Unplanned hospital readmissions following HeartMate 3 implantation: Readmission rates, causes, and impact on survival.

BACKGROUND: Hospital readmissions following left ventricular assist device (LVAD) remain a frequent comorbidity, associated with decreased quality of life and increased resources utilization. This study sought to determine causes, predictors, and impact on survival of hospitalizations during HeartMate 3 (HM3) support. METHODS: All patients implanted with HM3 between November 2014 to December 2019 at Columbia University Irving Medical Center were consecutively enrolled in the study. Demographics and clinical characteristics from the index admission and the first outpatient visit were collected and used to estimate 1-year and 900-day readmission-free survival and overall survival. Multivariable analysis was performed for subsequent readmissions. RESULTS: Of 182 patients who received a HM3 LVAD, 167 (92%) were discharged after index admission and experienced 407 unplanned readmissions over the median follow up of 727 (interquartile range (IQR): 410.5, 1124.5) days. One-year and 900-day mean cumulative number of all-cause unplanned readmissions was 0.43 (95%CI, 0.36, 0.51) and 1.13 (95%CI, 0.99, 1.29). The most frequent causes of rehospitalizations included major infections (29.3%), bleeding (13.2%), device-related (12.5%), volume overload (7.1%), and other (28%). One-year and 900-day survival free from all-cause readmission was 38% (95%CI, 31-46%) and 16.6% (95%CI, 10.3-24.4%). One-year and 900-day freedom from 2, 3, and ≥4 readmissions were 60.7%, 74%, 74.5% and 26.2%, 33.3%, 41.3%. One-year and 900-day survival were unaffected by the number of readmissions and remained >90%. Male sex, ischemic etiology, diabetes, lower serum creatinine, longer duration of index hospitalization, and a history of readmission between discharge and the first outpatient visit were associated with subsequent readmissions. CONCLUSIONS: Unplanned hospital readmissions after HM3 are common, with infections and bleeding accounting for the majority of readmissions. Irrespective of the number of readmissions, one-year survival remained unaffected.

Alterations in the sarcopenia index are associated with inflammation, gut, and oral microbiota among heart failure, left ventricular assist device, and heart transplant patients.

BACKGROUND: Sarcopenia, characterized by loss of muscle mass and function, is prevalent in heart failure (HF) and predicts poor outcomes. We investigated alterations in sarcopenia index (SI), a surrogate for skeletal muscle mass, in HF, left ventricular assist device (LVAD), and heart transplant (HT), and assessed its relationship with inflammation and digestive tract (gut and oral) microbiota. METHODS: We enrolled 460 HF, LVAD, and HT patients. Repeated measures pre/post-procedures were obtained prospectively in a subset of LVAD and HT patients. SI (serum creatinine/cystatin C) and inflammatory biomarkers (C-reactive protein, interleukin-6, tumor necrosis factor-alpha) were measured in 271 and 622 blood samples, respectively. Gut and saliva microbiota were assessed via 16S ribosomal ribonucleic acid sequencing among 335 stool and 341 saliva samples. Multivariable regression assessed the relationship between SI and (1) New York Heart Association class; (2) pre- versus post-LVAD or HT; and (3) biomarkers of inflammation and microbial diversity. RESULTS: Median (interquartile range) natural logarithm (ln)-SI was -0.13 (-0.32, 0.05). Ln-SI decreased across worsening HF class, further declined at 1 month after LVAD and HT, and rebounded over time. Ln-SI was correlated with inflammation (r = -0.28, p < 0.01), gut (r = 0.28, p < 0.01), and oral microbial diversity (r = 0.24, p < 0.01). These associations remained significant after multivariable adjustment in the combined cohort but not for all individual cohorts. The presence of the gut taxa Roseburia inulinivorans was associated with increased SI. CONCLUSIONS: SI levels decreased in symptomatic HF and remained decreased long-term after LVAD and HT. In the combined cohort, SI levels covaried with inflammation in a similar fashion and were significantly related to overall microbial (gut and oral) diversity, including specific taxa compositional changes.

The Hemodynamic Effects of Aortic Regurgitation in Patients Supported by a HeartMate 3 Left Ventricular Assist Device.

