Basic science of cardiac contractility modulation therapy: Molecular and electrophysiological mechanisms.

In heart failure with reduced ejection fraction and heart failure with preserved ejection fraction, profound cellular and molecular changes have recently been documented in the failing myocardium. These changes include altered calcium handling and metabolic efficiency of the cardiac myocyte, reactivation of the fetal gene program, changes in the electrophysiological properties of the heart, and accumulation of collagen (fibrosis) at the interstitial level. Cardiac contractility modulation therapy is an innovative device-based therapy currently approved for heart failure with reduced ejection fraction in patients with narrow QRS complex and under investigation for the treatment of heart failure with preserved ejection fraction. This therapy is based on the delivery of high-voltage biphasic electrical signals to the septal wall of the right ventricle during the absolute refractory period of the myocardium. At the cellular level, in patients with heart failure with reduced ejection fraction, cardiac contractility modulation therapy has been shown to restore calcium handling and improve the metabolic status of cardiac myocytes, reverse the heart failure-associated fetal gene program, and reduce the extent of interstitial fibrosis. This review summarizes the preclinical literature on the use of cardiac contractility modulation therapy in heart failure with reduced and preserved ejection fraction, correlating the molecular and electrophysiological effects with the clinical benefits demonstrated by this therapy.

Multimodality Cardiovascular Imaging of Cardiotoxicity Due to Cancer Therapy.

Cancer therapies have revolutionized patient survival rates, yet they come with the risk of cardiotoxicity, necessitating effective monitoring and management. The existing guidelines offer a limited empirical basis for practical approaches in various clinical scenarios. This article explores the intricate relationship between cancer therapy and the cardiovascular system, highlighting the role of advanced multimodality imaging in monitoring patients before, during, and after cancer treatment. This review outlines the cardiovascular effects of different cancer therapy classes, offering a comprehensive understanding of their dose- and time-dependent impacts. This paper delves into diverse imaging modalities such as echocardiography, cardiac magnetic resonance imaging, cardiac computed tomography, and nuclear imaging, detailing their strengths and limitations in various conditions due to cancer treatment, such as cardiac dysfunction, myocarditis, coronary artery disease, Takotsubo cardiomyopathy, pulmonary hypertension, arterial hypertension, valvular heart diseases, and heart failure with preserved ejection fraction. Moreover, it underscores the significance of long-term follow-up for cancer survivors and discusses future directions.

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.

Bridging the gap in the symptomatic heart failure patient journey: insights from the Italian scenario.

BACKGROUND: The prognosis for heart failure (HF) patients remains poor, with a high mortality rate, and a marked reduction in quality of life (QOL) and functional status. This study aims to explore the ongoing needs of HF management and the epidemiology of patients followed by Italian HF clinics, with a specific focus on cardiac contractility modulation (CCM). RESEARCH DESIGN AND METHODS: Data from patients admitted to 14 HF outpatients clinics over 4 weeks were collected and compared to the results of a survey open to physicians involved in HF management operating in Italian centers. RESULTS: One hundred and five physicians took part in the survey. Despite 94% of patients receive a regular follow-up every 3-6 months, available therapies are considered insufficient in 30% of cases. Physicians reported a lack of treatment options for 23% of symptomatic patients with reduced ejection fraction (EF) and for 66% of those without reduced EF. Approximately 3% of HF population (two patients per month per HF clinic) meets the criteria for immediate CCM treatment, which is considered a useful option by 15% of survey respondents. CONCLUSIONS: Despite this relatively small percentage, considering total HF population, CCM could potentially benefit numerous HF patients, particularly the elderly, by reducing hospitalizations, improving functional capacity and QOL.

Effect of sacubitril/valsartan on cardiac remodeling compared with other renin-angiotensin system inhibitors: a difference-in-difference analysis of propensity-score matched samples.

BACKGROUND: In patients with heart failure with reduced ejection fraction (HFrEF), treatment with sacubitril-valsartan (S/V) may reverse left ventricular remodeling (rLVR). Whether this effect is superior to that induced by other renin-angiotensin system (RAS) inhibitors is not well known. METHODS: HFrEF patients treated with S/V (n = 795) were compared, by propensity score matching, with a historical cohort of 831 HFrEF patients (non-S/V group) treated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (RAS inhibitors). All patients were also treated with beta-blockers and shared the same protocol with repeat echocardiogram 8-12 months after starting therapy. The difference-in-difference (DiD) analysis was used to evaluate the impact of S/V on CR indices between the two groups. RESULTS: After propensity score matching, compared to non-S/V group (n = 354), S/V group (n = 354) showed a relative greater reduction in end-diastolic and end-systolic volume index (ESVI), and greater increase in ejection fraction (DiD estimator = + 5.42 mL/m2, P = 0.0005; + 4.68 mL/m2, P = 0.0009, and + 1.76%, P = 0.002, respectively). Reverse LVR (reduction in ESVI ≥ 15% from baseline) was more prevalent in S/V than in non-S/V group (34% vs 26%, P = 0.017), while adverse LVR (aLVR, increase in ESVI at follow-up ≥ 15%) was more frequent in non-S/V than in S/V (16% vs 7%, P < 0.001). The beneficial effect of S/V on CR over other RAS inhibitors was appreciable across a wide range of patient's age and baseline end-diastolic volume index, but it tended to attenuate in more dilated left ventricles (P for interaction = NS for both). CONCLUSION: In HFrEF patients treated with beta-blockers, sacubitril/valsartan is associated with a relative greater benefit in LV reverse remodeling indices than other RAS inhibitors.

