Advanced Heart Failure: Therapeutic Options and Challenges in the Evolving Field of Left Ventricular Assist Devices.

Heart Failure is a chronic and progressively deteriorating syndrome that has reached epidemic proportions worldwide. Improved outcomes have been achieved with novel drugs and devices. However, the number of patients refractory to conventional medical therapy is growing. These advanced heart failure patients suffer from severe symptoms and frequent hospitalizations and have a dismal prognosis, with a significant socioeconomic burden in health care systems. Patients in this group may be eligible for advanced heart failure therapies, including heart transplantation and chronic mechanical circulatory support with left ventricular assist devices (LVADs). Heart transplantation remains the treatment of choice for eligible candidates, but the number of transplants worldwide has reached a plateau and is limited by the shortage of donor organs and prolonged wait times. Therefore, LVADs have emerged as an effective and durable form of therapy, and they are currently being used as a bridge to heart transplant, destination lifetime therapy, and cardiac recovery in selected patients. Although this field is evolving rapidly, LVADs are not free of complications, making appropriate patient selection and management by experienced centers imperative for successful therapy. Here, we review current LVAD technology, indications for durable MCS therapy, and strategies for timely referral to advanced heart failure centers before irreversible end-organ abnormalities.

The Han:SPRD Rat: A Preclinical Model of Polycystic Kidney Disease.

Autosomal Dominant Polycystic Kidney Disease (ADPKD) stands as the most prevalent hereditary renal disorder in humans, ultimately culminating in end-stage kidney disease. Animal models carrying mutations associated with polycystic kidney disease have played an important role in the advancement of ADPKD research. The Han:SPRD rat model, carrying an R823W mutation in the Anks6 gene, is characterized by cyst formation and kidney enlargement. The mutated protein, named Samcystin, is localized in cilia of tubular epithelial cells and seems to be involved in cystogenesis. The homozygous Anks6 mutation leads to end-stage renal disease and death, making it a critical factor in kidney development and function. This review explores the utility of the Han:SPRD rat model, highlighting its phenotypic similarity to human ADPKD. Specifically, we discuss its role in preclinical trials and its importance for investigating the pathogenesis of the disease and developing new therapeutic approaches.

Machine Learning Multicenter Risk Model to Predict Right Ventricular Failure After Mechanical Circulatory Support: The STOP-RVF Score.

Importance: The existing models predicting right ventricular failure (RVF) after durable left ventricular assist device (LVAD) support might be limited, partly due to lack of external validation, marginal predictive power, and absence of intraoperative characteristics. Objective: To derive and validate a risk model to predict RVF after LVAD implantation. Design, Setting, and Participants: This was a hybrid prospective-retrospective multicenter cohort study conducted from April 2008 to July 2019 of patients with advanced heart failure (HF) requiring continuous-flow LVAD. The derivation cohort included patients enrolled at 5 institutions. The external validation cohort included patients enrolled at a sixth institution within the same period. Study data were analyzed October 2022 to August 2023. Exposures: Study participants underwent chronic continuous-flow LVAD support. Main Outcome and Measures: The primary outcome was RVF incidence, defined as the need for RV assist device or intravenous inotropes for greater than 14 days. Bootstrap imputation and adaptive least absolute shrinkage and selection operator variable selection techniques were used to derive a predictive model. An RVF risk calculator (STOP-RVF) was then developed and subsequently externally validated, which can provide personalized quantification of the risk for LVAD candidates. Its predictive accuracy was compared with previously published RVF scores. Results: The derivation cohort included 798 patients (mean [SE] age, 56.1 [13.2] years; 668 male [83.7%]). The external validation cohort included 327 patients. RVF developed in 193 of 798 patients (24.2%) in the derivation cohort and 107 of 327 patients (32.7%) in the validation cohort. Preimplant variables associated with postoperative RVF included nonischemic cardiomyopathy, intra-aortic balloon pump, microaxial percutaneous left ventricular assist device/venoarterial extracorporeal membrane oxygenation, LVAD configuration, Interagency Registry for Mechanically Assisted Circulatory Support profiles 1 to 2, right atrial/pulmonary capillary wedge pressure ratio, use of angiotensin-converting enzyme inhibitors, platelet count, and serum sodium, albumin, and creatinine levels. Inclusion of intraoperative characteristics did not improve model performance. The calculator achieved a C statistic of 0.75 (95% CI, 0.71-0.79) in the derivation cohort and 0.73 (95% CI, 0.67-0.80) in the validation cohort. Cumulative survival was higher in patients composing the low-risk group (estimated <20% RVF risk) compared with those in the higher-risk groups. The STOP-RVF risk calculator exhibited a significantly better performance than commonly used risk scores proposed by Kormos et al (C statistic, 0.58; 95% CI, 0.53-0.63) and Drakos et al (C statistic, 0.62; 95% CI, 0.57-0.67). Conclusions and Relevance: Implementing routine clinical data, this multicenter cohort study derived and validated the STOP-RVF calculator as a personalized risk assessment tool for the prediction of RVF and RVF-associated all-cause mortality.

