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Left ventricular assist device (LVAD) implantation has been shown to increase allosensitization before orthotopic heart transplantation, but the influence of LVAD support on posttransplant rejection is controversial. This study examines the postoperative incidence of acute cellular rejection (ACR) in patients bridged with continuous flow LVAD (CF-LVAD) relative to primary transplant (Primary Tx). All patients who underwent orthotopic heart transplantation at our institution between July 2006 and March 2019 were retrospectively reviewed (n = 395). Patients were classified into Primary Tx (n = 145) and CF-LVAD (n = 207) groups. Propensity score matching on 13 covariates implemented a 0.1 caliper logistic model with nearest neighbor 1:1 matching. Development of moderate to severe (ie, 2R/3R) rejection was evaluated using a competing risks model. Potential predictors of 2R/3R ACR were evaluated using Fine-Gray regression on the marginal subdistribution hazard. Propensity score matching yielded 122 patients in each group (n = 244). At 12 and 24 months, the cumulative incidence of 2R/3R ACR was 17% and 23% for the CF-LVAD group and 26% and 31%, respectively, for the Primary Tx group (P =.170). CF-LVAD was not predictive of 2R/3R rejection on multivariable Fine-Gray regression (subdistribution hazard ratio, 0.73; 95% confidence interval, 0.40-1.33; P =.301). There was no difference in the 5-year incidence of antibody mediated rejection (10% [n = 12] vs 9% [n = 11]; P =.827). After adjusting for covariates, CF-LVAD was not associated with an increased risk of moderate to severe ACR during the 24 months after cardiac transplantation. Further investigation is warranted with larger cohorts, but CF-LVAD may have minimal influence on posttransplant ACR. Depiction of the competing risks model showing 2R/3R acute cellular rejection (ACR), death, and composite end point survival (alive and free from rejection). Patients were stratified based on bridge to transplant (BTT) strategy (continuous flow left ventricular assist device (LVAD) support vs primary transplant) and propensity matched on baseline characteristics. On competing risks analysis of the matched groups, there was no significant difference in the incidence of 2R/3R ACR between groups (P =.170). CIF , Cumulative incidence function; KM , Kaplan-Meier. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Patients with heart failure (HF) often have multiple chronic conditions that may impact health-related quality of life (HRQOL) despite HF therapy. We sought to determine the association between noncardiac comorbidities and HRQOL in ambulatory patients with advanced HF. Methods: Baseline data from 373 subjects in REVIVAL (Registry Evaluation of Vital Information for Ventricular Assist Devices in Ambulatory Life) were analyzed using multivariable general linear models to evaluate the relationship between comorbidities and HRQOL (EuroQol Visual Analogue Scale, EQ-5D-3L Index Score, and Kansas City Cardiomyopathy Questionnaire). The primary independent variables were a comorbidity index (sum of 14 noncardiac conditions), a residual comorbidity index (without depression), and depression alone. The median (25th to 75th percentile) number of comorbidities was 3 (2–4). Results: Increasing comorbidity burden was associated with a reduction in generic (EQ-5D Index, P =0.005) and HF-specific (Kansas City Cardiomyopathy Questionnaire, P =0.001) HRQOL. The residual comorbidity index was not associated with HRQOL when depression included in the model independently, while depression was associated with HRQOL across all measures. Participants with depression (versus without) scored on average 13 points (95% CI, 8–17) lower on the EuroQol Visual Analogue Scale, 0.15 points (95% CI, 0.12–0.18) lower on the EQ-5D Index, and 24.9 points (95% CI, 21.2–28.5) lower on the Kansas City Cardiomyopathy Questionnaire overall summary score. Conclusions: While noncardiac comorbidities were prevalent in ambulatory advanced HF patients, only depression was associated with decreased generic and HF-specific HRQOL. Other than depression, the presence of noncardiac comorbidities should not impact expected gains in HRQOL following ventricular assist device implantation, provided the conditions are not a contraindication to implant. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01369407. [ABSTRACT FROM AUTHOR]

Eighty percent of brain‐dead (BD) organ donors develop hypotension and are frequently hypovolemic. Fluid resuscitation in a BD donor is controversial. We have previously published our 4‐h goal‐directed stroke volume (SV)‐based fluid resuscitation protocol which significantly decreased time on vasopressors and increased transplanting four or more organs. The SV was measured by pulse‐contour analysis (PCA) or an esophageal doppler monitor, both of which are invasive. Thoracic bioreactance (BR) is a non‐invasive portable technology that measures SV but has not been studied in BD donors. We performed a randomized prospective comparative study of BR versus PCA technology in our fluid resuscitation protocol in BD donors. Eighty‐four donors (53.1%) were randomized to BR and 74 donors to PCA (46.8%). The two groups were well matched based on 24 demographic, social, and initial laboratory factors, without any significant differences between them. There was no difference in the intravenous fluid infused over the 4‐h study period [BR 2271 ± 823 vs. PCA 2230 ± 962 mL; p =.77]. There was no difference in the time to wean off vasopressors [BR 108.8 ± 61.8 vs. PCA 150.0 ± 68 min p =.07], nor in the number of donors off vasopressors at the end of the protocol [BR 16 (28.6%) vs. PCA 15 (29.4%); p =.92]. There was no difference in the total number of organs transplanted per donor [BR 3.25 ± 1.77 vs. PCA 3.22 ± 1.75; p =.90], nor in any individual organ transplanted. BR was equivalent to PCA in clinical outcomes and provides a simple, non‐invasive, portable technology to monitor fluid resuscitation in organ donors. [ABSTRACT FROM AUTHOR]

Open in new tab Download slide OBJECTIVES Malignancy is the leading cause of late mortality after orthotopic heart transplantation (OHT), and the burden of post-transplantation cancer is expected to rise in proportion to increased case volume following the 2018 heart allocation score change. In this report, we evaluated factors associated with de novo malignancy after OHT with a focus on skin and solid organ cancers. METHODS Patients who underwent OHT at our institution between 1999 and 2018 were retrospectively reviewed (n  = 488). Terminal outcomes of death and development of skin and/or solid organ malignancy were assessed as competing risks. Fine–Gray subdistribution hazards regression was used to evaluate the association between perioperative patient and donor characteristics and late-term malignancy outcomes. RESULTS By 1, 5 and 10 years, an estimated 2%, 17% and 27% of patients developed skin malignancy, while 1%, 5% and 12% of patients developed solid organ malignancy. On multivariable Fine–Gray regression, age [1.05 (1.03–1.08); P  <   0.001], government payer insurance [1.77 (1.20–2.59); P  =   0.006], family history of malignancy [1.66 (1.15–2.38); P  =   0.007] and metformin use [1.73 (1.15–2.59); P  =   0.008] were associated with increased risk of melanoma and basal or squamous cell carcinoma. Age [1.08 (1.04–1.12); P  <   0.001] and family history of malignancy [2.55 (1.43–4.56); P  =   0.002] were associated with an increased risk of solid organ cancer, most commonly prostate and lung cancer. CONCLUSIONS Vigilant cancer and immunosuppression surveillance is warranted in OHT recipients at late-term follow-up. The cumulative incidence of skin and solid organ malignancies increases temporally after transplantation, and key risk factors for the development of post-OHT malignancy warrant identification and routine monitoring. [ABSTRACT FROM AUTHOR]

