth of hypoplastic pulmonary artery (PA) tree in congenital heart disease with duct-dependent pulmonary circulation (CHD-DPC).BackgroundSignificant and balanced PA growth following AD stenting has already been consistently reported in the literature. However, no data are so far available about the role of this approach in severe PA hypoplasia, which significantly impacts the risk of surgical repair.MethodsPre-surgical angiographic PA evaluation was performed in 45 patients with confluent PAs submitted to neonatal AD stenting as palliation of CHD-DPC. PA growth was evaluated as Nakata Index and McGoon ratio as well as individual PA z-score changes, both in the whole population and according to the original vessel size (Nakata Index <100 mm²/m², Group I [n = 15] vs. Nakata Index >100 mm²/m², Group II [n = 30]).ResultsControl angiography was performed 7.5 ± 6.5 months (median 6 months) after duct stenting, showing significant and balanced PA growth. The Nakata Index increased from 143 ± 73 mm²/m² to 270 ± 88 mm²/m² (124 ± 118%, p < 0.0001); left PA z-score from −0.7 ± 1.7 to 1.0 ± 1.4; right PA z-score from −0.6 ± 1.3 to 1.2 ± 1.3 (p < 0.0001 for both comparisons). Group I showed a greater increase of global PA growth (Nakata Index increase 227 ± 141% vs. 72 ± 57%, p < 0.001) as compared with Group II. Final PA size did not significantly differ between the groups (246 ± 105 mm²/m² vs. 282 ± 78 mm²/m², p = NS).ConclusionsPercutaneous AD stenting is highly effective in promoting a significant and balanced catch-up growth of diminutive PAs, being therefore advisable in this subset of patients as a reliable alternative to surgical palliation.     

Diferencias de género en la titulación de fármacos de pacientes con insuficiencia cardiaca y fracción de eyección reducida del ensayo ETIFIC

Introduction and objectivesOptimal medical therapy decreases mortality and heart failure (HF) hospitalizations in HF patients with reduced left ventricular ejection fraction. Women have been underrepresented in clinical trials and not specifically evaluated. This study aimed to compare the safety and effectiveness of drug titration in women vs men.MethodsThis post hoc gender study of the ETIFIC multicenter randomized trial included hospitalized patients with new-onset HF with reduced ejection fraction and New York Heart Association II-III and no contraindications to beta-blockers. A structured 4-month titration process was implemented in HF clinics. The primary endpoint was the mean relative dose (% of target dose) of beta-blockers achieved by women vs men. Secondary endpoints included the mean relative doses of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and mineralocorticoid receptor antagonists, adverse events, and other clinical outcomes at 6 months.ResultsA total of 320 patients were included, 83 (25.93%) women and 237 (74.06%) men (76 vs 213 analyzed). The mean ± standard deviation of the relative doses achieved by women vs men were as follows: beta-blockers 62.08% ± 30.72% vs 64.4% ± 32.77%, with a difference of ?2.32% (95%CI, ?10.58-5.94), P = .580; and mineralocorticoid receptor antagonists 79.85% ± 27.72% vs 67.29% ± 31.43%, P =.003. No other differences in drug dosage were found. Multivariate analysis showed nonsignificant differences. CV mortality was 1 (1.20%) vs 3 (1.26%), P = 1, and HF hospitalizations 0 (0.00%) vs 10 (4.22%), P = .125.ConclusionsIn a post hoc analysis from the HF-titration ETIFIC trial, we found nonsignificant gender differences in drug dosage, cardiovascular mortality, and HF hospitalizations.Trial registry number: NCT02546856.     

3-Dimensional Strain Analysis of Hypertrophic Cardiomyopathy: Insights From the NHLBI International HCM Registry