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.

Clinical, Genetic, and Histological Characterization of Patients with Rare Neuromuscular and Mitochondrial Diseases Presenting with Different Cardiomyopathy Phenotypes.

Cardiomyopathies are mostly determined by genetic mutations affecting either cardiac muscle cell structure or function. Nevertheless, cardiomyopathies may also be part of complex clinical phenotypes in the spectrum of neuromuscular (NMD) or mitochondrial diseases (MD). The aim of this study is to describe the clinical, molecular, and histological characteristics of a consecutive cohort of patients with cardiomyopathy associated with NMDs or MDs referred to a tertiary cardiomyopathy clinic. Consecutive patients with a definitive diagnosis of NMDs and MDs presenting with a cardiomyopathy phenotype were described. Seven patients were identified: two patients with ACAD9 deficiency (Patient 1 carried the c.1240C>T (p.Arg414Cys) homozygous variant in ACAD9; Patient 2 carried the c.1240C>T (p.Arg414Cys) and the c.1646G>A (p.Ar549Gln) variants in ACAD9); two patients with MYH7-related myopathy (Patient 3 carried the c.1325G>A (p.Arg442His) variant in MYH7; Patient 4 carried the c.1357C>T (p.Arg453Cys) variant in MYH7); one patient with desminopathy (Patient 5 carried the c.46C>T (p.Arg16Cys) variant in DES); two patients with mitochondrial myopathy (Patient 6 carried the m.3243A>G variant in MT-TL1; Patient 7 carried the c.253G>A (p.Gly85Arg) and the c.1055C>T (p.Thr352Met) variants in MTO1). All patients underwent a comprehensive cardiovascular and neuromuscular evaluation, including muscle biopsy and genetic testing. This study described the clinical phenotype of rare NMDs and MDs presenting as cardiomyopathies. A multidisciplinary evaluation, combined with genetic testing, plays a main role in the diagnosis of these rare diseases, and provides information about clinical expectations, and guides management.

Artificial intelligence in cardiovascular prevention: new ways will open new doors.

Prevention and effective treatment of cardiovascular disease are progressive issues that grow in tandem with the average age of the world population. Over recent decades, the potential role of artificial intelligence in cardiovascular medicine has been increasingly recognized because of the incredible amount of real-world data (RWD) regarding patient health status and healthcare delivery that can be collated from a variety of sources wherein patient information is routinely collected, including patient registries, clinical case reports, reimbursement claims and billing reports, medical devices, and electronic health records. Like any other (health) data, RWD can be analysed in accordance with high-quality research methods, and its analysis can deliver valuable patient-centric insights complementing the information obtained from conventional clinical trials. Artificial intelligence application on RWD has the potential to detect a patient's health trajectory leading to personalized medicine and tailored treatment. This article reviews the benefits of artificial intelligence in cardiovascular prevention and management, focusing on diagnostic and therapeutic improvements without neglecting the limitations of this new scientific approach.

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.

Multimodality Imaging in Arrhythmogenic Left Ventricular Cardiomyopathy.

The term arrhythmogenic cardiomyopathy (ACM) describes a large spectrum of myocardial diseases characterized by progressive fibrotic or fibrofatty replacement, which gives the substrate for the occurrence of ventricular tachyarrhythmias and the development of ventricular dysfunction. This condition may exclusively affect the left ventricle, leading to the introduction of the term arrhythmogenic left ventricular cardiomyopathy (ALVC). The clinical features of ALVC are progressive fibrotic replacement with the absence or mild dilation of the LV and the occurrence of ventricular arrhythmias within the left ventricle. In 2019, the diagnostic criteria for the diagnosis of ALVC, based on family history and clinical, electrocardiographic, and imaging features, have been proposed. However, since the significant clinical and imaging overlap with other cardiac diseases, genetic testing with the demonstration of a pathogenic variant in an ACM-related gene is required for diagnostic confirmation. In ALVC, the multimodality imaging approach comprises different imaging techniques, such as echocardiography, cardiac magnetic resonance, and cardiac nuclear imaging. It provides essential information for the diagnosis, differential diagnosis, sudden cardiac death risk stratification, and management purposes. This review aims to elucidate the current role of the different multimodality imaging techniques in patients with ALVC.

Use of Levosimendan in Patients with Pulmonary Hypertension: What is the Current Evidence?

Pulmonary hypertension, defined as an increase in mean arterial pressure > 20 mmHg, is a chronic and progressive condition with high mortality and morbidity. Drug therapy of patients with pulmonary hypertension is based on the distinctive pathophysiologic aspect that characterizes the different groups. However, recently, levosimendan, a calcium-sensitizing agent with inotropic, pulmonary vasodilator, and cardioprotective properties, has been shown to be an effective and safe therapeutic strategy for patients with pulmonary arterial hypertension (in addition to specific drugs) and pulmonary hypertension associated with left heart disease (as possible treatment). This review provides a comprehensive overview of the current evidence on the use of levosimendan in patients with pulmonary hypertension.

