Burden and Outcomes of Heart Failure Hospitalizations in Adults With Chronic Kidney Disease

BackgroundData on rates of heart failure (HF) hospitalizations, recurrent hospitalizations, and outcomes related to HF hospitalizations in chronic kidney disease (CKD) are limited.ObjectivesThis study examined rates of HF hospitalizations and re-hospitalizations within a large CKD population and evaluated the burden of HF hospitalizations with the risk of subsequent CKD progression and death.MethodsThe prospective CRIC (Chronic Renal Insufficiency Cohort) study measured the estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (ACR) at baseline. The crude rates and rate ratios of HF hospitalizations and 30-day HF re-hospitalizations were calculated using Poisson regression models. Cox regression was used to assess the association of the frequency of HF hospitalizations within the first 2 years of follow-up with risk of subsequent CKD progression and death.ResultsAmong 3,791 participants, the crude rate of HF admissions was 5.8 per 100 person-years (with higher rates of HF with preserved ejection fraction vs. HF with reduced ejection fraction). The adjusted rate of HF was higher with a lower eGFR (vs. eGFR >45 ml/min/1.73 m²); the rate ratios were 1.7 and 2.2 for eGFR 30 to 44 and <30 ml/min/1.73 m² (vs. >45 ml/min/1.73 m²), respectively. Similarly, the adjusted rates of HF hospitalization were significantly higher in those with higher urine ACR (vs. urine ACR <30 mg/g); the rate ratios were 1.9 and 2.6 for urine ACR 30 to 299 and ≥300 mg/g, respectively. Overall, 20.6% of participants had a subsequent HF re-admission within 30 days. HF hospitalization within 2 years of study entry was associated with greater adjusted risks for CKD progression (1 hospitalization: hazard ratio [HR]: 1.93; 95% confidence interval [CI]: 1.40 to 2.67; 2+ hospitalizations: HR: 2.14; 95% CI: 1.30 to 3.54) and all-cause death (1 hospitalization: HR: 2.20; 95% CI: 1.71 to 2.84; 2+ hospitalizations: HR: 3.06; 95% CI: 2.23 to 4.18).ConclusionsWithin a large U.S. CKD population, the rates of HF hospitalizations and re-hospitalization were high, with even higher rates across categories of lower eGFR and higher urine ACR. Patients with CKD hospitalized with HF had greater risks of CKD progression and death. HF prevention and treatment should be a public health priority to improve CKD outcomes.     

Multiple Plasma Biomarkers for Risk Stratification in Patients With Heart Failure and Preserved Ejection Fraction

BackgroundBetter risk stratification strategies are needed to enhance clinical care and trial design in heart failure with preserved ejection fraction (HFpEF).ObjectivesThe purpose of this study was to assess the value of a targeted plasma multi-marker approach to enhance our phenotypic characterization and risk prediction in HFpEF.MethodsIn this study, the authors measured 49 plasma biomarkers from TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial participants (n = 379) using a Multiplex assay. The relationship between biomarkers and the risk of all-cause death or heart failure-related hospital admission (DHFA) was assessed. A tree-based pipeline optimizer platform was used to generate a multimarker predictive model for DHFA. We validated the model in an independent cohort of HFpEF patients enrolled in the PHFS (Penn Heart Failure Study) (n = 156).ResultsTwo large, tightly related dominant biomarker clusters were found, which included biomarkers of fibrosis/tissue remodeling, inflammation, renal injury/dysfunction, and liver fibrosis. Other clusters were composed of neurohormonal regulators of mineral metabolism, intermediary metabolism, and biomarkers of myocardial injury. Multiple biomarkers predicted incident DHFA, including 2 biomarkers related to mineral metabolism/calcification (fibroblast growth factor-23 and OPG [osteoprotegerin]), 3 inflammatory biomarkers (tumor necrosis factor-alpha, sTNFRI [soluble tumor necrosis factor-receptor I], and interleukin-6), YKL-40 (related to liver injury and inflammation), 2 biomarkers related to intermediary metabolism and adipocyte biology (fatty acid binding protein-4 and growth differentiation factor-15), angiopoietin-2 (related to angiogenesis), matrix metalloproteinase-7 (related to extracellular matrix turnover), ST-2, and N-terminal pro–B-type natriuretic peptide. A machine-learning–derived model using a combination of biomarkers was strongly predictive of the risk of DHFA (standardized hazard ratio: 2.85; 95% confidence interval: 2.03 to 4.02; p < 0.0001) and markedly improved the risk prediction when added to the MAGGIC (Meta-Analysis Global Group in Chronic Heart Failure Risk Score) risk score. In an independent cohort (PHFS), the model strongly predicted the risk of DHFA (standardized hazard ratio: 2.74; 95% confidence interval: 1.93 to 3.90; p < 0.0001), which was also independent of the MAGGIC risk score.ConclusionsVarious novel circulating biomarkers in key pathophysiological domains are predictive of outcomes in HFpEF, and a multimarker approach coupled with machine-learning represents a promising strategy for enhancing risk stratification in HFpEF.     

