Citations

Introduction: In patients with heart failure and reduced ejection fraction (HFrEF), increasing body mass index (BMI) is not associated with worsening prognosis, termed the obesity paradox. Although this phenomenon has been studied extensively, data on the African-American population are limited. The aim of this study was to examine the relationship between BMI and all-cause mortality in African Americans with HFrEF. Methods and Results: The African-American Heart Failure Trial (A-HeFT) database was utilized to conduct a retrospective analysis. In A-HeFT, 1050 self-identified black patients with BMI range of 15.7 to 69.4 kg/m 2 (median 30.3 kg/m 2 ) were followed for a median of 15 months, with 86 deaths. BMI was modeled as a curvilinear continuous variable using restricted cubic splines. Unadjusted Cox regression analysis of the relationship between BMI and all-cause mortality revealed a significant (p = 0.001) inverse relationship, with an increase in mortality risk below the median BMI of approximately 30 kg/m 2 (HR> 1.0) without an upward trend in mortality risk above a BMI > 30 kg/m 2 (Figure1). Adjustment for other variables including age, sex, comorbidities, and clinical assessments did not reveal an increase in HR above the median BMI. Conclusion: Consistent with the obesity paradox, the mortality risk increased with decreasing BMI and did not increase when the BMI exceeded the definition of obesity. Until the mechanisms of the obesity paradox are better understood, these results question whether weight reduction would be beneficial in the African American population with HFrEF.

Introduction: Atrial Fibrillation (AF) is an important contributor to insufficient left ventricular pacing and mortality in patients undergoing cardiac resynchronization therapy (CRT). The incidence and prevalence of AF post-CRT implant, in patients with and without previous history of AF, has not previously been described. Hypothesis: AF prevalence in CRT patients, despite history of AF, is higher than previously understood. Methods: Subjects implanted with a CRT-Defibrillator (CRT-D) enrolled in the PainFree SST study and with device data collection were analyzed. Subjects who exited within 30 days of implant, had < 27 days of available daily AT/AF burden data, or had ≥ 10% of daily AT/AF data missing were excluded. We defined incidence and prevalence of clinically meaningful device documented AF using previously published criteria (≥1 day with AF > 6 hours). History of AF at enrollment was documented based on clinical history. Results: The analysis included 944 patients (68±11 years; 78% male, EF 28±9%, QRS 152±29 ms; 59% NYHA III/IV). The duration from implant to study exit or death was 2.0 ± 0.8 years (IQR 1.5-2.5). History of AT/AF was documented in 37% of patients at baseline. Overall, any AT/AF was found in 85.2 % of subjects during follow-up. Clinically meaningful AT/AF was found in 30.3% of subjects. Of the 345 subjects with history of AF at baseline, 51.9% had clinically meaningful AT/AF during follow-up vs.17.9% for subjects without known AF (p<0.0001). 24.8% of subjects experienced at least one day of ≥ 23h of AT/AF. 6.9% of subjects had ≥ 23h of AT/AF for > 95% of days with data. Conclusions: AF occurs in a substantial proportion of CRT-D patients and clinically documented history of AF prior to CRT-D implant corresponds poorly with device documented AT/AF during follow-up. Device documented AF should be evaluated in CRT-D patients with and without previous history of AF to individualize strategies to maximize left ventricular pacing and minimize disruption due to AF.

