Role of HLA matching and donor specific antibody development in long-term survival, acute rejection and cardiac allograft vasculopathy.

Although there are different data supporting benefits of HLA matching in kidney transplantation, its role in heart transplantation is still unclear. HLA mismatch (MM) between donor and recipient can lead to the development of donor-specific antibodies (DSA) which produces negative events on the outcome of heart transplantation. Moreover, DSAs are involved in the development of antibody-mediated rejection (AMR) and are associated with an increase in cardiac allograft vasculopathy (CAV). In this study it is analyzed retrospectively the influence of HLA matching and anti-HLA antibodies on overall survival, AMR and CAV in heart transplantation. For this retrospective study are recruited heart transplanted patients at the Cardiac Transplantation Centre of Naples between 2000 and 2019. Among the 155 heart transplant patients, the mean number of HLA-A, B, -DR MM (0 to 6) between donor and recipient was 4.5 ± 1.1. The results show a negative association between MM HLA-DR and survival (p = 0.01). Comparison of patients with 0-1 MM at each locus to all others with 2 MM, for both HLA class I and class II, has not showed significant differences in the development of CAV. Our analysis detected DSA in 38.1% of patients. The production of de novo DSA reveals that there is not an influence on survival (p = 0.72) and/or AMR (p = 0.39). Instead, there is an association between the production of DSA class II and the probability of CAV development (p = 0.03). Mean fluorescence intensity (MFI) values were significantly higher in CAV-positive patients that CAV-negative patients (p = 0.02). Prospective studies are needed to evaluate HLA class II matching as an additional parameter for heart allocation, especially considering the increment of waiting list time.

How to Select Patients for Left Ventricular Assist Devices? A Guide for Clinical Practice.

In recent years, a significant improvement in left ventricular assist device (LVAD) technology has occurred, and the continuous-flow devices currently used can last more than 10 years in a patient. Current studies report that the 5-year survival rate after LVAD implantation approaches that after a heart transplant. However, the outcome is influenced by the correct selection of the patients, as well as the choice of the optimal time for implantation. This review summarizes the indications, the red flags for prompt initiation of LVAD evaluation, and the principles for appropriate patient screening.

The ABC of Heart Transplantation-Part 1: Indication, Eligibility, Donor Selection, and Surgical Technique.

Cardiac transplantation represents the gold standard of treatment for selected patients with advanced heart failure who have poor functional capacity and prognosis despite guideline-directed medical therapy and device-based therapy. Proper patient selection and appropriate referral of patients to centers for the treatment of advanced heart failure are the first but decisive steps for screening patients eligible for cardiac transplantation. The eligibility and the decision to list for cardiac transplantation, even for patients with relative contraindications, are based on a multidisciplinary evaluation of a transplant team. This review will discuss the practical indications, the process of patient eligibility for cardiac transplantation, the principle of donor selection, as well as the surgical technique.

Use of Levosimendan in Patients with Advanced Heart Failure: An Update.

Levosimendan is an inodilator drug that, given its unique pharmacological actions and safety profile, represents a viable therapeutic option in patients with heart failure with reduced ejection fraction in the advanced stage of the disease (advHFrEF). Pulsed levosimendan infusion in patients with advHFrEF improves symptoms and clinical and hemodynamic status, prevents recurrent hospitalizations, and enables optimization of guidelines-directed medical therapy. Furthermore, considering its proprieties on right ventricular function and pulmonary circulation, levosimendan could be helpful for the prevention and treatment of the right ventricular dysfunction post-implanting a left ventricular assist device. However, to date, evidence on this issue is scarce and has yielded mixed results. Finally, preliminary experiences indicate that treatment with levosimendan at scheduled intervals may serve as a "bridge to transplant" strategy in patients with advHFrEF. In this review, we summarized the clinical pharmacology of levosimendan, the available evidence in the treatment of patients with advHFrEF, as well as a hypothesis for its use in patients with advanced heart failure with preserved ejection fraction.

Levosimendan as a "Bridge to Optimization" in Patients with Advanced Heart Failure with Reduced Ejection-A Single-Center Study.