Pericardial Fat and the Risk of Heart Failure

BackgroundObesity is a well-established risk factor for heart failure (HF). However, implications of pericardial fat on incident HF is unclear.ObjectivesThis study sought to examine the association between pericardial fat volume (PFV) and newly diagnosed HF.MethodsThis study ascertained PFV using cardiac computed tomography in 6,785 participants (3,584 women and 3,201 men) without pre-existing cardiovascular disease from the MESA (Multi-Ethnic Study of Atherosclerosis). Cox proportional hazards regression was used to evaluate PFV as continuous and dichotomous variable, maximizing the J-statistic: (Sensitivity + Specificity – 1).ResultsIn 90,686 person-years (median: 15.7 years; interquartile range: 11.7 to 16.5 years), 385 participants (5.7%; 164 women and 221 men) developed newly diagnosed HF. PFV was lower in women than in men (69 ± 33 cm³ vs. 92 ± 47 cm³; p < 0.001). In multivariable analyses, every 1-SD (42 cm³) increase in PFV was associated with a higher risk of HF in women (hazard ratio [HR]: 1.44; 95% confidence interval [CI]: 1.21 to 1.71; p < 0.001) than in men (HR: 1.13; 95% CI: 1.01 to 1.27; p = 0.03) (interaction p = 0.01). High PFV (≥70 cm³ in women; ≥120 cm³ in men) conferred a 2-fold greater risk of HF in women (HR: 2.06; 95% CI: 1.48 to 2.87; p < 0.001) and a 53% higher risk in men (HR: 1.53; 95% CI: 1.13 to 2.07; p = 0.006). In sex-stratified analyses, greater risk of HF remained robust with additional adjustment for anthropometric indicators of obesity (p ≤ 0.008), abdominal subcutaneous or visceral fat (p ≤ 0.03) or biomarkers of inflammation and hemodynamic stress (p < 0.001) and was similar among Whites, Blacks, Hispanics, and Chinese (interaction p = 0.24). Elevated PFV predominantly augmented the risk of HF with preserved ejection fraction (p < 0.001) rather than reduced ejection fraction (p = 0.31).ConclusionsIn this large, community-based, ethnically diverse, prospective cohort study, pericardial fat was associated with an increased risk of HF, particularly HF with preserved ejection fraction, in women and men.     

Prognostic Significance of Cardiac 123I-MIBG SPECT Imaging in Heart Failure Patients With Preserved Ejection Fraction

ObjectivesThe authors sought to elucidate the prognostic value of cardiac sympathetic nerve dysfunction as evaluated using iodine-123-labeled metaiodobenzylguanidine (¹²³I-MIBG) single-photon emission computed tomography (SPECT) imaging in patients with heart failure (HF) with preserved left ventricular ejection fraction (HFpEF).BackgroundCardiac sympathetic nerve dysfunction assessed by ¹²³I-MIBG imaging is associated with poor outcomes in chronic HF patients with reduced left ventricular ejection fraction (HFrEF). However, no information is available on the prognostic vale of cardiac ¹²³I-MIBG SPECT imaging in patients with HFpEF.MethodsWe studied 148 patients admitted for acute decompensated HF (ADHF) with nonischemic HFpEF and who underwent cardiac ¹²³I-MIBG imaging at discharge. The cardiac ¹²³I-MIBG heart-to-mediastinum ratio (H/M) was measured on the delayed planar image (late H/M). SPECT analysis of the delayed image was conducted, and the tracer uptake in all 17 regions on the polar map was scored on a 5-point scale by comparison with a sex-matched normal control database. The total defect score (TDS) was calculated by summing the score of each of the 17 segments. The primary endpoint was the association between TDS and cardiac events (the composite of emergent HF hospitalization and cardiac death).ResultsDuring a mean follow-up period of 2.4 ± 1.6 years, 61 patients experienced cardiac events. TDS was significantly associated with cardiac events after multivariate Cox adjustment (P < 0.0001). Patients with high TDS levels had a significantly greater risk of cardiac events than those with middle or low TDS levels (63% vs 40% vs 20%, respectively; P < 0.0001; HR: 4.69; 95% CI: 2.29 to 9.61; and HR: 2.46; 95% CI: 1.14 to 5.29). C-statistic of TDS was 0.730 (95% CI: 0.651 to 0.799), which was significantly higher than that of late H/M (0.607; 95% CI: 0.524 to 0.686; P = 0.0228).ConclusionsCardiac ¹²³I-MIBG SPECT imaging provided useful prognostic information in nonischemic ADHF patients with HFpEF. (Clinical Trial: Osaka Prefectural Acute Heart Failure Syndrome Registry [OPAR]: UMIN000015246)     

Long-Term Prognostic Value of Stress CMR in Patients With Heart Failure and Preserved Ejection Fraction

