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.     

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.     

Rotational Atherectomy for Severely Calcified Lesions in Patients With Left Ventricular Systolic Dysfunction: One-Year Outcomes From aSingle-Center Registry Analysis

BackgroundHigh-risk percutaneous coronary intervention (PCI) in patients with left ventricular (LV) systolic dysfunction has been proven to induce reverse LV remodeling. However, the impact of high-risk PCI focusing on rotational atherectomy (RA) in patients with severe LV systolic dysfunction has not been completely addressed.MethodsAmong 4339 consecutive patients who underwent PCI, 178 patients with 192 lesions were treated with RA. The reduced ejection fraction (EF) group (LVEF ≤35%) included 25 patients, the mid-range EF group (LVEF 36–50%) included 44 patients, and the preserved EF group (LVEF >50%) included 109 patients. The primary outcome was a composite of cardiac death, non-fatal myocardial infarction, target-vessel revascularization, and ischemic stroke.ResultsThe cumulative 1-year incidence of the primary outcome was similar among the three groups (reduced EF, 29%; mid-range EF, 25%; preserved EF, 26%; p = 0.95). After adjusting for confounding factors, the incidence of the primary outcome in the reduced EF group (hazard ratio [HR], 1.07; 95% confidence interval [CI], 0.43–2.37; p = 0.87) and the mid-range EF group (HR, 0.99; 95% CI, 0.47–1.94; p = 0.97) was similar to that in the preserved EF group. LVEF was significantly improved in the reduced EF and mid-range EF groups compared with the preserved EF group (absolute change in LVEF: 13.6 ± 11.3%, 9.0 ± 10.1%, and −0.7 ± 7.8%, respectively; p < 0.0001).ConclusionsReduced EF was not associated with increase in the primary outcome in patients undergoing RA. This seemed to result from the improved LV function after PCI.Summary for annotated table of contentsThis single center analysis study investigated 1-year composite outcome of cardiac death, non-fatal myocardial infarction, target-vessel revascularization, and ischemic stroke in patients with severe LV systolic dysfunction undergoing RA compared with that in patients with preserved LV function. The cumulative 1-year incidence of the composite outcome was similar among the three groups (reduced EF, 29%; mid-range EF, 25%; preserved EF, 26%; p = 0.95). LVEF was significantly improved in the reduced EF and mid-range EF groups compared with the preserved EF group (absolute change in LVEF: 13.6 ± 11.3%, 9.0 ± 10.1%, and −0.7 ± 7.8%, respectively; p < 0.0001).     

Iron Deficiency Is Associated With Impaired Biventricular Reserve and Reduced Exercise Capacity in Patients With Unexplained Dyspnea

BackgroundIron deficiency (ID) is frequent and associated with diminished exercise capacity in heart failure (HF), but its contribution to unexplained dyspnea without a HF diagnosis at rest remains unclear.Methods and ResultsConsecutive patients with unexplained dyspnea and normal echocardiography and pulmonary function tests at rest underwent prospective standardized cardiopulmonary exercise testing with echocardiography in a tertiary care dyspnea clinic. ID was defined as ferritin of <300 µg/L and a transferrin saturation of <20% and its impact on peak oxygen uptake (peakVO₂), biventricular response to exercise, and peripheral oxygen extraction was assessed. Of 272 patients who underwent cardiopulmonary exercise testing with echocardiography, 63 (23%) had ID. For a similar respiratory exchange ratio, patients with ID had lower peakVO₂ (14.6 ± 7.6 mL/kg/minvs 17.8 ± 8.8 mL/kg/min; P = .009) and maximal workload (89 ± 50 watt vs 108 ± 56 watt P = .047), even after adjustment for the presence of anemia. At rest, patients with ID had a similar left ventricular and right ventricular (RV) contractile function. During exercise, patients with ID had lower cardiac output reserve (P < .05) and depressed RV function by tricuspid s' (P = .004), tricuspid annular plane systolic excursion (P = .034), and RV end-systolic pressure-area ratio (P = .038), with more RV–pulmonary artery uncoupling measured by tricuspid annular plane systolic excursion/systolic pulmonary arterial pressure ratio (P = .023). RV end-systolic pressure-area ratio change from rest to peak exercise, as a load-insensitive metric of RV contractility, was lower in patients with ID (2.09 ± 0.72 mm Hg/cm² vs 2.58 ± 1.14 mm Hg/cm²; P < .001). ID was associated with impaired peripheral oxygen extraction (peakVO₂/peak cardiac output; P = .036). Cardiopulmonary exercise testing with echocardiography resulted in a diagnosis of HF with preserved ejection fraction in 71 patients (26%) based on an exercise E/e' ratio of >14, with equal distribution in patients with (28.6%) or without ID (25.4%, P = .611). None of these findings were influenced in a sensitivity analysis adjusted for a final diagnosis of HFpEF as etiology for the unexplained dyspnea.ConclusionsIn patients with unexplained dyspnea without clear HF at rest, ID is common and associated with decreased exercise capacity, diminished biventricular contractile reserve, and decreased peripheral oxygen extraction.     

