Rodeheffer, Richard J.

Abstract Background Common genetic variation has been linked to an increased risk of developing dilated cardiomyopathy (DCM) in case-control studies. However, the phenotypic profile and biological mechanisms by which genetic background may predispose individuals to DCM and outcomes in the general population remain unclear. Aim The primary objectives of this study were twofold: (1) to validate a DCM polygenic score (PRS-1) based on a prior meta-analysis of case–control genetic association studies [Tadros R et al. Nat Genet (2021)]; and (2) To apply this PRS, along with two recently developed PRSs for DCM [PRS-2 from Zheng SL et al. Nat Genet (2024) and PRS-3 from Jurgens SJ et al. Nat Genet (2024)] to a general population that underwent comprehensive longitudinal phenotypic assessments and had long-term outcomes available. Methods While the PRS-1 was derived from only 13 SNPs, PRS-2 and PRS-3 were generated from 709,534 and 1,072,247 SNPs, respectively with significant overlap between them. These DCM-PRSs were applied to an unselected community-based cohort (n=1897) aged >45 years, who underwent a physical examination, echocardiogram, and blood sample at baseline. Subsequent clinical outcomes were collected over a median 16 year follow-up (IQR: 15-17). Results No significant differences between the quartiles were present in terms of age, sex (48% male), and cardiovascular risk factors (CV-RF) (such as hypertension, diabetes, and coronary artery disease). However, linear regression models demonstrated a significant correlation between all DCM-PRSs and left ventricular (LV) parameters, including LV ejection fraction, LV end-systolic diameter, and LV end-diastolic diameter (Table). Multivariable regression analysis confirmed that these correlations were independent of age, sex, CV-RF, and population stratification (adjusted for the first 10 principal components [PCs]). During follow-up, 47 individuals developed DCM. A logistic regression analysis, using a 3:1 matched cohort of non-DCM vs. DCM individuals based on age and sex and adjusted for the same 10 PCs, found a significant correlation between DCM development and both PRS-1 [OR=2.27 (1.06–4.85), p=0.03] and PRS-3 [OR=2.63 (1.20–5.75), p=0.02], while PRS-2 did not show a significant association [OR=1.85 (0.84–4.06), p=0.12]. No association was found between the DCM-PRSs and heart failure (HF) biomarkers (aldosterone, natriuretic peptides, ST2, Galectin-3) or HF outcomes (all-cause mortality/HF hospitalization). Conclusion PRS-1 for DCM despite being derived from only 13 risk alleles, performs at least as well as the newer and more extensive PRSs, in its correlation with LV function, dimensions, and DCM development (except for PRS-2) in a general population. The absence of correlation between these DCM-PRSs and the renin-angiotensin-aldosterone system or natriuretic peptides suggests that genetic background influences LV traits through mechanisms independent of these biological pathways.

ABSTRACT Aims Common genetic variants have been linked to an increased risk of non-ischaemic cardiomyopathy (NICM). The primary objective of this study was to evaluate the significance of these variants in a general population. Methods and results Thirteen NICM risk alleles, previously validated by meta-analyses of case-control genetic association studies, were used to determine genetic risk (GR) in a large, unselected cohort (n = 1897) of Olmsted County residents aged >45 years. Clinical and echocardiographic data, with biomarkers, were correlated with this NICM-GR over a median of 16 years of follow-up (interquartile range [IQR] 15–17). There were no significant differences between the study population quartiles, based on NICM-GR, in terms of age (median 61.6 [IQR 53.6–70.4]), sex (48% male), and cardiovascular risk factors. A significant correlation was detected by specific linear-regression models between NICM-GR and left ventricular (LV) ejection-fraction (beta [standard error]: −2.68 [0.68], p < 0.001), LV end-systolic-diameter (0.22 [0.06], p < 0.001), and LV end-diastolic-diameter (0.14 [0.06], p = 0.01). During follow-up, 46 subjects developed NICM. Using a 3:1 matched-cohort of non-NICM versus NICM patients, linear-regression analysis found a significant correlation between NICM-GR and NICM development (odds ratio 2.27, 95% confidence interval 1.06–4.85, p = 0.03). There was no significant association between these variants and heart failure biomarkers (aldosterone, natriuretic peptides, ST2, galectin-3). Conclusions The NICM-GR correlates with LV function and dimension, and subsequent development of NICM in the general population. The lack of correlation of these variants with cardiovascular risk factors and the renin–angiotensin–aldosterone axis or natriuretic peptides suggest different biological mechanisms involved. These findings support the need to explore newer pathophysiologic pathways in the development of NICM.