ObjectivesThe objectives of this study were to investigate the long-term prognostic value of inducible myocardial ischemia assessed by vasodilator stress cardiovascular magnetic resonance (CMR) in patients with HFpEF.BackgroundSome studies suggest that ischemia could play a key role in HF in patients with preserved ejection fraction (HFpEF).MethodsBetween 2008 and 2019, consecutive patients prospectively referred for stress CMR with HFpEF as defined by current guidelines, without known coronary artery disease (CAD), were followed for the occurrence of major adverse cardiovascular events (MACE), as defined by cardiovascular mortality or nonfatal myocardial infarction (MI). Secondary composite outcomes included cardiovascular mortality or hospitalization for acute HF. Cox regression analysis was performed to determine the prognostic value of inducible ischemia or late gadolinium enhancement (LGE) by CMR.ResultsAmong the 1,203 patients with HFpEF (73 ± 13 years of age; 29% males) who underwent stress CMR and completed follow-up (6.9 years interquartile range [IQR]: 6.7 to 7.7 years]), 108 experienced a MACE (9%). Kaplan-Meier analysis showed inducible ischemia and LGE were significantly associated with MACE (HR: 6.63; 95% confidence interval [CI]: 4.54 to 9.69; and HR: 2.56; 95% CI: 1.60 to 4.09, respectively; both p < 0.001) and secondary outcomes (HR: 8.40; 95% CI: 6.31 to 11.20; p < 0.001; and HR: 1.87; 95% CI: 1.27 to 2.76, respectively; p = 0.002). In multivariate analysis, inducible ischemia and LGE were independent predictors of MACE (HR: 6.10; 95% CI: 4.14 to 9.00; p < 0.001 and HR: 1.62; 95% CI: 1.06 to 2.49; p = 0.039; respectively).ConclusionsStress CMR-inducible myocardial ischemia and LGE have accurate discriminative long-term prognostic value in HFpEF patients without known CAD to predict the occurrence of MACE.     

Comparing CMR Mapping Methods and Myocardial Patterns Toward Heart Failure Outcomes in Nonischemic Dilated Cardiomyopathy

ObjectivesIn patients with nonischemic dilated cardiomyopathy (NIDCM), native T1, partition coefficient (λ_Gd), and extracellular volume fraction (ECV) mapping may offer prognostic values beyond late gadolinium enhancement (LGE), by scaling the range of myocardial changes.BackgroundIn patients with NIDCM, LGE is seen in 30% of patients and it indicates adverse prognosis.MethodsThe study mapped 6 anatomical locations using all 4 cardiac magnetic resonance (CMR) tissue-characterizing methods and associated with outcome. The authors performed T1 mapping of the myocardium and the blood pool, before and serially after contrast injection, using a Look-Locker cine gradient-echo technique to obtain T1 and the corresponding reciprocal R1 values. λ_Gd values were derived from the slopes of the least-squares regression lines for myocardial versus blood R1, then adjusted to serum hematocrit to yield ECV.ResultsConsecutive 240 NIDCM patients (49 ± 16 years of age; 38% women) underwent CMR for cardiac function, LGE, native T1, λ_Gd, and ECV. After a median of 3.8 years, 36 (15%) experienced major adverse cardiac events (MACE), including 22 heart failure hospitalizations and 14 deaths. Nonischemic LGE was detected in 34%, whereas ECV was elevated (≥1 location) in 58%. Comparing the 4 methods, mean ECV and λ_Gd both demonstrated strong association with MACE (both p < 0.001). In contrast to native T1 and LGE, ECV values from all 6 locations were associated with MACE and death, with the anteroseptum being the most significant (p < 0.0001). The number of abnormal ECV locations correlated linearly with annual MACE rates (p = 0.0003). Mean ECV was the only predictor to enter a prognostic model that contained age, sex, New York Heart Association functional class, and left ventricular ejection fraction. For every 10% increase, mean ECV portended to a 2.8-fold adjusted increase risk to MACE (p < 0.001).ConclusionsIn this study of patients with NIDCM, mapping the myocardial extent of abnormality using ECV offers prognostication toward heart failure outcomes incremental to LGE or native T1 mapping.     

Cardiopulmonary Hemodynamic Profile Predicts Mortality After Transcatheter Tricuspid Valve Repair in Chronic Heart Failure

ObjectivesThis study was designed to assess hemodynamic changes in response to transcatheter tricuspid valve edge-to-edge repair (TTVR) and to identify hemodynamic predictors associated with mortality.BackgroundSevere tricuspid regurgitation (TR) is associated with high mortality. TTVR effectively alleviates heart failure symptoms, but comprehensive hemodynamic characterization of patients undergoing TTVR is currently lacking.MethodsThis international, multicenter study included 236 patients undergoing TTVR. Data from clinical assessment, echocardiography, intraprocedural right heart catheterization, and noninvasive cardiac output measurement were analyzed. Hemodynamic predictors for mortality were identified using linear Cox regression analysis and were used for stratification of patients with subsequent analysis of survival time.ResultsPatients (median age 78 years, 53% women) were symptomatic (89% in New York Heart Association functional class III or IV) because of severe TR (grade ≥3+ in 100%). TTVR significantly reduced TR at discharge (grade ≥3+ in 16%; p < 0.001), with a corresponding 19% reduction of the right atrial v wave (21 mm Hg vs. 16 mm Hg; p < 0.001) and an improvement in cardiac output (from 3.5 to 4.0 l/min; p < 0.01). Invasive mean pulmonary artery pressure, transpulmonary gradient, pulmonary vascular resistance, and right ventricular stroke work were significant predictors of 1-year mortality (p < 0.05 for all). Hemodynamic stratification by mean pulmonary artery pressure and transpulmonary gradient best predicted 1-year survival (p < 0.001). Although patients with pre-capillary dominant pulmonary hypertension showed an unfavorable prognosis (1-year survival 38%), patients without or with post-capillary pulmonary hypertension had favorable outcome (1-year survival 92% or 78%, respectively).ConclusionsInvasive assessment of cardiopulmonary hemodynamic status predicts survival after TTVR. Invasive hemodynamic characterization may help identify patients profiting most from TTVR.     

