Current Approaches to Worsening Heart Failure: Pathophysiological and Molecular Insights.

Worsening heart failure (WHF) is a severe and dynamic condition characterized by significant clinical and hemodynamic deterioration. It is characterized by worsening HF signs, symptoms and biomarkers, despite the achievement of an optimized medical therapy. It remains a significant challenge in cardiology, as it evolves into advanced and end-stage HF. The hyperactivation of the neurohormonal, adrenergic and renin-angiotensin-aldosterone system are well known pathophysiological pathways involved in HF. Several drugs have been developed to inhibit the latter, resulting in an improvement in life expectancy. Nevertheless, patients are exposed to a residual risk of adverse events, and the exploration of new molecular pathways and therapeutic targets is required. This review explores the current landscape of WHF, highlighting the complexities and factors contributing to this critical condition. Most recent medical advances have introduced cutting-edge pharmacological agents, such as guanylate cyclase stimulators and myosin activators. Regarding device-based therapies, invasive pulmonary pressure measurement and cardiac contractility modulation have emerged as promising tools to increase the quality of life and reduce hospitalizations due to HF exacerbations. Recent innovations in terms of WHF management emphasize the need for a multifaceted and patient-centric approach to address the complex HF syndrome.

Sizing SGLT2 Inhibitors Up: From a Molecular to a Morpho-Functional Point of View.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i), or gliflozins, have recently been shown to reduce cardiovascular death and hospitalization in patients with heart failure, representing a revolutionary therapeutic tool. The purpose of this review is to explore their multifaceted mechanisms of actions, beyond their known glucose reduction power. The cardioprotective effects of gliflozins seem to be linked to the maintenance of cellular homeostasis and to an action on the main metabolic pathways. They improve the oxygen supply for cardiomyocytes with a considerable impact on both functional and morphological myocardial aspects. Moreover, multiple molecular actions of SGLT2i are being discovered, such as the reduction of both inflammation, oxidative stress and cellular apoptosis, all responsible for myocardial damage. Various studies showed controversial results concerning the role of SGLT2i in reverse cardiac remodeling and the lowering of natriuretic peptides, suggesting that their overall effect has yet to be fully understood. In addition to this, advanced imaging studies evaluating the effect on all four cardiac chambers are lacking. Further studies will be needed to better understand the real impact of their administration, their use in daily practice and how they can contribute to benefits in terms of reverse cardiac remodeling.

Telemedicine: an Effective and Low-Cost Lesson From the COVID-19 Pandemic for the Management of Heart Failure Patients.

PURPOSE: The purpose of this review is to explore the benefits and controversies that telemedicine (TM), applied to patients with heart failure (HF), can provide in terms of diagnosis, therapeutic management, and prognosis improvement. During the coronavirus disease 19 (COVID-19) outbreak, TM emerged as the most effective and feasible method available to ensure continuous care for chronic diseases. Among these, HF, characterized by high mortality, morbidity, and the need for frequent visits, may benefit of the TM role. HF patients are affected by frequent exacerbations undergoing a progressive prognosis impoverishment, strongly depending on the disease's management. A precise clinical handling is always required, with a constant optimization of the therapy, a continuous control of risk factors, and a sensitive attention to any change in symptoms, clinical signs, and laboratory tests. In this context, TM has shown to improve therapy adherence and HF: patients' self-care, impacting the prognosis even if specific results are controversial. Major evidence shows that TM may allow an adequate primary prevention, reducing the impact of the main cardiovascular risk factors. TM can also be useful for the secondary prevention, early detecting a likely HF exacerbation before it becomes clinically manifest, thereby lowering the need for hospitalization. Moreover, an optimal up-titration of the therapy and an increase in treatment adherence are feasible by using TM. However, some studies did not show unambiguous results, and uncertainties still remain.

Myocardial Infarction with Non-Obstructive Coronary Arteries (MINOCA): Focus on Coronary Microvascular Dysfunction and Genetic Susceptibility.

Among the most common causes of death worldwide, ischemic heart disease (IHD) is recognized to rank first. Even if atherosclerotic disease of the epicardial arteries is known as the leading cause of IHD, the presence of myocardial infarction with non-obstructive coronary artery disease (MINOCA) is increasingly recognized. Notwithstanding the increasing interest, MINOCA remains a puzzling clinical entity that can be classified by distinguishing different underlying mechanisms, which can be divided into atherosclerotic and non-atherosclerotic. In particular, coronary microvascular dysfunction (CMD), classifiable in non-atherosclerotic mechanisms, is a leading factor for the pathophysiology and prognosis of patients with MINOCA. Genetic susceptibility may have a role in primum movens in CMD. However, few results have been obtained for understanding the genetic mechanisms underlying CMD. Future studies are essential in order to find a deeper understanding of the role of multiple genetic variants in the genesis of microcirculation dysfunction. Progress in research would allow early identification of high-risk patients and the development of pharmacological, patient-tailored strategies. The aim of this review is to revise the pathophysiology and underlying mechanisms of MINOCA, focusing on CMD and actual knowledge about genetic predisposition to it.

