Cardiac Resynchronization Therapy for Patients with Mild to Moderately Reduced Ejection Fraction and Left Bundle Branch Block.

BACKGROUND: It is unknown if CRT would improve or halt the progression of heart failure (HF) in patients with mild-moderately reduced LVEF (HFmmrEF) and LBBB. OBJECTIVE: To investigate the outcomes of CRT in patients with HFmmrEF and LV conduction delay. METHODS: A prospective, randomized clinical trial sponsored by NHLBI included 76 patients who met the study inclusion criteria (LVEF 36-50% and LBBB). Patients received CRTP and were randomized to CRT-OFF (RV pacing 40bpm) or CRT-ON (BIV pacing 60-150bpm). At a 6-month follow-up, pacing programming was changed to the opposite settings. NYHA class, NT pro-BNP levels, and echocardiography were collected at baseline, 6-month, and 12-month. The primary study endpoint was the LV end-systolic volume (LVESV) change from baseline, and the primary randomized comparison was the comparison of 6-month to 12-month changes between randomized groups. RESULTS: The mean patient age was 68.4±9.8 years (male 71%). Baseline characteristics were similar between 2 randomized groups (all P>0.05). In patients randomized to CRT-OFF first, then ON, LVESV was reduced from baseline only after CRT-ON (baseline 116.1±36.5 mL, CRT-ON 87.6±26.0 mL, P<0.0001). The randomized analysis of LVEF showed a significantly better change from 6 to 12 months in the "OFF-ON" group, P=0.003. LVEF was improved by CRT (baseline 41.3±4.7%, CRT-ON 46.0±8.0%, P=0.002). In patients randomized to CRT-ON first, then OFF, LVESV was reduced both after CRT-ON and CRT-OFF (baseline 109.8±23.5 mL, CRT-ON 91.7±30.5 mL, P<0.0001; CRT-OFF 99.3±28.9 mL, P=0.012). However, the LVESV reduction effect became smaller between CRT-ON and OFF (P=0.027). LVEF improved both after CRT-ON and CRT-OFF (baseline 42.7±4.3%, CRT-ON 48.5±8.6%, P<0.001; CRT-OFF 45.9±7.7%, P=0.025). CONCLUSION: CRT for patients with HFmmrEF significantly improves LVEF and ventricular remodeling after 6 months of CRT. The study provides novel evidence that early CRT benefits patients with HFmmrEF with LBBB.

Arrhythmic manifestations and outcomes of definite and probable cardiac sarcoidosis.

BACKGROUND: The 2014 Heart Rhythm Society consensus statement defines histological (definite) and clinical (probable) diagnostic categories of cardiac sarcoidosis (CS), but few studies have compared their arrhythmic phenotypes and outcomes. OBJECTIVE: The purpose of this study was to evaluate the electrophysiological/arrhythmic phenotype and outcomes of patients with definite and probable CS. METHODS: We analyzed the arrhythmic/electrophysiological phenotype in a single-center North American cohort of 388 patients (median age 56 years; 39% female, n = 151) diagnosed with definite (n = 58) or probable (n = 330) CS (2000-2022). The primary composite outcome was survival to first ventricular tachycardia/fibrillation (VT/VF) event or sudden cardiac death. Key secondary outcomes were also assessed. RESULTS: At index evaluation, in situ cardiac implantable electronic devices and antiarrhythmic drug use were more common in definite CS. At a median follow-up of 3.1 years, the primary outcome occurred in 22 patients with definite CS (38%) and 127 patients with probable CS (38%) (log-rank, P = .55). In multivariable analysis, only a higher ratio of the 18F-fluorodeoxyglucose maximum standardized uptake value of the myocardium to the maximum standardized uptake value of the blood pool (hazard ratio 1.09; 95% confidence interval 1.03-1.15; P = .003, per 1 unit increase) was associated with the primary outcome. During follow-up, patients with definite CS had a higher burden of device-treated VT/VF events (mean 2.86 events per patient-year vs 1.56 events per patient-year) and a higher rate of progression to heart transplant/left ventricular assist device implantation but no difference in all-cause mortality compared with patients with probable CS. CONCLUSION: Patients with definite and probable CS had similarly high risks of first sustained VT/VF/sudden cardiac death and all-cause mortality, though patients with definite CS had a higher overall arrhythmia burden. Both CS diagnostic groups as defined by the 2014 Heart Rhythm Society criteria require an aggressive approach to prevent arrhythmic complications.

Outcomes of transcatheter aortic valve replacement in patients with and without amyloidosis: A nationwide analysis from the United States.