Cytolytic immunosuppression with OKT3 antibody has been shown to be highly effective in reducing the frequency of early allograft rejection in cardiac transplantation. Failure of OKT3 immunosuppression in the absence of anti‐OKT3 antibodies is a rare event, having been reported in only 3 patients who manifested predominantly vascular (humoral) rejection during OKT3 therapy. We report the first case of hemodynamically serious cellular rejection, without a demonstrable vascular rejection component, in a cardiac allograft recipient during OKT3 treatment. This case underscores the need to remain vigilant for signs of rejection in cardiac recipients during OKT3 immunosuppression.

Introduction: Aldosterone (Aldo) increases sodium and water reabsorption and mediates inflammatory processes. Its relationship to co-morbidities has not been well defined in the general population. Hypothesis: We addressed the hypothesis that plasma aldosterone concentration (PAC) is associated with metabolic and cardiorenal diseases in the general community. Methods: We determined PAC in a general community-based cohort from Olmsted County, MN (n=1,674), and defined correlations with cardiorenal, metabolic diseases and myocardial function and structure. Results: PAC was detected in all subjects and ranged from 2.5 to 91 ng/dl (mean value 6.7 ng/dl, +/- SD 6.6). Multivariate analysis adjusted for age, gender, BMI, ANP and BNP showed highly significant correlations between PAC and hypertension (HTN) (p<.0001, OR=2.28, CI:1.91-2.71), atrial fibrillation (p<.01), chronic kidney disease (CKD) (p<.0001, OR=1.64, CI:1.33-2.02), central obesity (p<.0001, OR=1.61, CI:1.27-2.05), hypertriglyceridemia (p<.003), prevalence of metabolic syndrome (MetS) (p<.0007, OR=1.40, CI=1.15-1.71), obesity (p<.0001, OR=1.48, CI:1.27-1.73), and concentric left ventricular hypertrophy (cLVH) (p=.01). Recognizing that ANP and BNP are known inhibitors of Aldo, we defined the relationship between these cardiac hormones (NTpro-ANP and NT-proBNP) and PAC and observed highly significant inverse relationships with NTpro-ANP (p=0.0009), NTpro-BNP (p=0.0003) in the general population. Conclusions: In conclusion, in the general community, PAC is strongly correlated with renal, metabolic and cardiovascular diseases as well as cardiac remodeling. Specifically, increasing PAC is strongly associated with HTN, CKD, obesity, MetS, cLVH, and lower levels of natriuretic peptides. Our data suggest a key role of Aldo as a possible biomarker and/or mediator of human cardiorenal and metabolic diseases even in the general adult population, prior to overt disease. This study also supports a possible counter regulatory relationship between cardiac natriuretic peptides and PAC. Further studies are warranted to evaluate possible therapeutic interventions targeting Aldo as a strategy to delay disease progression.

Background: A community based, cross-sectional echo survey demonstrated that pulmonary artery systolic pressure (PASP) increases with age and that PASP is associated with systemic arterial stiffness, Doppler estimated left ventricular (LV) filling pressures and lung function. Longitudinal assessment of PASP is needed to confirm cross-sectional observations. Objectives: To assess the whether PASP changes over time in longitudinally studied subjects and determine whether changes in PASP are associated with changes in systemic vascular stiffness, LV filling pressures or lung function. Methods: A random sample (n=2042) of the Olmsted County, MN population over age 40 underwent echo, record review and spirometry between 1997-2000 (Exam 1). A subset (n=1402) underwent repeat studies four years later (2001-2004; Exam 2). The current analysis includes the 723 subjects with paired PASP measurements. Changes ([[Unable to Display Character: ▵]]) in PASP, systemic arterial stiffness (pulse pressure; PP), LV filling pressure (E/e’) and lung function (% age/sex expected forced expiratory volume, %FEV1) were assessed. Results: At Exam 1, the median (interquartile range) age was 62 (69-70) years (62% female). Median time between exams was 48 (47-49) months. PASP increased from 26.1 (24.4-30.0) mmHg at Exam 1 to 28.0 (24.4-32.0) mmHg at Exam 2 (p<0.0001 by paired t test) for an average (SD) [[Unable to Display Character: ▵]] of 1.2 ± 5.5 mmHg. Adjusting for age and PASP at Exam 1, [[Unable to Display Character: ▵]]PASP was associated with [[Unable to Display Character: ▵]] age with an increase (parameter estimate (pe) ± standard error (se)) of 1.4±0.7 mmHg per year increase in age (p=0.046). [[Unable to Display Character: ▵]]PASP was not associated with sex and there was no age-sex interaction. Adjusting for age and PASP at Exam 1, [[Unable to Display Character: ▵]] age and Exam 1 values for PP, E/e or %FEV1 as appropriate, [[Unable to Display Character: ▵]]PASP was associated with [[Unable to Display Character: ▵]] PP (pe±se = 0.03±0.01 mmHg; p=0.01) [[Unable to Display Character: ▵]]E/e’ (pe±se = 0.21±0.06 mmHg, p=0.001) and [[Unable to Display Character: ▵]]%FEV1 (-0.09±0.02 mmHg, p<0.0001) suggesting that increases in PASP were related to increases in vascular stiffening, increases in LV filling pressures and declining lung function. Conclusions: In this longitudinal, population based study we find that PASP increases with aging and that increases in PASP over time are related to increases in systemic vascular stiffness and LV filling pressures and decreases in lung function.