BACKGROUND: Dilated cardiomyopathy (DCM) can lead to advanced disease, defined herein as necessitating a durable left ventricular assist device or a heart transplant (LVAD/HT). DCM is known to have a genetic basis, but the association of rare variant genetics with advanced DCM has not been studied. METHODS: We analyzed clinical and genetic sequence data from patients enrolled between 2016 and 2021 in the US multisite DCM Precision Medicine Study, which was a geographically diverse, multiracial, multiethnic cohort. Clinical evaluation included standardized patient interview and medical record query forms. DCM severity was classified into 3 groups: patients with advanced disease with LVAD/HT; patients with an implantable cardioverter defibrillator (ICD) only; or patients with no ICD or LVAD/HT. Rare variants in 36 DCM genes were classified as pathogenic or likely pathogenic or variants of uncertain significance. Confounding factors we considered included demographic characteristics, lifestyle factors, access to care, DCM duration, and comorbidities. Crude and adjusted associations between DCM severity and rare variant genetic findings were assessed using multinomial models with generalized logit link. RESULTS: Patients' mean (SD) age was 51.9 (13.6) years; 42% were of African ancestry, 56% were of European ancestry, and 44% were female. Of 1198 patients, 347 had LVAD/HT, 511 had an ICD, and 340 had no LVAD/HT or ICD. The percentage of patients with pathogenic or likely pathogenic variants was 26.2%, 15.9%, and 15.0% for those with LVAD/HT, ICD only, or neither, respectively. After controlling for sociodemographic characteristics and comorbidities, patients with DCM with LVAD/HT were more likely than those without LVAD/HT or ICD to have DCM-related pathogenic or likely pathogenic rare variants (odds ratio, 2.3 [95% CI, 1.5-3.6]). The association did not differ by ancestry. Rare variant genetic findings were similar between patients with DCM with an ICD and those without LVAD/HT or ICD. CONCLUSIONS: Advanced DCM was associated with higher odds of rare variants in DCM genes adjudicated as pathogenic or likely pathogenic, compared with individuals with less severe DCM. This finding may help assess the risk of outcomes in management of patients with DCM and their at-risk family members. [ABSTRACT FROM AUTHOR]

Key Points: Question: Does the rare variant genetic architecture of dilated cardiomyopathy differ between patients of African and European ancestry? Findings: In this cross-sectional study of 1198 patients with dilated cardiomyopathy, significantly fewer patients of African ancestry (8.2%) than those European ancestry (25.5%) had variants classified as pathogenic or likely pathogenic, a difference due in part to fewer predicted loss-of-function variants and less case-based evidence to support pathogenicity for variants found only in patients of African ancestry. Meaning: Assumptions regarding dilated cardiomyopathy genetic architecture derived from European ancestry may not be applicable to African ancestry; a current lack of case data limits clinical genetics care for patients of African ancestry with dilated cardiomyopathy. Importance: Black patients with dilated cardiomyopathy (DCM) have increased familial risk and worse outcomes than White patients, but most DCM genetic data are from White patients. Objective: To compare the rare variant genetic architecture of DCM by genomic ancestry within a diverse population of patients with DCM. Design: Cross-sectional study enrolling patients with DCM who self-identified as non-Hispanic Black, Hispanic, or non-Hispanic White from June 7, 2016, to March 15, 2020, at 25 US advanced heart failure programs. Variants in 36 DCM genes were adjudicated as pathogenic, likely pathogenic, or of uncertain significance. Exposure: Presence of DCM. Main Outcomes and Measures: Variants in DCM genes classified as pathogenic/likely pathogenic/uncertain significance and clinically actionable (pathogenic/likely pathogenic). Results: A total of 505, 667, and 26 patients with DCM of predominantly African, European, or Native American genomic ancestry, respectively, were included. Compared with patients of European ancestry, a lower percentage of patients of African ancestry had clinically actionable variants (8.2% [95% CI, 5.2%-11.1%] vs 25.5% [95% CI, 21.3%-29.6%]), reflecting the lower odds of a clinically actionable variant for those with any pathogenic variant/likely pathogenic variant/variant of uncertain significance (odds ratio, 0.25 [95% CI, 0.17-0.37]). On average, patients of African ancestry had fewer clinically actionable variants in TTN (difference, −0.09 [95% CI, −0.14 to −0.05]) and other genes with predicted loss of function as a disease-causing mechanism (difference, −0.06 [95% CI, −0.11 to −0.02]). However, the number of pathogenic variants/likely pathogenic variants/variants of uncertain significance was more comparable between ancestry groups (difference, −0.07 [95% CI, −0.22 to 0.09]) due to a larger number of non-TTN non–predicted loss of function variants of uncertain significance, mostly missense, in patients of African ancestry (difference, 0.15 [95% CI, 0.00-0.30]). Published clinical case-based evidence supporting pathogenicity was less available for variants found only in patients of African ancestry (P <.001). Conclusion and Relevance: Patients of African ancestry with DCM were less likely to have clinically actionable variants in DCM genes than those of European ancestry due to differences in genetic architecture and a lack of representation of African ancestry in clinical data sets. This study compares the rare variant genetic architecture of dilated cardiomyopathy (DCM) among patients with DCM who are of African ancestry compared with European ancestry. [ABSTRACT FROM AUTHOR]

Cardiovascular screening is recommended for first-degree relatives (FDRs) of patients with dilated cardiomyopathy (DCM), but the yield of FDR screening is uncertain for DCM patients without known familial DCM, for non-White FDRs, or for DCM partial phenotypes of left ventricular enlargement (LVE) or left ventricular systolic dysfunction (LVSD). This study examined the yield of clinical screening among reportedly unaffected FDRs of DCM patients. Adult FDRs of DCM patients at 25 sites completed screening echocardiograms and ECGs. Mixed models accounting for site heterogeneity and intrafamilial correlation were used to compare screen-based percentages of DCM, LVSD, or LVE by FDR demographics, cardiovascular risk factors, and proband genetics results. A total of 1,365 FDRs were included, with a mean age of 44.8 ± 16.9 years, 27.5% non-Hispanic Black, 9.8% Hispanic, and 61.7% women. Among screened FDRs, 14.1% had new diagnoses of DCM (2.1%), LVSD (3.6%), or LVE (8.4%). The percentage of FDRs with new diagnoses was higher for those aged 45 to 64 years than 18 to 44 years. The age-adjusted percentage of any finding was higher among FDRs with hypertension and obesity but did not differ statistically by race and ethnicity (16.2% for Hispanic, 15.2% for non-Hispanic Black, and 13.1% for non-Hispanic White) or sex (14.6% for women and 12.8% for men). FDRs whose probands carried clinically reportable variants were more likely to be identified with DCM. Cardiovascular screening identified new DCM-related findings among 1 in 7 reportedly unaffected FDRs regardless of race and ethnicity, underscoring the value of clinical screening in all FDRs. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Managing disease risk among first-degree relatives of probands diagnosed with a heritable disease is central to precision medicine. A critical component is often clinical screening, which is particularly important for conditions like dilated cardiomyopathy (DCM) that remain asymptomatic until severe disease develops. Nonetheless, probands are frequently ill-equipped to disseminate genetic risk information that motivates at-risk relatives to complete recommended clinical screening. An easily implemented remedy for this key issue has been elusive. Methods: The DCM Precision Medicine Study developed Family Heart Talk , a booklet designed to help probands with DCM communicate genetic risk and the need for cardiovascular screening to their relatives. The effectiveness of the Family Heart Talk booklet in increasing cardiovascular clinical screening uptake among first-degree relatives was assessed in a multicenter, open-label, cluster-randomized, controlled trial. The primary outcome measured in eligible first-degree relatives was completion of screening initiated within 12 months after proband enrollment. Because probands randomized to the intervention received the booklet at the enrollment visit, eligible first-degree relatives were limited to those who were alive the day after proband enrollment and not enrolled on the same day as the proband. Results: Between June 2016 and March 2020, 1241 probands were randomized (1:1) to receive Family Heart Talk (n=621) or not (n=620) within strata defined by site and self-identified race/ethnicity (non-Hispanic Black, non-Hispanic White, or Hispanic). Final analyses included 550 families (n=2230 eligible first-degree relatives) in the Family Heart Talk arm and 561 (n=2416) in the control arm. A higher percentage of eligible first-degree relatives completed screening in the Family Heart Talk arm (19.5% versus 16.0%), and the odds of screening completion among these first-degree relatives were higher in the Family Heart Talk arm after adjustment for proband randomization stratum, sex, and age quartile (odds ratio, 1.30 [1-sided 95% CI, 1.08–∞]). A prespecified subgroup analysis did not find evidence of heterogeneity in the adjusted intervention odds ratio across race/ethnicity strata (P =0.90). Conclusions: Family Heart Talk , a booklet that can be provided to patients with DCM by clinicians with minimal additional time investment, was effective in increasing cardiovascular clinical screening among first-degree relatives of these patients. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03037632. [ABSTRACT FROM AUTHOR]