BACKGROUND: Aortic regurgitation (AR) is a common complication following left ventricular assist device (LVAD) implantation. We evaluated the hemodynamic implications of AR in patients with HeartMate 3 (HM3) LVAD at baseline and in response to speed changes. METHODS AND RESULTS: Clinically stable outpatients supported by HM3 who underwent a routine hemodynamic ramp test were retrospectively enrolled in this analysis. Patients were stratified based on the presence of at least mild AR at baseline speed. Hemodynamic and echocardiographic parameters were compared between the AR and non-AR groups. Sixty-two patients were identified. At the baseline LVAD speed, 29 patients (47%) had AR, while 33 patients (53%) did not. Patients with AR were older and supported on HM3 for a longer duration. At baseline speed, all hemodynamic parameters were similar between the groups including central venous pressure, pulmonary capillary wedge pressure, pulmonary arterial pressures, cardiac output and index, and pulmonary artery pulsatility index (p > 0.05 for all). During the subacute assessment, AR worsened in some, but not all, patients, with increases in LVAD speed. There were no significant differences in 1-year mortality or hospitalization rates between the groups, however, at 1-year, ≥ moderate AR and right ventricular failure (RVF) were detected in higher rates among the AR group compared to the non-AR group (45% vs. 0%; p < 0.01, and 75% vs. 36.8%; p = 0.02, respectively). CONCLUSIONS: In a cohort of stable outpatients supported with HM3 who underwent a routine hemodynamic ramp test, the presence of mild or greater AR did not impact the ability of HM3 LVADs to effectively unload the left ventricle during early subacute assessment. Although the presence of AR did not affect mortality and hospitalization rates, it resulted in higher rates of late hemodynamic-related events in the form of progressive AR and RVF.

Experimentally Induced Peripheral Venous Congestion Exacerbates Inflammation, Oxidative Stress, and Neurohormonal and Endothelial Cell Activation in Patients With Systolic Heart Failure.

BACKGROUND: Venous congestion (VC) is a hallmark of symptomatic heart failure (HF) requiring hospitalization; however, its role in the pathogenesis of HF progression remains unclear. We investigated whether peripheral VC exacerbates inflammation, oxidative stress and neurohormonal and endothelial cell (EC) activation in patients with HF with reduced ejection fraction (HFrEF). METHODS AND RESULTS: Two matched groups of patients with HFrEF and with no peripheral VC vs without recent HF hospitalization were studied. We modeled peripheral VC by inflating a cuff around the dominant arm, targeting ∼ 30 mmHg increase in venous pressure (venous stress test [VST]). Blood and ECs were sampled before and after 90 minutes of VST. We studied 44 patients (age 53 ± 12 years, 32% female). Circulating endothelin-1, tumor necrosis factor-α, interleukin-6, isoprostane, angiotensin II (ang-2), angiopoietin-2, vascular cell adhesion molecule-1, and CD146 significantly increased after the VST. Enhanced endothelin-1 and angiopoietin-2 responses to the VST were present in patients with vs without recent hospitalization and were prospectively associated with incident HF-related events; 6698 messenger ribonucleic acid (mRNA probe sets were differentially expressed in ECs after VST. CONCLUSIONS: Experimental VC exacerbates inflammation, oxidative stress, neurohormonal and EC activation and promotes unfavorable transcriptome remodeling in ECs of patients with HFrEF. A distinct biological sensitivity to VC appears to be associated with high risk for HF progression.

Myocardial Recovery With HeartMate 3 Left Ventricular Assist Device: An Attainable Goal That Needs Better Precision.

Despite advances in our understanding of myocardial recovery among left ventricular assist device (LVAD) patients, with 10-30% of patients achieving substantial myocardial improvement, the rates of LVAD support cessation remain extremely low (1-2%). These numbers are in stark contrast to clinical trial data where successful LVAD cessation is reported in up to 47% of patients. The majority of LVAD programs lack structured recovery programs and targeted protocols, likely underscoring the heterogeneity that exists among LVAD patients with myocardial recovery. This perspective summarizes the current medical and surgical challenges with respect to 1) identifying the appropriate candidates for LVAD cessation; 2) methods to wean LVAD support; 3) reviewing surgical techniques for cessation of current generation HeartMate 3 LVAD; and 4) approaching shared decision making for LVAD cessation between patients and providers given the uncertainties that remain in the field.

The Difference Between Cystatin C- and Creatinine-Based Estimated GFR in Heart Failure With Reduced Ejection Fraction: Insights From PARADIGM-HF.

