Long-term post-transplantation outcomes in patients with hypertrophic cardiomyopathy: Single-center 35-year experience.

BACKGROUND: Heart transplantation (HT) is the only option for most patients with end-stage heart failure and hypertrophic cardiomyopathy (HCM) who fail medical therapy. Data on the long-term outcomes post-transplant in HCM individuals remain scarce. METHODS: We analyzed data of 319 adult patients who underwent HT between 1984 and 2019. Patients were followed for cardiac allograft rejection, cardiac allograft vasculopathy (CAV), death, or re-transplantation. RESULTS: Outcomes of 24 patients with HCM, 160 with ischemic, and 135 with dilated cardiomyopathy were compared. During a mean follow-up of 11.6 ± 7.2 (max 27.8), 16.7 ± 8.2 (max 32.7), and 16.1 ± 9.7 (max 34.6) years after HT in hypertrophic, ischemic, and dilated cardiomyopathy groups, respectively: 10-year survival rate was 67%, 62%, 69%, respectively (p = .04). Post-transplantation, HCM individuals more often than the other two studied groups required prolonged inotropic support (37%, 12%, 17%, respectively, p = .02), temporary mechanical circulatory support (45%, 13%, 14%, respectively, p < .01), and renal replacement therapy immediately post-HT (55%, 19%, 24%, respectively, p < .01). No significant inter-group differences were noted in the 10-year freedom from acute allograft rejection (38%, 46%, 43%, respectively, p = .38) or 10-year freedom from CAV (88%, 78%, 81%, respectively, p = .57). CONCLUSIONS: The long-term post-transplant prognosis of adult patients with hypertrophic cardiomyopathy is favorable despite more challenging immediate post-HT course.

Guidance for Timely and Appropriate Referral of Patients With Advanced Heart Failure: A Scientific Statement From the American Heart Association.

Among the estimated 6.2 million Americans living with heart failure (HF), ≈5%/y may progress to advanced, or stage D, disease. Advanced HF has a high morbidity and mortality, such that early recognition of this condition is important to optimize care. Delayed referral or lack of referral in patients who are likely to derive benefit from an advanced HF evaluation can have important adverse consequences for patients and their families. A 2-step process can be used by practitioners when considering referral of a patient with advanced HF for consideration of advanced therapies, focused on recognizing the clinical clues associated with stage D HF and assessing potential benefits of referral to an advanced HF center. Although patients are often referred to an advanced HF center to undergo evaluation for advanced therapies such as heart transplantation or implantation of a left ventricular assist device, there are other reasons to refer, including access to the infrastructure and multidisciplinary team of the advanced HF center that offers a broad range of expertise. The intent of this statement is to provide a framework for practitioners and health systems to help identify and refer patients with HF who are most likely to derive benefit from referral to an advanced HF center.

Proceedings from the metrics forum in heart transplantation for performance monitoring.

Regulatory oversight for heart transplant programs is currently under review by the United Network for Organ Sharing (UNOS). There is concern whether 1-year patient and graft survival truly represent heart transplant center performance. Thus, a forum was organized by the Thoracic and Critical Care Community of Practice (TCC COP) of the American Society of Transplantation (AST) for the heart transplant community to voice their opinions on matters involving program performance monitoring by UNOS. A TCC COP work group was formed to review outcome metrics for adult heart transplantation and culminated in a virtual community forum (72 participants representing 61 heart transplant programs) on November 12-13, 2020. One-year posttransplant survival is still considered an appropriate and important measure to assess program performance. Waitlist mortality and offer acceptance rate as pretransplant metrics could also be useful measures of program performance, recognizing that outside factors may influence these metrics. In depth discussion of these metrics and other issues including auditing thresholds, innovations to reduce risk-averse behavior and personally designed program scorecards are included in this meeting proceedings.

Dietary sugar intake and risk of Alzheimer's disease in older women.