Background During left ventricular assist device implantation, a surgical tunneling technique to keep the entire driveline (DL) velour portion in the subcutaneous tunnel, resulting in a silicone-skin interface (SSI) at the exit site, has been adopted by many centers. To assess long-term freedom from DL infection associated with this technique, a multicenter SSI registry was initiated. It was hypothesized that the modified tunneling technique is associated with at least 50% reduction in DL infection at 1 year post-implant compared with the velour-to-skin method used in the HeartMate II (HMII) Destination Therapy (DT) trial. Methods SSI is a retrospective and prospective registry of patients who have received the HMII device. Results are reported from the retrospective cohort, which consists of 200 patients who were implanted during the period 2009–2012 with the SSI tunneling method and on HMII support for at least 10 months at the time of enrollment. The prevalence and incidence of DL infection after left ventricular assist device implantation in the SSI retrospective cohort were determined and compared with a control group of 201 patients also on HMII support for at least 10 months from the HMII DT clinical trial who were implanted during the period 2007–2009 using the traditional method in which a small section of the velour portion of the DL was externalized. Results The 1-year and 2-year prevalence rates of DL infection were 9% and 19% in the SSI patient group compared with 23% and 35% in the control group (hazard ratio 0.49, 95% confidence interval 0.33–0.73, p < 0.001). The event-per-patient year was 0.11 and 0.22 for the SSI and control groups, respectively ( p < 0.001). Based on a multivariate analysis, age and DL exit side were the only independent variables associated with DL infection. Effects of management changes over the eras were not studied and could have contributed to the findings. Conclusions These results suggest that leaving the entire DL velour portion below the skin is associated with 50% reduction in DL infection compared with results from the HMII DT trial. [ABSTRACT FROM AUTHOR]

Patients with ambulatory advanced heart failure (HF) are increasingly considered for durable mechanical circulatory support (MCS) and heart transplantation and their effective triage requires careful assessment of the clinical trajectory. REVIVAL, a prospective, observational study, enrolled 400 ambulatory advanced HF patients from 21 MCS/transplant centers in 2015-2016. Study design included a clinical re-assessment of Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile within 120 days after enrollment. The prognostic impact of a worsening INTERMACS Profile assigned by the treating physician was assessed at 1 year after the Early Relook. Early Relook was done in 325 of 400 patients (81%), of whom 24% had a worsened INTERMACS Profile, associated with longer HF history and worse baseline INTERMACS profile, but no difference in baseline LVEF (median 0.20), 6-minute walk, quality of life, or other baseline parameters. Early worsening predicted higher rate of the combined primary endpoint of death, urgent MCS, or urgent transplant by 1 year after Early Relook, (28% vs 15%), with hazard ratio 2.2 (95% CI 1.2- 3.8; p =.006) even after adjusting for baseline INTERMACS Profile and Seattle HF Model score. Deterioration to urgent MCS occurred in 14% vs 5% (p =.006) during the year after Early Relook. Early Relook identifies worsening of INTERMACS Profile in a significant population of ambulatory advanced HF, who had worse outcomes over the subsequent year. Early reassessment of ambulatory advanced HF patients should be performed to better define the trajectory of illness and inform triage to advanced therapies. [ABSTRACT FROM AUTHOR]

Immune dysregulation is implicated in the development and clinical outcomes of peripartum cardiomyopathy (PPCM). 98 women with PPCM were enrolled and followed for 1 year postpartum (PP). LVEF was assessed at entry, 6-, and 12-months PP by echocardiography. Serum levels of soluble interleukin (IL)-2 receptor (sIL2R), IL-2, IL-4, IL-17, IL-22, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ were measured by ELISA at entry. Cytokine levels were compared between women with PPCM by NYHA class. Outcomes including myocardial recovery and event-free survival were compared by cytokine tertiles. For cytokines found to impact survival outcomes, parameters indicative of disease severity including baseline LVEF, medications, and use of inotropic and mechanical support were analyzed. Levels of proinflammatory cytokines including IL-17, IL-22, and sIL2R, were elevated in higher NYHA classes at baseline. Subjects with higher IL-22 levels were more likely to require inotropic or mechanical support. Higher levels of TNF-α and IL-22 were associated with poorer event-free survival. Higher TNF-α levels were associated with lower mean LVEF at entry and 12 months. In contrast, higher levels of immune-regulatory cytokines such as IL-4 and IL-2 were associated with higher LVEF during follow up. Proinflammatory cytokines IL-22 and TNF-α were associated with adverse event-free survival. IL-17 and IL-22 were associated with more severe disease. In contrast, higher levels of IL-2 and IL-4 corresponded with higher subsequent LVEF. Increased production of TH17 type cytokines in PPCM correlated with worse disease and outcomes, while an increased immune-regulatory response seems to be protective. Graphic 1: Depiction of naïve CD4 T-cell differentiation pathways. Increased levels of IFN-γ and IL-12 drive differentiation to TH1 T cells which further produce IFN-γ effector cytokines. Increased IL-6 and TGF-β stimulated CD4 T cells to differentiate into TH17 T cells which further produce IL-17 and IL-22 effector cytokine. Increased levels of IL-4 and IL-33 stimulate differentiation to TH2 T cells which then produce IL-4 effector cytokines. [Display omitted] • Immune dysregulation contributes to the pathogenesis and outcomes in patients with peripartum cardiomyopathy (PPCM). • 98 women with PPCM were followed postpartum with LVEF assessment, proinflammatory and immune-regulatory cytokine analysis. • Proinflammatory cytokines were associated with adverse outcomes, and immune-regulatory cytokines with myocardial recovery. [ABSTRACT FROM AUTHOR]

Acute kidney injury is a common complication following heart transplantation, and the factors contributing to acute kidney injury are not well understood. We conducted a retrospective cohort study evaluating patients who underwent heart transplantation between 2009 and 2016 at a single institution. The primary endpoint was incidence of acute kidney injury as defined by Kidney Disease Improving Global Outcomes criteria. Secondary endpoints included 30‐day hospital readmission, 30‐day mortality, and 1‐year mortality. A total of 228 heart transplant patients were included in the study for analysis. In total, 145 (64%) developed acute kidney injury, where 43 (30%) were classified as stage I, 28 (19%) as stage II, and 74 (51%) as stage III. Risk factors found to be associated with the presence of acute kidney injury included increased use of vasopressors and inotropes post‐transplant. Protective factors included cardiopulmonary bypass time <170 min. Acute kidney injury was found to be associated with increased 30‐day and 1‐year mortality. [ABSTRACT FROM AUTHOR]

