Vericiguat: The Fifth Harmony of Heart Failure with Reduced Ejection Fraction.

Heart failure with reduced ejection fraction is a chronic and progressive syndrome that continues to be a substantial financial burden for health systems in Western countries. Despite remarkable advances in pharmacologic and device-based therapy over the last few years, patients with heart failure with reduced ejection fraction have a high residual risk of adverse outcomes, even when treated with optimal guideline-directed medical therapy and in a clinically stable state. Worsening heart failure episodes represent a critical event in the heart failure trajectory, carrying high residual risk at discharge and dismal short- or long-term prognosis. Recently, vericiguat, a soluble guanylate cyclase stimulator, has been proposed as a novel drug whose use is already associated with a reduction in heart failure-related hospitalizations in patients in guideline-directed medical therapy. In this review, we summarized the pathophysiology of the nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate cascade in patients with heart failure with reduced ejection fraction, the pharmacology of vericiguat as well as the evidence regarding their use in patients with HFrEF. Finally, tips and tricks for its use in standard clinical practice are provided.

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.

Pathophysiology-Based Management of Acute Heart Failure.

Even though acute heart failure (AHF) is one of the most common admission diagnoses globally, its pathogenesis is poorly understood, and there are few effective treatments available. Despite an heterogenous onset, congestion is the leading contributor to hospitalization, making it a crucial therapeutic target. Complete decongestion, nevertheless, may be hard to achieve, especially in patients with reduced end organ perfusion. In order to promote a personalised pathophysiological-based therapy for patients with AHF, we will address in this review the pathophysiological principles that underlie the clinical symptoms of AHF as well as examine how to assess them in clinical practice, suggesting that gaining a deeper understanding of pathophysiology might result in significant improvements in HF therapy.

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.

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.

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.

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.

Insights from Cardiopulmonary Exercise Testing in Pediatric Patients with Hypertrophic Cardiomyopathy.

The usefulness of cardiopulmonary exercise test (CPET) in adult hypertrophic cardiomyopathy (HCM) patients is well-known, whereas its role in pediatric HCM patients has not yet been explored. The present study investigates possible insights from a CPET assessment in a cohort of pediatric HCM outpatients in terms of functional and prognostic assessment. Sixty consecutive pediatric HCM outpatients aged <18 years old were enrolled, each of them undergoing a full clinical assessment including a CPET; a group of 60 healthy subjects served as controls. A unique composite end-point of heart failure (HF) related and sudden cardiac death (SCD) or SCD-equivalent events was also explored. During a median follow-up of 53 months (25th-75th: 13-84 months), a total of 13 HF- and 7 SCD-related first events were collected. Compared to controls, HCM patients showed an impaired functional capacity with most of them showing peak oxygen uptake (pVO2) values of <80% of the predicted, clearly discrepant with functional New York Heart Association class assessment. The composite end-point occurred more frequently in patients with the worst CPETs' profiles. At the univariate analysis, pVO2% was the variable with the strongest association with adverse events at follow-up (C-index = 0.72, p = 0.025) and a cut-off value equal to 60% was the most accurate in identifying those patients at the highest risk. In a pediatric HCM subset, the CPET assessment allows a true functional capacity estimation and it might be helpful in identifying early those patients at high risk of events.

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 Blockers Up-Titration in Patients with Heart Failure Reduced Ejection Fraction and Cardiac Resynchronization Therapy, a Single Center Study.

Clinical trials have shown the benefits of ß-blockers therapy in patients with heart failure reduced ejection fraction. These benefits include improved survival and a reduced need for hospitalization. Cardiac resynchronization therapy has emerged as an essential device-based therapy for symptomatic patients with heart failure reduced ejection fraction despite optimal pharmacologic treatment. The extent to which ß-blockers are being utilized in patients receiving cardiac resynchronization therapy is not well known. In this study, we evaluate the possibility of increasing ß-blockers doses in an unselected cohort of heart failure reduced ejection patients after cardiac resynchronization therapy capable defibrillator system implantation and the correlation between ß-blockers treatments and clinical outcome. Methods and results: Patients with heart failure reduced ejection fraction in ß-blockers therapy that underwent cardiac resynchronization therapy capable defibrillator system implantation between July 2008, and December 2016 were enrolled in the study. The ß-blockers dose was determined at the time of discharge and during follow-up. Cardiovascular mortality, hospitalization for worsening heart failure or arrhythmic storm and appropriate intervention of the device, were recorded. The study cohort included 480 patients, 289 patients (60.3%) had ß-blockers doses equal to the dose before CRT (Group 1), 191 patients (39.7%) had higher ß-blockers doses than those before the CRT implant (Group 2). Comparing the two groups, Group 2 have lower cardiovascular mortality, heart failure-related hospitalization, and arrhythmic events than Group 1. Conclusion: After initiating CRT, ß-blockers could be safely up-titrated at higher doses with the reduction in mortality, heart failure-related hospitalization, and arrhythmic events.

Clinical and prognostic impact of chronotropic incompetence in patients with hypertrophic cardiomyopathy.

