Genome Editing and Heart Failure.

Heart failure is a leading and growing cause of morbidity and mortality worldwide and clinically is defined by the presence of typical symptoms and signs due structural or functional cardiac abnormalities. In addition to family history of heart failure, genetic predisposition to cardiomyopathies and exposure to cardiotoxic agents, risk factors for heart failure with reduced ejection fraction are the same as for chronic coronary syndrome. Genome editing technologies can provide the tools to correct genetic defects responsible for various diseases, including cardiomyopathies. These technologies aim to reverse specific mutations. The same methods can also be applied to modulate and improve heart function. This chapter will briefly explain the pathophysiological and genetic aspects of heart failure and then discuss the clinical applications of genome editing in patients with heart failure.

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.

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.

Echocardiography in Advanced Heart Failure for Diagnosis, Management, and Prognosis.

Advanced heart failure, an end-stage disease characterized by high mortality and morbidity despite standard medical therapy, requires various therapeutic strategies like heart transplant and long-term mechanical circulatory support. Echocardiography is the main imaging technique to identify transitions to advanced stages of disease and guide risk stratification and therapeutic decision-making processes. Progressive development of advanced echocardiographic techniques allows more comprehensive assessment of the hemodynamic and structural profiles of patients with advanced heart failure, and its use in clinical practice continues to expand. This article provides an overview of basic and emerging echocardiographic tools to assess patients with advanced heart failure.

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.

Appropriate ICD Interventions for Ventricular Arrhythmias Are Predicted by Higher Syntax Scores I and II in Patients with Ischemic Heart Disease.

AIMS: The occurrence of ventricular arrhythmias (VAs) in ischemic heart disease (IHD) patients is related to the presence and extent of fibrotic/scar tissue. As coronary atherosclerosis is the underlying cause of myocardial ischemia and fibrosis, in IHD patients implanted with an implantable cardioverter defibrillator (ICD) we investigated the relation between the VA burden and the complexity of coronary atherosclerotic lesions. METHODS AND RESULTS: In IHD patients who underwent coronary angiography and ICD implant, the Syntax scores I and II (SSI-II), as index of the severity of the coronary atherosclerotic disease, and the occurrence of VA were assessed. Overall 144 patients were included (123 males). Of these 22 patients (15%) experienced at least one episode of VA (cycle length 298 ± 19 msec) that required ICD intervention. The number of episodes per patient and per year was 4 ± 6 and 2.8 ± 4, respectively. Patients that experienced a VA compared to those free from arrhythmic events did not have distinct baseline clinical characteristics except for a higher SS I and SS II (21 (IQR 13-38) vs. 16 (IQR 10-23); p = 0.037; and 50 (IQR 39-62) vs. 42 (IQR 34-50); p = 0.012). In the binary logistic regression analyses the SS I and II were the only independent predictors of VA occurrence. A higher SS II was also associated with an earlier time to first event (p = 0.005). CONCLUSION: Higher SS I-II scores reflect a more severe coronary atherosclerosis and are associated with a greater VA burden. Further studies are needed to better clarify the ability of SSI-II to stratify the risk of IHD patients to develop life-threatening VA.

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.

Clinical relevance of transient worsening renal function after initiation of sacubitril/valsartan.

BACKGROUND: The worsening of renal function after the start of valsartan therapy is relatively common in clinical practice. However, few data are available on the incidence of worsening renal function after the beginning of therapy with sacubitril/valsartan. METHODS: We retrospectively enrolled 202 outpatients with HFrEF that started therapy with sacubitril/valsartan to evaluate the prevalence of worsening renal function and its clinical significance. RESULTS: At 1 month, a worsening renal function (defined as a > 20% decrease in eGFR occurring after 1 month of ARNi therapy) was found in 68 patients (33%), however after a mean follow-up of 650 ± 80 days, Kaplan-Meier analysis showed no significant in terms of HF-related deaths, HF-related hospitalizations, and the need for renal replacement therapy (25.2 vs. 23.6%; p = .812). In addition, the renal function recovered in patients with early WRF at 3 months (62 + 9.3 ml/min/1.73 m2 vs. 63 ± 13.8 ml/min/1.73 m2; p < .05), with an improvement in estimated glomerular filtration rate at 1 year compared with baseline value (62 ± 9.3 ml/min/1.73 m2 vs. 69 ± 8.6 ml/min/1.73 m2; p < .01). CONCLUSIONS: WRF occurs in nearly 30% of HFrEF patients without impacting clinical outcomes; HF specialists should be aware of these changes to avoid unnecessary discontinuation of sacubitril/valsartan therapy.