The Registry Evaluation of Vital Information for Ventricular Assist Devices (VADs) in Ambulatory Life study is a prospective multicenter cohort of 400 ambulatory patients with advanced chronic systolic heart failure (HF). The aim of the study is to better understand disease trajectory and optimal timing of advanced HF therapies. We examined patient health-related quality of life (HRQOL) data collected at enrollment and their association with patient treatment preferences for VAD placement. Baseline assessment of HRQOL included the Kansas City Cardiomyopathy Questionnaire (KCCQ) and the EuroQol EQ-5D-3L Visual Analogue Scale (VAS), along with patient self-assessment of remaining life (PSARL). Descriptive statistics were used to present baseline HRQOL data and Spearman correlation tests to assess the association between KCCQ, VAS, and VAD treatment preference with patient clinical characteristics of interest. The median age was 60 years, 75% were male, and the median left ventricular ejection fraction was 20%. The median (25th percentile, 75th percentile), baseline KCCQ summary score was 64 (48, 78), VAS score 65 (50, 75), and PSARL 7 years (5, 10). There were statistically significant associations of baseline KCCQ and VAS with New York Heart Association class and Interagency Registry of Mechanically Assisted Circulatory Support profile (p < 0.005 for all comparisons). Baseline KCCQ and VAS revealed a modest association with PSARL (correlation = 0.45 and 0.35, respectively; p < 0.001), and many patients were overly optimistic about their expected survival. VAD treatment preference was associated with KCCQ scores (p < 0.031), but the absolute differences were small. VAD treatment preference was independent of other key clinical characteristics such as subject age, VAS, and PSARL. We found a lack of strong association between HRQOL and patient preference for VAD therapy. Better understanding of patients' perceptions of their illness and how this relates to HRQOL outcomes, clinician risk assessment, and patient decision-making is needed. This may in turn allow better guidance toward available HF therapies in this vulnerable population. [ABSTRACT FROM AUTHOR]

Background: Cerebrovascular events (CVE) are among the most common and serious complications after implantation of continuous-flow left ventricular assist devices (CF-LVAD). We studied the incidence, subtypes, anatomical distribution, and pre- and post-implantation risk factors of CVEs as well as the effect of CVEs on outcomes after CF-LVAD implantation at our institution.Methods: Retrospective analysis of clinical and neuroimaging data of 372 patients with CF-LVAD between May 2005 and December 2013 using standard statistical methods.Results: CVEs occurred in 71 patients (19%), consisting of 35 ischemic (49%), 26 hemorrhagic (37%), and 10 ischemic+hemorrhagic (14%) events. History of coronary artery disease and female gender was associated with higher odds of ischemic CVE (OR 2.84 and 2.5, respectively), and diabetes mellitus was associated with higher odds of hemorrhagic CVE (OR 3.12). While we found a higher rate of ischemic CVEs in patients not taking any antithrombotic medications, no difference was found between patients with ischemic and hemorrhagic CVEs. Occurrence of CVEs was associated with increased mortality (HR 1.62). Heart transplantation was associated with improved survival (HR 0.02). In patients without heart transplantation, occurrence of CVE was associated with decreased survival.Conclusions: LVADs are associated with high rates of CVE, increased mortality, and lower rates of heart transplantation. Further investigations to identify the optimal primary and secondary stroke prevention measures in post-LVAD patients are warranted. [ABSTRACT FROM AUTHOR]

Background: The HeartMate 3 (HM3) Left Ventricular Assist System (LVAS) (Abbott) is a centrifugal, fully magnetically levitated, continuous-flow blood pump engineered to enhance hemocompatibility and reduce shear stress on blood components. The MOMENTUM 3 trial (Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy With HeartMate 3) compares the HM3 LVAS with the HeartMate II (HMII) LVAS (Abbott) in advanced heart failure refractory to medical management, irrespective of therapeutic intention (bridge to transplant versus destination therapy). This investigation reported its primary outcome in the short-term cohort (n=294; 6-month follow-up), demonstrating superiority of the HM3 for the trial primary end point (survival free of a disabling stroke or reoperation to replace the pump for malfunction), driven by a reduced need for reoperations. The aim of this analysis was to evaluate the aggregate of hemocompatibility-related clinical adverse events (HRAEs) between the 2 LVAS.Methods: We conducted a secondary end point evaluation of HRAE (survival free of any nonsurgical bleeding, thromboembolic event, pump thrombosis, or neurological event) in the short-term cohort (as-treated cohort n=289) at 6 months. The net burden of HRAE was also assessed by using a previously described hemocompatibility score, which uses 4 escalating tiers of hierarchal severity to derive a total score for events encountered during the entire follow-up experience for each patient.Results: In 289 patients in the as-treated group (151 the HM3 and 138 the HMII), survival free of any HRAE was achieved in 69% of the HM3 group and in 55% of the HMII group (hazard ratio, 0.62; confidence interval, 0.42-0.91; P=0.012). Using the hemocompatibility score, the HM3 group demonstrated less pump thrombosis requiring reoperation (0 versus 36 points, P<0.001) or medically managed pump thrombosis (0 versus 5 points, P=0.02), and fewer nondisabling strokes (6 versus 24 points, P=0.026) than the control HMII LVAS. The net hemocompatibility score in the HM3 in comparison with the HMII patients was 101 (0.67±1.50 points/patient) versus 137 (0.99±1.79 points/patient) (odds ratio, 0.64; confidence interval, 0.39-1.03; P=0.065).Conclusions: In this secondary analysis of the MOMENTUM 3 trial, the HM3 LVAS demonstrated greater freedom from HRAEs in comparison with the HMII LVAS at 6 months.Clinical Trial Registration: URL: http://clinicaltrials.gov. Unique identifier: NCT02224755. [ABSTRACT FROM AUTHOR]

Background: Continuous-flow left ventricular assist systems increase the rate of survival among patients with advanced heart failure but are associated with the development of pump thrombosis. We investigated the effects of a new magnetically levitated centrifugal continuous-flow pump that was engineered to avert thrombosis.Methods: We randomly assigned patients with advanced heart failure to receive either the new centrifugal continuous-flow pump or a commercially available axial continuous-flow pump. Patients could be enrolled irrespective of the intended goal of pump support (bridge to transplantation or destination therapy). The primary end point was a composite of survival free of disabling stroke (with disabling stroke indicated by a modified Rankin score >3; scores range from 0 to 6, with higher scores indicating more severe disability) or survival free of reoperation to replace or remove the device at 6 months after implantation. The trial was powered for noninferiority testing of the primary end point (noninferiority margin, -10 percentage points).Results: Of 294 patients, 152 were assigned to the centrifugal-flow pump group and 142 to the axial-flow pump group. In the intention-to-treat population, the primary end point occurred in 131 patients (86.2%) in the centrifugal-flow pump group and in 109 (76.8%) in the axial-flow pump group (absolute difference, 9.4 percentage points; 95% lower confidence boundary, -2.1 [P<0.001 for noninferiority]; hazard ratio, 0.55; 95% confidence interval [CI], 0.32 to 0.95 [two-tailed P=0.04 for superiority]). There were no significant between-group differences in the rates of death or disabling stroke, but reoperation for pump malfunction was less frequent in the centrifugal-flow pump group than in the axial-flow pump group (1 [0.7%] vs. 11 [7.7%]; hazard ratio, 0.08; 95% CI, 0.01 to 0.60; P=0.002). Suspected or confirmed pump thrombosis occurred in no patients in the centrifugal-flow pump group and in 14 patients (10.1%) in the axial-flow pump group.Conclusions: Among patients with advanced heart failure, implantation of a fully magnetically levitated centrifugal-flow pump was associated with better outcomes at 6 months than was implantation of an axial-flow pump, primarily because of the lower rate of reoperation for pump malfunction. (Funded by St. Jude Medical; MOMENTUM 3 ClinicalTrials.gov number, NCT02224755 .). [ABSTRACT FROM AUTHOR]