Background: Patients with advanced heart failure with reduced ejection fraction often cannot tolerate target doses of guideline-directed medical therapy due to symptomatic hypotension, renal dysfunction, and associated electrolyte abnormalities. While levosimendan can facilitate the titration of ß-blockers in patients with advanced HFrEF, it is unclear whether ambulatory levosimendan infusions would offer the same benefit. In this prospective study, we investigate the effects of intermittent ambulatory levosimendan infusions on the uptitration of disease-modifying drugs. Methods: We enrolled 37 patients with advanced HFrEF who received repeated ambulatory infusions of levosimendan between January 2018 and January 2021. The demographic, clinical, and laboratory data were acquired 24 h before the first and the last ambulatory levosimendan infusion. Results: At the 1 year follow-up, the enrolled patients were on significantly higher doses of guideline-directed medical therapy, including bisoprolol (3.2 ± 2.8 mg vs. 5.9 ± 4.1 mg; p = 0.02), sacubitril/valsartan (41.67 ± 32.48 mg vs. 68.5 ± 35.72 mg; p = 0.01), and eplerenone (12.7 ± 8.5 mg vs. 22.8 ± 13.6 mg; p = 0.03). Furthermore, a substantial decrease in the furosemide dose was observed (123.2 ± 32.48 mg vs. 81.6 ± 19.47 mg; p < 0.0001). Conclusions: Levosimendan facilitates the optimization of disease-modifying heart failure medications in previously intolerant advanced HFrEF patients.

Angiotensin-converting enzyme inhibitor therapy after heart transplant: From molecular basis to clinical effects.

The use of angiotensin-converting enzyme inhibitors is an important therapy for various cardiovascular diseases, such as hypertension, ischemic heart disease and heart failure (HF). In heart transplant recipients, angiotensin-converting enzyme inhibitors have been demonstrated to be a keystone for the treatment of hypertension with a wide spectrum of pleiotropic molecular effects ranging from improvement of the peripheral vascular system to regulation of the fluid and sodium balance. In addition, angiotensin-converting enzyme inhibitors may be also useful in the prevention of graft failure, cardiac allograft vasculopathy (CAV) and chronic kidney disease (CKD) progression. Further tailored multicenter and randomized studies are warranted to confirm the pleiotropic clinical effects of ACEi therapy in HTRs and to support more extended use in daily clinical practice. Finally in the near future, the use of novel pharmacological agents that inhibit the renin-angiotensin-aldosterone system (RAAS) such as the neprilysin inhibitor sacubitril should be investigated in heart transplant recipients.

Advanced heart failure: state of the art and future directions.

Advanced heart failure is a clinical challenge that requires a pathophysiological-based approach. As the field has been the subject of multiple reviews, the objective of this paper is not to duplicate these publications but rather to offer practical tips for the clinical cardiologist to enable the optimal management of patients with advanced heart failure. Advanced heart failure is defined as a clinical syndrome characterized by severe and persistent symptoms, most commonly with severe ventricular dysfunction, despite optimized medical therapy. This review covers the management of the advanced heart failure patient from pharmacologic therapy with disease-modifying drugs, to the use of electrical therapy devices, percutaneous valve repair and finally to the role of left ventricular assist devices and heart transplantation. The review also explores future directions in the management of advanced heart failure, including translational perspectives for the treatment of this syndrome.

Use of Cardiac Contractility Modulation as Bridge to Transplant in an Obese Patient With Advanced Heart Failure: A Case Report.

Cardiac contractility modulation (CCM) is a novel device-based therapy in patients with heart failure with reduced ejection fraction (HFrEF). In randomized clinical trials and real-life studies, CCM has been shown to improve exercise tolerance and quality of life, reverse left ventricular remodeling and reduce hospitalization in patients with HFrEF. In this case report, we describe for the first time the use of CCM as a "bridge to transplant" in a young obese patient with advanced heart failure due to non-ischemic dilated cardiomyopathy. The patient had a poor quality of life and frequent heart failure-related hospitalizations despite the optimal medical therapy and, due to obesity, a suitable heart donor was unlikely to be identified in the short term and due to severe obesity risk of complications after implantation of a left ventricular assist device (LVAD) was very high.

Hemodynamic Effects of Levosimendan in Outpatients With Advanced Heart Failure: An Echocardiographic Pilot Study.

ABSTRACT: Infusions of levosimendan delivered in ambulatory/outpatient settings have been shown to improve quality of life and reduce hospitalizations in patients with advanced heart failure (HF). The aim of this pilot study was to evaluate the effects of ambulatory infusion of levosimendan on echocardiographic markers of perfusion, congestion, and cardiovascular efficiency. Thirty patients with diagnosed advanced HF underwent ambulatorial infusion of levosimendan at a total dose of 6.25 mg as a part of a repetitive biweekly treatment strategy with the inotrope. Standardized transthoracic echocardiography and Doppler examinations, were performed 1 hour before and 48 hours after completion of ambulatory infusion. At 48 hours after ambulatory infusion of levosimendan, a significant increase in the stroke volume (37.47 ± 12.38 mL/beat vs. 45.47 ± 14.48 mL/beat; P < 0.05) and cardiac output (2.64 ± 0.66 L/min vs. 3.26 ± 0.57 L/min; P < 0.05) occurred. Significant postreductions versus prereductions were also recorded in left atrial pressure (27.37 ± 6.62 mm Hg vs. 22.82 ± 4.17 mm Hg; P < 0.01), mean pulmonary artery pressure (27.69 ± 4.64 mm Hg vs. 23.24 ± 5.32; P < 0.01), and inferior vena cava diameter (23.81 ± 7.63 mm vs. 18.53 ± 4.82 mm; P < 0.01). Significant improvements were noted in the resting cardiac power output (0.46 ± 0.15 watt vs. 0.53 ± 0.22 watt; P < 0.01) and the resting cardiac power index (0.24 ± 0.08 watt/m2 vs. 0.28 ± 0.11 watt/m2; P < 0.01). In outpatients with advanced HF, infusion of levosimendan was associated with hemodynamic responses that may contribute to the clinical benefit previously reported in such patients.

