The sympathetic nervous system in heart failure revisited.

Several attempts have been made, by the scientific community, to develop a unifying hypothesis that explains the clinical syndrome of heart failure (HF). The currently widely accepted neurohormonal model has substituted the cardiorenal and the cardiocirculatory models, which focused on salt-water retention and low cardiac output/peripheral vasoconstriction, respectively. According to the neurohormonal model, HF with eccentric left ventricular (LV) hypertrophy (LVH) (systolic HF or HF with reduced LV ejection fraction [LVEF] or HFrEF) develops and progresses because endogenous neurohormonal systems, predominantly the sympathetic nervous system (SNS) and the renin-angiotensin-aldosterone system (RAAS), exhibit prolonged activation following the initial heart injury exerting deleterious hemodynamic and direct nonhemodynamic cardiovascular effects. However, there is evidence to suggest that SNS overactivity often preexists HF development due to its association with HF risk factors, is also present in HF with preserved LVEF (diastolic HF or HFpEF), and that it is linked to immune/inflammatory factors. Furthermore, SNS activity in HF may be augmented by coexisting noncardiac morbidities and modified by genetic factors and demographics. The purpose of this paper is to provide a contemporary overview of the complex associations between SNS overactivity and the development and progression of HF, summarize the underlying mechanisms, and discuss the clinical implications as they relate to therapeutic interventions mitigating SNS overactivity.

Conduction system pacing: how far are we from the "electrical" bypass?

Conduction system pacing is an alternative practice to conventional right ventricular apical pacing. It is a method that maintains physiologic ventricular activation, based on a correct pathophysiological basis, in which the pacing lead bypasses the lesion of the electrical fibers and the electrical impulse transmits through the intact adjacent conduction system. For this reason, it might be reasonably characterized by the term "electrical bypass" compared to the coronary artery bypass in revascularization therapy. In this review, reference is made to the sequence of events in which conventional right ventricular pacing may cause adverse outcomes. Furthermore, there is a reference to alternative strategies and pacing sites. Interest focuses on the modalities for which there are data from the literature, namely for the right ventricular (RV) septal pacing, the His bundle pacing (HBP), and the left bundle branch pacing (LBBP). A more extensive reference is about the HBP, for which there are the most updated data. We analyze the considerations that limit HBP-wide application in three axes, and we also present the data for the implantation and follow-up of these patients. The indications with their most important studies to date are then described in detail, not only in their undoubtedly positive findings but also in their weak aspects, because of which this pacing mode has not yet received a strong recommendation for implementation. Finally, there is a report on LBBP, focusing mainly on its points of differentiation from HBP.

Autonomic Nervous System Dysfunction in Peritoneal Dialysis Patients: An Underrecognized Cardiovascular Risk Factor?

BACKGROUND: In patients with end-stage kidney disease (ESKD) receiving peritoneal dialysis (PD), cardiovascular events represent the predominant cause of morbidity and mortality, with cardiac arrhythmias and sudden death being the leading causes of death in this population. Autonomic nervous system (ANS) dysfunction is listed among the non-traditional risk factors accounting for the observed high cardiovascular burden, with a plethora of complex and not yet fully understood pathophysiologic mechanisms being involved. SUMMARY: In recent years, preliminary studies have investigated and confirmed the presence of ANS dysfunction in PD patients, while relevant results from cohort studies have linked ANS dysfunction with adverse clinical outcomes in these patients. In light of these findings, ANS dysfunction has been recently receiving wider consideration as an independent cardiovascular risk factor in PD patients. The aim of this review was to describe the mechanisms involved in the pathogenesis of ANS dysfunction in ESKD and particularly PD patients and to summarize the existing studies evaluating ANS dysfunction in PD patients. KEY MESSAGES: ANS dysfunction in PD patients is related to multiple complex mechanisms that impair the balance between SNS/PNS, and this disruption represents a crucial intermediator of cardiovascular morbidity and mortality in this population.

Beyond Quadruple Therapy and Current Therapeutic Strategies in Heart Failure with Reduced Ejection Fraction: Medical Therapies with Potential to Become Part of the Therapeutic Armamentarium.