Readmission and Mortality After Hospitalization for Myocardial Infarction and Heart Failure

BackgroundReadmission rates after acute myocardial infarction (AMI) and heart failure (HF) hospitalizations have decreased in the United States since the implementation of the Hospital Readmissions Reduction Program.ObjectivesThis study was designed to examine the temporal trends of readmission and mortality after AMI and HF in Ontario, Canada, where reducing hospital readmissions has not had a policy incentive.MethodsThe cohort was comprised of AMI or HF patients 65 years of age or older who had been hospitalized from 2006 to 2017. Primary outcomes were 30-day readmission and post-discharge mortality. Secondary outcomes included in-hospital mortality, 30-day mortality from admission, and in-hospital mortality or 30-day mortality post-discharge. Adjusted monthly trends for each outcome were examined over the study period.ResultsOur cohorts included 152,808 AMI and 223,283 HF patients. Age- and sex-standardized AMI hospitalization rates in Ontario declined 32% from 2006 to 2017 while HF hospitalization rates declined slightly (9.1%). For AMI, risk-adjusted 30-day readmission rates declined from 17.4% in 2006 to 14.7% in 2017. All AMI risk-adjusted mortality rates also declined from 2006 to 2017 with 30-day post-discharge mortality from 5.1% to 4.4%. For HF, overall risk-adjusted 30-day readmission was largely unchanged from 2006 to 2014 at 21.9%, followed by a decline to 20.8% in 2017. Risk-adjusted 30-day post-discharge mortality declined from 7.1% in 2006 to 6.6% in 2017.ConclusionsThe patterns of outcomes in Ontario are consistent with the United States for AMI, but diverge for HF. For AMI and HF, admissions, readmissions, and mortality rates declined over this period. The reasons for the country-specific patterns for HF need further exploration.     

Incident Heart Failure and Long-Term Risk for Venous Thromboembolism

BackgroundHeart failure (HF) hospitalization places patients at increased short-term risk for venous thromboembolism (VTE). Long-term risk for VTE associated with incident HF, HF subtypes, or structural heart disease is unknown.ObjectivesIn the ARIC (Atherosclerosis Risk In Communities) cohort, VTE risk associated with incident HF, HF subtypes, and abnormal echocardiographic measures in the absence of clinical HF was assessed.MethodsDuring follow-up, ARIC identified incident HF and subcategorized HF with preserved ejection fraction or reduced ejection fraction. At the fifth clinical examination, echocardiography was performed. Physicians adjudicated incident VTE using hospital records. Adjusted Cox proportional hazards models were used to evaluate the association between HF or echocardiographic exposures and VTE.ResultsOver a mean of 22 years in 13,728 subjects, of whom 2,696 (20%) developed incident HF, 729 subsequent VTE events were identified. HF was associated with increased long-term risk for VTE (adjusted hazard ratio: 3.13; 95% confidence interval: 2.58 to 3.80). In 7,588 subjects followed for a mean of 10 years, the risk for VTE was similar for HF with preserved ejection fraction (adjusted hazard ratio: 4.71; 95% CI: 2.94 to 7.52) and HF with reduced ejection fraction (adjusted hazard ratio: 5.53; 95% confidence interval: 3.42 to 8.94). In 5,438 subjects without HF followed for a mean of 3.5 years, left ventricular relative wall thickness and mean left ventricular wall thickness were independent predictors of VTE.ConclusionsIn this prospective population-based study, incident hospitalized HF (including both heart failure with preserved ejection fraction and reduced ejection fraction), as well as echocardiographic indicators of left ventricular remodeling, were associated with greatly increased risk for VTE, which persisted through long-term follow-up. Evidence-based strategies to prevent long-term VTE in patients with HF, beyond time of hospitalization, are needed.     

Impact of Persistent Microvascular Obstruction Late After STEMI on Adverse LV Remodeling: A CMR Study

BackgroundLittle is known about the occurrence and implications of persistent microvascular obstruction (MVO) after reperfused ST-segment elevation myocardial infarction (STEMI).ObjectivesThe authors used cardiac magnetic resonance (CMR) to characterize the impact of persistent MVO on adverse left ventricular remodeling (ALVR).MethodsA prospective registry of 471 STEMI patients underwent CMR 7 (IQR: 5-10) days and 198 (IQR: 167-231) days after infarction. MVO (≥1 segment) and ALVR (relative increase >15% at follow-up CMR) of left ventricular end-diastolic index (LVEDVI) and left ventricular end-systolic volume index (LVESVI) were determined.ResultsOne-week MVO occurred in 209 patients (44%) and persisted in 30 (6%). The extent of MVO (P = 0.026) and intramyocardial hemorrhage (P = 0.001) at 1 week were independently associated with the magnitude of MVO at follow-up CMR. Compared with patients without MVO (n = 262, 56%) or with MVO only at 1 week (n = 179, 38%), those with persistent MVO at follow-up (n = 30, 6%) showed higher rates of ALVR-LVEDVI (22%, 27%, and 50%; P = 0.003) and ALVR-LVESVI (20%, 21%, and 53%; P < 0.001). After adjustment, persistent MVO at follow-up (≥1 segment) was independently associated with ΔLVEDVI (relative increase, %) (P < 0.001) and ΔLVESVI (P < 0.001). Compared with a 1:1 propensity score–matched population on CMR variables made up of 30 patients with MVO only at 1 week, patients with persistent MVO more frequently displayed ALVR-LVEDVI (12% vs 50%; P = 0.003) and ALVR-LVESVI (12% vs 53%; P = 0.001).ConclusionsMVO persists in a small percentage of patients in chronic phase after STEMI and exerts deleterious effects in terms of LV remodeling. These findings fuel the need for further research on microvascular injury repair.     