The Role of Echocardiography in the Management of Heart Transplant Recipients.

Transthoracic echocardiography is the primary non-invasive modality for the investigation of heart transplant recipients. It is a versatile tool that provides comprehensive information on cardiac structure and function. Echocardiography is also helpful in diagnosing primary graft dysfunction and evaluating the effectiveness of therapeutic approaches for this condition. In acute rejection, echocardiography is useful with suspected cellular or antibody-mediated rejection, with findings confirmed and quantified by endomyocardial biopsy. For identifying chronic rejection, ultrasound has a more significant role and, in some specific patients (e.g., patients with renal failure), it may offer a role comparable to coronary angiography to identify cardiac allograft vasculopathy. This review highlights the usefulness of echocardiography in evaluating normal graft function and its role in the management of heart transplant recipients.

Inotropes in Patients with Advanced Heart Failure: Not Only Palliative Care.

Patients with advanced heart failure suffer from severe and persistent symptoms, often not responding disease-modifying drugs, a marked limitation of functional capacity and poor quality of life that can ameliorate with inotropic drugs therapy. In small studies, pulsed infusions of classical inotropes (ie, dobutamine and milrinone) are associated with improvement in hemodynamic parameters and quality of life in patients with advanced heart failure. However, because of the adverse effects of these drugs, serious safety issues have been raised. Levosimendan is a calcium-sensitizing inodilators with a triple mechanism of action, whose infusion results in hemodynamic, neurohormonal, and inflammatory cytokine improvements in patients with chronic advanced HF. In addition, levosimendan has important pleiotropic effects, including protection of myocardial, renal, and liver cells from ischemia-reperfusion injury, and anti-inflammatory and antioxidant effects; these properties possibly make levosimendan an "organ protective" inodilator. In clinical trials and real-world evidence, infusion of levosimendan at fixed intervals is safe and effective in patients with advanced HF, alleviating clinical symptoms, reducing hospitalizations, and improving the quality of life. Therefore, the use of repeated doses of levosimendan could represent the therapy of choice as a bridge to transplant/left ventricular assist device implantation or as palliative therapy in patients with advanced heart failure.

Left Ventricular Assist Device Implantation in a Thrombosed Apical Aneurysm.

Left ventricular assist device implantation is a challenging procedure in the presence of a giant thrombosed aneurysm, and no standard surgical techniques are currently recommended in this setting. In this case, we report the successful implantation of a left ventricular assist device (HeartMate III) in a patient with a massive thrombosed apical aneurysm. The patient presented with extended antero-apical necrosis as a result of a delay in hospital admission for acute coronary syndrome due to the patient's concerns about the COVID-19 pandemic outbreak.

Use of sacubitril/valsartan as 'bridge to transplant' in patients with end-stage hypertrophic cardiomyopathy.

The end stage or burned-out phase is an uncommon but challenging clinical evolution of hypertrophic cardiomyopathy (HCM). The management of end-stage HCM is empirically based on the use of drugs approved for heart failure with reduced ejection fraction; however, cardiac transplantation often represents the best option to improve survival. In our case, we describe the use of sacubitril/valsartan as a 'bridge to transplant' in a patient with end-stage HCM. After introducing the drug, enhancements in functional capacity, a reduction in natriuretic peptides and an increase in left ventricular ejection fraction occurred. Given their improved volume of oxygen consumption (VO2) peak and hemodynamic parameters, our patient was left off the waiting list for cardiac transplant and continues to be regularly followed-up with every 3 months.

Exercise-based rehabilitation strategies in heart transplant recipients: Focus on high-intensity interval training.

Despite progressive improvement in medical therapy and standard care, the exercise capacity of heart transplant recipients is reduced compared with age-matched healthy individuals. Exercise-based rehabilitation programs have been shown to improve the exercise capacity of transplant patients through a multifactorial effect. In this context, high-intensity interval exercise is a growing field of research, with current evidence suggesting a major benefit in heart transplant recipients compared with a conventional training protocol. Therefore, this study aimed to provide an overview of the mechanisms involved in the reduced exercise capacity of heart transplant patients and a review of current rehabilitation strategies with a special focus on the mechanisms and clinical effects of high-intensity interval training exercise.