Introduction: Cardiorenal fibrotic remodeling (CFR), often in the setting of heart failure (HF) and kidney disease (CKD), is a major cause for increased risk in mortality, for which there are no effective drugs. C-type natriuretic peptide (CNP) is a 22 amino acid (AA) ligand for the particulate guanylyl cyclase receptor-B (GC-B) and exerts anti-fibrotic actions, with little effect on blood pressure (BP) or renal function, via its second messenger cGMP. To overcome CNP’s limited efficacy with its short half-life, we designed 2 novel CNP-based peptides (C53 and CU32). C53 consists of CNP plus a 31 AA N-terminus extension, while CU32 is the CNP ring fused with the N- and C-termini of urodilatin (GC-A agonist). Here we investigated the cGMP generating actions of C53 and CU32, with the goal of advancing novel GC-B/cGMP therapeutics for CFR. Hypotheses: We hypothesized that C53 and CU32 would have cGMP activating actions in vivo, however only C53 would generate cGMP production selectively via GC-B in vitro. We also hypothesize that the addition of the C-termini to CU32 would form a non-selective GC-B/cGMP agonist with renal and BP lowering actions. Methods: HEK293 cells expressing human GC-B or -A and human fibroblasts (hFs), where GC-B is abundant, were stimulated with C53 or CU32 (10-8M) for 10 min. Two groups of normal rats (n=8) received a 75 min equimolar IV infusion of C53 or CU32. Change in mean arterial pressure (ΔMAP), sodium (Na) excretion and plasma and urinary cGMP were assessed. *p<0.05. Results: C53 and CU32 activated cGMP in GC-B cells (C53: 75±9, CU32: 24±2 pmol/well*), while only CU32 activated cGMP in GC-A cells (C53: 0±0, CU32: 50±3 pmol/well*). In hFs, both C53 and CU32 generated cGMP. In vivo, plasma cGMP (C53: 91±4, CU32: 94±6 pmol/ml) and urinary cGMP excretion (C53: 177±28, CU32: 227±28 pmol/min) were similar with both peptides. Yet, CU32 induced a greater reduction in ΔMAP (C53: -7±1, CU32: -16±3 mmHg*) and increased Na excretion (C53: 1.4±0.2, CU32: 2.4±0.2 uEq/m*) compared to C53. Conclusions: We report the engineering of a selective (C53) and non-selective (CU32) GC-B agonist that has favorable cGMP generating action in hFs and in vivo. Thus, C53 and CU32 may represent novel GC-B therapeutics that could be tailored to specific phases of HF or CKD to prevent CFR.

Background: In spite of aggressive preventive therapy, patients with type 2 diabetes (T2D) and stable ischemic heart disease (SIHD) remain at high risk for major cardiovascular events and death. Understanding the pathophysiologic determinants of that residual risk could help identify effective preventive therapies. Methods and Results: In this Ancillary Study of the BARI 2D trial, we examined the predictive value of biomarkers from 6 distinct pathophysiologic pathways in 2285 men and women with T2D and SIHD who were followed for a median (IQR) of 5.0 (4.1-6.0) years. The endpoint for this Ancillary Study was a composite of myocardial infarction, stroke, heart failure, or all-cause mortality. The 5-year Kaplan-Meier event rate was 31%. The pathophysiologic processes evaluated included dysglycemia (HbA1c), dyslipidemia (LDL-C), myocardial strain (NT-proBNP), myocardial injury (high-sensitivity cardiac troponin T [hsTnT]), subclinical inflammation (high-sensitivity C-reactive protein [hsCRP]), and nephropathy (presence/absence of macroalbuminuria). In Cox proportional hazards models adjusted for baseline risk factors, angiographic severity of disease, and ejection fraction, each marker except LDL-C was a significant predictor of outcome (Figure) in this population with 74% baseline statin use. After mutual adjustment for all 6 markers and baseline risk factors, the hazard ratio (95% CI) per 1-SD of natural logarithm transformed concentration was largest for NT-proBNP [1.29 (1.17, 1.42)], followed by hsTnT [1.16 (1.07, 1.26)], HbA1c [1.12 (1.03, 1.21)], and hsCRP [1.11 (1.03, 1.20). Macroalbuminuria was not a significant predictor after adjustment for the other markers (Figure). Conclusions: In this high-risk population of patients with type 2 diabetes and stable ischemic heart disease, strategies to target myocardial strain, myocardial injury, and subclinical inflammation may lead to improvements in cardiovascular outcome.

Background: Aortic Valve Calcification (AVC) is intrinsic to aortic stenosis (AS). While established concepts assume homogeneous calcification causing AS, wide variability in hemodynamic severity at any given AVC burden suggests other operative mechanisms. Multidetector computed tomography (MDCT) now accurately measures global AVC, but AVC spatial distribution remains elusive due to imaging orientation. Methods and Results: We developed ‘en-face’ imaging by re-registration of 4D-MDCT to quantify AVC spatial distribution and analyzed global AVC load and AVC distribution in 418 patients with AS (76±9 years; mean gradient 35±17 mmHg). 4D-volume-rendered MDCT datasets were re-oriented to en-face view of aortic valve for AVC spatial scoring with individual cusp calcification load, cusp-edge calcification and AVC asymmetry. Despite high total AVC load (450 [250-666] AU/cm 2 ), asymmetry was frequent (50%), with a difference between most- and least-calcified cusp of 112 [66-182] AU/cm 2 . Maximum AVC was in the non-coronary cusp in 61% (p<0.001). Cusp edge calcification was none-mild in 26%, moderate in 62% and severe in 12%. Adjusting for total AVC, severe AS (mean gradient >40 mmHg) was more likely with symmetrical AVC (odds ratio [OR] 2.36, p<0.001) and with edge calcification moderate (OR 4.16, p=0.001 vs none-mild) to severe (OR 10.7, p=0.001). Inclusion of AVC distribution improved models predicting AS severity over total AVC (p<0.001). Conclusions: Four-dimensional MDCT en-face re-registration and AVC quantitation provides new insight into AS pathophysiology. Contrary to classical concepts, AVC is frequently inhomogeneous and asymmetric. Hemodynamic AS severity is independently affected not only by global AVC but also by variations in AVC distribution and location within cusps, emphasizing the importance of 4D AVC assessment in AS. Impact of quantified AVC asymmetry and location on outcome of transcutaneous aortic valve replacement should be evaluated.