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.     

Prognostic Role of CMR and Conventional Risk Factors in Myocardial Infarction With Nonobstructed Coronary Arteries

ObjectivesThis study sought to assess the prognostic impact of cardiac magnetic resonance (CMR) and conventional risk factors in patients with myocardial infarction with nonobstructed coronaries (MINOCA).BackgroundMyocardial infarction with nonobstructed coronary arteries (MINOCA) represents a diagnostic dilemma, and the prognostic markers have not been clarified.MethodsA total of 388 consecutive patients with MINOCA undergoing CMR assessment were identified retrospectively from a registry database and prospectively followed for a primary clinical endpoint of all-cause mortality. A 1.5-T CMR was performed using a comprehensive protocol (cines, T2-weighted, and late gadolinium enhancement sequences). Patients were grouped into 4 categories based on their CMR findings: myocardial infarction (MI) (embolic/spontaneous recanalization), myocarditis, cardiomyopathy, and normal CMR.ResultsCMR (performed at a median of 37 days from presentation) was able to identify the cause for the troponin rise in 74% of the patients (25% myocarditis, 25% MI, and 25% cardiomyopathy), whereas a normal CMR was identified in 26%. Over a median follow-up of 1,262 days (3.5 years), 5.7% patients died. The cardiomyopathy group had the worst prognosis (mortality 15%; log-rank test: 19.9; p < 0.001), MI had 4% mortality, and 2% in both myocarditis and normal CMR. In a multivariable Cox regression model (including clinical and CMR parameters), CMR diagnosis of cardiomyopathy and ST-segment elevation on presentation electrocardiogram (ECG) remained the only 2 significant predictors of mortality. Using presentation with ECG ST-segment elevation and CMR diagnosis of cardiomyopathy as risk markers, the mortality risk rates were 2%, 11%, and 21% for presence of 0, 1, and 2 factors, respectively (p < 0.0001).ConclusionsIn a large cohort of patients with MINOCA, CMR (median 37 days from presentation) identified a final diagnosis in 74% of patients. Cardiomyopathy had the highest mortality, followed by MI. The strongest predictors of mortality were a CMR diagnosis of cardiomyopathy and ST-segment elevation on presentation ECG.     

Relationship of Mechanical Dyssynchrony and LV Remodeling With Improvement of Mitral Regurgitation After CRT

ObjectivesThe aim of this study was to explore the association between mechanical dyssynchrony of the left ventricle before cardiac resynchronization therapy (CRT) and improvement of mitral regurgitation (MR) after CRT.BackgroundMR is very frequent among patients with dilated cardiomyopathy and conduction delay.MethodsEchocardiograms (pre-CRT and 12 ± 3.8 months thereafter) of 314 patients with dilated cardiomyopathy and any degree of MR, who underwent CRT device implantation according to guidelines, were analyzed. Left ventricular (LV) mechanical dyssynchrony was assessed by apical rocking (ApRock) and septal flash (SF), while MR severity was graded from I to IV on the basis of vena contracta width, regurgitation jet size, and proximal isovelocity surface area.ResultsAt baseline, 30% of patients presented with severe MR (grade III or IV). In 62% of patients, MR decreased after CRT, and these patients more frequently had left bundle branch block, had more severe MR, had more dilated left ventricles, had lower ejection fractions, and more often had ApRock and SF. Reverse remodeling was more frequent among patients with MR reduction (ΔLV end-systolic volume ?35.5% ± 27.2% vs ?4.1% ± 33.2%; P < 0.001). In a multivariable logistic stepwise regression, only ApRock (odds ratio [OR]: 3.8; 95% CI: 1.7-8.5; P = 0.001), SF (OR: 3.6; 95% CI: 1.6-7.9; P = 0.002), and baseline MR (OR: 1.4; 95% CI: 1.0-1.9; P = 0.046) remained significantly associated with MR reduction.ConclusionsApRock, SF, and severity of MR at baseline are strongly associated with MR reduction after CRT, while LV reverse remodeling is its underlying mechanism. Therefore, in patients with heart failure with LV dyssynchrony on optimal medical treatment, CRT should be the primary treatment attempt for relevant MR.     