BACKGROUND: Amyloidosis is a common comorbidity in elderly patients with aortic stenosis (AS) referred for transcatheter aortic valve replacement (TAVR). This study aims to assess the impact of amyloidosis on the clinical outcomes of TAVR. METHODS: This is a retrospective study of the National Inpatient Sample database that identified adult patients (≥18 years) with AS hospitalized for TAVR from 2016 through 2020 to compare outcomes in those with versus without amyloidosis. Our primary outcome was in-hospital mortality. Secondary outcomes included procedural complications, hospital length of stay (LOS), and total costs. TAVR trends in both cohorts were also evaluated. RESULTS: The total cohort included 304,710 patients with AS undergoing TAVR, of whom 410 had amyloidosis. Over the study period, TAVR trends increased significantly in patients with and without amyloidosis (both ptrend < 0.01). Patients with amyloidosis were more likely to be older males with atrial fibrillation/flutter, congestive heart failure, renal disease, and dementia compared to non-amyloidosis patients. After adjustment for baseline characteristics, patients with amyloidosis had similar odds of in-hospital mortality (adjusted odds ratio [aOR] 1.66, 95 % confidence interval [CI] 0.34-3.63), heart block (aOR 1.33, 95 % CI 0.84-2.10), permanent pacemaker insertion (aOR 0.67, 95 % CI 0.27-1.66), stroke (aOR 0.90, 95 % CI 0.32-3.13), acute kidney injury, major bleeding, blood transfusion, vascular complications, in addition to similar LOS (p = 0.21) and total costs (p = 0.18) compared to patients without amyloidosis. CONCLUSION: In patients with AS undergoing TAVR, comorbid amyloidosis is associated with similar in-hospital mortality and procedural complications compared to patients without amyloidosis.

Cardiac fludeoxyglucose-18 positron emission tomography in genotype-positive arrhythmogenic cardiomyopathy.

BACKGROUND: Myocardial inflammation contributes to the pathogenesis of arrhythmogenic cardiomyopathy (ACM), a clinically and genetically heterogenous disorder. Due to phenotypic overlap, some patients with genetic ACM may be evaluated for an underlying inflammatory cardiomyopathy. However, the cardiac fludeoxyglucose (FDG) positron emission tomography (PET) findings in ACM patients have not been elucidated. METHODS: All genotype-positive patients in the Mayo Clinic ACM registry (n = 323) who received a cardiac FDG PET were included in this study. Pertinent data were extracted from the medical record. RESULTS: Collectively, 12/323 (4%; 67% female) genotype-positive ACM patients received a cardiac PET FDG scan as part of their clinical evaluation (median age at scan 49 ± 13 years). Amongst these patients, pathogenic/likely pathogenic variants were detected in LMNA (n = 7), DSP (n = 3), FLNC (n = 1) and PLN (n = 1). Of note, 6/12 (50%) had abnormal myocardial FDG uptake, including diffuse (entire myocardium) uptake in 2/6 (33%), focal (1-2 segments) uptake in 2/6 (33%) and patchy (3+ segments) in 2/6 (33%). Median myocardial standardized uptake value ratio was 2.1. Interestingly, LMNA-positive patients accounted for 3 out of 6 (50%) positive studies (diffuse uptake in 2 and focal uptake in 1). CONCLUSION: Abnormal myocardial FDG uptake is common in genetic ACM patients undergoing cardiac FDG PET. This study further supports the role of myocardial inflammation in ACM. Further investigation is needed to determine role of FDG PET in diagnosis and management of ACM and investigate the role of inflammation in ACM.

Routine Laboratory Biomarkers As Prognostic Indicators of Cardiac Sarcoidosis Outcomes.

Background: Biomarkers to monitor disease activity and predict major adverse cardiac events (MACE) in CS have not been described previously. We aimed to identify biomarkers to predict MACE in cardiac sarcoidosis (CS). Methods: Patients (N=232) diagnosed with CS were retrospectively enrolled. Biomarkers including angiotensin-converting enzyme (ACE), N-terminal brain natriuretic peptide (NT-proBNP), troponin T, and creatinine levels were evaluated against a primary end point of left ventricular assist device implantation, heart transplantation, or death, and a secondary end point of cardiac hospitalization-free survival. Results: Troponin T (hazard ratio [HR], 1.06 per 0.01 ng/mL; P=.006), NT-proBNP (HR, 1.31 per 1,000 pg/mL; P<.001), and creatinine (HR, 4.02 per mg/dL; P=.01) were associated with the primary end point, even after adjusting for ejection fraction. NT-proBNP, B-type natriuretic peptide (BNP), creatinine, albumin, and calcium were associated with the secondary end point (P<.05). ACE levels were associated with presence of late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) imaging (mean difference, 14.7; P=.03); 1,25 dihydroxyvitamin D (1,25-OHVit-D) was associated with uptake on cardiac 18F-flurodeoxyglucose position emission tomography (FDG-PET, P=.03). Conclusions: Troponin T, NT-proBNP, and creatinine predict clinically significant outcomes in CS. ACE levels correlated with LGE on CMR, and 1,25-OHVit-D levels correlated with FDG-PET activity.