Beta-blocker therapy in heart transplant recipients: A review.

Beta-blockers are essential drugs for the treatment of many cardiovascular diseases, such as heart failure, acute and chronic ischemic heart disease, tachyarrhythmias, and hypertension. However, these drugs have not been used in cardiac transplant patients for many years owing to the fear that they could reduce cardiac output and functional capacity. In recent years, however, some evidence has shown that even in cardiac transplanted patients, ß-blockers are useful and effective in the treatment of sinus tachycardia, supraventricular and ventricular tachyarrhythmias, left ventricular systolic dysfunction, and arterial hypertension. Furthermore, some data have shown that the use of ß-blockers is associated with reduced mortality in heart transplant recipients. In this review, we summarize this evidence with particular emphasis on the practical aspects of the use of ß-blockers in post-transplantation patients to promote the use of this important class of drugs in clinical practice.

Berlin Heart EXCOR® pediatric ventricular assist device in a patient with Sotos syndrome: a case report.

INTRODUCTION: Berlin Heart EXCOR® pediatric ventricular assist device is a mechanical circulatory support device currently used in pediatric patients. Sotos syndrome is a well-described multiple anomaly syndrome characterized by overgrowth, distinctive craniofacial appearance, cardiac abnormalities, and variable learning disabilities. CASE PRESENTATION: We describe a 7-year-old female Caucasian child with classic Sotos syndrome features subjected to implantation of Berlin Heart EXCOR® pediatric biventricular assist device mechanical support. A heart transplant was carried out after a support time of 459 days. After 5 years of follow-up, our patient is clinically stable and the performance of the transplanted heart is excellent. CONCLUSION: This case confirms that Berlin Heart EXCOR® pediatric ventricular assist device can provide satisfactory and safe circulatory support for children with end-stage heart diseases, even in those with Sotos syndrome. The syndrome is not a contraindication to implantation, since the complications are the same as those observed in patients without the syndrome and the prognosis is not affected by the disease.

Aortic erosion during negative pressure therapy in a pediatric heart transplant recipient.

A happy-ending "series of unfortunate events" is reported of the successful emergency treatment of an erosion of the ascending aorta during negative pressure sternal wound therapy for a relapse of Berlin Heart driveline infection in a pediatric transplant recipient. Several key issues related to assist device-related infections and negative pressure complications are discussed in this peculiar setting.

Mitral mechanical replacement in young rheumatic women: analysis of long-term survival, valve-related complications, and pregnancy outcomes over a 3707-patient-year follow-up.

OBJECTIVE: A follow-up study was performed to assess long-term survival, valve-related complications, and pregnancy outcomes in young rheumatic women undergoing isolated mitral mechanical replacement. The influence of prosthetic type on outcomes was also investigated. METHODS: Between 1975 and 2003, 267 isolated mitral mechanical prostheses were implanted. Follow-up reached 3707.8 patient-years. RESULTS: Actuarial survival at 1, 5, 10, 15, 20, and 25 years was 97% +/- 0.01%, 90.4% +/- 0.017%, 85.3% +/- 0.023%, 82.3% +/- 0.025%, 71.7% +/- 0.036%, and 70.2% +/- 0.038%, respectively. At multivariate analysis, atrial fibrillation at follow-up was identified as an independent risk factor for late mortality, whereas left ventricular ejection fraction at 12 postoperative months proved to be a protective factor. Freedom from thromboembolism at 1, 5, 10, 15, 20, and 25 years was 98.1% +/- 0.01%, 94.1% +/- 0.015%, 89.1% +/- 0.021%, 85.9% +/- 0.025%, 81.1% +/- 0.031%, and 75.3% +/- 0.063%, respectively. Atrial fibrillation and Carbomedics device were significantly associated with an increase in thromboembolic events. Freedom from reoperation at 1, 5, 10, 15, 20, and 25 years was 99.2% +/- 0.005%, 95% +/- 0.014%, 91.6% +/- 0.018%, 88.6% +/- 0.022%, and 85.7% +/- 0.041%. Type of prosthesis (tilting disc) was identified as a predictor of reoperation. At the end of the study, 208 patients were still alive: 94.7% were in New York Heart Association class I or II. When receiving warfarin therapy, no patient undertaking pregnancy (n = 35) experienced adverse cardiac or valve-related events. Fetal events were significantly less frequent with a daily warfarin dose less than 5 mg. CONCLUSIONS: Mechanical devices provided excellent performance, safety, and durability. The prognostic role of left ventricular function and atrial fibrillation overwhelmed any differences that might exist between different prosthetic designs. Pregnancies entail virtually no maternal risk and predictable fetal complications.