Survival After Implantable Cardioverter-Defibrillator Shocks

BackgroundThere are conflicting data on the impact of implantable cardioverter-defibrillator (ICD) shocks on subsequent mortality.ObjectivesThe aim of this study was to determine whether the arrhythmic substrate leading to ICD therapy or the therapy itself increases mortality.MethodsThe study cohort included 5,516 ICD recipients who were enrolled in 5 landmark ICD trials (MADIT-II, MADIT-RISK, MADIT-CRT, MADIT-RIT, RAID). The authors evaluated the association of device therapy with subsequent mortality in 4 separate time-dependent models: model I, type of ICD therapy; model II, type of arrhythmia for which ICD therapy was delivered; model III, combined assessment of all arrhythmia and therapy types during follow-up; and model IV, incremental risk associated with repeated ICD shocks.ResultsWhen analyzed by the type of ICD therapy (model I), a first appropriate ICD shock was associated with increased risk of subsequent mortality with or without concomitant occurrence of inappropriate shock during follow-up (hazard ratio [HR]: 2.78 and 2.31; p < 0.001 and p = 0.12), whereas inappropriate shock alone was not associated with mortality risk (HR: 1.23; p = 0.42). Similarly, ICD therapy for ventricular tachycardia (VT) ≥200 beats/min or ventricular fibrillation (VF) (model II) was associated with increased risk of death with or without concomitant therapy for VT <200 beats/min (HRs: 2.25 and 2.62; both p < 0.001), whereas appropriate therapy for VT <200 beats/min or inappropriate therapy (regardless of etiology) did not reach statistical significance (all p > 0.10). Combined assessment of all therapy and arrhythmia types during follow-up (model III) showed that appropriate ICD shocks for VF, shocks for fast VT (≥200 beats/min) without prior antitachycardia pacing (ATP), as well as shocks for fast VT delivered after failed ATP, were associated with the highest risk of subsequent death (HR: all >2.8; p < 0.001). Finally, 2 or more ICD appropriate shocks were not associated with incremental risk to the first appropriate ICD shock (model IV).ConclusionThe combined data from 5 landmark ICD trials suggest that the underlying arrhythmic substrate rather than the ICD therapy is the more important determinant of mortality in ICD recipients.     

Age-Related Outcomes After Transcatheter Mitral Valve Repair in Patients With Heart Failure: Analysis From COAPT

ObjectivesThe aim of this study was to assess the impact of age on outcomes in patients undergoing transcatheter edge-to-edge repair (TEER) from the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation) trial.BackgroundIn the COAPT trial, TEER with the MitraClip device in patients with heart failure (HF) and moderate to severe or severe secondary mitral regurgitation (SMR) reduced the risk for HF hospitalization (HFH) and all-cause mortality compared with maximally tolerated guideline-directed medical therapy (GDMT) alone. There are limited data regarding the effectiveness of MitraClip therapy in elderly patients.MethodsPatients (n = 614) were grouped by median age at randomization (74 years) and by MitraClip treatment vs GDMT alone. The primary endpoint was the 2-year rate of death or HFH assessed by multivariable Cox regression.ResultsDeath or HFH within 2 years occurred less frequently after treatment with the MitraClip vs GDMT alone in patients <74 years of age (37.3% vs 64.5%; adjusted HR: 0.41; 95% CI: 0.29-0.59) and ≥74 years of age (51.7% vs 69.6%; adjusted HR: 0.58; 95% CI: 0.42-0.81) (P_int = 0.17). Mortality was also consistently reduced with MitraClip treatment in young and elderly patients (P_int = 0.42). In contrast, elderly patients treated with the MitraClip vs GDMT alone tended to have a lesser reduction of HFH than younger patients (P_int = 0.03). Younger and older patients had similar improvements in quality of life after treatment with the MitraClip compared with GDMT alone.ConclusionsIn the COAPT trial, MitraClip treatment of moderate to severe and severe SMR reduced the composite risk for death or HFH and improved survival and quality of life regardless of age. As such, young and elderly patients with HF and severe SMR benefit from TEER, although elderly patients may not have as great a benefit from the MitraClip device in reducing HFH.     

Myocardial Angiotensin Metabolism in End-Stage Heart Failure

BackgroundThe myocardium exhibits an adaptive tissue-specific renin-angiotensin system (RAS), and local dysbalance may circumvent the desired effects of pharmacologic RAS inhibition, a mainstay of heart failure with reduced ejection fraction (HFrEF) therapy.ObjectivesThis study sought to investigate human myocardial tissue RAS regulation of the failing heart in the light of current therapy.MethodsFifty-two end-stage HFrEF patients undergoing heart transplantation (no RAS inhibitor: n = 9; angiotensin-converting enzyme [ACE] inhibitor: n = 28; angiotensin receptor blocker [ARB]: n = 8; angiotensin receptor neprilysin-inhibitor [ARNi]: n = 7) were enrolled. Myocardial angiotensin metabolites and enzymatic activities involved in the metabolism of the key angiotensin peptides angiotensin 1-8 (AngII) and Ang1-7 were determined in left ventricular samples by mass spectrometry. Circulating angiotensin concentrations were assessed for a subgroup of patients.ResultsAngII and Ang2-8 (AngIII) were the dominant peptides in the failing heart, while other metabolites, especially Ang1-7, were below the detection limit. Patients receiving an ARB component (i.e., ARB or ARNi) had significantly higher levels of cardiac AngII and AngIII (AngII: 242 [interquartile range (IQR): 145.7 to 409.9] fmol/g vs 63.0 [IQR: 19.9 to 124.1] fmol/g; p < 0.001; and AngIII: 87.4 [IQR: 46.5 to 165.3] fmol/g vs 23.0 [IQR: <5.0 to 59.3] fmol/g; p = 0.002). Myocardial AngII concentrations were strongly related to circulating AngII levels. Myocardial RAS enzyme regulation was independent from the class of RAS inhibitor used, particularly, a comparable myocardial neprilysin activity was observed for patients with or without ARNi. Tissue chymase, but not ACE, is the main enzyme for cardiac AngII generation, whereas AngII is metabolized to Ang1-7 by prolyl carboxypeptidase but not to ACE2. There was no trace of cardiac ACE2 activity.ConclusionsThe failing heart contains considerable levels of classical RAS metabolites, whereas AngIII might be an unrecognized mediator of detrimental effects on cardiovascular structure. The results underline the importance of pharmacologic interventions reducing circulating AngII actions, yet offer room for cardiac tissue-specific RAS drugs aiming to limit myocardial AngII/AngIII peptide accumulation and actions.     