RATIONALE & OBJECTIVE: The clinical implications of the discrepancy between cystatin C (cysC)- and serum creatinine (Scr)-estimated glomerular filtration rate (eGFR) in patients with heart failure (HF) and reduced ejection fraction (HFrEF) are unknown. STUDY DESIGN: Post-hoc analysis of randomized trial data. SETTING & PARTICIPANTS: 1,970 patients with HFrEF enrolled in PARADIGM-HF with available baseline cysC and Scr measurements. EXPOSURE: Intraindividual differences between eGFR based on cysC (eGFRcysC) and Scr (eGFRScr; eGFRdiffcysC-Scr). OUTCOMES: Clinical outcomes included the PARADIGM-HF primary end point (composite of cardiovascular [CV] mortality or HF hospitalization), CV mortality, all-cause mortality, and worsening kidney function. We also examined poor health-related quality of life (HRQoL), frailty, and worsening HF (WHF), defined as HF hospitalization, emergency department visit, or outpatient intensification of therapy between baseline and 8-month follow-up. ANALYTICAL APPROACH: Fine-Gray subdistribution hazard models and Cox proportional hazards models were used to regress clinical outcomes on baseline eGFRdiffcysC-Scr. Logistic regression was used to investigate the association of baseline eGFRdiffcysC-Scr with poor HRQoL and frailty. Linear regression models were used to assess the association of WHF with eGFRcysC, eGFRScr, and eGFRdiffcysC-Scr at 8-month follow-up. RESULTS: Baseline eGFRdiffcysC-Scr was higher than +10 and lower than-10mL/min/1.73m2 in 13.0% and 35.7% of patients, respectively. More negative values of eGFRdiffcysC-Scr were associated with worse outcomes ([sub]hazard ratio per standard deviation: PARADIGM-HF primary end point, 1.18; P=0.008; CV mortality, 1.34; P=0.001; all-cause mortality, 1.39; P<0.001; worsening kidney function, 1.31; P=0.05). For a 1-standard-deviation decrease in eGFRdiffcysC-Scr, the prevalences of poor HRQoL and frailty increased by 29% and 17%, respectively (P≤0.008). WHF was associated with a more pronounced decrease in eGFRcysC than in eGFRScr, resulting in a change in 8-month eGFRdiffcysC-Scr of-4.67mL/min/1.73m2 (P<0.001). LIMITATIONS: Lack of gold-standard assessment of kidney function. CONCLUSIONS: In patients with HFrEF, discrepancies between eGFRcysC and eGFRScr are common and are associated with clinical outcomes, HRQoL, and frailty. The decline in kidney function associated with WHF is more marked when assessed with eGFRcysC than with eGFRScr. PLAIN-LANGUAGE SUMMARY: Kidney function assessment traditionally relies on serum creatinine (Scr) to establish an estimated glomerular filtration rate (eGFR). However, this has been challenged with the introduction of an alternative marker, cystatin C (cysC). Muscle mass and nutritional status have differential effects on eGFR based on cysC (eGFRcysC) and Scr (eGFRScr). Among ambulatory patients with heart failure enrolled in PARADIGM-HF, we investigated the clinical significance of the difference between eGFRcysC and eGFRScr. More negative values (ie, eGFRScr>eGFRcysC) were associated with worse clinical outcomes (including mortality), poor quality of life, and frailty. In patients with progressive heart failure, which is characterized by muscle loss and poor nutritional status, the decline in kidney function was more pronounced when eGFR was estimated using cysC rather than Scr.

The impact of pre-existing hematologic disorders on morbidity and mortality following heart transplantation: Focus on early graft dysfunction.

BACKGROUND: Heart transplantation (HT) is the gold standard therapy for advanced heart failure, providing excellent long-term outcomes. However, postoperative outcomes are limited by bleeding, infections, and primary graft dysfunction (PGD) that contribute to early mortality after HT. HT candidates with pre-existing hematologic disorders, bleeding, and clotting, may represent a higher risk population. We assessed the short- and long-term outcomes of patients with pre-existing hematologic disorders undergoing HT. METHODS AND RESULTS: Medical records of all adult patients who received HT from January 2010 to December 2019 at our institution were retrospectively reviewed. Hematologic disorders were identified via chart review and adjudicated by a board-certified hematologist. Inverse probability weighting and multivariable models were used to adjust for potential pretransplant confounders. Four hundred and ninety HT recipients were included, of whom 29 (5.9%) had a hematologic disorder. Hematologic disorders were associated with severe PGD requiring mechanical circulatory support (aOR 3.15 [1.01-9.86]; p = .049), postoperative infections (aOR 2.93 [1.38-6.23]; p = .01), and 3-year acute cellular rejection (ACR) (≥1R/1B) (aSHR 2.06 [1.09-3.87]; p = .03). There was no difference in in-hospital mortality (aOR 1.23 [.20-7.58], p = .82) or 3-year mortality (aHR 1.58 [.49-5.12], p = .44). CONCLUSIONS: Patients with hematologic disorders undergoing HT are at increased risk of severe PGD, postoperative infections, and ACR, while in-hospital and 3-year mortality remain unaffected.