Heart failure with reduced ejection fraction (HFrEF) is a complex clinical syndrome with significant morbidity and mortality and seems to be responsible for approximately 50% of heart failure cases and hospitalizations worldwide. First-line treatments of patients with HFrEF, according to the ESC and AHA guidelines, include ß-blockers, angiotensin receptor/neprilysin inhibitors, sodium-glucose cotransporter 2 inhibitors, and mineralocorticoid receptor antagonists. This quadruple therapy should be initiated during hospital stay and uptitrated to maximum doses within 6 weeks after discharge according to large multicenter controlled trials. Quadruple therapy improves survival by approximately 8 years for a 55-year-old heart failure patient. Additional therapeutic strategies targeting other signaling pathways such as ivabradine, digoxin, and isosorbide dinitrate and hydralazine combination for African Americans, as well as adjunctive symptomatic therapies, seem to be necessary in the management of HFrEF. Although second-line medications have not achieved improvements in mortality, they seem to decrease heart failure hospitalizations. There are novel medical therapies including vericiguat, omecamtiv mecarbil, genetic and cellular therapies, and mitochondria-targeted therapies. Moreover, mitraclip for significant mitral valve regurgitation, ablation in specific atrial fibrillation cases, omecamtiv mecarbil are options under evaluation in clinical trials. Finally, the HeartMate 3 magnetically levitated centrifugal left ventricular assist device (LVAD) has extended 5-year survival for stage D HF patients who are candidates for an LVAD.

Association between Ranolazine, Ischemic Preconditioning, and Cardioprotection in Patients Undergoing Scheduled Percutaneous Coronary Intervention.

Background and Objectives: Remote ischemic preconditioning (RIPC) has demonstrated efficacy in protecting against myocardial ischemia-reperfusion injury when applied before percutaneous coronary revascularization. Ranolazine, an anti-ischemic drug, has been utilized to minimize ischemic events in chronic angina patients. However, there is a lack of trials exploring the combined effects of ranolazine pretreatment and RIPC in patients undergoing percutaneous coronary interventions (PCIs). Materials and Methods: The present study is a prospective study which enrolled 150 patients scheduled for nonemergent percutaneous coronary revascularization. Three groups were formed: a control group undergoing only PCIs, an RIPC group with RIPC applied to either upper limb before the PCI (preconditioning group), and a group with RIPC before the PCI along with prior ranolazine treatment for stable angina (ranolazine group). Statistical analyses, including ANOVAs and Kruskal-Wallis tests, were conducted, with the Bonferroni correction for type I errors. A repeated-measures ANOVA assessed the changes in serum enzyme levels (SGOT, LDH, CRP, CPK, CK-MB, troponin I) over the follow-up. Statistical significance was set at p < 0.05. Results: The ranolazine group showed (A) significantly lower troponin I level increases compared to the control group for up to 24 h, (B) significantly lower CPK levels after 4, 10, and 24 h compared to the preconditioning group (p = 0.020, p = 0.020, and p = 0.019, respectively) and significantly lower CPK levels compared to the control group after 10 h (p = 0.050), and (C) significantly lower CK-MB levels after 10 h compared to the control group (p = 0.050). Conclusions: This study suggests that combining RIPC before scheduled coronary procedures with ranolazine pretreatment may be linked to reduced ischemia induction, as evidenced by lower myocardial enzyme levels.

Targeting Key Inflammatory Mechanisms Underlying Heart Failure: A Comprehensive Review.

Inflammation is a major component of heart failure (HF), causing peripheral vasculopathy and cardiac remodeling. High levels of circulating inflammatory cytokines in HF patients have been well recognized. The hallmark of the inflammatory imbalance is the insufficient production of anti-inflammatory mediators, a condition that leads to dysregulated cytokine activity. The condition progresses because of the pathogenic consequences of the cytokine imbalance, including the impact of endothelial dysfunction and adrenergic responsiveness deterioration, and unfavorable inotropic effects on the myocardium. Hence, to develop possible anti-inflammatory treatment options that will enhance the outcomes of HF patients, it is essential to identify the potential pathophysiological mechanisms of inflammation in HF. Inflammatory mediators, such as cytokines, adhesion molecules, and acute-phase proteins, are elevated during this process, highlighting the complex association between inflammation and HF. Therefore, these inflammatory markers can be used in predicting prognosis of the syndrome. Various immune cells impact on myocardial remodeling and recovery. They lead to stimulation, release of alarmins and risk-related molecule patterns. Targeting key inflammatory mechanisms seems a quite promising therapy strategy in HF. Cytokine modulation is only one of several possible targets in the fight against inflammation, as the potential molecular targets for therapy in HF include immune activation, inflammation, oxidative stress, alterations in mitochondrial bioenergetics, and autophagy.

Reduction of Adverse Events With Phosphodiesterase 5 Inhibitors Post LVAD Implantation: Is It Time for a Randomized Trial?