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.

Use of disease-modifying drugs in diabetic patients with heart failure with reduced ejection fraction.

Type 2 diabetes mellitus and heart failure are closely related, patients with type 2 diabetes mellitus have a higher risk of developing heart failure, and those with heart failure are at increased risk of developing type 2 diabetes. Although no specific randomized clinical trials have been conducted to test the effect of cardiovascular therapies (drugs and/or devices) in diabetic patients with heart failure, a lot of evidence shows that all interventions effective in improving prognosis in patients with heart failure reduced ejection fraction are equally beneficial in patients with and without diabetes. However, the use of disease-modifying drugs in patients with diabetes and heart failure reduced ejection fraction is a clinical challenge due to the increased risk of adverse effects. For example, ß-blockers are underutilized in diabetic patients due to the theoretical unfavorable effects on glucose metabolism as well as the use of drugs that interact with the renin-angiotensin system can be challenged in patients with diabetic nephropathy because of the risk of hyperkalemia. This review outlines the current use of disease-modifying drugs in diabetic patients with heart failure reduced ejection fraction. In addition, the role of novel pharmacologic agents as type 2 sodium-glucose co-transporter inhibitors (SGLT2ii) is discussed.

Effects of Cardiac Contractility Modulation Electrodes on Tricuspid Regurgitation in Patients with Heart Failure with Reduced Ejection Fraction: A Pilot Study.

BACKGROUND: Cardiac contractility modulation (CCM) is an innovative therapy for heart failure with reduced ejection fraction delivered by a cardiac implantable device (Optimizer Smart®). One of the most prominent periprocedural complications common to all cardiac implantable devices (CIDs) is tricuspid regurgitation (TR) due to the placement of the right ventricular endocardial leads. To date, no published studies have assessed the changes in the TR degree in patients with heart failure with reduced ejection fraction (HFrEF) who received an implantable cardioverter-defibrillator (ICD) after the implantation of cardiac contractility modulation therapy devices. OBJECTIVE: This study aimed to evaluate the effect of the implantation of the trans-tricuspid leads required to deliver CCM therapy on the severity of TR in patients with HFrEF who previously underwent ICD implantation. METHODS: We enrolled 30 HFrEF patients who underwent CCM therapy between November 2020 and October 2021. For all the patients, echocardiographic evaluations of TR were performed according to current guidelines 24 h before and six months after the Optimizer Smart® implant was applied. RESULTS: At the 6-month follow-up, the grade of TR remained unchanged compared to the preimplant grade. The value of the vena contracta (VC) of TR was 0.40 ± 0.19 cm in the preimplant period and 0.45 ± 0.21 cm at the 6-month follow-up (p = 0.33). Similarly, the TR proximal isovelocity surface area (PISA) radius value was unchanged at follow-up (0.54 ± 0.22 cm vs. 0.62 ± 0.20 cm; p = 0.18). No statistically significant difference existed between the preimplant VC and PISA radius values, irrespective of the device type. CONCLUSIONS: The implantation of right ventricular electrodes for the delivery of CCM therapy did not worsen tricuspid regurgitation in patients with HFrEF and ICD.

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.

The Effects of Device-Based Cardiac Contractility Modulation Therapy on Left Ventricle Global Longitudinal Strain and Myocardial Mechano-Energetic Efficiency in Patients with Heart Failure with Reduced Ejection Fraction.

BACKGROUND: Virtually all patients with heart failure with reduced ejection fraction have a reduction of myocardial mechano-energetic efficiency (MEE). Cardiac contractility modulation (CCM) is a novel therapy for the treatment of patients with HFrEF, in whom it improves the quality of life and functional capacity, reduces hospitalizations, and induces biventricular reverse remodeling. However, the effects of CCM on MEE and global longitudinal strain (GLS) are still unknown; therefore, this study aims to evaluate whether CCM therapy can improve the MEE of patients with HFrEF. METHODS: We enrolled 25 patients with HFrEF who received an Optimizer Smart implant (the device that develops CCM therapy) between January 2018 and January 2021. Clinical and echocardiographic evaluations were performed in all patients 24 h before and six months after CCM therapy. RESULTS: At six months, follow-up patients who underwent CCM therapy showed an increase of left ventricular ejection fraction (30.8 ± 7.1 vs. 36.1 ± 6.9%; p = 0.032) as well a rise of GLS 10.3 ± 2.7 vs. -12.9 ± 4.2; p = 0.018), of MEE (32.2 ± 10.1 vs. 38.6 ± 7.6 mL/s; p = 0.013) and of MEE index (18.4 ± 6.3 vs. 24.3 ± 6.7 mL/s/g; p = 0.022). CONCLUSIONS: CCM therapy increased left ventricular performance, improving left ventricular ejection fraction, GLS, as well as MEE and MEEi.