Treatment Strategies and Outcomes of Right Ventricular Failure Post Left Ventricular Assist Device Implantation: An INTERMACS Analysis.

Right heart failure (RHF) management after left ventricular assist device (LVAD) implantation includes inotropes, right ventricular mechanical support, and heart transplantation. The purpose of this study is to compare different RHF treatment strategies in patients with a magnetically levitated centrifugal LVAD. A total of 6,632 Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) patients from 2013 to 2020 were included. Of which, 769 (69.6%) patients (group 1) were supported with inotropes (≥14 days post-LVAD implantation), 233 (21.1%) patients (group 2) were supported with temporary right ventricular assist device (RVAD) that was implanted during LVAD implant, 77 (7.0%) patients (group 3) with durable centrifugal RVAD implanted during the LVAD implant, and 26 (2.4%) patients (group 4) were supported with RVAD (temporary or permanent), which was implanted at a later stage. Groups 1 and 4 had higher survival rates in comparison with group 2 (hazard ratio [HR] = 0.513, 95% confidence intervals [CIs] = 0.402-0.655, p < 0.001, versus group 1) and group 3 (HR = 0.461, 95% CIs = 0.320-0.666, p < 0.001, versus group 1). Patients in group 3 showed higher heart transplantation rates at 12 and 36 months as compared with group 1 (40.4% and 46.6% vs. 21.9% and 37.4%, respectively), group 2 (40.4% and 46.6% vs. 25.8% and 39.3%, respectively), and group 4 (40.4% and 46.6% vs. 3.8% and 12.0%, respectively). Severe RHF post-LVAD is associated with poor survival. Patients with LVAD who during the perioperative period are in need of right ventricular temporary or durable mechanical circulatory support constitute a group at particular risk. Improvement of devices tailored for right ventricular support is mandatory for further evolution of the field.

Prospective Phenotyping of Right Ventricle Function Following Intra-Aortic Balloon Pump Counterpulsation in Left Ventricular Assist Device Candidates: Outcomes and Predictors of Response.