The improved survival of patients with advanced heart failure after left ventricular assist device (LVAD) implantation together with the scarcity of donor hearts has significantly increased the population of LVAD-supported patients. However, despite the improvement in LVAD technology and the advent of third-generation continuous flow LVADs, complications such as those related to hemocompatibility and stroke rates remain ongoing clinical challenges. Thus, improvement in LVAD technology should be coupled with innovative medical management to further reduce adverse events. We have previously shown a strong association between post LVAD implant phosphodiesterase-5 inhibitors (PDE-5i) use and fewer thrombotic events, as well as improved survival in 2 observational studies. We caution, nevertheless, the use of PDE-5i based on these observations and encourage clinicians to support enrollment in a randomized control trial. A randomized control trial will determine the efficacy and safety of PDE-5i use after implantation in patients with a centrifugal flow LVAD.

Therapeutic augmentation of NO-sGC-cGMP signalling: lessons learned from pulmonary arterial hypertension and heart failure.

The nitric oxide (NO)-guanylate cyclase (GC)-cyclic guanosine monophosphate (cGMP) pathway plays an important role in cardiovascular, pulmonary and renal function. Phosphodiesterase-5 inhibitors (PDE-5i) inhibit cGMP degradation, whereas both soluble guanylate cyclase (sGC) stimulators and sGC activators directly increase sGC. PDE-5i (e.g. sildenafil, tadalafil) and sGC stimulators (e.g. riociguat, vericiguat) have been extensively used in pulmonary artery hypertension (PAH) and heart failure (HF). PDE-5i have also been used in end-stage HF before and after left ventricular (LV) assist device (LVAD) implantation. Augmentation of NO-GC-cGMP signalling with PDE-5i causes selective pulmonary vasodilation, which is highly effective in PAH but may have controversial, potentially adverse effects in HF, including pre-LVAD implant due to device unmasking of PDE-5i-induced RV dysfunction. In contrast, retrospective analyses have demonstrated that PDE-5i have beneficial effects when initiated post LVAD implant due to the improved haemodynamics of the supported LV and the pleiotropic actions of these compounds. sGC stimulators, in turn, are effective both in PAH and in HF due to their balanced pulmonary and systemic vasodilation, and as such they are preferable to PDE-5i if the use of a pulmonary vasodilator is needed in HF patients, including those listed for LVAD implantation. Regarding the effectiveness of PDE-5i and sGC stimulators when initiated post LVAD implant, these two groups of compounds should be tested in a randomized control trial.

Pathogenesis of chronic heart failure: cardiovascular aging, risk factors, comorbidities, and disease modifiers.

Chronic heart failure (HF) is rare in the young and common in the elderly in the Western world. HF in the young is usually due to specific causes, predominantly or exclusively affecting the heart (adult congenital heart disease, different types of cardiomyopathies, myocarditis, or cardiotoxicity). In contrast, the mechanisms underlying HF development in the elderly have not been completely delineated. We propose that in most elderly patients, HF, regardless of the left ventricular ejection fraction (LVEF), is the consequence of the acceleration of cardiovascular aging by specific risk factors (usually hypertension, obesity, type 2 diabetes mellitus [T2DM], coronary artery disease [CAD], and valvular heart disease [VHD]), most affecting both the heart and the vasculature. These risk factors act individually or more commonly in groups, directly or indirectly (hypertension, obesity, and T2DM may lead to HF through an intervening myocardial infarction). The eventual HF phenotype and outcomes in the elderly are additionally dependent on the presence and/or development of comorbidities (atrial fibrillation, anemia, depression, kidney disease, pulmonary disease, sleep disordered breathing, other) and disease modifiers (race, sex, genes, other). The clinical implications of this paradigm are that aggressive treatment of hypertension, obesity, T2DM (preferably with metformin and sodium-glucose cotransporter-2 inhibitors), CAD, and VHD on top of measures that retard cardiovascular aging are the steadfast underpinning for HF prevention in the elderly, which represent the vast majority of HF patients.

Obesity, inflammation, and heart failure: links and misconceptions.

Obesity has been linked with heart failure (HF) with preserved left ventricular (LV) ejection fraction (HFpEF). This link has been attributed to obesity-induced metabolic and inflammatory disturbances leading to HFpEF. However, HF is a syndrome in which disease evolvement is associated with a dynamic unraveling of functional and structural changes leading to unique disease trajectories, creating a spectrum of phenotypes with overlapping distinct characteristics extending beyond the LV ejection fraction (LVEF). In this regard, despite quantitative differences between the two extremes (HFpEF and HF with reduced LVEF, HFrEF), there is important overlap between the phenotypes along the entire spectrum. In this paper, we describe the systemic pro-inflammatory state that is present throughout the HF spectrum and emphasize that obesity intertwines with HF beyond the LVEF construct.