The Effects of Race on Peak Oxygen Consumption and Survival in Patients With Systolic Dysfunction

BackgroundThe relationship of peak exercise oxygen consumption (VO₂) to survival in black heart failure (HF) patients is not well established. We examined the effects of race on peak VO₂ values and survival in HF patients with systolic dysfunction.Methods and ResultsThis study evaluated consecutive ambulatory HF patients who underwent symptom-limited stress tests with breath-by-breath expired gas analyses using ramped treadmill protocols. The relationship between cardiopulmonary exercise parameters and patient transplant-free survival was assessed by race. This study included 580 HF patients (mean age 52 ± 12 years; 28% females; 22% blacks; mean left ventricular ejection fraction 26 ± 12%; mean body mass index 28.7 ± 5.4; 73% on β-blocker). Black patients had a significantly lower peak VO₂ than white patients (14.2 ± 5.2 versus 16.4 ± 7.0; P < .0001), despite adjusting for identified covariates. However, there was no significant difference in the 1-year transplant-free survival between black and white HF patients (87% versus 85%; P = NS). Peak VO₂ was significantly associated with survival in both racial groups.ConclusionsBlack HF patients had significantly lower peak VO₂, but yet had equivalent survival rates at 1 year. Further study is warranted to clarify the impact of these racial differences on the timing of cardiac transplantation black HF patients.     

Analysis of Skeletal Muscle Gene Expression Patterns and the Impact of Functional Capacity in Patients With Systolic Heart Failure

BackgroundDeclining physical function is common among systolic heart failure (HF) patients and heralds poor clinical outcomes. We hypothesized that coordinated shifts in expression of ubiquitin-mediated atrophy-promoting genes are associated with muscle atrophy and contribute to decreased physical function.MethodsSystolic HF patients (left ventricular ejection fraction [LVEF] ≤40%) underwent skeletal muscle biopsies (nondominant vastus lateralis) and comprehensive physical assessments. Skeletal muscle gene expression was assessed with the use of real-time polymerase chain reaction. Aerobic function was assessed with the use of cardiopulmonary exercise and 6-minute walk tests. Strength capacity was assessed with the use of pneumatic leg press (maximum strength and power). Serologic inflammatory markers also were assessed.Results54 male patients (66.6 ± 10.0 years) were studied: 24 systolic HF patients (mean LVEF 28.9 ± 7.8%) and 30 age-matched control subjects. Aerobic and strength parameters were diminished in HF versus control. FoxO1 and FoxO3 were increased in HF versus control (7.9 ± 6.2 vs 5.0 ± 3.5, 6.5 ± 4.3 vs 4.3 ± 2.8 relative units, respectively; P ≤ .05 in both). However, atrogin-1 and MuRF-1 were similar in both groups. PGC-1α was also increased in HF (7.9 ± 5.4 vs. 5.3 ± 3.6 relative units; P < .05). Muscle levels of insulin-like growth factor (IGF) 1 as well as serum levels of tumor necrosis factor α, C-reactive protein, interleukin (IL) 1β, and IL-6 were similar in HF and control.ConclusionExpression of the atrophy-promoting genes FoxO1 and FoxO3 were increased in skeletal muscle in systolic HF compared with control, but other atrophy gene expression patterns (atrogin-1 and MuRF-1), as well as growth promoting patterns (IGF-1), were similar. PGC-1α, a gene critical in enhancing mitochondrial function and moderating FoxO activity, may play an important counterregulatory role to offset ubiquitin pathway–mediated functional decrements.     