Background Depression is a risk factor for morbidity and mortality in patients with coronary heart disease. Finding effective methods for identifying and treating depression in these patients is a high priority. The purpose of this study was to determine whether collaborative care (CC) for patients who screen positive for depression during an outpatient cardiology visit results in greater improvement in depression symptoms and better medical outcomes than seen in patients who screen positive for depression but receive only usual care (UC). Methods Two hundred-one patients seen in an outpatient cardiology clinic who screened positive for depression during an outpatient visit were randomized to receive either CC or UC. Recommendations for depression treatment and ongoing support and monitoring of depression symptoms were provided to CC patients and their primary care physicians (PCPs) for up to 6 months. Results There were no differences between the arms in mean Beck Depression Inventory-II scores(CC, 15.9; UC, 17.4; p = .45) or in depression remission rates(CC, 32.5%; UC, 26.2%; p = 0.34) after 6 months, or in the number of hospitalizations after 12 months (p = 0.73). There were fewer deaths among the CC (1/100) than UC patients (8/101) (p = 0.03). Conclusions This trial did not show that CC produces better depression outcomes than UC. Screening led to a higher rate of depression treatment than was expected in the UC group, and delays in obtaining depression treatment from PCPs may have reduced treatment effectiveness for the CC patients. A different strategy for depression treatment following screening in outpatient cardiology services is needed. [ABSTRACT FROM AUTHOR]

Heart failure (HF) claims 250,000 lives per year in the US, and nearly half of these deaths are sudden and presumably due to ventricular tachyarrhythmias. QT interval and action potential (AP) prolongation are hallmark proarrhythmic changes in the failing myocardium, which potentially result from alterations in repolarizing potassium currents. Thus, we aimed to examine whether decreased expression of the rapid delayed rectifier potassium current, I Kr , contributes to repolarization abnormalities in human HF. To map functional I Kr expression across the left ventricle (LV), we optically imaged coronary-perfused LV free wall from donor and end-stage failing human hearts. The LV wedge preparation was used to examine transmural AP durations at 80% repolarization (APD80), and treatment with the I Kr -blocking drug, E-4031, was utilized to interrogate functional expression. We assessed the percent change in APD80 post-I Kr blockade relative to baseline APD80 (∆APD80) and found that ∆APD80s are reduced in failing versus donor hearts in each transmural region, with 0.35-, 0.43-, and 0.41-fold reductions in endo-, mid-, and epicardium, respectively ( p = 0.008, 0.037, and 0.022). We then assessed hERG1 isoform gene and protein expression levels using qPCR and Western blot. While we did not observe differences in hERG1a or hERG1b gene expression between donor and failing hearts, we found a shift in the hERG1a:hERG1b isoform stoichiometry at the protein level. Computer simulations were then conducted to assess I Kr block under E-4031 influence in failing and nonfailing conditions. Our results confirmed the experimental observations and E-4031-induced relative APD80 prolongation was greater in normal conditions than in failing conditions, provided that the cellular model of HF included a significant downregulation of I Kr . In human HF, the response to I Kr blockade is reduced, suggesting decreased functional I Kr expression. This attenuated functional response is associated with altered hERG1a:hERG1b protein stoichiometry in the failing human LV, and failing cardiomyoctye simulations support the experimental findings. Thus, of I Kr protein and functional expression may be important determinants of repolarization remodeling in the failing human LV. [ABSTRACT FROM AUTHOR]

Background: Data from a cardiopulmonary exercise (CPX) test are used to determine prognosis in patients with chronic heart failure (HF). However, few published studies have simultaneously compared the relative prognostic strength of multiple CPX variables. Objectives: The study sought to describe the strength of the association among variables measured during a CPX test and all-cause mortality in patients with HF with reduced ejection fraction (HFrEF), including the influence of sex and patient effort, as measured by respiratory exchange ratio (RER). Methods: Among patients (n = 2,100, 29% women) enrolled in the HF-ACTION (HF-A Controlled Trial Investigating Outcomes of exercise traiNing) trial, 10 CPX test variables measured at baseline (e.g., peak oxygen uptake [Vo2], exercise duration, percent predicted peak Vo2 [%ppVo2], ventilatory efficiency) were examined. Results: Over a median follow-up of 32 months, there were 357 deaths. All CPX variables, except RER, were related to all-cause mortality (all p < 0.0001). Both %ppVo2 and exercise duration were equally able to predict (Wald chi-square: ∼141) and discriminate (c-index: 0.69) mortality. Peak Vo2 (ml·kg(-1)·min(-1)) was the strongest predictor of mortality among men (Wald chi-square: 129) and exercise duration among women (Wald chi-square: 41). Multivariable analyses showed that %ppVo2, exercise duration, and peak Vo2 (ml·kg(-1)·min(-1)) were similarly able to predict and discriminate mortality. In men, a 10% 1-year mortality rate corresponded to a peak Vo2 of 10.9 ml·kg(-1)·min(-1) versus 5.3 ml·kg(-1)·min(-1) in women. Conclusions: Peak Vo2, exercise duration, and % ppVo2 carried the strongest ability to predict and discriminate the likelihood of death in patients with HFrEF. The prognosis associated with a given peak Vo2 differed by sex. (Exercise Training Program to Improve Clinical Outcomes in Individuals With Congestive Heart Failure; NCT00047437). [ABSTRACT FROM AUTHOR]

Background The basis for increased mortality after heart transplantation in African Americans and other non-Caucasian racial groups is poorly defined. We hypothesized that increased risk of adverse events is driven by biologic factors. To test this hypothesis in the Invasive Monitoring Attenuation through Gene Expression (IMAGE) study, we determined whether the event rate of the primary outcome of acute rejection, graft dysfunction, death, or retransplantation varied by race as a function of calcineurin inhibitor (CNI) levels and gene expression profile (GEP) scores. Methods We determined the event rate of the primary outcome, comparing racial groups, stratified by time after transplant. Logistic regression was used to compute the relative risk across racial groups, and linear modeling was used to measure the dependence of CNI levels and GEP score on race. Results In 580 patients monitored for a median of 19 months, the incidence of the primary end point was 18.3% in African Americans, 22.2% in other non-Caucasians, and 8.5% in Caucasians ( p < 0.001). There were small but significant correlations of race and tacrolimus trough levels to the GEP score. Tacrolimus levels were similar among the races. Of patients receiving tacrolimus, other non-Caucasians had higher GEP scores than the other racial groups. African American recipients demonstrated a unique decrease in expression of the FLT3 gene in response to higher tacrolimus levels. Conclusions African Americans and other non-Caucasian heart transplant recipients were 2.5-times to 3-times more likely than Caucasians to experience outcome events in the Invasive Monitoring Attenuation through Gene Expression study. The increased risk of adverse outcomes may be partly due to the biology of the alloimmune response, which is less effectively inhibited at similar tacrolimus levels in minority racial groups. [ABSTRACT FROM AUTHOR]

Introduction Secondary pulmonary hypertension ( PH) and right ventricular dysfunction are common and associated with poor prognosis in HF patients with left ventricular assist devices ( LVADs). The role of pulmonary vasodilator therapy for these patients is currently unclear. Aims We sought to evaluate the safety and clinical course of patients treated with bosentan, an endothelin receptor antagonist, after the implementation of a LVAD. Results Between 10/2008 and 5/2011, 50 consecutive patients with mean PAP >25 mmHg were treated with bosentan after LVAD implantation for a mean duration of 15.7 (±12.4) months. Ten patients discontinued the drug for possible side effects, including three for LFT abnormalities. Comparison of baseline to 6-month follow-up data revealed laboratory evidence for decongestion with a decrease in bilirubin (2.3-0.6, P < 0.0001) and an improvement in pulmonary hemodynamics with echocardiographically calculated mean PVR decreasing 1.4 woods units (3.93 ± 1.53 to 2.58 ± 1.05, P < 0.0001). Conclusion In this single-centered retrospective case series, we provide evidence that the tolerability of bosentan in LVAD-supported patients with secondary PH is comparable to prior experience in patients with heart failure. [ABSTRACT FROM AUTHOR]