Evolution of Myocardial Tissue Injury: A CMR Study Over a Decade After STEMI

BackgroundIn patients with a first ST-segment elevation myocardial infarction (STEMI), the multi-annual evolution of myocardial tissue injury parameters, as assessed by cardiac magnetic resonance (CMR), has not yet been described.ObjectivesThis study examined myocardial tissue injury dynamics over a decade after STEMI.MethodsSequential CMR examinations (within the first week after STEMI, and at 4, 12, months, and 9 years thereafter) were conducted in 74 patients with STEMI treated with primary percutaneous coronary intervention. Left ventricular function, infarct size (IS), and microvascular obstruction (MVO) were assessed at all time points. T21, T2, and T1 mapping (n = 59) were added at 9-year scan to evaluate the presence of iron and edema within the infarct core, respectively.ResultsIS decreased progressively and significantly between all CMR time points (all P < 0.001), with an average reduction rate of 5.8% per year (IQR: 3.5%-8.8%) and a relative reduction of 49% (IQR: 39%-76%) over a decade. MVO was present in 61% of patients at baseline, but was not present at the follow-up examinations. At 9-year CMR, 17 of 59 (29%) patients showed iron deposition within the infarct core, whereas 82% had persistent edema. Persistent iron and edema were associated with greater IS on any occasion (all P < 0.001), as well as the presence of MVO (P < 0.001). Patients with persistent iron and edema showed a lower relative regression of IS (P = 0.005 and P = 0.032, respectively) and greater end-systolic volumes over a decade (all P < 0.012 and P > 0.023, respectively). A T1 hypointense infarct core without evidence of T21 iron deposition (14 of 59 [24%] patients) was attributed to lipomatous metaplasia of the infarct.ConclusionsThe evolution of IS is a dynamic process that extends well beyond the first few months after STEMI. Persistence of iron and edema within the infarct core occurs up to a decade after STEMI and is associated with initial infarct severity and poor infarct healing.     

Moderate Aortic Stenosis in Patients With Heart Failure and Reduced Ejection Fraction

BackgroundThe study investigators previously reported that moderate aortic stenosis (AS) is associated with a poor prognosis in patients with heart failure (HF) with reduced left ventricular ejection fraction (LVEF) (HFrEF). However, the respective contribution of moderate AS versus HFrEF to the outcomes of these patients is unknown.ObjectivesThis study sought to determine the impact of moderate AS on outcomes in patients with HFrEF.MethodsThe study included 262 patients with moderate AS (aortic valve area >1.0 and <1.5 cm²; and peak aortic jet velocity >2 and <4 m/s, at rest or after dobutamine stress echocardiography) and HFrEF (LVEF <50%). These patients were matched 1:1 for sex, age, estimated glomerular filtration rate, New York Heart Association functional class III to IV, presence of diabetes, LVEF, and body mass index with patients with HFrEF but no AS (i.e., peak aortic jet velocity <2 m/s). The endpoints were all-cause mortality and the composite of death and HF hospitalization.ResultsA total of 262 patients with HFrEF and moderate AS were matched with 262 patients with HFrEF and no AS. Mean follow-up was 2.9 ± 2.2 years. In the moderate AS group, mean aortic valve area was 1.2 ± 0.2 cm², and mean gradient was 14.5 ± 4.7 mm Hg. Moderate AS was associated with an increased risk of mortality (hazard ratio [HR]: 2.98; 95% confidence interval [CI]: 2.08 to 4.31; p < 0.0001) and of the composite of HF hospitalization and mortality (HR: 2.34; 95% CI: 1. 72 to 3.21; p < 0.0001). In the moderate AS group, aortic valve replacement (AVR) performed in 44 patients at a median follow-up time of 10.9 ± 16 months during follow-up was associated with improved survival (HR: 0.59; 95% CI: 0.35 to 0.98; p = 0.04). Notably, surgical AVR was not significantly associated with improved survival (p = 0.92), whereas transcatheter AVR was (HR: 0.43; 95% CI: 0.18 to 1.00; p = 0.05).ConclusionsIn this series of patients with HFrEF, moderate AS was associated with a marked incremental risk of mortality. AVR, and especially transcatheter AVR during follow-up, was associated with improved survival in patients with HFrEF and moderate AS. These findings provide support to the realization of a randomized trial to assess the effect of early transcatheter AVR in patients with HFrEF and moderate AS.     

