Association of Psychosocial Risk Factors With Quality of Life and Readmissions 1 Year After LVAD Implantation.

BACKGROUND: Among patients with advanced heart failure (HF), treatment with a left ventricular assist device (LVAD) improves health-related quality of life (HRQOL). We investigated the association between psychosocial risk factors, HRQOL and outcomes after LVAD implantation. METHODS: A retrospective cohort (n = 9832) of adults aged ≥ 19 years who received durable LVADs between 2008 and 2017 was identified by using the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS). Patients were considered to have psychosocial risk factors if ≥ 1 of the following were present: (1) substance abuse; (2) limited social support; (3) limited cognitive understanding; (4) repeated nonadherence; and (5) major psychiatric disease. Multivariable logistic and linear regression models were used to evaluate the association between psychosocial risk factors and change in Kansas City Cardiomyopathy Questionnaire (KCCQ)-12 scores from baseline to 1 year, persistently poor HRQOL (KCCQ-12 score < 45 at baseline and 1 year), and 1-year rehospitalization. RESULTS: Among the final analytic cohort, 2024 (20.6%) patients had ≥ 1 psychosocial risk factors. Psychosocial risk factors were associated with a smaller improvement in KCCQ-12 scores from baseline to 1 year (mean ± SD, 29.1 ± 25.9 vs 32.6 ± 26.1; P = 0.015) for a difference of -3.51 (95% confidence interval [CI]: -5.88 to -1.13). Psychosocial risk factors were associated with persistently poor HRQOL (adjusted odds ratio [aOR] 1.35, 95% confidence interval [CI] 1.04-1.74), and 1-year all-cause readmission (adjusted hazard ratio [aHR] 1.11, 95% CI 1.05-1.18). Limited social support, major psychiatric disorder and repeated nonadherence were associated with persistently poor HRQOL, while major psychiatric disorder was associated with 1-year rehospitalization. CONCLUSION: The presence of psychosocial risk factors is associated with lower KCCQ-12 scores and higher risk for readmission at 1 year after LVAD implantation. These associations are statistically significant, but further research is needed to determine whether these differences are clinically meaningful.

Prevention of Fibrosis and Pathological Cardiac Remodeling by Salinomycin.

[Figure: see text].

Confirm Rx insertable cardiac monitor for primary atrial fibrillation detection in high-risk heart failure patients (Confirm-AF trial).

BACKGROUND: Patients with heart failure (HF) represent a large population of patients who are at high risk for complications related to undiagnosed atrial fibrillation (AF). However, currently there are limited modalities available for early AF detection in this high-risk population. An implantable cardiac monitor (ICM) is inserted subcutaneously and can provide long-term arrhythmia information via remote monitoring. METHODS AND RESULTS: Confirm-AF is a prospective randomized, nonblinded, two arm, multicenter clinical trial to be performed in the United States, enrolling 477 patients with a history of HF hospitalization and left ventricular ejection fraction >35% from 30 medical sites. Patients will be randomized in a 2:1 fashion to undergo ICM implant with remote monitoring and symptom-triggered mobile app transmissions versus (vs.) Non-ICM management and follow-up. The primary objective of this trial is to compare the time to first detection of AF lasting > 5 min using an Abbott ICM compared to non-ICM monitoring in symptomatic HF patients. This article describes the design and analytic plan for the Confirm-AF trial. CONCLUSIONS: The Confirm-AF trial seeks to accurately define the burden of AF in high-risk HF patients with LVEF > 35% using an Abbott ICM. A finding showing significantly higher incidence of AF along with improved clinical outcomes with ICM monitoring is expected to have substantial clinical implications and may change the method of monitoring high-risk HF patients.

Racial differences in clinical characteristics and readmission burden among patients with a left ventricular-assist device.