Background Stroke is a significant complication in patients supported with continuous-flow left ventricular assist devices (CF-LVAD) and hypertension is a significant risk factor for stroke, but the association between blood pressure and stroke in LVAD patients is not well characterized. Methods We identified 275 consecutive patients who survived implant hospitalization between January 2005 and April 2013. Patients were grouped according to systolic blood pressure (SBP) as above a median and below a median of 100 mm Hg by their averaged systolic blood pressure during the 48 hours before discharge from implantation hospitalization. The groups were compared for the primary outcome of time to stroke. Results The above-median SBP group had mean SBP of 110 mm Hg and the below-median SBP group had mean SBP of 95 mm Hg. There were no significant between-group differences in body mass index, smoking, vascular disease, hypertension, atrial fibrillation, or prior stroke. During a mean follow-up of 16 months, stroke occurred in 16% of the above-median SBP group vs in 7% of the below-median SBP group (hazard ratio, 2.38; 95% confidence interval, 1.11–5.11), with a similar proportion of hemorrhagic and ischemic strokes in each group. In Cox proportional hazard models adjusting for age, diabetes, or prior stroke, the hazard ratio remained statistically significant. SBP as a continuous variable predictor of stroke had an area under the curve of 0.64 in a receiver operating characteristic curve analysis. Conclusions In this large, CF-LVAD cohort, elevated SBP was independently associated with a greater risk of subsequent stroke. These results identify management of hypertension as a potential modifiable risk factor for reducing the incidence of stroke in patients supported by CF-LVAD. [ABSTRACT FROM AUTHOR]

Background Although atrial arrhythmias (AAs) are common in heart failure, the incidence of AAs subsequent to the placement of left ventricular assist devices (LVADs) has not been elucidated. Methods Patients receiving a HeartMate II LVAD in the bridge to transplant (n = 490) and destination therapy (n = 634) trials were included (n = 1125). AAs requiring treatment were recorded, regardless of symptoms. Using Cox models with and without a 60-day blanking period, risk factors for early and late AAs were determined. Results In total, there were 271 AAs in 231 patients (21%), most of which occurred within the first 60 days. Patients with and without AAs had similar survival (p = 0.16). Serum creatinine (hazard ratio [HR] = 1.49 per unit increase, 1.18 to 1.88; p < 0.001) and ejection fraction (HR = 0.98 per 1% increase, 0.95 to 0.999; p = 0.04) were associated with AAs in a multivariable model. Although quality of life (QoL) and functional status improved in all patients, those with AAs had worse unadjusted QoL (p < 0.001) and a decreased rate of improvement in six-minute walk distance over six to 24 months postimplant (p = 0.016). Conclusions Approximately one-fifth of LVAD patients have AAs, most commonly within the first 60 days of support. Preoperative creatinine is a strong risk factor for early and late AAs. Although AAs do not impact survival, they are associated with decreased functional status and QoL improvements during LVAD support. doi: 10.1111/jocs.12336 (J Card Surg 2014;29:572-580) [ABSTRACT FROM AUTHOR]

Background: The purpose of these studies was to determine the incidence and survival of patients with specific malignancies with respect to age and transplant year and to compare the data with the normal non-transplant population. Methods: Data from 6,211 primary cardiac transplants between July 31, 1993, and December 30, 2008, were collected by 35 institutions participating in the Cardiac Transplant Research Database. Data were compared with information collected by the Surveillance Epidemiology and End Results (SEER) Cancer Statistics Review 1975–2006. Results: Multivariable analysis showed older age (relative risk [RR], 2.1; p < 0.0001) and earlier transplant year (RR, 1.8; p < 0.0001) were highly significant risk factors. Aggregate malignancy incidence in the modern era (2001 to 2008) did not differ significantly from the normal population, which appeared to be attributable to a lower rate of malignancies other than lung cancer, lymphoma, and melanoma (actual/expected ratio, 0.71). From 2001 to 2008, rates were significantly higher for lung cancer (actual/expected ratio, 1.86; p = 0.006) and lymphoma (actual/expected ratio, 4.3, p < 0.0001) than in the normal population. The highest risk for lymphoma was in younger adults who received transplants at ages 18 to 35 years (actual/expected ratio, 27). The highest risk for lung cancer was in patients who underwent transplantation at ages 55 to 65 years (actual/expected ratio, 28). Once diagnosed with malignancy, subsequent survival at 5 years was 21% for lung cancer and 32% for lymphoma. Conclusions: The risk of malignancy has markedly declined during a 15-year period such that the aggregate rate of malignancy approached that of the general population in the United States. However, the distribution of malignancies was not the same, with a greater prominence of lung cancer and lymphoproliferative disease. [Copyright &y& Elsevier]

The article discusses a study that examined the occurrence of pump thrombosis and elevated lactate dehydrogenase (LDH) levels, LDH levels presaging thrombosis and associated hemolysis, and outcomes of different management strategies in patients who received the HeartMate II left ventricular assist device. Findings confirmed pump thromboses in 66 patients, and 36 thromboses in unique devices were suspected. The increasing rate of pump thrombosis related to the use of the device is noted.

Background: Hemolysis is becoming increasingly recognized as a major complication of left ventricular assist device (LVAD) support. Data regarding risk factors, prevalence, and outcomes are limited. To better define the characteristics and prognosis of hemolysis, we present a retrospective case-control study of LVAD patients in our institution. Methods: A detailed record review was conducted of 18 patients supported with the HeartMate II (HMII; Thoratec Corp, Pleasanton, CA) who were diagnosed with hemolysis, and their data were compared with 82 patients who received an LVAD implant during the same period who did not develop hemolysis. Patients were excluded if they did not survive hospitalization at the time of LVAD implantation. The primary end points of this analysis were time to death and time to first hospitalization. Results: Of 100 total patients, 18 HMII patients (18%) were diagnosed with hemolysis. Those with hemolysis were younger, had significantly higher lactate dehydrogenase and bilirubin levels, lower international normalized ratio, and no difference in cannula velocities by transthoracic echocardiography. Patient survival in the hemolysis group was markedly decreased at 1 year (38.9% vs 89.3%, p < 0.001), but no differences in hospitalization (p = 0.57) were observed. Partial to complete thrombosis was noted in all of the pumps at explant. Conclusions: These findings demonstrate that hemolysis is associated with high mortality, likely serving as a marker of pump thrombosis. Elevated lactate dehydrogenase and bilirubin levels are important indicators for hemolysis, and lower international normalized ratio may pre-dispose for this worrisome condition. Diagnosis should prompt clinicians to consider pump exchange or explant, listing for transplantation, or intensifying anti-coagulation. [Copyright &y& Elsevier]