Protection against Ischemic Heart Disease: A Joint Role for eNOS and the KATP Channel.

Genetic susceptibility may influence ischemic heart disease (IHD) predisposition and affect coronary blood flow (CBF) regulation mechanisms. The aim of this study was to investigate the association among single nucleotide polymorphisms (SNPs) of genes encoding for proteins involved in CBF regulation and IHD. A total of 468 consecutive patients were enrolled and divided into three groups according to coronary angiography and intracoronary functional tests results: G1, patients with coronary artery disease (CAD); G2, patients with coronary microvascular dysfunction (CMD); and G3, patients with angiographic and functionally normal coronary arteries. A genetic analysis of the SNPs rs5215 of the potassium inwardly rectifying channel subfamily J member 11 (KCNJ11) gene and rs1799983 of the nitric oxide synthase 3 (NOS3) gene, respectively encoding for the Kir6.2 subunit of ATP sensitive potassium (KATP) channels and nitric oxide synthase (eNOS), was performed on peripheral whole blood samples. A significant association of rs5215_G/G of KCNJ11 and rs1799983_T/T of NOS3 genes was detected in healthy controls compared with CAD and CMD patients. Based on univariable and multivariable analyses, the co-presence of rs5215_G/G of KCNJ11 and rs1799983_T/T of NOS3 may represent an independent protective factor against IHD, regardless of cardiovascular risk factors. This study supports the hypothesis that SNP association may influence the crosstalk between eNOS and the KATP channel that provides a potential protective effect against IHD.

Heart Failure Pharmacological Management: Gaps and Current Perspectives.

Proper therapeutic management of patients with heart failure (HF) is a major challenge for cardiologists. Current guidelines indicate to start therapy with angiotensin converting enzyme inhibitors/angiotensin receptor neprilysin inhibitors (ACEi/ARNI), beta blockers (BB), mineralocorticoid receptor antagonists (MRAs) and sodium glucose cotransporter 2 inhibitors (SGLT2i) to reduce the risk of death and hospitalization due to HF. However, certain aspects still need to be defined. Current guidelines propose therapeutic algorithms based on left ventricular ejection fraction values and clinical presentations. However, these last do not always reflect the precise hemodynamic status of patients and pathophysiological mechanisms involved, particularly in the acute setting. Even in the field of chronic management there are still some critical points to discuss. The guidelines do not specify which of the four pillar drugs to start first, nor at what dosage. Some authors suggest starting with SGLT2i and BB, others with ACEi or ARNI, while one of the most recent approach proposes to start with all four drugs together at low doses. The aim of this review is to revise current gaps and perspectives regarding pharmacological therapy management in HF patients, in both the acute and chronic phase.

The Mutual Relationship among Cardiovascular Diseases and COVID-19: Focus on Micronutrients Imbalance.

Micronutrients are ions and vitamins humbly required by the human body. They play a main role in several physiological mechanisms and their imbalance is strongly associated with potentially-fatal complications. Micronutrient imbalance is associated with many cardiovascular diseases, such as arrythmias, heart failure, and ischemic heart disease. It has been also observed in coronavirus disease 2019 (COVID-19), particularly in most severe patients. The relationship between cardiovascular diseases and COVID-19 is mutual: the latter triggers cardiovascular disease onset and worsening while patients with previous cardiovascular disease may develop a more severe form of COVID-19. In addition to the well-known pathophysiological mechanisms binding COVID-19 and cardiovascular diseases together, increasing importance is being given to the impact of micronutrient alterations, often present during COVID-19 and able to affect the balance responsible for a good functioning of the cardiovascular system. In particular, hypokalemia, hypomagnesemia, hyponatremia, and hypocalcemia are strongly associated with worse outcome, while vitamin A and D deficiency are associated with thromboembolic events in COVID-19. Thus, considering how frequent the cardiovascular involvement is in patients with COVID-19, and how it majorly affects their prognosis, this manuscript provides a comprehensive review on the role of micronutrient imbalance in the interconnection between COVID-19 and cardiovascular diseases.