Treatment of AL Amyloidosis: Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) Consensus Statement 2020 Update.

Immunoglobulin light chain (AL) amyloidosis is a clonal plasma cell disorder leading to progressive and life-threatening organ failure. The heart and the kidneys are the most commonly involved organs, but almost any organ can be involved. Because of the nonspecific presentation, diagnosis delay is common, and many patients are diagnosed with advanced organ failure. In the era of effective therapies and improved outcomes for patients with AL amyloidosis, the importance of early recognition is further enhanced as the ability to reverse organ dysfunction is limited in those with a profound organ failure. As AL amyloidosis is an uncommon disorder and given patients' frailty and high early death rate, management of this complex condition is challenging. The treatment of AL amyloidosis is based on various anti-plasma cell therapies. These therapies are borrowed and customized from the treatment of multiple myeloma, a more common disorder. However, a growing number of phase 2/3 studies dedicated to the AL amyloidosis population are being performed, making treatment decisions more evidence-based. Supportive care is an integral part of management of AL amyloidosis because of the inherent organ dysfunction, limiting the delivery of effective therapy. This extensive review brings an updated summary on the management of AL amyloidosis, sectioned into the 3 pillars for survival improvement: early disease recognition, anti-plasma cell therapy, and supportive care.

Identification of a novel presumed cardiac sarcoidosis category for patients at high risk of disease.

BACKGROUND: Histologic evidence is required for a definitive diagnosis of cardiac sarcoidosis (CS) by published guidelines; however, the sporadic nature of the disease may produce false negative biopsy results, causing CS to be underdiagnosed. We sought to establish a clinical category of CS absent histologic findings. METHODS: Patients evaluated for CS were stratified into 3 groups: probable CS and definite CS based on Heart Rhythm Society (HRS) criteria and presumed CS, ie, patients without any histologic evidence of sarcoidosis, but with unexplained high-grade atrioventricular block or ventricular arrhythmia and findings suggestive of CS on either cardiac magnetic resonance imaging or positron emission tomography. The primary end point was hospitalization-free and overall survival at 10 years. RESULTS: A total of 383 patients were included in the study: 59, definite CS; 223, probable CS; and 101, presumed CS (62, isolated CS and 39, systemic CS). Compared with patients meeting HRS criteria for CS, patients with presumed CS had lower odds of New York Heart Association class III or IV symptoms (odds ratio [OR], 0.44 [95% CI, 0.23-0.83]; P = .01) but greater odds of previous ventricular tachycardia (OR, 2.4 [95% CI, 1.4-4.0]; P = .001) or history of resuscitated sudden cardiac arrest (OR, 2.9 [95% CI, 1.0-8.6]; P = .05). Hospitalization-free and overall survival were similar among groups (P = .51 and P = .71, respectively). CONCLUSIONS: Clinical categorization of patients with presumed CS identified a high-risk cohort comparable to patients with histologic evidence of disease, although caution should be exercised in reaching this diagnosis without paying due diligence to the differential diagnosis.

Imaging and Quantification of Cardiac Sarcoidosis.

Cardiac sarcoidosis (CS) refers to the increasingly recognized cardiac involvement of an incompletely understood systemic disease entity-sarcoidosis. Endomyocardial biopsy can provide definitive diagnosis but is limited by its invasiveness and poor sensitivity. In the absence of a reliable gold standard, a combination of clinical, electrocardiographic, imaging, and histologic criteria are relied upon to provide probabilistic diagnosis. Within the last few years, societal documents have included advanced cardiovascular imaging modalities, 18F-FDG-PET/CT and cardiac magnetic resonance in their diagnostic algorithms. The current article provides a review of the imaging modalities used for screening and detection of CS, highlighting the principal findings of each with a specific focus on quantification, whenever applicable, and concluding with a proposed approach to the imaging of patients with suspected CS.

A Proteomic Atlas of Cardiac Amyloid Plaques.