Exercise training (ET) in patients with heart failure (HF), as demonstrated in the Heart Failure: A Controlled Trial Investigating Outcomes of Exercise TraiNing (HF-ACTION), was associated with improved exercise tolerance and health status and a trend toward reduced mortality or hospitalization. The present analysis of the HF-ACTION cohort examined the effect of ET in overweight and obese subjects compared to normal weight subjects with HF. Of 2,331 subjects with systolic HF randomized to aerobic ET versus usual care in the HF-ACTION, 2,314 were analyzed to determine the effect of ET on all-cause mortality, hospitalizations, exercise parameters, quality of life, and body weight changes by subgroups of body mass index (BMI). The strata included normal weight (BMI 18.5 to 24.9 kg/m2), overweight (BMI 25.0 to 29.9 kg/m2), obese I (BMI 30 to 34.9 kg/m2), obese II (BMI 35 to 39.9 kg/m2), and obese III (BMI ≥40 kg/m2). At enrollment, 19.4% of subjects were normal weight, 31.3% were overweight, and 49.4% were obese. A greater BMI was associated with a nonsignificant increase in all-cause mortality or hospitalization. ET was associated with nonsignificant reductions in all-cause mortality and hospitalization in each weight category (hazard ratio 0.98, 0.95, 0.92, 0.89, and 0.86 in the normal weight, overweight, obese I, obese II, and obese III categories, respectively; all p >0.05). Modeled improvement in exercise capacity (peak oxygen consumption) and quality of life in the ET group was seen in all BMI categories. In conclusion, aerobic ET in subjects with HF was associated with a nonsignificant trend toward decreased mortality and hospitalization and a significant improvement in quality of life across the range of BMI categories. [Copyright &y& Elsevier]

Abstract: Humoral immune responses to mismatched donor human leukocyte antigen (HLA) and major histocompatibility complex (MHC) class I–related chain A (MICA) have been reported to contribute to immunopathogenesis of antibody-mediated rejection (AMR) in the early period and cardiac allograft vasculopathy (CAV) in the late period after cardiac transplantation (HTx). The goal of this study is to define the roles of donor-specific antibodies (DSA) and anti-MICA in AMR and CAV. A total of 95 post-HTx recipients were enrolled; 43 patients in the early period (≤12 months post-HTx) and 52 patients in the late period (>12 months post-HTx). Development of DSA and anti-MICA were serially monitored using Luminex. Development of DSA (AMR+: n = 6/8.75%, AMR−: n = 4/35.11%, p = 0.009) and anti-MICA (AMR+: n = 5/8.63%, AMR−: n = 4/35.11%, p = 0.002) was significantly associated with AMR. AMR+DSA+ patients demonstrated increased anti-MICA levels compared with AMR+DSA− patients (p=0.01). Serial monitoring revealed DSA (2.7 ± 1.4 months) preceded development of anti-MICA (6.5 ± 2.1 months) in recipients diagnosed with AMR at 8.3 ± 2.5 months post-HTx. Development of DSA (CAV+: n = 8/12.67%, CAV−: n = 5/40.13%, p = 0.004) and anti-MICA (CAV+: n = 9/12.75%, CAV−: n = 5/40.13%, p = 0.001) was significantly associated with CAV. CAV+DSA+ patients demonstrated increased anti-MICA levels compared with CAV+DSA− patients (p = 0.01). Antibodies to HLA are associated with and precede development of anti-MICA in AMR and CAV. Therefore, DSA and anti-MICA can be used as noninvasive markers for monitoring AMR and CAV. [Copyright &y& Elsevier]

Background: Herein we study the role of donor-specific antibodies (DSA) to mismatched human leukocyte antigen (HLA) and antibodies (Abs) to the cardiac self-antigens myosin (MYO) and vimentin (VIM) in the pathogenesis of acute antibody-mediated rejection (AMR) in the early post-transplant period (EP, <12 months) and cardiac allograft vasculopathy (CAV) in the late post-transplant period (LP, >12 months) after heart transplantation (HTx). Methods: One hundred forty-eight HTx recipients (65 in EP, 83 in LP) were enrolled in the study. Development of DSA was determined by Luminex. Circulating Abs against MYO and VIM in sera were measured using enzyme-linked immunoassay (ELISA). Frequency of CD4+ T-helper cells (CD4+ Th) secreting interferon (IFN)-γ, interleukin (IL)-17, IL-10 or IL-5 specific to either MYO or VIM were analyzed in vitro using ELISpot assays. Results: AMR patients were more likely DSA positive (AMR−: 15%; AMR+: 70%; p = 0.03) and demonstrated increased Abs to MYO (AMR−: 144 ± 115 μg/ml; AMR+: 285 ± 70 μg/ml; p = 0.033) and VIM (AMR−: 37 ± 19 μg/ml; AMR+: 103 ± 43 μg/ml; p = 0.014). AMR patients demonstrated increased IL-5 CD4+ Th cells specific to MYO (5.2 ± 0.9 fold, p = 0.003) and VIM (7.3 ± 2.9-fold, p = 0.004) and decreased IL-10 CD4+ Th cells specific to MYO (2.2 ± 0.4-fold, p = 0.009) and VIM (1.7 ± 0.2-fold, p = 0.03). CAV patients were more likely DSA positive (CAV−: 25%; CAV+: 79%; p = 0.03) and demonstrated increased Abs to MYO (CAV−: 191 ± 120 μg/ml; CAV+: 550 ± 98 μg/ml; p = 0.025) and VIM (CAV−: 55 ± 25 μg/ml; CAV+: 255 ± 49 μg/ml; p = 0.001). CAV patients demonstrated increased IL-17 CD4+ Th cells specific to MYO (10.5 ± 7.3-fold, p = 0.002) and VIM (7.0 ± 3.9-fold, p = 0.003). Conclusions: The presence of DSA in AMR and CAV is significantly associated with development of Abs to MYO and VIM in post-HTx patients. Induction of high CD4+ Th cells specific to cardiac self-antigens that secrete predominantly IL-5 and IL-17 plays a significant role in the development of Abs to self-antigens leading to AMR and CAV, respectively. [Copyright &y& Elsevier]

Background: Endomyocardial biopsy is the standard method of monitoring for rejection in recipients of a cardiac transplant. However, this procedure is uncomfortable, and there are risks associated with it. Gene-expression profiling of peripheral-blood specimens has been shown to correlate with the results of an endomyocardial biopsy. Methods: We randomly assigned 602 patients who had undergone cardiac transplantation 6 months to 5 years previously to be monitored for rejection with the use of gene-expression profiling or with the use of routine endomyocardial biopsies, in addition to clinical and echocardiographic assessment of graft function. We performed a noninferiority comparison of the two approaches with respect to the composite primary outcome of rejection with hemodynamic compromise, graft dysfunction due to other causes, death, or retransplantation. Results: During a median follow-up period of 19 months, patients who were monitored with gene-expression profiling and those who underwent routine biopsies had similar 2-year cumulative rates of the composite primary outcome (14.5% and 15.3%, respectively; hazard ratio with gene-expression profiling, 1.04; 95% confidence interval, 0.67 to 1.68). The 2-year rates of death from any cause were also similar in the two groups (6.3% and 5.5%, respectively; P=0.82). Patients who were monitored with the use of gene-expression profiling underwent fewer biopsies per person-year of follow-up than did patients who were monitored with the use of endomyocardial biopsies (0.5 vs. 3.0, P<0.001). Conclusions: Among selected patients who had received a cardiac transplant more than 6 months previously and who were at a low risk for rejection, a strategy of monitoring for rejection that involved gene-expression profiling, as compared with routine biopsies, was not associated with an increased risk of serious adverse outcomes and resulted in the performance of significantly fewer biopsies. (ClinicalTrials.gov number, NCT00351559.) N Engl J Med 2010;362:1890-900. [ABSTRACT FROM AUTHOR]