BACKGROUND: There are limited data regarding racial disparities in outcomes after left ventricular assist device (LVAD) implantation. The purpose of this study was to compare clinical characteristics and the burden of readmissions by race among patients with LVAD. METHODS: The study population included 461 patients implanted with LVADs at the University of Rochester Medical Center, NY from May 2008 to March 2020. Patients were stratified by race as White patients (N = 396 [86%]) and Black patients (N = 65 [14%]). The Anderson-Gill recurrent regression analysis was used to assess the independent association between race and the total number of admissions after LVAD implant during an average follow-up of 2.45 ± 2.30 years. RESULTS: Black patients displayed significant differences in baseline clinical characteristics compared to White patients, including a younger age, a lower frequency of ischemic etiology, and a higher baseline serum creatinine. Black patients had a significantly higher burden of readmissions after LVAD implantation as compared with White patients 10 versus 7 (average number of hospitalizations per patient at 5 years of follow-up, respectively) translated into a significant 39% increased risk of recurrent readmissions after multivariate adjustment (Hazard ratio 1.39, 95% CI; 1.07-1.82, p 0.013). CONCLUSION: Black LVAD patients experience an increased burden of readmissions compared with White patients, after adjustment for baseline differences in demographics and clinical characteristics. Future studies should assess the underlying mechanisms for this increased risk including the effect of social determinants of health on the risk of readmissions in LVAD recipients.

Genetic and Phenotypic Landscape of Peripartum Cardiomyopathy.

BACKGROUND: Peripartum cardiomyopathy (PPCM) occurs in ≈1:2000 deliveries in the United States and worldwide. The genetic underpinnings of PPCM remain poorly defined. Approximately 10% of women with PPCM harbor truncating variants in TTN (TTNtvs). Whether mutations in other genes can predispose to PPCM is not known. It is also not known if the presence of TTNtvs predicts clinical presentation or outcomes. Nor is it known if the prevalence of TTNtvs differs in women with PPCM and preeclampsia, the strongest risk factor for PPCM. METHODS: Women with PPCM were retrospectively identified from several US and international academic centers, and clinical information and DNA samples were acquired. Next-generation sequencing was performed on 67 genes, including TTN, and evaluated for burden of truncating and missense variants. The impact of TTNtvs on the severity of clinical presentation, and on clinical outcomes, was evaluated. RESULTS: Four hundred sixty-nine women met inclusion criteria. Of the women with PPCM, 10.4% bore TTNtvs (odds ratio=9.4 compared with 1.2% in the reference population; Bonferroni-corrected P [P*]=1.2×10-46). We additionally identified overrepresentation of truncating variants in FLNC (odds ratio=24.8, P*=7.0×10-8), DSP (odds ratio=14.9, P*=1.0×10-8), and BAG3 (odds ratio=53.1, P*=0.02), genes not previously associated with PPCM. This profile is highly similar to that found in nonischemic dilated cardiomyopathy. Women with TTNtvs had lower left ventricular ejection fraction on presentation than did women without TTNtvs (23.5% versus 29%, P=2.5×10-4), but did not differ significantly in timing of presentation after delivery, in prevalence of preeclampsia, or in rates of clinical recovery. CONCLUSIONS: This study provides the first extensive genetic and phenotypic landscape of PPCM and demonstrates that predisposition to heart failure is an important risk factor for PPCM. The work reveals a degree of genetic similarity between PPCM and dilated cardiomyopathy, suggesting that gene-specific therapeutic approaches being developed for dilated cardiomyopathy may also apply to PPCM, and that approaches to genetic testing in PPCM should mirror those taken in dilated cardiomyopathy. Last, the clarification of genotype/phenotype associations has important implications for genetic counseling.

Left atrial appendage exclusion with less invasive left ventricular assist device implantation.