Intra-aortic balloon pump (IABP) may be applied to optimize advanced heart failure (AHF) patients and improve right ventricular (RV) function before left ventricular assist device (LVAD) implantation. We aimed to evaluate the outcome of this intervention and define RV response predictors. Decompensated AHF patients, not eligible for LVAD because of poor RV function, who required IABP for stabilization were enrolled. Echocardiography and invasive hemodynamics were serially applied to determine fulfillment of prespecified "LVAD eligibility RV function" criteria (right atrium pressure [RA] <12 mm Hg, pulmonary artery pulsatility index [PAPi] >2.00, RA/pulmonary capillary wedge pressure [PCWP] <0.67, RV strain <-14.0%). Right ventricular-free wall tissue was harvested to assess interstitial fibrosis. Eighteen patients (12 male), aged 38 ± 14 years were supported with IABP for 55 ± 51 (3-180) days. In 11 (61.1%), RV improved and fulfilled the prespecified criteria, while seven (38.9%) showed no substantial improvement. Histopathology revealed an inverse correlation between RV interstitial fibrosis and functional benefit following IABP: interstitial fibrosis correlated with post-IABP RA ( r = 0.63, p = 0.037), RA/PCWP ( r = 0.87, p = 0.001), PAPi ( r = -0.83, p = 0.003). Conclusively, IABP improves RV function in certain AHF patients facilitating successful LVAD implantation. Right ventricular interstitial fibrosis quantification may be applied to predict response and guide preoperative patient selection and optimization. http://links.lww.com/ASAIO/A995.

Phenotype Characterization and Course of Patients With Arrhythmogenic Right Ventricular Cardiomyopathy and Biventricular Advanced Heart Failure: A Report of 3 Cases.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) may be complicated by heart failure. Management of advanced heart failure in this context is challenging. METHODS: We reviewed our center's experience with advanced heart failure therapies in patients with ARVC. Three rapidly deteriorating patients with ARVC with biventricular heart failure were found. Their management and outcomes are presented. Data on ventricular fibrosis were available in 2 of them and are also included. RESULTS: The first patient underwent initially successful paracorporeal pulsatile biventricular assist device (BiVAD) implantation. However, a large ischemic stroke occurred 2 weeks later, and the patient died after 2 months. The second patient underwent urgent BiVAD implantation after extracorporeal membrane oxygenation support because of cardiogenic shock, but his course was complicated by multiorgan failure due to systemic infection and the patient died. The last patient, being at Interagency Registry for Mechanically Assisted Circulatory Support 3-4 profile, underwent heart transplant with uneventful recovery. Extensive fibrosis was present in both ventricles of 2 patients undergoing pathology examination. CONCLUSIONS: Patients with ARVC and advanced biventricular heart failure are characterized by extensive ventricular fibrosis and considerable risk, but data on their management are limited. Biventricular circulatory support is associated with suboptimal outcomes, and prioritization for heart transplant seems preferable.

LVAD as a Bridge to Remission from Advanced Heart Failure: Current Data and Opportunities for Improvement.

Left ventricular assist devices (LVADs) are an established treatment modality for advanced heart failure (HF). It has been shown that through volume and pressure unloading they can lead to significant functional and structural cardiac improvement, allowing LVAD support withdrawal in a subset of patients. In the first part of this review, we discuss the historical background, current evidence on the incidence and assessment of LVAD-mediated cardiac recovery, and out-comes including quality of life after LVAD support withdrawal. In the second part, we discuss current and future opportunities to promote LVAD-mediated reverse remodeling and improve our pathophysiological understanding of HF and recovery for the benefit of the greater HF population.

Circulating and Myocardial Cytokines Predict Cardiac Structural and Functional Improvement in Patients With Heart Failure Undergoing Mechanical Circulatory Support.