BackgroundAbnormal global longitudinal strain (GLS) has been independently associated with adverse cardiac outcomes in both obstructive and nonobstructive hypertrophic cardiomyopathy.ObjectivesThe goal of this study was to understand predictors of abnormal GLS from baseline data from the National Heart, Lung, and Blood Institute (NHLBI) Hypertrophic Cardiomyopathy Registry (HCMR).MethodsThe study evaluated comprehensive 3-dimensional left ventricular myocardial strain from cine cardiac magnetic resonance in 2,311 patients from HCMR using in-house validated feature-tracking software. These data were correlated with other imaging markers, serum biomarkers, and demographic variables.ResultsAbnormal median GLS (> –11.0%) was associated with higher left ventricular (LV) mass index (93.8 ± 29.2 g/m² vs 75.1 ± 19.7 g/m²; P < 0.0001) and maximal wall thickness (21.7 ± 5.2 mm vs 19.3 ± 4.1 mm; P < 0.0001), lower left (62% ± 9% vs 66% ± 7%; P < 0.0001) and right (68% ± 11% vs 69% ± 10%; P < 0.01) ventricular ejection fractions, lower left atrial emptying functions (P < 0.0001 for all), and higher presence and myocardial extent of late gadolinium enhancement (6 SD and visual quantification; P < 0.0001 for both). Elastic net regression showed that adjusted predictors of GLS included female sex, Black race, history of syncope, presence of systolic anterior motion of the mitral valve, reverse curvature and apical morphologies, LV ejection fraction, LV mass index, and both presence/extent of late gadolinium enhancement and baseline N-terminal pro–B-type natriuretic peptide and troponin levels.ConclusionsAbnormal strain in hypertrophic cardiomyopathy is associated with other imaging and serum biomarkers of increased risk. Further follow-up of the HCMR cohort is needed to understand the independent relationship between LV strain and adverse cardiac outcomes in hypertrophic cardiomyopathy.     

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

BackgroundCardiac 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 ResultsWe 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).ConclusionsDespite 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.     

Evolution of non-invasive myocardial work variables after transcatheter aortic valve implantation in patients with severe aortic stenosis

IntroductionGuidelines recommend aortic valve replacement in patients with severe aortic stenosis who present with symptoms or left ventricular ejection fraction < 50%, both conditions representing a late stage of the disease. Whereas global longitudinal strain is load dependent, but interesting for assessing prognosis, myocardial work has emerged.AimTo evaluate acute changes in myocardial work occurring in patients undergoing transcatheter aortic valve implantation (TAVI).MethodsPatients who underwent TAVI were evaluated before and after by echocardiography. Complete echocardiographies were considered. Myocardial work indices (global work index, global constructive work, global work efficiency, global wasted work) were calculated integrating mean transaortic pressure gradient and brachial cuff systolic pressure.ResultsOne hundred and twenty-five patients underwent successful TAVI, with a significant decrease in mean transaortic gradient (from 52.5 ± 16.1 to 12.2 ± 5.0; P < 0.0001). There was no significant change in left ventricular ejection fraction after TAVI. Myocardial work data after TAVI showed a significant reduction in global work index (1389 ± 537 vs. 2014 ± 714; P < 0.0001), global constructive work (1693 ± 543 vs. 2379 ± 761; P < 0.0001) and global work efficiency (85.0 ± 7.06 vs. 87.1 ± 5.98; P = 0.0034). The decrease in global work index and global constructive work after TAVI was homogeneous among different subgroups, based on global longitudinal strain, left ventricular ejection fraction and New York Heart Association status before TAVI. We observed a significant association between global work index and global constructive work before TAVI, and global longitudinal strain degradation after TAVI.ConclusionsMyocardial work variables show promising potential in best understanding the left ventricular myocardial consequences of aortic stenosis and its correction. Given their ability to discriminate between New York Heart Association status and global longitudinal strain evolution, we can hypothesize about their clinical value.     

Safety and Long-term Outcomes of Defibrillator Therapy in Patients With Right-Sided Implantable Cardiac Devices in Adults With Congenital Heart Disease