Background: Evaluation of obese patients with suspected CAD is challenging because obesity is a CV risk factor, but adiposity itself may mimic symptoms of CAD and reduce the accuracy of diagnostic testing. Optimal testing strategies in obese patients are not known. Methods: Patients with stable symptoms suggestive of cardiac ischemia from the PROMISE trial (n=9230) were classified according to BMI. Providers specified a functional test modality prior to stratified randomization to functional (stress testing) or anatomical (CTA) testing. We assessed relationships between BMI, physician’s preference of functional test, test positivity and results of catheter angiography (cath) using logistic regression. Results: Providers were more likely to choose SPECT over other functional tests as BMI increased (OR 1.04 per unit increase in BMI above 27, p<0.001). In patients with BMI ≥ 35 vs. < 35, the rate of positivity with CTA was similar (10% vs. 12%; see Table). The same was true for stress echo and stress ECG (positivity 8-13%, p>0.8 for both). In contrast, SPECT was significantly more likely to be positive in those with BMI ≥ 35 vs. <35 (18% vs. 13%; p=0.001). The likelihood of finding obstructive CAD at cath did not differ with BMI ≥ 35 vs. <35 in patients having CTA (59% vs. 52%, p=0.22), but among SPECT patients, positivity was only 29% with BMI ≥ 35 compared to 52% with BMI < 35 (p=0.005; Table). Conclusions: Increasing levels of obesity were associated with stronger physician preference for SPECT over other noninvasive tests. In patients receiving SPECT, higher levels of obesity were associated with a higher rate of positive results, but a lower cath yield for obstructive CAD. In contrast, in patients receiving CTA, positivity rates and cath yield did not vary by BMI. Obesity appears to significantly influence provider decision-making with regard to noninvasive test choice, probability of abnormal test results and probability of finding obstructive disease at cath.

Introduction: Soluble ST2 (sST2) is a serum marker of cardiomyocyte stress associated with a large risk of death and heart failure after myocardial infarction (MI). The relationship between sST2 and cardiac structure and function after MI however remains incompletely defined, and greater characterization is required prior to clinical application. Methods: Olmsted County, Minnesota residents who experienced their first MI between 2007 and 2012 were prospectively recruited. MIs were validated using standardized criteria and patients underwent simultaneous comprehensive Doppler echocardiography and sST2 measurement. The association between cardiac morphology and hemodynamics and sST2 were examined. Published normal values were used as referent ranges for sST2 levels. Results: Among 316 patients (mean age 65 [SD 14] years, 67% men, 32% ST-elevation MI), sST2 was measured 2.5 [SD 1.6] days after MI and within 0.7 [SD 2.3] days of echocardiography. Soluble ST2 was elevated in 33% of patients and univariately associated with decreased LV ejection fraction (LVEF), increased LV mass, impaired LV diastolic function and increased pulmonary artery pressure (ePAP) (Table). After adjustment for age, sex, LVEF and key measures of LV filling pressures, elevated sST2 was independently associated with reduced LVEF (p=0.01) mitral valve deceleration time (p=0.03), greater left atrial volume (p=0.03) and mitral regurgitation (≥mild; p=0.09). LVEF and ePAP exhibited the strongest associations with elevated sST2 (both p<0.001). Conclusions: Soluble ST2 is frequently elevated following MI and is strongly associated with the morphologic and hemodynamic determinants of adverse LV remodeling that infer poor long-term outcome after MI.