Background Recent prospective multicenter data from patients with advanced heart failure demonstrated that left ventricular assist device (LVAD) support combined with standard heart failure medications, induced significant cardiac structural and functional improvement, leading to high rates of LVAD weaning in selected patients. We investigated whether preintervention myocardial and systemic inflammatory burden could help identify the subset of patients with advanced heart failure prone to LVAD-mediated cardiac improvement to guide patient selection, treatment, and monitoring. Methods and Results Ninety-three patients requiring durable LVAD were prospectively enrolled. Myocardial tissue and blood were acquired during LVAD implantation, for measurement of inflammatory markers. Cardiac structural and functional improvement was prospectively assessed via serial echocardiography. Eleven percent of the patients showed significant reverse remodeling following LVAD support (ie, responders). Circulating tumor necrosis factor alpha, interleukin (IL)-4, IL-5, IL-6, IL-7, IL-13, and interferon gamma were lower in responders, compared with nonresponders (P<0.05, all comparisons). The myocardial tissue signal transducer and activator of transcription-3, an inflammatory response regulator, was less activated in responders (P=0.037). Guided by our tissue studies and a multivariable dichotomous regression analysis, we identified that low levels of circulating interferon gamma (odds ratio [OR], 0.06; 95% CI, 0.01-0.35) and tumor necrosis factor alpha (OR, 0.05; 95% CI, 0.00-0.43), independently predict cardiac improvement, creating a 2-cytokine model effectively predicting responders (area under the curve, 0.903; P<0.0001). Conclusions Baseline myocardial and systemic inflammatory burden inversely correlates with cardiac improvement following LVAD support. A circulating 2-cytokine model predicting significant reverse remodeling was identified, warranting further investigation as a practical preintervention tool in identifying patients prone to LVAD-mediated cardiac improvement and device weaning.

The effect of paracorporeal pulsatile biventricular assist devices on allosensitization in adults: A comparison with left ventricular assist devices.

Ventricular assist devices (VADs) have been associated with the development of anti-HLA antibodies ('allosensitization'), but data on devices providing biventricular support in adults are limited. We sought to characterize differences in anti-HLA antibody formation in adult patients receiving left- (LVAD) versus biventricular- (BiVAD) assist devices as bridge to transplantation (BTT) by retrospectively reviewing the records of adult patients who have undergone VAD implantation at our institution. We assessed 82 patients supported with a pulsatile-flow paracorporeal BiVAD and compared them with 40 patients receiving LVAD till 2018. Forty-eight (58.5%) of the BiVAD and 23 (57.5%) of the LVAD patients were eventually transplanted (p = 0.91) with an average time to transplantation 559 and 598 days, respectively (p = 0.73). Evidence of sensitization pre-VAD was found in 11.0% of the BiVAD patients and 15.0% of the LVAD ones (p = 0.53); these percentages rose to 43.9% (p < 0.001) and 40.0% (p = 0.01), respectively. The post-VAD sensitization status was not significantly different between the BiVAD and the LVAD group (p = 0.68). De novo sensitization was comparable between the two groups (p = 0.55). Post-transplantation outcomes regarding rejections and cardiac allograft vasculopathy were also similar. Conclusively, BiVAD- and LVAD- induced allosensitization do not appear to differ significantly.

Left ventricular deformation mechanics over time in patients with thalassemia major with and without iron overload.

BACKGROUND: Myocardial iron overload in patients with thalassemia major (TM) is one of the most important complications. The purpose of the study was to identify advanced echocardiography parameters for early identification of myocardial dysfunction during follow-up of patients with TM. METHODS: Forty TM patients who were 41 ± 5 years old were included in the study and divided into two groups according to cardiac magnetic resonance T2* results (Group 1: Τ2* > 25 ms, Group 2: Τ2* ≤ 25 ms). Liver T2* parameters were also measured. Conventional and deformational echocardiographic parameters were measured at baseline and approximately 2 years later. RESULTS: Thirty-two patients had Τ2* = 34 ± 4 ms (Group 1), and 8 had Τ2* = 17 ± 9 ms (Group 2). Blood consumption was 185 ± 60 and 199 ± 37 ml/kg/yr (p = 0.64), and liver T2* was 4 ± 5 and 17 ± 21 ms (p = 0.01) in Groups 1 and 2, respectively. At baseline, Group 1 had better left ventricular global longitudinal strain (GLS) (- 22 ± 3 vs. - 18 ± 5, p = 0.01) and similar left ventricular ejection fraction (LVEF) (62 ± 5% vs. 58 ± 10%, p = 0.086) than Group 2. At the 28 ± 11-month follow-up, LVEF, GLS, and T2* values in Group 1 (63 ± 3%, - 21 ± 3%, 34 ± 4 ms) and Group 2 (56 ± 11%, - 17 ± 4%, 17 ± 9 ms) did not change significantly compared to their corresponding baseline values. In 8 patients from Group 1, a worsening (> 15%) in LS (p = 0.001) was detected during follow-up, with a marginal reduction in LVEF. CONCLUSIONS: GLS seems to be an efficient echocardiographic parameter for detecting hemochromatosis-related cardiac dysfunction earlier than LVEF. It also seems to be affected by other factors (free radical oxygen, immunogenetic mechanisms or viral infections) in a minority of patients, underscoring the multifactorial etiology of cardiomyopathy.