BACKGROUND: The immunologic risk associated with preformed donor-specific allo-antibodies (DSA) against human leukocyte antigens (HLA) in heart transplant (HTX) recipients is unclear. The goal of this study was to evaluate potential role of DSA on the progression of cardiac allograft vasculopathy (CAV) in HTX recipients. METHODS: The presence of DSA against HLA was evaluated using solid phase Single Antigen Bead assay (One Lambda, Inc., Canoga Park, CA; Luminex platform) before transplant in 35 HTX recipients. Using alloantibody specification analysis, 11% (4/35) and 20% (7/35) had DSA against donor Class I and II HLA respectively including the one patient who had both (DSA I & II+) . 71% (25/35) of patients had no demonstrable DSA (DSA-). All patients had negative cytotoxicity cross match. Baseline three-dimensional intravascular ultrasound studies (3D IVUS) were performed at 1.0 [0.18, 1.4] year after transplant. Follow up 3D IVUS exams were performed 0.92 [0.85, 1.04] years after the baseline exam. RESULTS: The increase in mean plaque (media and intima) volume (PV) was accelerated in the DSA II+ group as compared to the DSA- group (0.87±1.9 mm (3)/mm vs. 0.16±1.8 mm (3)/mm) but the vessel volume index (follow up vessel volume/ baseline vessel volume) was similar between groups (1.08±0.5 vs. 1.09± 0.4; p=0.9). Plaque index (PI) (PV/vessel volume x 100 [%]) increased significantly in the DSA II+ group (17.9±6.3%) but not in the DSA- group (-13.6±13.2%, P=0.02). None of these values were significant in the DSA I+ only group. Treatment with Sirolimus did not affect PI progression between the DSA II+ and DSA- groups (PI progression: 15.9±8.7% vs. -11.7±7.1%, P=0.03). Age, gender, lipid and uric acid levels, prevalence of diabetes, ischemic time, time between IVUS examinations, the use of steroids, mycophenolate vs. azathioprine or calcineurin inhibitors vs. sirolimus were not different between the groups (P>0.4 for all). CONCLUSIONS: Heart transplant recipients with clearly defined anti-Class II DSA are at risk for accelerated cardiac allograft vasculopathy. Whether interventions to minimize the risk of DSA such as virtual crossmatch, desensitization and complement inhibition will retard CAV remains to be proven.