OBJECTIVES: The objective of this single-center, pilot, prospective, and historical control study is to evaluate safety and feasibility outcomes associated with left atrial appendage exclusion (LAAE) concomitant with left ventricular assist device (LVAD) implantation via less invasive surgery (LIS) as a stroke prevention strategy. METHODS: A predefined number of 30 eligible subjects scheduled for LIS LVAD with LAAE were enrolled in the prospective arm between January 2020 and February 2021. Eligible retrospective LIS LVAD patients without LAAE were propensity-matched in a 1:1 ratio with the prospective arm subjects. The primary study objectives were to evaluate the safety, feasibility, and efficacy of the LAAE concomitant with LIS LVAD. RESULTS: Preoperative characteristics of patients in the Non-LAAE and LAAE groups were similar. LAAE was successfully excluded in all prospective patients (100%). Primary safety endpoints of chest tube output within the first 24 postoperative hours, Reoperation for bleeding within 48 h, and index hospitalization mortality demonstrated comparable safety of LAAE versus Non-LAAE with LIS LVAD. Cox proportional hazard regression demonstrated that LAAE with LIS LVAD was associated with 37% and 49% reduction in the risk of stroke and disabling stroke, respectively (p > .05). CONCLUSION: Results from our pilot study demonstrated the safety and feasibility of LAAE concomitant with LIS LVAD as a stroke prevention strategy. This is the first prospective study describing LAAE performed concomitantly to less invasive LVAD implantation. The efficacy of LAAE in long-term stroke prevention needs to be confirmed in future prospective randomized clinical trials.

Impact of surgical approach for left ventricular assist device implantation on postoperative invasive hemodynamics and right ventricular failure.

BACKGROUND: Right ventricular failure (RVF) remains one of the major causes of morbidity and mortality after left ventricular assist device (LVAD) implantation. We sought to compare immediate postoperative invasive hemodynamics and the risk of RVF following two different surgical approaches: less invasive surgery (LIS) versus full sternotomy (FS). METHODS: The study population comprised all 231 patients who underwent implantation of a HeartMate 3 (Abbott) LVAD at our institution from 2015 to 2020, utilizing an LIS (n = 161; 70%) versus FS (n = 70; 30%) surgical approach. Outcomes included postoperative invasive hemodynamic parameters, vasoactive-inotropic score (VIS), RVF during index hospitalization, and 6-month mortality. RESULTS: Baseline clinical characteristics of the two groups were similar. Multivariate analysis showed that LIS, compared with FS, was associated with the improved cardiac index (CI) at the sixth postoperative hour (p = .036) and similar CI at 24 h, maintained by lower VIS at both timepoints (p = .002). The LIS versus FS approach was also associated with a three-fold lower incidence of in-hospital severe RVF (8.7% vs. 28.6%, p < .001) and need for RVAD support (5.0% vs. 17.1%, p = .003), and with 68% reduction in the risk of 6-month mortality after LVAD implantation (Hazard ratio, 0.32; CI, 0.13-0.78; p = .012). CONCLUSION: Our findings suggest that LIS, compared with FS, is associated with a more favorable hemodynamic profile, as indicated by similar hemodynamic parameters maintained by lower vasoactive-inotropic support during the acute postoperative period. These findings were followed by a reduction in the risk of severe RVF and 6-month mortality in the LIS group.

Enhanced Recovery After Surgery in Patients Implanted with Left Ventricular Assist Device.

INTRODUCTION: We sought to develop and implement a comprehensive enhanced recovery after surgery (ERAS) protocol for patients implanted with a left ventricular assist device (LVAD). METHODS AND RESULTS: In this article, we describe our approach to the development and phased implementation of the protocol. Additionally, we reviewed prospectively collected data for patients who underwent LVAD implantation at our institution from February 2019 to August 2020. To compare early outcomes in our patients before and after protocol implementation, we dichotomized patients into two 6-month cohorts (the pre-ERAS and ERAS cohorts) separated from each other by 6 months to allow for staff adoption of the protocol. Of the 115 LVAD implants, 38 patients were implanted in the pre-ERAS period and 46 patients in the ERAS period. Preoperatively, the patients` characteristics were similar between the cohorts. Postoperatively, we observed a decrease in bleeding (chest tube output of 1006 vs 647.5 mL, P < .001) and blood transfusions (fresh frozen plasma 31.6% vs 6.7%, P = .04; platelets 42.1% vs 8.7%, P = .001). Opioid prescription at discharge were 5-fold lower with the ERAS approach (P < .01). Furthermore, the number of patients discharged to a rehabilitation facility decreased significantly (20.0% vs 2.4%, P = .02). The index hospitalization length of stay and survival were similar between the groups. CONCLUSIONS: ERAS for patients undergoing LVAD implantation is a novel, evidence-based, interdisciplinary approach to care with multiple potential benefits. In this article, we describe the details of the protocol and early positive changes in clinical outcomes. Further studies are needed to evaluate benefits of an ERAS protocol in an LVAD population.Lay Summary: Enhanced recovery after surgery (ERAS) is the implementation of standardized clinical pathways that ensures the use of best practices and decreased variation in perioperative care. Multidisciplinary teams work together on ERAS, thereby enhancing communication among health care silos. ERAS has been used for more than 30 years by other surgical services and has been shown to lead to a decreased length of stay, fewer complications, lower mortality, fewer readmissions, greater job satisfaction, and lower costs. Our goal was to translate these benefits to the perioperative care of complex patients with a left ventricular assist device. Early results suggest that this goal is possible; we have observed a decrease in transfusions, discharge on opioids, and discharge to a rehabilitation facility.