BACKGROUND: Despite some reports of cardiometabolic disorders associated with the risk of Alzheimer's disease (AD), limited studies have been conducted to examine the association between excessive sugar intake (a risk factor for cardiometabolic disorders) and AD risk. AIM: The purpose of our study was to evaluate if excessive sugar intake has a significant long-term effect on the risk of AD. METHODS: A population sample of 37,689 participants, who enrolled in the United States (US) Women's Health Initiative - Dietary Modification Trial (WHI-DM) in 1993-2005 and its extended observational follow-up study through 1 March 2019, were analyzed. Dietary sugar intake was measured using food frequency questionnaires. AD was classified by reports using a standard questionnaire. A dietary pattern that explained the maxima variations in sugar intake was constructed using reduced rank regression (RRR) technique. Associations of RRR dietary pattern scores and sugar intake (g/day) by quartiles (Q1 through Q4) with AD risk were examined using Cox proportional hazards regression analysis with adjusting for key covariates. RESULTS: During a mean follow-up of 18.7 years, 4586 participants reported having incident AD. The total incidence rate (95% confidence interval [CI]) of AD was 6.5 (6.3-6.7) per 1000 person-years (PYs). The incidence rates (95% CI) of AD by total sugar intake were 6.2 (5.8-6.6), 6.4 (6.0-6.8), 6.6 (6.3-7.0), and 6.9 (6.5-7.3) per 1000 PYs among those in quartiles (Q) 1 to Q4 (toward higher sugar consumption) of total sugar intake, respectively (test for trend of AD incident rates, p < 0.001). Individuals in Q4 of total sugar intake had a 1.19 higher risk of incident AD than those in Q1 (hazard ratio [HR] = 1.19, 95% CI: 1.05-1.34, p = 0.01). An estimated increase of 10 g/day in total sugar intake (about 2.4 teaspoons) was associated with an increased AD risk by 1.3-1.4%. Of six subtypes of sugar intake, lactose was significantly associated with AD risk. CONCLUSIONS: Our study indicates that excessive total sugar intake was significantly associated with AD risk in women. Of six subtypes of sugar intake, lactose had a stronger impact on AD risk.

Mechanistic Target of Rapamycin (mTOR) Inhibitors.

Mechanistic target of rapamycin (mTOR) inhibitors are macrocyclic lactone antibiotics derived from Streptomyces hygroscopicus that prevent T lymphocyte activation and B cell differentiation. Unlike calcineurin inhibitors (CNIs) that inhibit cytokine production, mTOR inhibitors block the cytokine signal transduction to arrest cells in the G1 to S phase. This class of drugs is commonly used for post-transplantation and cancer management because of its immunosuppressive and antiproliferative properties, respectively. The potential uses of mTOR inhibitors are heavily explored because of their impact on cell growth and proliferation. However, mTOR inhibitors have a broad range of effects that can result in adverse reactions, but side effects can occur with other immunosuppressive agents as well. Thus, the performance of mTOR inhibitors is compared to the outcomes and adverse effects of other immunosuppressive drugs or the combination of other immunosuppressants and mTOR inhibitors. Because mTOR regulates many downstream pathways, mTOR inhibitors can affect these pathways to manage various diseases. Sirolimus (rapamycin) is approved by the Food and Drug Administration (FDA) to treat post-renal transplantation and lymphangioleiomyomatosis (LAM). Everolimus is approved by the FDA to treat postmenopausal advanced hormone receptor-positive, HER2-negative breast cancer in women, progressive neuroendocrine tumors of pancreatic origin (PNET), advanced renal cell carcinoma (RCC), renal angiomyolipoma (AML) and tuberous sclerosis complex (TSC), and subependymal giant cell astrocytoma (SEGA) associated with TSC as well as renal and liver transplantation. Temsirolimus is approved by the FDA to treat advanced RCC. Opportunities to use mTOR inhibitors as therapy for other transplantation, metabolic disease, and cancer management are being researched. mTOR inhibitors are often called proliferation signal inhibitors (PSIs) because of their effects on proliferation pathways.

Novel Immunosuppression in Solid Organ Transplantation.