Predictors and Outcomes of “Super-response” to Cardiac Resynchronization Therapy

BackgroundCardiac resynchronization therapy (CRT) has been shown to improve heart failure (HF) symptoms and survival. We hypothesized that a greater improvement in left-ventricular ejection fraction (LVEF) after CRT is associated with greater survival benefit.Methods and ResultsIn 693 patients across 2 international centers, the improvement in LVEF after CRT was determined. Patients were grouped as non-/modest-, moderate-, or super-responders to CRT, defined as an absolute change in LVEF of ≤5%, 6–15%, and >15%, respectively. Changes in New York Heart Association (NYHA) functional class and left ventricular end-diastolic dimension (LVEDD) were assessed for each group. There were 395 non-/modest-, 186 moderate-, and 112 super-responders. Super-responders were more likely to be female and to have nonischemic cardiomyopathy, lower creatinine, and lower pulmonary artery systolic pressure than non-/modest- and moderate-responders. Super-responders were also more likely to have lower LVEF than non-/modest-responders. There was no difference in NYHA functional class, mitral regurgitation grade, or tricuspid regurgitation grade between groups. Improvement in NYHA functional class (−0.9 ± 0.9 vs −0.4 ± 0.8 [P < .001] and −0.6 ± 0.8 [P = .02]) and LVEDD (−8.7 ± 9.9 mm vs −0.5 ± 5.0 and −2.4 ± 5.8 mm [P < .001 for both]) was greatest in super-responders. Kaplan-Meier survival analysis revealed that super-responders achieved better survival compared with non-/modest- (P < .001) and moderate-responders (P = .049).ConclusionsImprovement in HF symptoms and survival after CRT is proportionate to the degree of improvement in LV systolic function. Super-response is more likely in women, those with nonischemic substrate, and those with lower pulmonary artery systolic pressure.     

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.     

Acetazolamide and Inhaled Carbon Dioxide Reduce Periodic Breathing During Exercise in Patients With Chronic Heart Failure

BackgroundPeriodic breathing (PB) during sleep and exercise in heart failure (HF) is related to respiratory acid-base status, CO₂ chemosensitivity, and temporal dynamics of CO₂ and O₂ sensing. We studied inhaled CO₂ and acetazolamide to alter these factors and reduce PB.Methods and ResultsWe measured expired and arterial gases and PB amplitude and duration in 20 HF patients during exercise before and after acetazolamide given acutely (500 mg intravenously) and prolonged (24 hours, 2 g orally), and we performed overnight polysomnography. We studied CO₂ inhalation (1%–2%) during constant workload exercise. PB disappeared in 19/20 and 2/7 patients during 2% and 1% CO₂. No changes in cardiorespiratory parameters were observed after acute acetazolamide. With prolonged acetazolamide at rest: ventilation +2.04 ± 4.0 L/min (P = .001), tidal volume +0.11 ± 1.13 L (P = .003), respiratory rate +1.24 ± 4.63 breaths/min (NS), end-tidal PO₂ +4.62 ± 2.43 mm Hg (P = .001), and end-tidal PCO₂ −2.59 ± 9.7 mm Hg (P < .001). At maximum exercise: Watts −10% (P < .02), VO₂ −61 ± 109 mL/min (P = .04) and VCO₂ 101 ± 151 mL/min (P < .02). Among 20 patients, PB disappeared in 1 and 7 subjects after acute and prolonged acetazolamide, respectively. PB was present 80% ± 26, 65% ± 28, and 43% ± 39 of exercise time before and after acute and prolonged acetazolamide, respectively. Overnight apnea/hypopnea index decreased from 30.8 ± 83.8 to 21.1 ± 16.9 (P = .003).ConclusionsIn HF, inhaled CO₂ and acetazolamide reduce exercise PB with additional benefits of acetazolamide on sleep PB.     