BACKGROUND: In vivo mechanisms of amyloid clearance and cardiac tissue damage in cardiac amyloidosis are not well understood. OBJECTIVES: We aimed to define and quantify the amyloid plaque proteome in cardiac transthyretin amyloidosis (ATTR) and light chain amyloidosis (AL) and identify associations with patient characteristics and outcomes. METHODS: A proteomics approach was used to identify all proteins in cardiac amyloid plaques, and to compare both normal and diseased controls. All proteins identified within amyloid plaques were defined as the expanded proteome; only proteins that were enriched in comparison to normal and disease controls were defined as the amyloid-specific proteome. RESULTS: Proteomic data from 292 patients with ATTR and 139 patients with AL cardiac amyloidosis were included; 160 and 161 unique proteins were identified in the expanded proteomes, respectively. In the amyloid-specific proteomes, we identified 28 proteins in ATTR, 19 in AL amyloidosis, with 13 proteins overlapping between ATTR and AL. ATTR was characterized by a higher abundance of complement and contractile proteins and AL by a higher abundance of keratins. We found that the proteome of kappa AL had higher levels of clusterin, a protective chaperone, and lower levels of light chains than lambda despite higher levels of circulating light chains. Hierarchical clustering identified a group of patients with worse survival in ATTR, characterized by high levels of PIK3C3, a protein with a central role in autophagy. CONCLUSIONS: Cardiac AL and ATTR have both common and distinct pathogenetic mechanisms of tissue damage. Our findings suggest that autophagy represents a pathway that may be impaired in ATTR and should be further studied.

Adverse Renal Response to Decongestion in the Obese Phenotype of Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Patients with heart failure (HF) with preserved ejection fraction (HFpEF) and obesity display a number of pathophysiologic features that may render them more or less vulnerable to negative effects of decongestion on renal function, including greater right ventricular remodeling, plasma volume expansion and pericardial restraint. We aimed to contrast the renal response to decongestion in obese compared to nonobese patients with HFpEF METHODS AND RESULTS: National Institutes of Health heart failure network studies that enrolled patients with acute decompensated HFpEF (EF ≥ 50%) were included (DOSE, CARRESS, ROSE, and ATHENA). Obese HFpEF was defined as a body mass index ≥ 30 kg/m2. Compared to nonobese HFpEF (n = 118), patients with obese HFpEF (n = 214) were an average of 9 years younger (71 vs 80 years,< 0.001), were more likely to have diabetes (64% vs 31%, P< 0.001) but had less atrial fibrillation (56% vs 75%, P< 0.001). Renal dysfunction (glomerular filtration rate < 60 mL/min/1.73m2) was present in 82% of patients, and there was no difference at baseline between obese and nonobese patients. Despite similar weight loss through decongestive therapies, obese patients with HFpEF demonstrated greater rise in creatinine (Cr) and decline in glomerular filtration rate, with a 2-fold higher incidence of mild worsening renal function (rise in Cr ≥ 0.3 mg/dL) (28 vs 14%, P = 0.008) and a substantially greater increase in severe worsening of renal function (rise in Cr > 0.5 mg/dL) (9 vs 0%, P = 0.002). CONCLUSIONS: Despite being nearly a decade younger, obese patients with HFpEF experience greater deterioration in renal function during decongestion than do nonobese patients with HFpEF. Further study to elucidate the complex relationships between volume distribution, cardiorenal hemodynamics and adiposity in HFpEF is needed.

Right ventricular function in heart failure with preserved ejection fraction: a community-based study.

BACKGROUND: The prevalence and clinical significance of right ventricular (RV) systolic dysfunction (RVD) in patients with heart failure and preserved ejection fraction (HFpEF) are not well characterized. METHODS AND RESULTS: Consecutive, prospectively identified HFpEF (Framingham HF criteria, ejection fraction ≥50%) patients (n=562) from Olmsted County, Minnesota, underwent echocardiography at HF diagnosis and follow-up for cause-specific mortality and HF hospitalization. RV function was categorized by tertiles of tricuspid annular plane systolic excursion and by semiquantitative (normal, mild RVD, or moderate to severe RVD) 2-dimensional assessment. Whether RVD was defined by semiquantitative assessment or tricuspid annular plane systolic excursion ≤15 mm, HFpEF patients with RVD were more likely to have atrial fibrillation, pacemakers, and chronic diuretic therapy. At echocardiography, patients with RVD had slightly lower left ventricular ejection fraction, worse diastolic dysfunction, lower blood pressure and cardiac output, higher pulmonary artery systolic pressure, and more severe RV enlargement and tricuspid valve regurgitation. After adjustment for age, sex, pulmonary artery systolic pressure, and comorbidities, the presence of any RVD by semiquantitative assessment was associated with higher all-cause (hazard ratio=1.35; 95% confidence interval, 1.03-1.77; P=0.03) and cardiovascular (hazard ratio=1.85; 95% confidence interval, 1.20-2.80; P=0.006) mortality and higher first (hazard ratio=1.99; 95% confidence interval, 1.35-2.90; P=0.0006) and multiple (hazard ratio=1.81; 95% confidence interval, 1.18-2.78; P=0.007) HF hospitalization rates. RVD defined by tricuspid annular plane systolic excursion values showed similar but weaker associations with mortality and HF hospitalizations. CONCLUSIONS: In the community, RVD is common in HFpEF patients, is associated with clinical and echocardiographic evidence of more advanced HF, and is predictive of poorer outcomes.