Solid organ transplantation and survival has improved tremendously in the last few decades, much of the success has been attributed to the advancements in immunosuppression. While steroids are being replaced and much of the immunosuppressive strategies focus on steroid free regimens, novel agents have introduced in the induction, maintenance, and treatment of acute rejection phase. MTOR inhibitors have helped with the renal sparing side effect from the calcineurin inhibitors, newer agents such as rituximab have decreased the incidence of donor-specific antibodies which led to decreased incidence of acute rejection reactions. In this chapter we discuss the newer therapies directed specifically for solid organ transplantation.

Antiproliferatives and Transplantation.

Antiproliferative agents include Mycophenolic acid and Azathioprine (which is less commonly used unless in certain conditions). They were initially identified for use in autoimmune and cancer research due to their role in disruption of cellular replication. They have now become the cornerstone of antirejection maintenance therapy in solid organ transplant. In this chapter we will describe the major times that lead to discovery, mechanisms of action, side effects, use during pregnancy and the major clinical trials.

Autonomic Testing Optimizes Therapy for Heart Failure and Related Cardiovascular Disorders.

PURPOSE OF REVIEW: Cardiovascular autonomic control is an intricately balanced dynamic process. Autonomic dysfunction, regardless of origin, promotes and sustains the disease processes, including in patients with heart failure (HF). Autonomic control is mediated through the two autonomic branches: parasympathetic and sympathetic (P&S). HF is arguably the disease that stands to most benefit from P&S manipulation to reduce mortality risk. This review article briefly summarizes some of the more common types of autonomic dysfunction (AD) that are found in heart failure, suggests a mechanism by which AD may contribute to HF, reviews AD involvement in common HF co-morbidities (e.g., ventricular arrhythmias, AFib, hypertension, and Cardiovascular Autonomic Neuropathy), and summarizes possible therapy options for treating AD in HF. RECENT FINDINGS: Autonomic assessment is important in diagnosing and treating CHF, and its possible co-morbidities. Autonomic assessment may also have importance in predicting which patients may be susceptible to sudden cardiac death. This is important since most CHF patients with sudden cardiac death have preserved left ventricular ejection fraction and better discriminators are needed. Many life-threatening cardiovascular disorders will require invasive testing for precise diagnoses and therapy planning when modulating the ANS is important. In cases of non-life-threatening disorders, non-invasive ANS testing techniques, especially those that individually assess both ANS branches simultaneously and independently, are sufficient to diagnose and treat serially.

Cardiac Amyloidosis: Evolving Diagnosis and Management: A Scientific Statement From the American Heart Association.

Transthyretin amyloid cardiomyopathy (ATTR-CM) results in a restrictive cardiomyopathy caused by extracellular deposition of transthyretin, normally involved in the transportation of the hormone thyroxine and retinol-binding protein, in the myocardium. Enthusiasm about ATTR-CM has grown as a result of 3 simultaneous areas of advancement: Imaging techniques allow accurate noninvasive diagnosis of ATTR-CM without the need for confirmatory endomyocardial biopsies; observational studies indicate that the diagnosis of ATTR-CM may be underrecognized in a significant proportion of patients with heart failure; and on the basis of elucidation of the mechanisms of amyloid formation, therapies are now approved for treatment of ATTR-CM. Because therapy for ATTR-CM may be most effective when administered before significant cardiac dysfunction, early identification of affected individuals with readily available noninvasive tests is essential. This scientific statement is intended to guide clinical practice and to facilitate management conformity by covering current diagnostic and treatment strategies, as well as unmet needs and areas of active investigation in ATTR-CM.

Frailty in heart transplantation: Report from the heart workgroup of a consensus conference on frailty.