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.     

Associations of Methylarginines and Homoarginine With Diastolic Dysfunction and Cardiovascular Risk Factors in Patients With Preserved Left Ventricular Ejection Fraction

BackgroundAsymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and homoarginine are considered to modulate nitric oxide synthesis. We evaluated whether ADMA, SDMA, and homoarginine are associated with diastolic dysfunction.Methods and ResultsWe investigated primary care patients at cardiovascular risk with preserved left ventricular ejection fraction from the multicenter DIAST-CHF study. We measured serum concentrations of ADMA, SDMA, and homoarginine and performed standardized echocardiographic examinations. Among 1,396 patients (mean age 65.3 ± 8.3 y, 54.6% women), diastolic dysfunction was ruled out in 261 patients (18.7%). Mild and moderate/severe grades of diastolic dysfunction were present in 900 (64.5%) and 235 (16.8%) study participants, respectively. After adjustments for cardiovascular risk factors, ADMA and SDMA were positively and homoarginine negatively associated with N-terminal pro–B-type natriuretic peptide and midregional pro-adrenomedullin (P < .05 for all). Lower homoarginine levels were associated with diastolic dysfunction, and higher ADMA and SDMA levels were associated with the severity of diastolic dysfunction (P < .05 for all).ConclusionsHigher levels of ADMA and SDMA and lower levels of homoarginine are associated with an adverse cardiovascular risk profile and diastolic dysfunction. Further studies should clarify the potential of these amino acid derivatives for the therapy of cardiovascular diseases.     

Safety and efficacy of adaptive servo-ventilation in patients with severe systolic heart failure

Background and purposeIt is unclear whether adaptive servo-ventilation (ASV) is safe and effective in patients with severe systolic heart failure (HF). Our aim in this study was to estimate the safety and efficacy of ASV therapy for patients with severe systolic HF.Methods and subjectsSeventy-six HF patients (age: 69 ± 12 years; 53 men), categorized as New York Heart Association (NYHA) Class II–IV, with left ventricular ejection fraction (LVEF) of <50%, received ASV therapy after optimal medical therapy to determine the safety and efficacy of ASV. Patients were divided into 2 groups based on their LVEF: group L (LVEF < 30%; n = 42) and group H (LVEF ≥ 30%; n = 34). After 6 months of ASV therapy, we compared the changes in LVEF, brain natriuretic peptide (BNP), and incidence of fatal cardiovascular events between the groups.ResultsThe groups differed significantly with respect to beta-blocker treatment before ASV therapy (p < 0.0001). After 6 months of ASV therapy, LVEF and BNP levels had improved in both groups. In group L, LVEF had improved from 24.1 ± 5.6% to 35.2 ± 10.6% (p < 0.0001) and BNP from 591 (273–993) pg/ml to 142 (39–325) pg/ml (p = 0.002). Moreover, 1-year follow-up data showed a tendency toward improvement of NYHA classification in group L (group L: 50%; group H: 29%; p = 0.07), and showed no significant difference with regard to fatal cardiovascular events between the 2 groups (group L: 11.9%; group H: 5.9%; p = 0.36).ConclusionsOur study demonstrated that ASV therapy is safe and effective for use in very severe systolic HF patients as well as in relatively mild systolic HF patients.     