Small proline-rich protein 2B drives stress-dependent p53 degradation and fibroblast proliferation in heart failure.

Heart disease is associated with the accumulation of resident cardiac fibroblasts (CFs) that secrete extracellular matrix (ECM), leading to the development of pathological fibrosis and heart failure. However, the mechanisms underlying resident CF proliferation remain poorly defined. Here, we report that small proline-rich protein 2b (Sprr2b) is among the most up-regulated genes in CFs during heart disease. We demonstrate that SPRR2B is a regulatory subunit of the USP7/MDM2-containing ubiquitination complex. SPRR2B stimulates the accumulation of MDM2 and the degradation of p53, thus facilitating the proliferation of pathological CFs. Furthermore, SPRR2B phosphorylation by nonreceptor tyrosine kinases in response to TGF-ß1 signaling and free-radical production potentiates SPRR2B activity and cell cycle progression. Knockdown of the Sprr2b gene or inhibition of SPRR2B phosphorylation attenuates USP7/MDM2 binding and p53 degradation, leading to CF cell cycle arrest. Importantly, SPRR2B expression is elevated in cardiac tissue from human heart failure patients and correlates with the proliferative state of patient-derived CFs in a process that is reversed by insulin growth factor-1 signaling. These data establish SPRR2B as a unique component of the USP7/MDM2 ubiquitination complex that drives p53 degradation, CF accumulation, and the development of pathological cardiac fibrosis.

HeartMate 3 pump exchange via sternal-sparing bilateral minithoracotomies.

As median survival for left ventricular assist device (LVAD) patients increases, the incidence of adverse events requiring device exchange is likely to increase as well. Less invasive surgical approaches for device exchange of older generation pumps have demonstrated multiple potential benefits compared with median sternotomy. However, there remains a paucity of data in regard to less invasive surgical techniques for the exchange of the newest generation intrapericardial devices. In this report we describe a complete sternal-sparing technique for the LVAD exchange of a HeartMate 3 via bilateral minithoracotomies.

Mechanosensitive Gene Regulation by Myocardin-Related Transcription Factors Is Required for Cardiomyocyte Integrity in Load-Induced Ventricular Hypertrophy.

BACKGROUND: Hypertrophic cardiomyocyte growth and dysfunction accompany various forms of heart disease. The mechanisms responsible for transcriptional changes that affect cardiac physiology and the transition to heart failure are not well understood. The intercalated disc (ID) is a specialized intercellular junction coupling cardiomyocyte force transmission and propagation of electrical activity. The ID is gaining attention as a mechanosensitive signaling hub and hotspot for causative mutations in cardiomyopathy. METHODS: Transmission electron microscopy, confocal microscopy, and single-molecule localization microscopy were used to examine changes in ID structure and protein localization in the murine and human heart. We conducted detailed cardiac functional assessment and transcriptional profiling of mice lacking myocardin-related transcription factor (MRTF)-A and MRTF-B specifically in adult cardiomyocytes to evaluate the role of mechanosensitive regulation of gene expression in load-induced ventricular remodeling. RESULTS: We found that MRTFs localize to IDs in the healthy human heart and accumulate in the nucleus in heart failure. Although mice lacking MRTFs in adult cardiomyocytes display normal cardiac physiology at baseline, pressure overload leads to rapid heart failure characterized by sarcomere disarray, ID disintegration, chamber dilation and wall thinning, cardiac functional decline, and partially penetrant acute lethality. Transcriptional profiling reveals a program of actin cytoskeleton and cardiomyocyte adhesion genes driven by MRTFs during pressure overload. Indeed, conspicuous remodeling of gap junctions at IDs identified by single-molecule localization microscopy may partially stem from a reduction in Mapre1 expression, which we show is a direct mechanosensitive MRTF target. CONCLUSIONS: Our study describes a novel paradigm in which MRTFs control an acute mechanosensitive signaling circuit that coordinates cross-talk between the actin and microtubule cytoskeleton and maintains ID integrity and cardiomyocyte homeostasis in heart disease.