A consensus conference on frailty in solid organ transplantation took place on February 11, 2018, to discuss the latest developments in frailty, adopt a standardized approach to assessment, and generate ideas for future research. The findings and consensus of the Frailty Heart Workgroup (American Society of Transplantation's Thoracic and Critical Care Community of Practice) are presented here. Frailty is defined as a clinically recognizable state of increased vulnerability resulting from aging-associated decline in reserve and function across multiple physiologic systems such that the ability to cope with every day or acute stressors is compromised. Frailty is increasingly recognized as a distinct biologic entity that can adversely affect outcomes before and after heart transplantation. A greater proportion of patients referred for heart transplantation are older and have more complex comorbidities. However, outcomes data in the pretransplant setting, particularly for younger patients, are limited. Therefore, there is a need to develop objective frailty assessment tools for risk stratification in patients with advanced heart disease. These tools will help to determine appropriate recipient selection for advanced heart disease therapies including heart transplantation and mechanical circulatory support, improve overall outcomes, and help distinguish frailty phenotypes amenable to intervention.

New French heart allocation system: Comparison with Eurotransplant and US allocation systems.

Graft allocation rules for heart transplantation are necessary because of the shortage of heart donors, resulting in high waitlist mortality. The Agence de la biomédecine is the agency in charge of the organ allocation system in France. Assessment of the 2004 urgency-based allocation system identified challenging limitations. A new system based on a score ranking all candidates was implemented in January 2018. In the revised system, medical urgency is defined according to candidate characteristics rather than the treatment modalities, and an interplay between urgency, donor-recipient matching, and geographic sharing was introduced. In this article, we describe in detail the new allocation system and compare these allocation rules to Eurotransplant and US allocation policies.

Discovery of non-HLA antibodies associated with cardiac allograft rejection and development and validation of a non-HLA antigen multiplex panel: From bench to bedside.

We analyzed humoral immune responses to nonhuman leukocyte antigen (HLA) after cardiac transplantation to identify antibodies associated with allograft rejection. Protein microarray identified 366 non-HLA antibodies (>1.5 fold, P < .5) from a discovery cohort of HLA antibody-negative, endothelial cell crossmatch-positive sera obtained from 12 cardiac allograft recipients at the time of biopsy-proven rejection. From these, 19 plasma membrane proteins and 10 autoantigens identified from gene ontology analysis were combined with 48 proteins identified through literature search to generate a multiplex bead array. Longitudinal sera from a multicenter cohort of adult cardiac allograft recipients (samples: n = 477 no rejection; n = 69 rejection) identified 18 non-HLA antibodies associated with rejection (P < .1) including 4 newly identified non-HLA antigenic targets (DEXI, EMCN, LPHN1, and SSB). CART analysis showed 5/18 non-HLA antibodies distinguished rejection vs nonrejection. Antibodies to 4/18 non-HLA antigens synergize with HLA donor-specific antibodies and significantly increase the odds of rejection (P < .1). The non-HLA panel was validated using an independent adult cardiac transplant cohort (n = 21 no rejection; n = 42 rejection, >1R) with an area under the curve of 0.87 (P < .05) with 92.86% sensitivity and 66.67% specificity. We conclude that multiplex bead array assessment of non-HLA antibodies identifies cardiac transplant recipients at risk of rejection.

The Implication of Cardiac Injury Score on In-hospital Mortality of Coronavirus Disease 2019.

BACKGROUNDS: The severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) has spread worldwide. Cardiac injury after SARS-CoV-2 infection is a major concern. The present study investigated impact of the biomarkers indicating cardiac injury in coronavirus disease 2019 (COVID-19) on patients' outcomes. METHODS: This study enrolled patients who were confirmed to have COVID-19 and admitted at a tertiary university referral hospital between February 19, 2020 and March 15, 2020. Cardiac injury was defined as an abnormality in one of the following result markers: 1) myocardial damage marker (creatine kinase-MB or troponin-I), 2) heart failure marker (N-terminal-pro B-type natriuretic peptide), and 3) electrical abnormality marker (electrocardiography). The relationship between each cardiac injury marker and mortality was evaluated. Survival analysis of mortality according to the scoring by numbers of cardiac injury markers was also performed. RESULTS: A total of 38 patients with COVID-19 were enrolled. Twenty-two patients (57.9%) had at least one of cardiac injury markers. The patients with cardiac injuries were older (69.6 ± 14.9 vs. 58.6 ± 13.9 years old, P = 0.026), and were more male (59.1% vs. 18.8%, P = 0.013). They showed lower initial oxygen saturation (92.8 vs. 97.1%, P = 0.002) and a trend toward higher mortality (27.3 vs. 6.3%, P = 0.099). The increased number of cardiac injury markers was significantly related to a higher incidence of in-hospital mortality which was also evidenced by Kaplan-Meier survival analysis (P = 0.008). CONCLUSION: The increased number of cardiac injury markers is related to in-hospital mortality in patients with COVID-19.