Right Heart Dysfunction and Readmission Risk Across Left Ventricular Ejection Fraction Status in Patients With Acute Heart Failure

BackgroundRight heart dysfunction (RHD) parameters are increasingly important in heart failure (HF). This study aimed to evaluate the association of advanced RHD with the risk of recurrent admissions across the spectrum of left ventricular ejection fraction (LVEF).Methods and ResultsWe included 3383 consecutive patients discharged for acute HF. Of them, in 1435 patients (42.4%), the pulmonary artery systolic pressure could not be measured accurately, leaving a final sample size of 1948 patients. Advanced RHD was defined as the combination of a ratio of tricuspid annular plane systolic excursion/pulmonary artery systolic pressure of less than 0.36 and significant tricuspid regurgitation (n = 196, 10.2%). Negative binomial regression analyses were used to evaluate the risk of recurrent admissions. At a median follow-up of 2.2 years (interquartile range 0.63–4.71), 3782 readmissions were registered in 1296 patients (66.5%). Patients with advanced RHD showed higher readmission rates, but only if the LVEF was 40% or greater (P < .001). In multivariable analyses, this differential association persisted for cardiovascular and HF recurrent admissions (P value for interaction = .015 and P = .016; respectively). Advanced RHD was independently associated with the risk of recurrent cardiovascular and HF admissions if HF with an LVEF of 40% or greater (incidence rate ratio 1.64, 95% confidence interval 1.18–2.26, P = .003; and incidence rate ratio 1.73; 95% confidence interval 1.25–2.41, P = .001;respectively). In contrast, it was not associated with readmission risks if the LVEF was less than 40%.ConclusionsAfter an admission for acute HF, advanced RHD was strongly associated with a higher risk of recurrent cardiovascular and HF admissions, but only in patients with an LVEF of 40% or greater.     

Clonal Hematopoiesis and Risk of Progression of Heart Failure With Reduced Left Ventricular Ejection Fraction

BackgroundClonal hematopoiesis driven by somatic mutations in hematopoietic cells, frequently called clonal hematopoiesis of indeterminate potential (CHIP), has been associated with adverse cardiovascular outcomes in population-based studies and in patients with ischemic heart failure (HF) and reduced left ventricular ejection fraction (LVEF). Yet, the impact of CHIP on HF progression, including nonischemic etiology, is unknown.ObjectivesThe purpose of this study was to assess the clinical impact of clonal hematopoiesis on HF progression irrespective of its etiology.MethodsThe study cohort comprised 62 patients with HF and LVEF <45% (age 74 ± 7 years, 74% men, 52% nonischemic, and LVEF 30 ± 8%). Deep sequencing was used to detect CHIP mutations with a variant allelic fraction >2% in 54 genes. Patients were followed for at least 3.5 years for various adverse events including death, HF-related death, and HF hospitalization.ResultsCHIP mutations were detected in 24 (38.7%) patients, without significant differences in all-cause mortality (p = 0.151). After adjusting for risk factors, patients with mutations in either DNA methyltransferase 3 alpha (DNMT3A) or Tet methylcytosine dioxygenase 2 (TET2) exhibited accelerated HF progression in terms of death (hazard ratio [HR]: 2.79; 95% confidence interval [CI]: 1.31 to 5.92; p = 0.008), death or HF hospitalization (HR: 3.84; 95% CI: 1.84 to 8.04; p < 0.001) and HF-related death or HF hospitalization (HR: 4.41; 95% CI: 2.15 to 9.03; p < 0.001). In single gene-specific analyses, somatic mutations in DNMT3A or TET2 retained prognostic significance with regard to HF-related death or HF hospitalization (HR: 4.50; 95% CI: 2.07 to 9.74; p < 0.001, for DNMT3A mutations; HR: 3.18; 95% CI: 1.52 to 6.66; p = 0.002, for TET2 mutations). This association remained significant irrespective of ischemic/nonischemic etiology.ConclusionsSomatic mutations that drive clonal hematopoiesis are common among HF patients with reduced LVEF and are associated with accelerated HF progression regardless of etiology.     