Left ventricular hypertrophy and sudden cardiac death.

Sudden cardiac death (SCD) is among the leading causes of death worldwide, and it remains a public health problem, as it involves young subjects. Current guideline-directed risk stratification for primary prevention is largely based on left ventricular (LV) ejection fraction (LVEF), and preventive strategies such as implantation of a cardiac defibrillator (ICD) are justified only for documented low LVEF (i.e., ≤ 35%). Unfortunately, only a small percentage of primary prevention ICDs, implanted on the basis of a low LVEF, will deliver life-saving therapies on an annual basis. On the other hand, the vast majority of patients that experience SCD have LVEF > 35%, which is clamoring for better understanding of the underlying mechanisms. It is mandatory that additional variables be considered, both independently and in combination with the EF, to improve SCD risk prediction. LV hypertrophy (LVH) is a strong independent risk factor for SCD regardless of the etiology and the severity of symptoms. Concentric and eccentric LV hypertrophy, and even earlier concentric remodeling without hypertrophy, are all associated with increased risk of SCD. In this paper, we summarize the physiology and physiopathology of LVH, review the epidemiological evidence supporting the association between LVH and SCD, briefly discuss the mechanisms linking LVH with SCD, and emphasize the need to evaluate LV geometry as a potential risk stratification tool regardless of the LVEF.

Renin-angiotensin-system inhibition in the context of corona virus disease-19: experimental evidence, observational studies, and clinical implications.

Coronavirus disease 2019 (COVID-19) is due to severe acute respiratory syndrome coronavirus (SARS-CoV)-2 which binds and enters the host cells through the angiotensin-converting enzyme (ACE)2. While the potential for benefit with the use of renin-angiotensin-aldosterone system inhibitors (RAASi) and the risks from stopping them is more evident, potential harm by RAΑSi may also be caused by the increase in the activity of the ACE2 receptor, the inefficient counter regulatory axis in the lungs in which the proinflammatory prolyloligopeptidase (POP) is the main enzyme responsible for the conversion of deleterious angiotensin (ANG) II to protective ANG [1-7] and the proinflammatory properties of ACE2(+) cells infected with SARS-CoV-2. Acknowledging the proven RAΑSi benefit in patients with several diseases such as hypertension, heart failure, coronary disease, and diabetic kidney disease in the non-COVID-19 era, it is a reasonable strategy in this period of uncertainty to use these agents judiciously with careful consideration and to avoid the use of RAASi in select patients whenever possible, until definitive evidence becomes available.

The Counter Regulatory Axis of the Lung Renin-Angiotensin System in Severe COVID-19: Pathophysiology and Clinical Implications.

The severe acute respiratory syndrome coronavirus (SARS-CoV)-2, which is responsible for coronavirus disease 2019 (COVID-19), uses angiotensin (ANG)-converting enzyme 2 (ACE2) as the entrance receptor. Although most COVID-19 cases are mild, some are severe or critical, predominantly due to acute lung injury. It has been widely accepted that a counter regulatory renin-angiotensin system (RAS) axis including the ACE2/ANG [1-7]/Mas protects the lungs from acute lung injury. However, recent evidence suggests that the generation of protective ANG [1-7] in the lungs is predominantly mediated by proinflammatory prolyl oligopeptidase (POP), which has been repeatedly demonstrated to be involved in lung pathology. This review contends that acute lung injury in severe COVID-19 is characterised by a) ACE2 downregulation and malfunction (inflammatory signalling) due to viral occupation, and b) dysregulation of the protective RAS axis, predominantly due to increased activity of proinflammatory POP. It follows that a reasonable treatment strategy in COVID-19-related acute lung injury would be delivering functional recombinant (r) ACE2 forms to trap the virus. Additionally, or alternatively to rACE2 delivery, the potential benefits resulting from lowering POP activity should also be explored. These treatment strategies deserve further investigation.

Adult congenital heart disease with pulmonary arterial hypertension: mechanisms and management.

Adult congenital heart disease (ACHD) encompasses a range of structural cardiac abnormalities present before birth attributable to abnormal foetal cardiac development. The pulmonary circulation of patients with ACHD and intracardiac or extracardiac defects is often exposed to increased blood flow and occasionally to systemic pressures. Depending on the location and magnitude of the defect as well as the time of surgical correction, the patient with ACHD is at risk of developing pulmonary arterial hypertension (PAH), which dramatically increases morbidity and mortality. It is encouraging that therapies applied in idiopathic PAH and significantly improve outcome are also effective in ACHD-related PAH (ACHD-PAH). This review summarizes the challenges encountered in the diagnosis and management of ACHD-PAH.