Prevalence and Prognostic Significance of Microvascular Dysfunction in Heart Failure With Preserved Ejection Fraction

BackgroundThe pathophysiological and clinical significance of microvascular dysfunction (MVD) in patients with heart failure with preserved ejection fraction (HFpEF) remains uncertain.ObjectivesThe aim of this study was to use cardiovascular magnetic resonance to: 1) quantify coronary microvascular function; 2) examine the relationship between perfusion and fibrosis; and 3) evaluate the impact of MVD and fibrosis on long-term clinical outcomes.MethodsIn a prospective, observational study, patients with HFpEF and control subjects underwent multiparametric cardiovascular magnetic resonance (comprising assessment of left ventricular volumetry, perfusion, and fibrosis [focal by late gadolinium enhancement and diffuse by extracellular volume]). The primary endpoint was the composite of death or hospitalization with heart failure.ResultsOne hundred and one patients with HFpEF (mean age 73 ± 9 years, mean ejection fraction 56% ± 5%) and 43 control subjects (mean age 73 ± 5 years, mean ejection fraction 58% ± 5%) were studied. Myocardial perfusion reserve (MPR) was lower in patients with HFpEF versus control subjects (1.74 ± 0.76 vs 2.22 ± 0.76; P = 0.001). MVD (defined as MPR <2.0) was present in 70% of patients with HFpEF (vs 48% of control subjects; P = 0.014). There was no significant linear correlation between MPR and diffuse fibrosis (r = ?0.10; P = 0.473) and no difference in MPR between those with and without focal fibrosis (mean difference ?0.03; 95% CI: ?0.37 to 0.30). In the HFpEF group, during median follow-up of 3.1 years, there were 45 composite events. MPR was independently predictive of clinical outcome following adjustment for clinical, blood, and imaging parameters (1 SD increase: HR: 0.673 [95% CI: 0.463 to 0.978; P = 0.038]; HR: 0.694 [95% CI: 0.491 to 0.982; P = 0.039]; and HR: 0.690 [95% CI: 0.489 to 0.973; P = 0.034], respectively).ConclusionsMVD is highly prevalent among patients with HFpEF and is an independent predictor of prognosis. The lack of correlation between MVD and fibrosis may challenge the assertion of a direct causal link between these entities. (Developing Imaging and Plasma Biomarkers in Describing Heart Failure With Preserved Ejection Fraction [DIAMONDHFpEF]; NCT03050593)     

A Noncontrast CMR Risk Score for Long-Term Risk Stratification in Reperfused ST-Segment Elevation Myocardial Infarction

ObjectivesThis study compared the prognostic value of a noncontrast CMR risk score for the composite of all-cause death, nonfatal myocardial infarction, and new congestive heart failure.BackgroundA cardiovascular magnetic resonance (CMR) risk score including left ventricular ejection fraction (LVEF), myocardial infarct (MI) size, and microvascular obstruction (MVO) was recently proposed to risk-stratify patients with ST-segment elevation myocardial infarction (STEMI).MethodsThe Eitel CMR risk score and GRACE (Global Registry of Acute Coronary Events) score were used as a reference (Score 1: acute MI size ≥19% LV, LVEF ≤47%, MVO >1.4% LV and GRACE score). MVO was replaced by intramyocardial hemorrhage (IMH) in Score 2 (acute MI size ≥19% LV, LVEF ≤47%, IMH, and GRACE score). Score 3 included only LVEF ≤45%, IMH, and GRACE score.ResultsThere were 370 patients in the derivation cohort and 234 patients in the validation cohort. In the derivation cohort, the 3 scores performed similarly and better than GRACE score to predict the 1-year composite endpoint with C-statistics of 0.83, 0.83, 0.82, and 0.74, respectively. In the validation cohort, there was good discrimination and calibration of score 3, with a C-statistic of 0.87 and P = 0.71 in a Hosmer-Lemeshow test for goodness of fit, on the 1-year composite outcome. Kaplan-Meier curves for 5-year composite outcome showed that those with LVEF ≤45% (high-risk) and LVEF >45% and IMH (intermediate-risk) had significantly higher cumulative events than those with LVEF >45% and no IMH (low-risk), log-rank tests: P = 0.02 and P = 0.03, respectively. The HR for the high-risk group was 2.3 (95% CI: 1.1-4.7) and for the intermediate-risk group was 2.0 (95% CI: 1.0-3.8), and these remained significant after adjusting for the GRACE score.ConclusionsThis noncontrast CMR risk score has performance comparable to an established risk score, and patients with STEMI could be stratified into low risk (LVEF >45% and no IMH), intermediate risk (LVEF >45% and IMH), and high risk (LVEF ≤45%). (A Trial of Low-dose Adjunctive alTeplase During prIMary PCI [T-TIME]; NCT02257294) (Detection and Significance of Heart Injury in ST Elevation Myocardial Infarction [BHF MR-MI]; NCT02072850)