Pulmonary Production of Osteopontin in Humans: Effects of Left Ventricular Systolic Dysfunction and Cardiopulmonary Bypass

BackgroundWe evaluated pulmonary production of osteopontin (OPN) in left ventricular systolic dysfunction (LVSD) and after cardiopulmonary bypass surgery (CPB). OPN is a phosphoglycoprotein involved in inflammation and remodeling. In subjects with LVSD, plasma OPN correlates with prognosis but its origin is unknown. We hypothesized that the lungs produce OPN and that this could be affected by LVSD and CPB.Methods and ResultsSubjects with (n = 57; left ventricular ejection fraction [LVEF] 32 ± 8%) and without (n = 63; LVEF 59 ± 7%) LVSD were studied during CPB. Arterial and venous OPN plasma levels were determined. Arterial and venous OPN levels were higher in LVSD (P = .0290). For both groups, levels dropped 1 hour after surgery and nearly doubled 24 hours after (P < .0001 vs basal). Notably, there was a significant positive arteriovenous gradient with arterial levels higher than venous levels. Arteriovenous differences were statistically significant at baseline (P = .0120) and 1 hour (P < .0001) but not at 24 hours (P = .0649). Arterial levels in heart failure correlated inversely with renal function (P = .016) and positively with mean pulmonary pressure (P = .028), heart rate (P = .036), and C-reactive protein (P = .047).ConclusionsThere is production of circulating OPN by the lungs, unaffected by LVSD or CPB. This likely represents an overflow from local lung production and does not contribute to increased levels in LVSD or after CPB.     

Assessment of Right Ventricular-Pulmonary Arterial Coupling in Chronic Pulmonary Regurgitation

BackgroundWe hypothesized that noninvasively measured right ventricular (RV) to pulmonary arterial (RV-PA) coupling would be abnormal in chronic pulmonary regurgitation (PR) even in the setting of normal RV ejection fraction, and that RV-PA coupling indices would have a better correlation with peak oxygen consumption (VO₂) compared with RV systolic indices alone.MethodsThis was a retrospective study of 129 adults (repaired tetralogy of Fallot [TOF] n = 84 and valvular pulmonic stenosis [VPS] with previous intervention n = 45) with ≥ moderate native PR and RV ejection fraction > 50%. The 84 TOF patients were propensity matched with 84 patients with normal echocardiogram (control); age 28 ± 7 years and male sex n = 39 (46%). RV-PA coupling was measured according to fractional area change (FAC)/RV systolic pressure (RVSP) and tricuspid annular plane systolic excursion (TAPSE)/RVSP.ResultsRV systolic function indices were similar between TOF and control groups (FAC 43 ± 6% vs 41 ± 5% [P = 0.164] and TAPSE 22 ± 5 mm vs 24 ± 6 mm [P = 0.263]). However, RV-PA coupling was lower in the TOF group (FAC/RVSP 1.10 ± 0.29 vs 1.48 ± 0.22 [P < 0.001]; TAPSE/RVSP 0.51 ± 0.15 vs 0.78 ± 0.11 [P < 0.001]) because of higher RV afterload (RVSP 42 ± 3 mm Hg vs 31 ± 3 mm Hg [P = 0.012]). FAC/RVSP (r = 0.61; P < 0.001) and TAPSE/RVSP (r = 0.69; P < 0.001) correlated with peak VO₂ especially in the patients with impaired exercise capacity whereas FAC and TAPSE were independent of peak VO₂. Similar comparisons between VPS and control groups showed no difference in TAPSE and FAC between groups, but lower FAC/RVSP and TAPSE/RVSP in the VPS group.ConclusionsThere is abnormal RV-PA coupling in chronic PR, and noninvasively measured RV-PA coupling might potentially be prognostic because of its correlation with exercise capacity.     