BACKGROUND: A blunted heart rate (HR) response is associated with an impaired peak oxygen uptake (pVO2), a powerful outcome predictor in hypertrophic cardiomyopathy (HCM). The present multicenter study sought to determine the prognostic role for exercise-induced HR response in HCM. METHODS: A total of 681 consecutive HCM outpatients on optimized treatment were recruited. The heart failure (HF) end-point was death due to HF, cardiac transplantation, NYHA III-IV class progression, HF worsening leading to hospitalization and severe functional deterioration leading to septal reduction. The sudden cardiac death (SCD) end-point included SCD, aborted SCD and appropriate implantable cardioverter defibrillator discharges. RESULTS: During a median follow-up of 4.2 years (25-75th centile: 3.9-5.2), 81 patients reached the HF and 23 the SCD end-point. Covariates with independent effects on the HF end-point were left atrial diameter, left ventricular ejection fraction, maximal left ventricular outflow tract gradient and exercise cardiac power (ECP = pVO2∗systolic blood pressure) (C-Index = 0.807) whereas the HCM Risk-SCD score and the ECP remained associated with the SCD end-point (C-Index = 0.674). When the VO2-derived variables were not pursued, peak HR (pHR) re-entered in the multivariate HF model (C-Index = 0.777) and, marginally, in the SCD model (C-index = 0.656). A pHR = 70% of the maximum predicted resulted as the best cut-off value in predicting the HF-related events. CONCLUSIONS: The cardiopulmonary exercise test is pivotal in the HCM management, however the pHR remains a meaningful alternative parameter. A pHR < 70% identified a HCM population at high risk of HF-related events, thus calling for a reappraisal of the chronotropic incompetence threshold in HCM.

Hypertriglyceridemia, an Underestimated Cardiovascular Risk Factor: An Epidemiological Study of the Rome Area.

INTRODUCTION: Hypertriglyceridemia (triglycerides ≥200 mg/dL) is a major cardiovascular risk factor. Despite the high incidence of this condition in the Italian population, epidemiological information remains limited. AIM: To analyze a large database of clinical charts from general practitioners in the Rome area of Italy. METHODS: In this study, the DATAMEG database of patients treated in the Rome area between 2000 and 2015 was analyzed. The database was searched for information on (1) all patients diagnosed with hypertriglyceridemia, (2) all prescriptions for the treatment of hypertriglyceridemia, and (3) all patients who had an acute myocardial infarction. RESULTS: The overall prevalence of hypertriglyceridemia was 4.4% (3647/82,595). Among patients followed from January 1, 2015 onwards, 2786/55,345 (5.0%) were diagnosed with hypertriglyceridemia. Of these, 418 (15.0%) received at least one prescription of triglyceride-lowering treatment. Over the same period, 1653 patients had at least three measurements of triglycerides ≥200 mg/dL, with only 357 (21.6%) receiving at least one prescription of triglyceride-lowering drugs in the year following the last measurement. Furthermore, 513 patients had at least one measurement of ≥500 mg/dL. Of these, only 246 (48.0%) received at least one prescription of triglyceride-lowering drugs in the year following the last measurement. In total, 3485 patients had an acute myocardial infarction (prevalence, 4.3%) in 2015. Of these, only 288 (8.3%) received at least one prescription of triglyceride-lowering drugs in the year following this event. CONCLUSION: These findings confirmed a pattern of inadequate treatment of hypertriglyceridemia in the Rome area.

Pediatric Heart Failure: A Practical Guide to Diagnosis and Management.

Pediatric heart failure represents an important cause of morbidity and mortality in childhood. Currently, there are well-established guidelines for the management of heart failure in the adult population, but an equivalent consensus in children is lacking. In the clinical setting, ensuring an accurate diagnosis and defining etiology is essential to optimal treatment. Diuretics and angiotensin-converting enzyme inhibition are the first-line therapies, whereas beta-blockers and devices for electric therapy are less used in children than in adults. In the end-stage disease, heart transplantation is the best choice of treatment, while a left ventricular assist device can be used as a bridge to transplantation (due to the difficulties in finding organ donors), recovery (in the case of myocarditis), or destination therapy (for patients with systemic disease).

Management of Arrhythmias in Heart Failure.

Heart failure patients are predisposed to develop arrhythmias. Supraventricular arrhythmias can exacerbate the heart failure symptoms by decreasing the effective cardiac output and their control require pharmacological, electrical, or catheter-based intervention. In the setting of atrial flutter or atrial fibrillation, anticoagulation becomes paramount to prevent systemic or cerebral embolism. Patients with heart failure are also prone to develop ventricular arrhythmias that can present a challenge to the managing clinician. The management strategy depends on the type of arrhythmia, the underlying structural heart disease, the severity of heart failure, and the range from optimization of heart failure therapy to catheter ablation. Patients with heart failure, irrespective of ejection fraction are at high risk for developing sudden cardiac death, however risk stratification is a clinical challenge and requires a multiparametric evaluation for identification of patients who should undergo implantation of a cardioverter defibrillator. Finally, patients with heart failure can also develop symptomatic bradycardia, caused by sinus node dysfunction or atrio-ventricular block. The treatment of bradycardia in these patients with pacing is usually straightforward but needs some specific issue.