Background/Hypothesis: Women have higher morbidity and mortality associated with CABG procedures than men. The extent intra-operative red blood cell (RBC) transfusions contribute to gender differences in surgical outcomes is not established. We hypothesized that women are at increased risk for RBC transfusions due to lower pre-op hematocrit (Hct) and blood volume, but that other factors may also contribute. Methods: Consecutive, non-reoperative CABG procedures from 189 institutions (2012 -2015) were reviewed. Gender differences and odds ratios for intra-operative transfusion were evaluated with logistic regression models adjusting for age, blood volume (Nadler formula-to normalize for height and weight), procedure acuity, net extracorporeal circuit prime volume, use of retrograde autologous priming, first Hct in OR, nadir Hct on cardiopulmonary bypass (CPB), volume added on CPB, ultra-filtration volume, urine output on CPB, and procedure duration. Results: Among 54,122 patients (25.3% female), 21.9% (n=11,901) received a RBC transfusion. Compared to men, female patients were older (66 yrs vs. 64 yrs, p<.001), had lower blood volumes (4.3L vs. 5.6L, p<.001), and lower pre-op Hct (32.9% vs. 37.2%, p<.001). Transfusion rates were 3-fold higher in women vs. men (45.1% vs 13.7%, p<.001). Even after adjustment for independent predictors of intra-operative transfusion, women remained at increased risk vs men (OR = 1.3, 95% CI = 1.2 -1.4). No gender differences in transfusion rates were observed for Hct 21%-23% (Figure). Conclusions: Women have an increased risk of intra-operative RBC transfusion vs men. After adjusting for height and weight, much of this risk is due to gender differences in pre-op Hct and blood volume, however a residual significant risk remained after adjustment. Perfusion strategies aimed at gender differences may minimize unnecessary transfusions. Future study on the impact of gender on transfusion practice in cardiac surgery is warranted.

Introduction: Electro-anatomic mapping (EAM) has been studied as a modality to improve the sensitivity and reduce false negative rates with endomyocardial biopsy (EMB). We systematically reviewed the literature describing EAM guided EMB. Methods: An experienced librarian developed search strategies for Ovid MEDLINE, Ovid Embase, Ovid CDR, Cochrane Central, Scopus and Web of Science. There were no restrictions on language or publication date. Animal studies were excluded. Search strategy included MESH headings and keywords including endomyocardial biopsy and electroanatomic mapping. Results: Out of 139 studies initially identified, 16 (9 case series, 7 case reports) were included in this systematic review. EAM guided EMB was performed in 152 patients and results of 241 biopsies were available for analysis. The most common indications for EAM guided EMB were suspected arrhythmogenic right ventricular cardiomyopathy (ARVC), myocarditis and cardiac sarcoidosis (CS). While fluoroscopic visualization of the bioptome close to mapping catheter was the most commonly utilized biopsy technique (n=7 studies), direct visualization of bioptome on CARTO (n=4) and on NavX (n=2) were used as well. Low voltage areas had abnormal myocardial histology more commonly (range 60-100%) than normal voltage areas (range 11-52%). Sensitivity of low voltage areas for abnormal myocardium ranged from 60% to 82%. EAM guided EMB appears safe and adverse events were noted in only one study (remote hemopericardium). Conclusions: EAM guided EMB is a safe and efficacious method to improve the sensitivity and reduce the false negative rate of conventional fluoroscopy guided biopsy.

Introduction: Limited data is available regarding the incidence of new-onset diabetes mellitus (NODM) after heart transplantation and it`s impact on patient survival. Hypothesis: Methods: From the United Network of Organ Sharing database (January 2004 to September 2014), we identified 13,353 patients without pre-operative diabetes mellitus undergoing heart transplantation. Multivariable Cox regression was implemented to determine predictors for the development of NODM. A matched cohort of New-onset Diabetes mellitus (NODM (+)) and NODM (-) was generated by 1:1 nearest neighbor propensity-matching. The association of NODM with long-term survival was then estimated with robust Cox regression. Results are presented at the 95% Confidence level; all tests are two-tailed. Results: During the study period, 1,921 of 13,353 (14%) developed NODM. Estimated freedom from NODM was 97% (96-98%) & 77% (76 - 78%) at the end of 1 and 5 years respectively. Predictors for the development of NODM were recipient age > 50 years (HR 1.2 95% CI1.05, 1.3; p < 0.01), recipient BMI > 30 (HR 1.4 95% CI1.2, 1.6; p < 0.01) and race (African American vs Caucasian (HR 1.3 95% CI1.2, 1.5; p < 0.01)). Cox-regression of a propensity-matched cohort of 1921 NODM+ve and NODM-ve recipient-pairs demonstrates that NODM is associated with poorer survival (HR for mortality: 1.3 95% CI 1.1, 1.5; p < 0.001). Conclusions: More than one in ten heart transplant recipients develop NODM post heart transplantation. Obesity, older age, and African American race patients to be at higher risk for NODM. New onset diabetes was independently associated with an almost 30% reduced long-term survival. More than one in ten heart transplant recipients develop NODM post heart transplantation. Obesity, older age, and African American race patients to be at higher risk for NODM. New onset diabetes was independently associated with an almost 30% reduced long-term survival.