Left ventricular function assessment after aortic and renal intervention in Takayasu arteritis by speckle tracking echocardiography: A pilot study

BackgroundOvert left ventricular (LV) dysfunction and congestive heart failure are known entities in Takayasu arteritis (TA). Subclinical LV dysfunction may develop in these patients despite normal LV ejection fraction (LVEF). Moreover, effect of treatment of aortic or renal artery narrowing in such patients is unknown.MethodsThis study included 15 angiographically confirmed TA patients undergoing aortic and/or renal intervention. A comprehensive clinical, biochemical and echocardiographic (2-dimensional, speckle tracking and tissue doppler imaging) evaluation were done at baseline, 72 h, and six months post intervention.ResultsSix patients (40%) had reduced LVEF (<50%) at baseline while rest 9 (60%) patients had reduced global longitudinal strain (GLS) but normal EF. Diastolic filling pattern was abnormal in all the patients. In patients with baseline reduced EF, mean EF improved from 24.62 ± 12.14% to 45.6 ± 9.45% (p = 0.001), E/e’ ratio decreased from 15.15 ± 3.19 to 10.8 ± 2.56 (p = 0.005) and median NT pro BNP decreased from 1673 pg/ml (970–2401 pg/ml) to 80 pg/ml (40–354 pg/ml) (p = 0.001) at 6 months after interventional procedure. In patients with baseline normal EF, median NT pro BNP decreased from 512 pg/ml (80–898.5 pg/ml) to 34 pg/ml (29–70.8 pg/ml) (p < 0.01), mean GLS improved from ?8.80 ± 0.77% to ?16.3 ± 0.78% (p < 0.001) and mean E/e’ decreased from 12.93 ± 2.63 to 7.8 ± 2.73 (p = 0.005) at 6 months follow up.ConclusionLV dysfunction is common in patients with TA and obstructive lesions in aorta or renal arteries. GLS can be used to assess subclinical systolic dysfunction in these patients. Timely intervention can improve LV dysfunction and can even reverse the subclinical changes.     

Cardiac resynchronization therapy in patients with heart failure and moderately reduced ejection fraction: Could it trigger a super-response?

Background/AimDespite the well-established benefits of cardiac resynchronization therapy (CRT) in heart failure (HF) patients with left ventricular ejection fraction (LVEF) ≤35%, many patients with less reduced EF remain refractory to optimized medical treatment and at high risk of morbidity and mortality. The objective of the study is to evaluate the effects of CRT in optimally treated patients with New York Heart Association (NYHA) classes II–IV, LVEF of 36–45%, and left bundle branch (LBBB), including clinical, structural and biochemical response.MethodsA selected group of HF patients have been implanted with CRT-P devices and were followed up for 6 months at 4, 12 and 24 weeks. Clinical assessment included NYHA class, quality of life and 6-min walk distance (6 MWD) test. Echocardiographic assessment included LV dimensions and function and left atrial volume. Serum N-terminal pro b-type natriuretic peptide (NT-ProBNP) was measured at the same intervals.ResultsThis prospective single center study included 23 patients. NYHA functional class significantly improved after CRT-P (p < 0.0001), associated with improvement in QOL (p < 0.0001) and 6 MWD, which increased, from 145.7 ± 20.1 m to 219.5 ± 42.2 m (p < 0.0001). Mean QRS duration showed significant shortening from 164.4 ± 13.2 ms to 126.4 ± 13.6 ms (p < 0.0001). CRT induced reverse remodeling with reduction in both left ventricular end diastolic diameter (LVEDD) from 68.95 ± 5.05 mm to 62.8 ± 4.47 mm, p = 0.0002 and left ventricular end systolic diameter (LVESD) from 54.1 ± 4.5 mm to 46.5 ± 4.1 mm, p < 0.0001, and significant increase in LVEF (from 40.3 ± 2.8 to 48.3 ± 4.2 mm, p < 0.0001). The biochemical response to CRT showed significant reduction in serum NT-ProBNP from 1025.6 ± 363.1 pg/ml to 594.9 ± 263.5 pg/ml (p < 0.0001).ConclusionsSymptomatic HF patients on maximal optimized medical treatment who have LBBB and baseline LVEF 35–45% appeared to derive significant clinical and structural benefit from CRT.     