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.

Effects of Sacubitril/Valsartan on the Right Ventricular Arterial Coupling in Patients with Heart Failure with Reduced Ejection Fraction.

BACKGROUND: right ventricle-pulmonary artery (RV-PA) coupling assessed by measuring the tricuspid anular plane systolic excursion (TAPSE)/pulmonary artery systolic pressure (PASP) ratio has been recently proposed as an early marker of right ventricular dysfunction in patients with heart failure with a reduced ejection fraction (HFrEF). METHODS: As the effects of sacubitril/valsartan therapy on RV-PA coupling remain unknown, this study aimed to analyse the effect of this drug on TAPSE/PASP in patients with HFrEF. We retrospectively analysed all outpatients with HFrEF referred to our unit between October 2016 and July 2018. RESULTS: At the 1-year follow-up, sacubitril/valsartan therapy was associated with a significant improvement in TAPSE (18.26 ± 3.7 vs. 19.6 ± 4.2 mm, p < 0.01), PASP (38.3 ± 15.7 vs. 33.7 ± 13.6, p < 0.05), and RV-PA coupling (0.57 ± 0.25 vs. 0.68 ± 0.30 p < 0.01). These improvements persisted at the 2-year follow-up. In the multivariable analysis, the improvement in the RV-PA coupling was independent of the left ventricular remodelling. CONCLUSIONS: in patients with HFrEF, sacubitril/valsartan improved the RV-PA coupling; however, further trials are necessary to evaluate the role of sacubitril/valsartan in the treatment of right ventricle (RV) dysfunction either associated or not associated with left ventricular dysfunction.

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.

Atrial Fibrillation and Mitral Regurgitation: Clinical Performance of Direct Oral Anticoagulants in a Real-World Setting.

BACKGROUND: Atrial fibrillation (AF) is the most common cardiac arrhythmia and is frequently present in patients with mitral regurgitation (MR). Currently, there is a lack of real-world evidence specifically addressing the clinical performance of direct oral anticoagulants (DOACs) in patients with AF and concomitant MR. Therefore, the aim of the present study was to assess the efficacy and safety profile of DOACs therapy in patients with AF and MR. METHODS: Data for this study were sourced from the Atrial Fibrillation Research Database in the Department of Cardiology at Monaldi Hospital. The database was queried for AF patients with MR who were prescribed DOACs therapy. The primary safety outcome was defined as the annual incidence rate of major bleeding events and the primary effectiveness outcome as the annual incidence rate of all events classified as ischemic stroke, transient ischemic attacks, and systemic embolisms. RESULTS: Consecutive AF patients with concomitant mild to severe MR who received DOACs therapy (n = 259) were included. Patients were dichotomized in 2 groups according to MR severity: a mild-to-moderate group (MR 1-2+; n = 151) and a moderate-to-severe group (MR 3-4+; n = 108). The incidence rate of major bleedings was significantly higher in MR 3-4+ group (3.92%) compared with the MR 1-2+ group (1.18%; hazard ratio [HR]: 3.2; 95% CI: 1.4-7.3; P = .0059). The incidence rate of thromboembolic events between MR 3-4+ group (0.66%) and MR 1-2+ group (0.62%) was not significantly different (HR: 0.75; P = .823). CONCLUSIONS: In the present study, there was no difference in the efficacy profile of DOACs between AF patients with mild-to-moderate and moderate-to-severe MR. Considering the increased bleeding risk, a close and careful follow-up should be warranted for patients with moderate-to-severe MR.

Clinical Outcome of Edoxaban vs. Vitamin K Antagonists in Patients with Atrial Fibrillation and Diabetes Mellitus: Results from a Multicenter, Propensity-Matched, Real-World Cohort Study.