Changes in Drug Utilization and Outcome With Cardiac Resynchronization Therapy: A MADIT-CRT Substudy.

BACKGROUND: This study sought to assess the association between medication utilization, outcome, and the efficacy of resynchronization therapy in the MADIT-CRT study. METHODS AND RESULTS: Medication use by patients in the MADIT-CRT study was analyzed. Time-dependent Cox proportional hazard regression analyses were performed to assess differences in hospitalization for heart failure (HF) or death. The greater the efficacy of cardiac resynchronization therapy (CRT) as measured by reduction in left ventricular end-systolic volume (LVESV) and increase in left ventricular ejection fraction (LVEF) between baseline and 1 year of follow-up, the greater the likelihood that patients remained on an angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB) and avoided use of or reduced treatment with diuretics. Treatment with diuretics was associated with a significantly increased risk of HF hospitalization or death (hazard ratio [HR] 1.87, 95% confidence interval [CI] 1.45-2.41; P < .001). In contrast, treatment with an ACE-I/ARB was associated with a significantly decreased risk of HF hospitalization or death (HR 0.58, 95% CI 0.42-0.80; P = .001). CONCLUSIONS: In HF patients in New York Heart Association functional classes I and II and with wide QRS complexes, efficacy of CRT as measured by improvement in LVESV and LVEF was associated with an increased likelihood of remaining on an ACE-I/ARB and discontinuing diuretic therapy. Discontinuation of diuretics was reflective of improved hemodynamic response to CRT.

Ventricular fibrillation complicating endomyocardial biopsy of transplanted heart.

Life-threatening arrhythmia is an unusual complication of endomyocardial biopsy in transplanted heart. Herein we described a case of VF during endomyocardial biopsy. The possibility of VF during a biopsy necessitates immediate access to defibrillation during endomyocardial biopsy.

Less Invasive Left Ventricular Assist Device Implantation Is Safe and Feasible in Patients With Smaller Body Surface Area.

OBJECTIVE: Smaller body surface area (BSA) frequently precludes patients from left ventricular assist device (LVAD) therapy. We sought to investigate the clinical outcomes in patients with small BSA undergoing less invasive LVAD implantation. METHODS: We conducted a retrospective review of 216 patients implanted with HeartMate 3 LVAD (Abbott, Chicago, IL) via less invasive surgery at our institution. Patients were dichotomized based on their preimplant BSA for comparison between small BSA (≤1.8 m2) and normal/large BSA (>1.8 m2). We analyzed patient perioperative characteristics and outcomes. RESULTS: In our study, small BSA was found in 32 patients (14.8%), while 184 patients (85.2%) had normal/large BSA. Women were more prevalent in the small BSA group (50.0% vs 13.0%, P < 0.001). Preoperative and intraoperative data showed comparable results. Major complications and hospital length of stay did not differ by BSA group. Patients with smaller BSA had significantly decreased pump parameters at discharge, including LVAD flow (4.11 ± 0.49 vs 4.60 ± 0.54 L/min, P < 0.001) and pump speed (5,200 vs 5,400 rpm, P < 0.001). Survival to discharge and within 6 months after implantation were similar between the groups. CONCLUSIONS: Our study results suggest that less invasive HeartMate 3 implantation can be safely performed and demonstrates equivalent outcomes in patients with smaller body habitus. Randomized trials are required to confirm our data.