Acutely decompensated versus acute heart failure: two different entities.

Heart failure (HF) has been classified in chronic HF (CHF) and acute HF (AHF). The latter has been subdivided in acutely decompensated chronic HF (ADCHF) defined as the deterioration of preexisting CHF and de novo AHF defined as the rapid development of new symptoms and signs of HF that requires urgent medical attention. However, ADCHF and de novo AHF have fundamental pathophysiological differences. Most importantly, the typical illness trajectory of HF, which is similar to that of other chronic organ diseases including lung, renal, and liver failure, features a gradual decline, with acute episodes usually related to disease evolution followed by partial recovery. Thus, ADCHF should be considered part of the natural history of CHF and renamed CHF exacerbation (CHFE) in accordance with the appropriate terminology used in chronic obstructive pulmonary disease. AHF, in turn, should include only acute de novo HF. The clinical implications of this paradigm shift will be in CHFE the change in focus from in-hospital to optimal ambulatory CHF management aiming at primary and secondary CHFE prevention, while in AHF, the institution of measures for in-hospital limitation of cardiac injury and prevention or retardation of symptomatic CHF development.

Heart failure and sepsis: practical recommendations for the optimal management.

Acute heart failure (AHF) is a common clinical challenge that a wide spectrum of physicians encounters in every practice. In many cases, AHF is due to decompensation of chronic heart failure. This decompensation may be triggered by various reasons, with sepsis being a notable one. Sepsis is defined as a life-threatening organ dysfunction caused by the dysregulated host response to infection and is associated with a very high mortality, which may reach 25%. Alarmingly, the increase in the mortality rate of patients with combined cardiac dysfunction and sepsis is extremely high (may reach 90%). Thus, these patients need urgent intervention. Management of patients with AHF and sepsis is challenging since cornerstone interventions for AHF may be contraindicated in sepsis and vice versa (e.g., diuretic treatment). Unfortunately, no relevant guidelines are yet available, and treatment remains empirical. This review attempts to shed light on the intricacies of the available interventions and suggests routes of action based on the existing bibliography.

Coexisting Morbidities in Heart Failure: No Robust Interaction with the Left Ventricular Ejection Fraction.

PURPOSE OF REVIEW: Heart failure (HF) patients often present with multiple coexisting morbidities. In this review, we contend that coexisting morbidities are highly prevalent and clinically important regardless of the left ventricular ejection fraction (LVEF). RECENT FINDINGS: Multimorbidity is prevalent in the ambulatory subjects of the community and increases with age. Differences in the prevalence of coexisting morbidities between HF with preserved LVEF (> 50%), mid-range LVEF (40-50%), and reduced LVEF (< 40%) are either not demonstrable or whenever present are small and unrelated to morbidity and mortality. The constellation of coexisting morbidities together with the disease modifiers (age, sex, genes, other) defines the HF phenotype and outcome. There is no robust evidence supporting an interaction in HF patients between the prevalence and clinical significance of coexisting morbidities and the LVEF.

Contemporary Management of Acute Decompensated Heart Failure and Cardiogenic Shock.

Cardiogenic shock (CS) is a life-threatening condition characterized by end-organ hypoperfusion and hypoxia primarily due to cardiac dysfunction and low cardiac output. Unfortunately, the mortality and morbidity associated with CS have remained high despite notable advances in heart failure management. Treatment should be carefully guided by hemodynamics assessment. Although inotropes, vasopressors, mechanical circulatory support, and catheter intervention for critical valve lesion are not always recommended, they are helpful in selected patients. Early diagnosis, accurate hemodynamic assessment, and prompt therapeutic intervention are crucial in the management of acute decompensated heart failure with CS.

DPP-4 inhibitors and heart failure: a potential role for pharmacogenomics.

There remains an ongoing controversy regarding the safety of dipeptidyl peptidase-4 (DPP-4) inhibitors and the risk of developing heart failure (HF). In addition, none of the animal studies suggested a mechanism for the DPP-4 inhibitors and HF risk. To date, advances in pharmacogenomics have enabled the identification of genetic variants in DPP-4 gene. Studies have shown that genetic polymorphisms in the gene encoding DPP-4 may be associated with potential pathways involved in HF risk. This review discusses the contradictory findings of DPP-4 inhibitors and HF and a potential role for pharmacogenomics. Pharmacogenomics of DPP-4 inhibitors is promising, and genetic information from randomized control trials is urgently needed to gain a full understanding of the safety of DPP-4 inhibitors and the risk of HF.