Diabetes mellitus (DM) is a chronic metabolic disease which is independently associated with unfavorable clinical outcomes in patients with atrial fibrillation (AF). Few real-world data are available about the clinical performance of non-vitamin K oral anticoagulants (NOACs) among patients with atrial fibrillation and diabetes. The aim of our propensity score-matched cohort study was to compare the safety and effectiveness of Edoxaban versus well-controlled vitamin K antagonists (VKAs) therapy among this population. In this study, we considered patients with AF and diabetes on Edoxaban or VKAs therapy included in the multicenter Atrial Fibrillation Research Database (NCT03760874). The occurrence of major bleedings (MB) and thromboembolic events (a composite of ischemic stroke, transient ischemic attack, systemic embolism) was respectively considered primary safety and effectiveness outcome. We identified 557 AF patients with diabetes who received Edoxaban (n: 230) or VKAs (n: 327) treatment. After propensity score matching analysis, 135 Edoxaban and 135 VKA recipients with similar clinical characteristics were evaluated. The mean follow-up was 27 ± 3 months. The incidence rate of thromboembolic events (TE) was 3.0 per 100 person-years (1.11 in Edoxaban vs. 1.9 in the VKA group, hazard ratio (HR): 0.59; 95% confidence interval (CI), 0.14 to 2.52; p = 0.48). The incidence rate of major bleedings (MB) was 3.7 per 100 person-years (1.2 in Edoxaban vs. 2.7 in the VKA group, HR: 0.43; 95% CI, 0.10 to 1.40; p = 0.14). The incidence rate of intracranial hemorrhage was 0.35 per 100 person-years in Edoxaban vs. 0.74 in the VKA group (HR: 0.49; 95% CI: 0.05 to 5.54; p = 0.56). A positive net clinical benefit (NCB) of Edoxaban over VKAs was found (+1.39). Insulin therapy (HR: 1.76, p = 0.004) and glycated hemoglobin (HR: 1.17, p = 0.002) were found to be independent predictors of TE; moreover, the concomitant use of antiplatelet drugs (HR: 2.41, p = 0.001) was an independent predictor of MB. Conclusions: Our data support the hypothesis of the safety and efficacy of Edoxaban for use in patients with AF and diabetes, justified by a favorable NCB over VKAs.

Update on Direct Oral Anticoagulants in Atrial Fibrillation Patients Undergoing Cardiac Interventional Procedures: From Clinical Trials to Real-World Evidence.

Direct oral anticoagulants (DOACs) are considered a first-line therapy for long-term stroke prevention in patients with nonvalvular atrial fibrillation (AF) and high thromboembolic risk. The potential role of DOACs in cardiac interventional procedures is a pressing clinical question, considering the increasing number of procedures and the growing prevalence of patients in DOAC therapy. The aim of this review is to provide an update on available evidence about the clinical performance of DOACs in AF patients undergoing different interventional procedures (AF cardioversion and ablation, and percutaneous coronary and structural heart disease interventions) and to explore the possible role of DOACs as an alternative therapeutic strategy in cardiac interventional procedures among non-AF patients.

Arrhythmias and Sudden Cardiac Death in Beta-Thalassemia Major Patients: Noninvasive Diagnostic Tools and Early Markers.

Beta-thalassemias are a group of inherited, autosomal recessive diseases, characterized by reduced or absent synthesis of beta-globin chains of the hemoglobin tetramer, resulting in variable phenotypes, ranging from clinically asymptomatic individuals to severe anemia. Three main forms have been described: heterozygotes, homozygotes ß+, and homozygotes ß°. Beta-thalassemia major (ß-TM), the most serious form, is characterized by an absent synthesis of globin chains that are essential for hemoglobin formation, causing chronic hemolytic anemia. Cardiac complications represent a leading cause of mortality in ß-TM patients, although an important and progressive increase of life expectancy has been demonstrated after the introduction of chelating therapies. Iron overload is the primary factor of cardiac damage resulting in thalassemic cardiomyopathy, in which diastolic dysfunction usually happens before systolic impairment and overt heart failure (HF). Although iron-induced cardiomyopathy is slowly progressive and it usually takes several decades for clinical and laboratory features of cardiac dysfunction to manifest, arrhythmias or sudden death may be present without signs of cardiac disease and only if myocardial siderosis is present. Careful analysis of electrocardiograms and other diagnostic tools may help in early identification of high-risk ß-TM patients for arrhythmias and sudden cardiac death.

Diagnosis and Management of Left Atrium Appendage Thrombosis in Atrial Fibrillation Patients Undergoing Cardioversion.

Atrial fibrillation is the most common cardiac arrhythmia and is associated with an increased risk of stroke and thromboembolic complications. A rhythm control strategy with both electrical and pharmacological cardioversion is recommended for patients with symptomatic atrial fibrillation. Anticoagulant therapy for 3-4 weeks prior to cardioversion is recommended in order to avoid thromboembolic events deriving from restoring sinus rhythm. Transesophageal echocardiography has a pivotal role in this setting, excluding the presence of left atrial appendage thrombus before cardioversion. The aim of this review is to discuss the epidemiology and risk factors for left atrial appendage thrombosis, the role of echocardiography in the decision making before cardioversion, and the efficacy of different anticoagulant regimens on the detection and treatment of left atrial appendage thrombosis.