Clinical Characteristics and Outcomes of Patients Screened for but Deemed Clinically Not Suitable for Transcatheter Mitral Valve Replacement: DECLINE-TMVR Registry.

BACKGROUND: Transcatheter therapies are a recognized alternative intervention in patients with severe mitral regurgitation who are at high surgical risk. The purpose of this study was to characterize patients screened for transcatheter mitral valve replacement (TMVR), establish the clinical and anatomic reasons for unsuitability, and determine clinical course and early outcomes. METHODS: International multicentre registry was conducted of consecutive patients screened for TMVR at 12 centres in Europe, the United States, and Canada between April 2015 and September 2018. Patient-level retrospective data were collected for all patients screened. RESULTS: From a total of 294 patients, 87 (30%) patients were suitable for and underwent TMVR, whereas 207 (70%) patients were unsuitable for TMVR. There was no difference in Society of Thoracic Surgeons predicted risk of mortality (6.3% ± 4.3% vs 6.7 ± 6.1%, P = 0.52) for mitral valve replacement between the groups. The most common reasons for TMVR unsuitability were mitral annular size outside therapeutic range (28%) and small predicted neo-LVOT (25%). Preprocedural multidetector computed tomographic demonstrated that patients unsuitable for TMVR had smaller predicted neo-left ventricular outflow tract (LVOT) area (318 ±192 mm2 vs 495 ± 202 mm2, P = 0.04). At 30 days, there was no difference in rates of rehospitalization (8% vs 8%, P = 0.21), stroke (1% vs 2%, P = 0.42), or mortality (4% vs 10%, P = 0.10), unadjusted for procedural risk, between unsuitable for TMVR and TMVR groups, respectively. CONCLUSIONS: Two-thirds of patients failed screening as anatomically unsuitable for TMVR. The findings of this study have important clinical implications, highlighting an unmet clinical need and provide a target for design innovation in future iterations of TMVR devices.

Effect of Left Ventricular Unloading by Pump Speed Adjustment on Myocardial Flow in Continuous-flow Left Ventricular Assist Device Patients.

Resting myocardial blood flow (MBF) and myocardial flow reserve (MFR) are reduced in heart failure (HF) patients supported by pulsatile left ventricular assist devices (LVADs). The effect of continuous-flow (CF) physiology on these parameters is underexplored in CF-LVAD patients. We investigated the impact of CF-LVADs on resting MBF and MFR under two left ventricular (LV) loading conditions. Nine HeartMate II patients (42 ± 12 years, 100% male) on support for 370 ± 281 days were enrolled. Results were compared with 9 HF patients (58 ± 13 years, 67% male, LV ejection fraction 27 ± 9%) and 10 healthy volunteers (56 ± 10 years, 20% male). CF-LVAD patients underwent transthoracic echocardiography with ramp study. MBF and MFR were measured utilizing positron emission/computed tomography imaging under two LV loading conditions: "high-speed" (HS), promoting aortic valve (AV) closure and LV unloading; "low-speed" (LS), promoting AV opening and LV loading. Global resting MBF was similar in HS, LS, HF, and healthy: 0.8 ± 0.3, 0.7 ± 0.3, 0.7 ± 0.1, 0.9 ± 0.2 ml/min/g, respectively; p = NS. HS global MFR was reduced compared with LS and HF: 1.6 ± 0.6 versus 1.9 ± 0.5, p = 0.004; 1.6 ± 0.6 versus 2.4 ± 0.5, p = 0.01, respectively. HS regional MFR was reduced compared with LS in the left anterior descending (1.7 ± 0.7 vs. 2.0 ± 0.6, p = 0.027) and left circumflex (1.8 ± 0.7 vs. 2.2 ± 0.9, p = 0.008), but not in right coronary artery (1.7 ± 0.7 vs. 1.7 ± 0.6, p = 0.76). Resting MBF is preserved among CF-LVAD patients and is similar to HF and healthy. Promoting LV ventricular unloading with higher speed was associated with lower global and regional left coronary MFR, while right coronary MFR did not change.