Prophylactic use of the implantable cardioverter-defibrillator and its effect on the long-term survival, cardiovascular and sudden cardiac death in nonischemic cardiomyopathy patients-a systematic review and meta-analysis.

Implantable cardioverter-defibrillator (ICD) has shown to reduce sudden cardiac death and overall mortality in patients with dilated cardiomyopathy. The recently published DANISH trial has shown conflicting outcomes on the long-term survival in patients with prophylactic implantation of ICD in Non-Ischemic Cardiomyopathy (NICM). Two independent reviewers searched MEDLINE, PUBMED, Ovid, CINAHL, clinicaltrials.gov , and Cochrane Registry for randomized control trials (RCT's) comparing ICD to medical treatment (MT). Six RCT's enrolling 3389 patients (ICD = 1554 and MT = 1835) were included for final analysis. The primary outcomes were mortality comparing ICD to MT, 231 vs 337 (OR = 0.74, CI = 0.62-0.90, p = 0.002, and I2 = 0%) favoring ICD. On comparing to amiodarone only, there were 47 deaths in the ICD arm vs 71 deaths in amiodarone arm, (OR = 0.66, CI = 0.44-0.98, p = 0.04, I2 0%), to placebo and usual care only (excluding amiodarone); there were 225 deaths in ICD patients compared to 266 in the placebo and usual care arm, (OR = 0.73, CI = 0.59-0.92, p = 0.007, I2 = 15%). The results of our analysis from these six RCTs clearly support the ongoing benefit of prophylactic ICD implantation and support current recommendations for ICD implantation in NICM patients. More RCT's at a larger scale are needed to further elucidate benefits of both ICD and CRT-D in this post PARADIGM era where MT is at a pinnacle in reducing morbidity and mortality in heart failure patients.

Genetics of Dilated Cardiomyopathy.

PURPOSE OF REVIEW: Dilated cardiomyopathy (DCM) is characterized by left ventricular dilation and systolic function and is the most common among all cardiomyopathies. Familial DCM makes up a significant portion of cases, and approximately 40 genes are identified as involved in the pathogenesis of heart failure, each affecting a specific part of cellular mechanisms. The purpose of this review is to summarize recent findings and the current understanding of the most common gene mutations identified associated with DCM. RECENT FINDINGS: Next-generation sequencing is a comprehensive gene analysis technique used to discover more mutation variants and also to learn about the impact of mutations in relationship to clinical presentations. A variety of techniques are utilized to study different gene mutations, such as genotype-phenotype association analysis or whole-exome sequencing, to understand the natural history of diseases. For certain genetic abnormalities, information is helpful in developing potential therapeutic treatment targeting mutations. More treatment options are hopeful with the understanding of specific genetic mutations and their pathogenic mechanism. It also suggests the importance of genetic assessment and counseling for family members of an affected patient, in order to provide potential early diagnosis and better clinical management of DCM.

Readmission rate after ultrafiltration in acute decompensated heart failure: a systematic review and meta-analysis.