Background: Quantification of donor-associated risk in a specific heart transplant recipient is often difficult. Our aim was to identify donor characteristics that affect survival in the contemporary era. Methods: Between 1990 and 2006, 7,322 patients from 32 centers in the Cardiac Transplant Research Database underwent heart transplantation. Multivariable logistic regression analysis was used to identify donor-associated risk predictors and important interactions between these donor characteristics. Recipient survival was examined using parametric regression analysis in the hazard function domain. Results: Donor characteristics associated with post-transplant death included donor age, donor requirement for vasoactive therapy, positive donor cytomegalovirus serology, longer graft ischemic time, and lower donor body weight. Several interactions between individual donor characteristics affected survival. In male donors, history of hypertension and diabetes mellitus were risk factors for death (p = 0.006, p = 0.04, respectively), but not in female donors (p = 0.5, p = 0.8, respectively). There was a significant interaction between donor age and recipient-donor weight difference. If the donor was of younger age, increasing recipient-donor weight difference did not result in increased death. With increasing donor age, weight difference did result in compromised survival (p < 0.0003). Donor and recipient gender further modified the degree of risk: risk was higher in female donors and when recipients were male (p < 0.0003). Conclusions: This multi-institutional analysis identified important interactions between donor characteristics that affect post-transplant survival that explain some of the discrepancies in the results of previous studies. The results are likely to aid in efficient organ allocation. [Copyright &y& Elsevier]

Macitentan is a dual endothelin receptor antagonist (ERA) approved for treating pulmonary arterial hypertension (PAH). SOPRANO evaluated the efficacy and safety of macitentan versus placebo in pulmonary hypertension (PH) patients after left ventricular assist device (LVAD) implantation. SOPRANO was a phase 2, multicenter, double-blind, randomized, placebo-controlled, parallel-group study. Patients with an LVAD implanted within the prior 90 days who had persistent PH (i.e., mean pulmonary arterial pressure ≥25 mmHg, pulmonary artery wedge pressure [PAWP] ≤18 mmHg, and pulmonary vascular resistance [PVR] >3 Wood units [WU]) were randomized (1:1) to macitentan 10 mg or placebo once daily for 12 weeks. The primary endpoint was change in PVR. Secondary endpoints included change in right-heart catheterization hemodynamic variables, N-terminal prohormone of brain natriuretic peptide levels, World Health Organization functional class, and safety/tolerability. Fifty-seven patients were randomized to macitentan ( n  = 28) or placebo ( n  = 29). A statistically significant reduction in PVR from baseline to Week 12 was observed with macitentan versus placebo (placebo-corrected geometric mean ratio, 0.74; 95% confidence interval, 0.58-0.94; p  = .0158). No statistically significant differences were observed in secondary endpoints. In a post-hoc analysis, 66.7% of patients receiving macitentan achieved PVR <3 WU versus 40.0% receiving placebo ( p  = .0383). Macitentan was generally well tolerated; adverse events were consistent with those in previous PAH studies with macitentan. In conclusion, macitentan showed promising tolerability and significantly reduced PVR in PH patients with persistently elevated PVR after LVAD implantation. ClinicalTrials. gov identifier: NCT02554903., Competing Interests: Robert P. Frantz is receiving grants and research support from United Therapeutics, Medtronic, and Gossamer Bio, and is scientific medical advisor to Altavant, ShouTi, Liquidia Corporation, Merck, Tenax Therapeutics, and Janssen Pharmaceutical Companies of Johnson & Johnson. His institution has received funding from Bayer and Gossamer Bio. Shashank S. Desai has served on the speakers’ bureau for Abbott. Gregory Ewald is on the speakers’ bureau and is a consultant with Abbott. Veronica Franco's institution receives research support from Acceleron/Merck, Gossamer, Janssen, United Therapeutics, Aerovate Therapeutics, Respira, and Cereno Scientific. Antoine Hage is receiving grants and research support from United Therapeutics, Lung LLC, Arena, Reata, and Bayer, and is a stockholder in Johnson & Johnson and Pfizer. Evelyn M. Horn's institution has received funding from Gossamer, Acceleron/Merck, Abbott, and Cereno Scientific. Stacy Mandras is a speaker and consultant for United Therapeutics and Bayer Pharmaceuticals. Myung H. Park is a scientific medical advisor with AstraZeneca. Ashwin K. Ravichandran is consulting/speaking for Abbott, Medtronic and speaking for United Therapeutics, Janssen, and Bayer; he personally receives no grants from these companies, but his institution does. Ronald Zolty is a consultant for Janssen Pharmaceutical Companies of Johnson & Johnson, Bayer, United Therapeutics, and Alnylam. Mark A. Rocco, Mona Selej, and Carol Zhao were employees of Actelion Pharmaceuticals US, Inc., South San Francisco, CA (at the time of manuscript development) and are current stockholders of Johnson & Johnson. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 Actelion Pharmaceuticals US, Inc. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Background: Clinical genetic evaluation of dilated cardiomyopathy (DCM) is implemented variably or not at all. Identifying needs and barriers to genetic evaluations will enable strategies to enhance precision medicine care., Methods: An online survey was conducted in June 2024 among cardiologist investigators of the DCM Consortium from US advanced heart failure/transplant (HF/TX) programs to collect demographics, training, program characteristics, genetic evaluation practices for DCM, and implementation needs. An in-person discussion followed., Results: Twenty-five cardiologists (28% female, 12% Hispanic, 68% White) participated in the survey and 15 in the discussion; genetics training backgrounds varied greatly. Clinical genetic testing for DCM was conducted by all programs with annual uptake ranging from 5%-70% (median 25%). Thirteen respondents (52%) did not use selection criteria for testing whereas others selected patients based on specific clinical and family history data. Eight (32%) ordered testing by themselves, and the remainder had testing managed mostly by a genetic counselor or others with genetic expertise (16/17; 94%). Six themes were distilled from open-ended responses regarding thoughts for the future and included access to genetics services, navigating uncertainty, knowledge needs, cost concerns, family-based care barriers, and institutional infrastructure limitations. Following an in-person discussion, four areas were identified for focused effort: improved reimbursement for genetic services, genetic counselor integration with HF/TX teams, improved provider education resources, and more research to find missing heritability and to resolve uncertain results., Conclusions: HF/TX programs have implementation challenges in the provision of DCM genetic evaluations; targeted plans to facilitate precision medicine for DCM are needed.

Background: Activin A has been implicated in the pathogenesis of patients with chronic hypertension and heart failure as well as patients with hypertensive disorders of pregnancy (HDP). Whether activin A correlates with blood pressure in patients with peripartum cardiomyopathy (PPCM) and HDP history has not previously been explored., Methods and Results: 82 women with PPCM w/ and w/out HDP or hypertension history were selected for analysis from the Investigations in Pregnancy Associated Cardiomyopathy (IPAC) study. Serum biomarkers and blood pressure were assessed at the time of enrollment (median postpartum day 24). Levels of both sFlt-1 (SBP: r 0.47, p = 0.008; DBP: r 0.57, p < 0.001) and activin A (SBP: r 0.59, p < 0.001;DBP: r 0.68, p < 0.001) were noted to significantly correlate with blood pressure in patients with a history of HDP who went on to develop PPCM, but not in patients with chronic hypertension or no hypertensive history. The strongest correlation was between activin A levels and postpartum diastolic blood pressure for the subset with preeclampsia (DBP: r0.82, p < 0.001). This remained significant in multivariable linear regression analysis (DBP: β = 0.011, p = 0.015)., Conclusion: In patients with PPCM, activin A and sFlt-1 levels had direct correlations with both systolic (SBP) and diastolic blood pressures (DBP), but only in participants with history of HDP. This correlation was more evident for activin A and strongest with a history of preeclampsia. Our findings suggest that activin A may play an important role in blood pressure modulation in women with HDP who subsequently develop PPCM., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: SR reports serving as a consultant for Roche Diagnostics, Thermo Fisher, Beckman Coulter, Siemens, and has received research funding from Roche Diagnostics and Siemens for work related to angiogenic biomarkers that are unrelated to the submitted work., (Copyright © 2023 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)