Ultrasound guidance for volume management in patients with heart failure.

Congestion is one of the most prominent characteristics of patients presented with decompensated heart failure and it implies unfavorable prognosis for the heart failure patient. Neurohumoral and immuno-inflammatory activation secondary to cardiac dysfunction constitute the pivotal mechanisms driving the heart failure syndrome that results in progressive fluid accumulation. In addition, fluid redistribution between different vascular compartments in human body guided from sympathetic activity constitutes another mechanism for heart failure decompensation. Ultrasound applied in the form of echocardiography provides invaluable data for the assessment of intracardiac filling pressures. The type of renal venous flow can provide the degree of renal congestion and probably insight into the pathophysiology of the decompensation of heart failure. Assessment of lung congestion in the patient with heart failure can be accomplished by lung ultrasonography. Additionally, clinical studies on the role of ultrasound in the management and prognosis of the congested patient are reviewed. Special heart failure population supported with left ventricular assist devices and extracorporeal membrane oxygenation support constitute an area where ultrasound guidance of fluid management has gained important role.

Myocardial Strain and Cardiac Output are Preferable Measurements for Cardiac Dysfunction and Can Predict Mortality in Septic Mice.

Background Sepsis is the overwhelming host response to infection leading to shock and multiple organ dysfunction. Cardiovascular complications greatly increase sepsis-associated mortality. Although murine models are routinely used for preclinical studies, the benefit of using genetically engineered mice in sepsis is countered by discrepancies between human and mouse sepsis pathophysiology. Therefore, recent guidelines have called for standardization of preclinical methods to document organ dysfunction. We investigated the course of cardiac dysfunction and myocardial load in different mouse models of sepsis to identify the optimal measurements for early systolic and diastolic dysfunction. Methods and Results We performed speckle-tracking echocardiography and assessed blood pressure, plasma inflammatory cytokines, lactate, B-type natriuretic peptide, and survival in mouse models of endotoxemia or polymicrobial infection (cecal ligation and puncture, [ CLP ]) of moderate and high severity. We observed that myocardial strain and cardiac output were consistently impaired early in both sepsis models. Suppression of cardiac output was associated with systolic dysfunction in endotoxemia or combined systolic dysfunction and reduced preload in the CLP model. We found that cardiac output at 2 hours post- CLP is a negative prognostic indicator with high sensitivity and specificity that predicts mortality at 48 hours. Using a known antibiotic (ertapenem) treatment, we confirmed that this approach can document recovery. Conclusions We propose a non-invasive approach for assessment of cardiac function in sepsis and myocardial strain and strain rate as preferable measures for monitoring cardiovascular function in sepsis mouse models. We further show that the magnitude of cardiac output suppression 2 hours post- CLP can be used to predict mortality.

The evolving field of nonpharmacological therapies to improve functional capacity in chronic heart failure.

Clinical investigations in chronic heart failure (HF) have been increasingly including endpoints related to functional and exercise capacity. Noninvasive ventilation support (NIVS) constitutes a therapeutic option that could improve several markers of cardiovascular performance and functional capacity along with improvements in HF symptoms such as dyspnea. NIVS with bilevel positive airway pressure (BiPAP) is a therapeutic option that can be better tolerated by patients than continuous positive airway pressure (cPAP) and potentially improve the adherence of patients with HF to NIVS. Future investigations should improve our understanding as to how to select patients with HF most amenable to respond favorably, elucidate the frequency and duration of NIVS session required to maintain the observed short-term beneficial effects for a long period of time, and shed additional light on the mechanisms associated with these benefits. In summary, NIVS appears to be a promising nonpharmacological therapy to improve exercise capacity and quality of life in chronic HF.