AbstractBackgroundGastrointestinal bleeding (GIB) in patients with continuous flow left ventricular assist devices (CF‐LVADs) is often related to GI angiodysplasia (GIAD). We previously reported data on VEGF inhibition with IV bevacizumab in the treatment of LVAD‐associated GIAD bleeding, and now present follow‐up data on patients treated with IV bevacizumab and/or low‐dose oral pazopanib.MethodsAll consecutive adult patients with LVAD‐associated GIB from GIAD treated with bevacizumab or pazopanib, from July 20, 2017 to June 22, 2022, were included in the analysis. Data on hospitalizations, GI endoscopic procedures, and blood transfusions were obtained from first admission for GIB up to a median of 35.7 months following treatment initiation (range 1.3–59.8 months).ResultsEleven patients (91% male, mean 69.5 ± 8.9 years) were included. Eight patients (73%) received IV bevacizumab, two patients (18%) received oral pazopanib, and one patient (9%) received bevacizumab followed by pazopanib therapy. We observed a significantly decreased number of annualized hospitalizations for GIB (median difference − 2.87, p = 0.002), blood transfusions (median difference − 20.9, p = 0.01), and endoscopies (median difference − 6.95, p = 0.007) in patients pre‐ and post‐anti‐angiogenic therapy (bevacizumab and/or pazopanib). Similarly, a significant improvement in these clinical outcomes was noted in the bevacizumab group with decreased annualized hospitalizations (median difference − 2.75, p = 0.014), blood transfusions (median difference − 24.5, p = 0.047), and number of endoscopies (median differences −6.88, p = 0.006).ConclusionAnti‐angiogenic therapy with IV bevacizumab and/or low‐dose oral pazopanib appears to provide benefits in patients with LVAD‐associated GIB with reduced hospitalizations, blood transfusions, and need for GI endoscopic procedures.

Introduction: Common genetic variation has been linked to an increased risk of developing dilated cardiomyopathy (DCM). However, the phenotypic profile, outcomes, and biological mechanisms by which such genetic background may predispose individuals to DCM are still unknown. Hypothesis: The primary objectives of this study were to develop a DCM polygenic risk score (PRS) based on prior case control-DCM GWAS and to apply this PRS to a well clinical characterized general population. Methods: The DCM-PRS was derived from 13 DCM risk alleles that were assayed in an unselected cohort (n=1897) of unrelated Olmsted County residents age >45 years who did not have a history of heart failure (HF) or CM and underwent physical examination, echocardiography, and blood analyses. Results: The entire population was equally divided into quartiles based on the DCM-PRS. No significant differences were present in terms of age (median 62 years) and sex (48% male). However, a significant correlation was detected between the DCM-PRS and left ventricle ejection fraction (LVEF) (Beta: -2.68, p<0.001), LV end-systolic diameter (Beta: 0.22, p<0.001), and LV end-diastolic diameter (Beta: 0.14, p=0.01). During a follow-up of 16 years (IQR: 15-17), 47 subjects developed DCM. Using a 3:1 non-DCM vs DCM matched cohort, a logistic regression analysis, found a significant correlation between median DCM-PRS and DCM development [OR=2.27 (1.06, 4.85), p=0.03]. However, there was no association between the DCM-PRS and HF biomarkers (aldosterone, natriuretic peptides, ST2, Galectin-3). Conclusions: DCM-PRS correlates with decreased LVEF, increased LV dimensions, and DCM development in a general population without significant differences in baseline clinical features. The absence of correlation between the DCM-PRS and available HF biomarkers suggests that this genetic background affects LV traits and DCM development independent of these biological mechanisms.

AbstractBackgroundSilent or unrecognized myocardial infarction (UMI) diagnosed by surveillance electrocardiography (ECG) carries similarly poor prognosis as recognized MI (RMI) for poorly understood reasons.MethodsThis study included 5430 consecutive patients who presented to the nuclear laboratory and underwent 2‐day stress and rest Tc‐99m sestamibi and ECG studies between March 1991 and June 1999. UMI was diagnosed if ECG showed Q‐wave MI in the absence of a history of RMI. We measured infarct size (% defect size as compared with the entire left ventricular sestamibi uptake), ejection fraction (EF, %), and summed difference score (SDS, sestamibi uptake by myocardium in stress minus sestamibi uptake in rest images as a marker of ischemia). Survival was determined by follow‐up survey (median 6 years).ResultsWe identified 346 UMIs, 628 RMIs, and 4456 subjects without MI (No MI). As compared with RMI, UMI patients had lesser abnormalities on nuclear scans (p < .0001 for all), including smaller infarct size (5.7% vs. 12.2%), higher EF (58% vs. 53%), and lesser ischemia (SDS; 3.9% vs. 2.7%). UMI prognosis was as poor as that of RMI (annual mortality rate 4.7% vs. 4.8% with No MI rate of 2.9%; p < .001 for all comparisons), and this persisted after multivariate analysis. Infarct size quantification successfully risk‐stratified ECG‐UMI patients, but UMI patients continued to predict mortality even if the infarct size was 0%.ConclusionsAlthough UMI patients have lesser abnormalities on nuclear scans, ECG‐based UMI continues to independently predict mortality, indicating the continuing relevance of ECG in clinical practice.