Significance of ultrafiltration in acute decompensated heart failure remains unclear. We performed meta-analysis to determine its role in reducing readmissions after acute decompensated heart failure. MEDLINE was searched using PUBMED from inception to March 22, 2017 for prospective randomized control trials comparing ultrafiltration to diuretics in acute decompensated heart failure. Five hundred ninety studies were found; nine studies with 820 patients were included. Studies with renal replacement therapy bar ultrafiltration, chronic decompensated heart failure, and non-English language were excluded. RevMan Version 5.3 was used for analysis. The primary outcomes analyzed were cumulative and 90 days readmissions secondary to heart failure and all-cause readmissions. Baseline characteristics were similar. One hundred eighty-eight patients were readmitted with heart failure, 77 vs 111 favoring ultrafiltration; risk ratio (RR) = 0.71 (95% confidence interval (CI), 0.49-1.02, p = 0.07, I 2  = 47%). Ninety days readmissions were 43 vs 67 favoring ultrafiltration; RR = 0.65 (95%CI, 0.47-0.90, p = 0.01, I 2  = 0%). Ultrafiltration showed significantly higher fluid removal and weight loss. Hypotension was common in ultrafiltration (24 vs 13, OR = 2.06, 95%CI = 0.98-4.32, p = 0.06, I 2  = 0%). Ultrafiltration showed reduced 90 days heart failure readmissions and trend towards reduced cumulative hospital readmissions. Renal and cardiovascular outcomes and hospital stay were similar.

Pharmacologic Management for Heart Failure and Emerging Therapies.

PURPOSE OF REVIEW: This review aims to summarize the growing body of literature of HF with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF) with a focus on recent pharmacologics. RECENT FINDINGS: HFrEF continues to be more widely investigated than HFpEF. Ivabradine and combinatorial treatment with sacubitril and valsartan are promising newly approved therapies. Other experimental therapies have emerged, which include Serelaxin, Empagliflozin, Neuregulin, and Omecamtive mecarbil, among others. These drugs need to continue to be investigated for safety and efficacy. We predict ivabradine and combinatorial treatment with sacubitril-valsartan to develop as a widespread therapy. New therapies should be aimed at treating HFpEF or target the cardiomyocyte itself.

Ethical Considerations in the Long-Term Ventricular Assist Device Patient.

PURPOSE OF REVIEW: As the heart failure population continues to age, the need for definitive therapies such as ventricular assist devices (VADs) to extend life and alleviate suffering from end-stage disease directly increases. The goal of this article is to examine the ethical principles of autonomy, beneficence, non-maleficence, and justice within the context of long-term VAD patients. RECENT FINDINGS: Survival rates in VAD-implanted patients have improved in parallel with modernization of device design and surgical technique, reaching that of cardiac transplantation at 1 year post-procedure. Even the sickest patients, those once deemed transplant-ineligible, have been proven to benefit from device implantation and in some cases to a point of becoming eligible for cardiac transplantation. Nevertheless, VAD implantation remains a high-risk procedure with in-hospital mortality rates reaching up to 27% post-procedure and requires intensive upkeep even after successful implantation. Furthermore, end-of-life decisions are complicated by consideration of device deactivation in patients who may not die immediately from an otherwise lethal pathophysiology. Ethical considerations in selection of patients, goals of implantation, and length of therapy become important to preserve the efficacy of treatment and maximize resource utilization. Advanced directives, shared decision-making, and multi-disciplinary approach to treatment have been shown to improve outcomes with respect to both survival and quality of life.

New role of mechanical assist device as bridge to transplant: USA perspective.

PURPOSE OF REVIEW: Cardiac transplant remains the gold standard of care for patients with end-stage heart failure. Unfortunately, due to the limited availability of donor hearts in the United States, not all eligible candidates are able to be transplanted. Since the introduction of mechanical assist devices for the treatment of advanced heart failure, patients gain a significant survival benefit while awaiting transplant. With rapidly evolving technology, it is important to appreciate the advances in the current use of mechanical assist devices. RECENT FINDINGS: Following a comprehensive analysis of novel therapies in end-stage heart failure, there is an enhancement in quality of life and life expectancy following implantation of left ventricular (LV) assist devices (LVADs). When implanted in suitable patients as bridge-to-transplant or 'destination therapy', recipients demonstrate superior outcomes and survival compared with those who remain on optimal medical therapy. SUMMARY: The use of LV assist devices (LVADs) as bridge to transplantation has gained popularity over the last decade. It is recognized as an integral treatment modality in end-stage heart failure to those awaiting heart transplantation. When implanted in the appropriately chosen patient, it is superior to medical treatment alone and has shown noninferiority to heart transplantation while allowing for optimal functional status and preservation of end organ function.