Oral and gut microbiome alterations in heart failure: Epidemiology, pathogenesis and response to advanced heart failure therapies.

Despite significant advances in therapies, heart failure (HF) remains a progressive disease that, once advanced, is associated with significant death and disability. Cardiac replacement therapies with left ventricular assist device (LVAD) and heart transplantation (HT) are the only treatment options for advanced HF, while lifesaving they can also be lifespan limiting due to the associated complications. Systemic inflammation is mechanistically important in HF pathophysiology and progression. However, directly targeting inflammation in HF has not been beneficial thus far. These failed attempts at therapeutics might be related to our limited understanding of the factors that cause inflammation in HF, and, therefore, to our inability to investigate these triggers in interventional studies. Observational studies have consistently demonstrated associations between alterations in the digestive (gut and oral) microbiome, inflammation and HF risk and progression. Additionally, recent data indicate that these microbial perturbations persist following LVAD and HT, along with residual inflammation and oxidative stress. Furthermore, there is rising recognition of the critical contribution of the microbiome to the metabolism of immunosuppressive drugs after HT. Cumulatively, these findings might posit a mechanistic link between microbiome alterations, systemic inflammation, and adverse outcomes in HF patients before and after cardiac replacement therapies. This review (1) provides an update on available data linking changes in digestive tract microbiota, inflammation, and oxidative stress, to HF pathogenesis and progression; (2) describes evolution of these relationships following LVAD and HT; and (3) outlines present and future intervention strategies that can manipulate the microbiome and possibly modify HF disease trajectory.

Temporal shifts in safety and efficacy profile of mycophenolate mofetil 2 g versus 3 g daily early after heart transplantation.

STUDY OBJECTIVE: Mycophenolate mofetil (MMF) is the gold-standard immunosuppressive agent in heart transplantation (HT), but dose-dependent toxicities (e.g., neutropenia) are frequent. Gut bacteria ß-d-glucuronidases (GUS) modulate MMF bioavailability, and changes in the intestinal flora may influence the pharmacokinetics of MMF. The objective of this study was to evaluate the safety and efficacy of MMF 1.5 g every 12 h (q12) [high-dose, HD] versus 1 g q12 [low-dose, LD] and explore the association between neutropenia and GUS. MEASUREMENTS: We compared the incidence of acute cellular rejection (ACR) and neutropenia during the first 6 months post-HT. The association between neutropenia and GUS was investigated in an exploratory analysis on a subset of patients with prospectively collected stool data. Stool samples were analyzed using 16S rRNA sequencing. MAIN RESULTS: A total of 168 patients (120 MMF-HD, 48 MMF-LD; mean age 55.7 years, 79% male) were studied. Neutropenia occurred in 38.6% of patients at a median of 106 [64-143] days. Freedom from neutropenia was lower in MMF-HD compared with MMF-LD (57% vs. 73%, p = 0.03). ACR (≥1R/1B) occurred in 37.5% of patients at a median of 20 [10-96] days, while high-grade ACR (≥2R/3A) occurred in 11.3% at a median of 14 [9-89] days. Freedom from ACR was similar between groups. MMF-LD was associated with more high-grade ACR (hazard ratio [HR] 3.47, 95% confidence interval [CI] 1.09-11.08, p = 0.03) during the first month, but less neutropenia (HR 0.54, 95% CI 0.29-1.00, p = 0.05) between 1 and 6 months. GUS-producing bacteria were more abundant in neutropenic patients. CONCLUSIONS: MMF-LD was associated with higher rates of early high-grade ACR and lower rates of later neutropenia. Further studies are warranted to test whether temporal MMF dose adjustments and gut microbial composition could improve clinical outcomes post-HT.

Emerging Technologies for Percutaneous Mitral Valve Repair.

Mitral regurgitation (MR) is a common disease affecting more than 4 million people in the United States and the European Union. A significant number of percutaneous valves have been developed recently, specifically designed for the mitral anatomy, and with a promising evidence of good procedural and echocardiographic outcomes. However, even if transcatheter mitral valve replacement (TMVR) will have a role in the future of percutaneous treatment of both functional and degenerative mitral regurgitation, percutaneous mitral valve repair will always play a vital role in the treatment of MR because of the favorable safety profile and the fact that it respects the native anatomy. In this review, we will discuss the new emerging technologies under development to treat mitral regurgitation focusing on different devices that aim to target different components of the mitral anatomy.