UAP56 is a novel interacting partner of Bcr in regulating vascular smooth muscle cell DNA synthesis.

Bcr is a serine/threonine kinase that is a critical regulator of vascular smooth muscle cell inflammation and proliferation. We have previously demonstrated that Bcr acts in part via phosphorylation and inhibition of PPARγ. We have identified the RNA helicase UAP56 as another substrate of Bcr. In this report we demonstrate that knockdown of UAP56 blocks Bcr induced DNA synthesis in vascular smooth muscle cells (VSMC). We also found that over expression of Bcr increased the expression of cyclin E and decreased the expression of p27. Knockdown of UAP56 reversed the effect of Bcr on cyclin E and p27 expression. Furthermore, we found that Bcr binds to UAP56 and demonstrate that binding of UAP56 to Bcr is critical for Bcr induced DNA synthesis in VSMC. Our data identify UAP56 as an important binding partner of Bcr and a novel target for inhibiting vascular smooth muscle cell proliferation.

Implantable cardiac defibrillators and sudden death in recent onset nonischemic cardiomyopathy: results from IMAC2.

BACKGROUND: Given the potential for recovery in recent onset nonischemic cardiomyopathy (ROCM), the timing and need for implantable cardioverter-defibrillator (ICDs) remains controversial. We examined the utilization of ICDs and the impact on survival for subjects with ROCM. METHODS AND RESULTS: An National Heart, Lung, and Blood Institute sponsored registry enrolled 373 subjects with ROCM, all with a left ventricular ejection fraction (LVEF) ≤0.40 and ≤6 months of symptoms. The mean age was 45 ± 14 years, 38% were female, 21% black, 75% New York Heart Association II/III, and the mean LVEF was 0.24 ± 0.08. Survival was comparable for subjects with an ICD within 1 month of entry (n = 43, 1/2/3 year % survival = 97/97/92) and those with no ICD at 1 month (n = 330, % survival = 98/97/95, P = .30) and between those with and without an ICD at 6 months (ICD, n = 73, 1/2/3 year % survival = 98/98/95; no ICD, n = 300, % survival = 98/96/95, P = .95). There were only 6 sudden cardiac deaths (SCD) noted (% survival free from SCD = 99/98/97) and these occurred in 1.9% of subjects without ICD and 0.9% of those with a device (P = .50). CONCLUSIONS: In a multicenter cohort of ROCM the risk of SCD was low at 1% per year. Early ICD placement did not impact survival and can be deferred while assessing potential for myocardial recovery.

Myocardial recovery in peripartum cardiomyopathy: prospective comparison with recent onset cardiomyopathy in men and nonperipartum women.

BACKGROUND: Whether myocardial recovery occurs more frequently in peripartum cardiomyopathy (PPCM) than in recent onset cardiomyopathies in men and nonperipartum women has not been prospectively evaluated. This was examined through an analysis of outcomes in the Intervention in Myocarditis and Acute Cardiomyopathy 2 (IMAC2) registry. METHODS AND RESULTS: IMAC2 enrolled 373 subjects with recent onset nonischemic dilated cardiomyopathy. Left ventricular ejection fraction (LVEF) was assessed at entry and 6 months, and subjects followed for up to 4 years. Myocardial recovery was compared between men (group 1), nonperipartum women (group 2) and subjects with PPCM (group 3). The cohort included 230 subjects in group 1, 104 in group 2, and 39 in group 3. The mean LVEF at baseline in groups 1, 2, and 3 was 0.23 ± 0.08, 0.24 ± 0.08, and 0.27 ± 0.07 (P = .04), and at 6 months was 0.39 ± 0.12, 0.42 ± 0.11, and 0.45 ± 0.14 (P = .007). Subjects in group 3 had a much greater likelihood of achieving an LVEF >0.50 at 6 months than groups 1 or 2 (19 %, 34%, and 48% respectively, P = .002). CONCLUSIONS: Prospective evaluation confirms myocardial recovery is greatest in women with PPCM, poorest in men, and intermediate in nonperipartum women. On contemporary therapy, nearly half of women with PPCM normalize cardiac function by 6 months.