Cardiac Rotational Mechanics As a Predictor of Myocardial Recovery in Heart Failure Patients Undergoing Chronic Mechanical Circulatory Support: A Pilot Study.

BACKGROUND: Impaired qualitative and quantitative left ventricular (LV) rotational mechanics predict cardiac remodeling progression and prognosis after myocardial infarction. We investigated whether cardiac rotational mechanics can predict cardiac recovery in chronic advanced cardiomyopathy patients. METHODS AND RESULTS: Sixty-three patients with advanced and chronic dilated cardiomyopathy undergoing implantation of LV assist device (LVAD) were prospectively investigated using speckle tracking echocardiography. Acute heart failure patients were prospectively excluded. We evaluated LV rotational mechanics (apical and basal LV twist, LV torsion) and deformational mechanics (circumferential and longitudinal strain) before LVAD implantation. Cardiac recovery post-LVAD implantation was defined as (1) final resulting LV ejection fraction ≥40%, (2) relative LV ejection fraction increase ≥50%, (iii) relative LV end-systolic volume decrease ≥50% (all 3 required). Twelve patients fulfilled the criteria for cardiac recovery (Rec Group). The Rec Group had significantly less impaired pre-LVAD peak LV torsion compared with the Non-Rec Group. Notably, both groups had similarly reduced pre-LVAD LV ejection fraction. By receiver operating characteristic curve analysis, pre-LVAD peak LV torsion of 0.35 degrees/cm had a 92% sensitivity and a 73% specificity in predicting cardiac recovery. Peak LV torsion before LVAD implantation was found to be an independent predictor of cardiac recovery after LVAD implantation (odds ratio, 0.65 per 0.1 degrees/cm [0.49-0.87]; P=0.014). CONCLUSIONS: LV rotational mechanics seem to be useful in selecting patients prone to cardiac recovery after mechanical unloading induced by LVADs. Future studies should investigate the utility of these markers in predicting durable cardiac recovery after the explantation of the cardiac assist device.

Clinical and histopathological effects of heart failure drug therapy in advanced heart failure patients on chronic mechanical circulatory support.

AIMS: Adjuvant heart failure (HF) drug therapy in patients undergoing chronic mechanical circulatory support (MCS) is often used in conjunction with a continuous-flow left ventricular assist device (LVAD), but its potential impact is not well defined. The objective of the present study was to examine the effects of conventional HF drug therapy on myocardial structure and function, peripheral organ function and the incidence of adverse events in the setting of MCS. METHODS AND RESULTS: Patients with chronic HF requiring LVAD support were prospectively enrolled. Paired myocardial tissue samples were obtained prior to LVAD implantation and at transplantation for histopathology. The Meds group comprised patients treated with neurohormonal blocking therapy (concurrent beta-blocker, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, and aldosterone antagonist), and the No Meds group comprised patients on none of these. Both the Meds (n = 37) and No Meds (n = 44) groups experienced significant improvements in cardiac structure and function over the 6 months following LVAD implantation. The degree of improvement was greater in the Meds group, including after adjustment for baseline differences. There were no differences between the two groups in arrhythmias, end-organ injury, or neurological events. In patients with high baseline pre-LVAD myocardial fibrosis, treatment with HF drug therapy was associated with a reduction in fibrosis. CONCLUSIONS: Clinical and histopathological evidence showed that adjuvant HF drug therapy was associated with additional favourable effects on the structure and function of the unloaded myocardium that extended beyond the beneficial effects attributed to LVAD-induced unloading alone. Adjuvant HF drug therapy did not influence the incidence of major post-LVAD adverse events during the follow-up period.