BackgroundImplantable cardioverter-defibrillators (ICDs) have been proven to prevent sudden cardiac death in adult congenital heart disease (ACHD) patients. Although the left side is chosen by default, implantation from the right side is often required. However, little is known about the efficacy and safety of right-sided ICDs in ACHD patients.MethodsIn this study we reviewed a total of 191 ACHD patients undergoing ICD/cardioverter resynchronisation therapy-defibrillator (CRT-D) implantation at our hospital between 2001 and 2019 (134 men and 57 women; age [mean ± standard deviation], 41.5 ± 14.8 years).ResultsTwenty-seven patients (14.1%) had right-sided devices. The most common causes of right-sided implantation were persistent left superior vena cava and vein occlusion (37.0%). Although procedure time (202.8 ± 60.5 minutes vs 143.8 ± 69.1 minutes, P = 0.008) was longer and the procedural success was lower (92.6% vs 99.4%, P = 0.008) for right-sided devices, no difference in R-wave and pacing threshold were noted. Among the 47 patients (24.6%) who underwent defibrillation threshold testing (DFT), no difference in DFT was observed (25.2 ± 5.3 J vs 23.8 ± 4.1 J, P = 0.460). During the median follow-up of 42.4 months, appropriate ICD therapy was observed in 5 (18.5%) and 30 (18.3%) patients for right- and left-sided ICDs/CRTDs, respectively (P = 0.978). No significant difference was seen in complications between them.ConclusionsImplantation of an ICD on the right side is technically challenging, but it is feasible as an alternative approach for ACHD patients with contraindications to left-sided device implantation.     

Closing the Heart Failure Management Gap in the Community: Managing Hypotension and Impact on Outcomes

BackgroundPerception of risk in using recommended therapy in heart failure (HF) patients with hypotension adds to the problems of undertreatment in management. We aimed to determine the feasibility and outcomes of therapy in hypotensive HF patients.Methods and ResultsData were collected from HF clinic patients between 1999 and 2003. Exclusion criteria were: left ventricular ejection fraction (LVEF) >45%; myocardial infarction or revascularization within 3 months of referral; and consult-only visits. Criteria were met by 500 patients. Median follow-up was 6.8 years, with end points of total mortality and combined death and hospitalizations. Blood pressure measurements were done by the nursing staff after the patient was seated for at least 5 minutes. Two measures were taken per each patient encounter and the average of 2 systolic values is recorded for group categorization. Group 1 (hypotension, n = 112) subjects were younger (65 ± 14 vs. 69 ± 12; P = .003) and had lower mean LVEF (22 ± 10% vs. 25 ± 9%; P = .012) than group 2 (no hypotension, n = 338). Drug utilization was similar at 3 months, 1 year, and long-term. Systolic blood pressure (SBP) increased in group 1, but decreased in group 2. Mortality was similar at years 1 and 5 (12.8% vs. 9.9%, P = NS; 45.5% vs. 41.4%, P = .507); however, combined death and hospitalizations were negatively and independently affected by failure to receive therapy.ConclusionsWhen treated successfully with recommended therapy, SBP improved and patients with hypotension at baseline enjoyed significant benefits in outcomes. More effort is needed on mechanisms to implement guidelines to improve HF management.     

Adverse myocardial effects of B-vitamin therapy in subjects with chronic kidney disease and hyperhomocysteinaemia

Background & aimsHyperhomocysteinaemia (HHCY), a common finding in patients with chronic kidney disease (CKD), has been shown to contribute to adverse cardiac remodelling and failure. We hypothesised that in human subjects with CKD, HHCY would be associated with myocardial dysfunction, and that homocysteine (HCY)-lowering therapy would improve myocardial remodelling and heart-failure (HF) outcomes.Methods and resultsPost hoc analysis of the Homocysteinemia in Kidney and End Stage Renal Disease (HOST) trial (n = 2056) was performed to determine if HCY-lowering therapy with high dose B vitamins affects HF outcomes in patients with CKD. In addition, effects on myocardial remodelling were assessed in a subgroup of 220 trial subjects who had transthoracic echocardiograms done before study randomisation and during the course of the study as part of their routine clinical care. HF outcomes were not significantly affected by treatment compared to the placebo. HCY levels were inversely correlated with diastolic function (R = ?0.21; p = 0.038). Vitamin therapy resulted in a significant increase in left atrial size (+0.15 ± 0.8 cm vs. ?0.13 ± 0.07 cm; p = 0.0095). No other echocardiographic parameters were significantly associated with baseline HCY levels or changes with vitamin therapy.ConclusionHHCY is associated with diastolic dysfunction in patients with CKD. However, B-vitamin therapy did not improve HF outcomes despite lowering of plasma HCY levels, and was associated with an increase in left atrial size, which is a surrogate for worsening left ventricular diastolic dysfunction. These findings suggest that high-dose B vitamin therapy may be harmful in patients with CKD.