Differences in Clinical Profile of African-American Women With Peripartum Cardiomyopathy in the United States

BackgroundPeripartum cardiomyopathy (PPCM) is a rare and heterogeneous disease with a higher prevalence in African Americans (AAs) in the USA. The clinical features and prognosis of PPCM in AAs have not been sufficiently characterized.MethodsWe studied 52 AA patients with PPCM and compared clinical characteristics and outcome with those of 104 white patients.ResultsAA patients were significantly younger (26 ± 7 vs 30 ± 6 years; P < .001), had a higher prevalence of gestational hypertension (61% vs 41%; P = .03), and were diagnosed more commonly postpartum rather then antepartum (83% vs 64%; P = .03). The rate of left ventricular (LV) recovery (LV ejection fraction [LVEF] ≥50%) was significantly lower in AAs (40% vs 61%; P = .02). AA women also had a larger LV end-diastolic diameter (57 ± 10 vs 51 ± 6 mm; P = .004) as well as lower LVEF (40% ± 16.7% vs 46% ± 14%; P = .002) at the last follow-up. Moreover, AA patients had a significantly higher incidence of the combined end points of mortality and cardiac transplantation (P = .03) and showed a strong trend (P = .09) for increased mortality.ConclusionsAA patients with PPCM in the USA have a different clinical profile and worse prognosis compared with white patients. Further research to evaluate potentially correctable causes for these differences is warranted.     

Usefulness of right atrial volume index in predicting outcome in chronic systolic heart failure

BackgroundRight ventricular (RV) dysfunction is associated with poor prognosis in patients with heart failure (HF). Echocardiographic assessment of RV systolic function is challenging. The ability to visualize the right atrium (RA) allows a quantitative, highly reproducible assessment of RA volume.ObjectiveThe aim is to study the relationship between the right atrial volume index (RAVI) and prognosis in patients with chronic systolic HF.Methods120 patients with chronic systolic HF and left ventricular ejection fraction (LVEF) <40% were enrolled. The RA volume was calculated by Simpson’s method using single-plane RA area and indexed to body surface area (RAVI). RV systolic assessment was done using the RV fractional area change (RVFAC), and peak systolic velocity (Sa_tri) using tissue Doppler imaging at the tricuspid annulus. The primary endpoint was death, urgent transplantation, or acute HF episode requiring hospital admission during a follow-up of 1 year.ResultsFollow up was complete for 117 of 120 patients. Fifty-two patients reached the primary endpoint. The mean RAVI was higher in patients with adverse events (45.5 ± 15 ml/m² versus 25.2 ± 11 ml/m², p < 0.001), and increased with worsening LVEF, RVFAC, Sa_tri (Spearman’s r = −0.46, r = −0.45, r = −0.59, p < 0.001 for all). RAVI was not correlated with estimates of RV diastolic dysfunction. The cut-off threshold for RAVI to predict the primary endpoint using receiver-operating characteristic curve was 29 ml/m² (area under the curve was 0.89%, 95% confidence interval: 0.82–0.95) with a sensitivity of 92%, and a specificity of 75%. NYHA > 2 (OR = 2.1, p < 0.01), and RAVI (OR = 1.6, p < 0.05) were found to be independent predictors of adverse outcome.ConclusionIn patients with chronic systolic HF, RAVI is an independent predictor of adverse outcome with a threshold value of 29 ml/m².