Coronavirus Disease 2019: Where are we and Where are we Going? Intersections Between Coronavirus Disease 2019 and the Heart

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), which has become a pandemic affecting every country in the world. In the province of Bergamo, Italy, more than 2,200 cases of COVID-19 have been reported, which include more than 300 deaths. Most hospitalisations have been at the Papa Giovanni XXIII Hospital. This has imposed a significant burden on our hospital in terms of healthcare personnel, dedicated spaces (including intensive care areas) and time spent by clinicians, who are committed to assisting COVID-19 patients. In this short expert opinion, the authors will focus on new insights related to COVID-19 and the cardiovascular system, and try to investigate the grey areas and uncertainties in this field

Sodium–Glucose Cotransporter 2 Inhibitors in Heart Failure with Preserved Ejection Fraction: Rationale for and Practical Use of a Successful Therapy

Heart failure (HF) with preserved left ventricular ejection fraction is a common disease with a poor prognosis and rising prevalence in the community. The current paradigm of treatment includes symptomatic therapy, such as diuretics, and risk factor control and treatment of comorbidities. According to European guidelines, there is no effective therapy for patients with HF with left ventricular ejection fraction (LVEF) ≥50%, while drugs normally used in HF with reduced LVEF might also be effective for patients with mildly reduced LVEF (40–50%), with a IIB class of recommendation. The recently published EMPEROR-Preserved trial has challenged current guidelines, demonstrating improved outcomes in patients with HF and LVEF >40% with the sodium–glucose cotransporter 2 inhibitor (SGLT2I) empagliflozin, compared with placebo. This result was consistent in patients with and without diabetes as well as in those with LVEF below and above 50%. The authors describe the rationale for this therapy, presenting the main results of the EMPEROR-Preserved trial, and provide some recommendations for the everyday clinical management of HF with preserved left ventricular ejection with an SGLT2I

Rationale for and Practical Use of Sacubitril/Valsartan in the Patient’s Journey with Heart Failure and Reduced Ejection Fraction

Sacubitril with valsartan (sacubitril/valsartan) is a relatively novel compound that has become a milestone in the treatment of patients with chronic heart failure (HF) with reduced ejection fraction (HFrEF) in the last decade. Contemporary data suggest that sacubitril/valsartan is associated with improved outcomes compared with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, and has a greater beneficial effect on myocardial reverse remodelling. Additionally, two recent trials have shown that sacubitril/valsartan is well-tolerated even in the acute HF setting, thus enabling a continuum of use in the patient’s journey with HFrEF. This article summarises available data on the effectiveness and tolerability of sacubitril/valsartan in patients with HFrEF, and provides the clinician with practical insights to facilitate the use of this drug in every setting, with an emphasis on acute HF, hypotension, electrolyte imbalance and renal insufficiency

Treating Patients Following Hospitalisation for Acute Decompensated Heart Failure: An Insight into Reducing Early Rehospitalisations

Heart failure (HF) is a pandemic syndrome characterised by raised morbidity and mortality. An acute HF event requiring hospitalisation is associated with a poor prognosis, in both the short and the long term. Moreover, early rehospitalisation after discharge negatively affects HF management and survival rates. Cardiovascular and non-cardiovascular conditions combine to increase rates of HF hospital readmission at 30 days. A tailored approach for HF pharmacotherapy while the patient is in hospital and immediately after discharge could be useful in reducing early adverse events that cause rehospitalisation and, consequently, prevent worsening HF and readmission during the vulnerable phase after discharge

Lipoprotein (a), Inflammation, and Atherosclerosis

Growing evidence has shown that high levels of lipoprotein (a) (Lp(a)) and chronic inflammation may be responsible for the residual risk of cardiovascular events in patients managed with an optimal evidence-based approach. Clinical studies have demonstrated a correlation between higher Lp(a) levels and several atherosclerotic diseases including ischemic heart disease, stroke, and degenerative calcific aortic stenosis. The threshold value of Lp(a) serum concentrations associated with a significantly increased cardiovascular risk is >125 nmol/L (50 mg/dL). Current available lipid-lowering drugs have modest-to-no impact on Lp(a) levels. Chronic inflammation is a further condition potentially implicated in residual cardiovascular risk. Consistent evidence has shown an increased risk of cardiovascular events in patients with high sensitivity C reactive protein (>2 mg/dL), an inflammation biomarker. A number of anti-inflammatory drugs have been investigated in patients with or at risk of cardiovascular disease. Of these, canakinumab and colchicine have been found to be associated with cardiovascular risk reduction. Ongoing research aimed at improving risk stratification on the basis of Lp(a) and vessel inflammation assessment may help refine patient management. Furthermore, the identification of these conditions as cardiovascular risk factors has led to increased investigation into diagnostic and therapeutic strategies targeting them in order to reduce atherosclerotic cardiovascular disease burden

NGF AND HEART: IS THERE A ROLE IN HEART DISEASE?

The review emphasizes the role of NGF, the most representative member of the neurotrophins family, in cardiac physiopathology with a particular focus on healing and sprouting processes occurring after tissue damage. Cardiac and circulating NGF levels dramatically increase following myocardial injury (MI). A very early rise of this neurotrophin is indeed observed soon after MI (hours). Such a rise may lead to sympathetic nerve sprouting which may underlie the later genesis of arrhythmias but may also favor the healing process. At later times (months after), when heart failure develops, the opposite is detected and NGF tissue levels are below the normal range, an event that may in turn participate to defective innervation and cardiac failure. Through a careful analysis of preclinical and clinical studies, this review proposes that time is the key variable when studying these opposite changes in NGF expression observed following MI and attempting to interpret and correlate them with cardiac physiopathology. The examination of the results leads to the speculation that NGF modulation may be a pharmacological target for interventions in specific stages of heart dysfunction following MI

Prognostic Value of sST2 in Heart Failure

In recent years, there has been growing interest in the risk stratification for heart failure, and the use of multiple biomarkers to identify different pathophysiological processes associated with this condition. One such biomarker is soluble suppression of tumorigenicity-2 (sST2), which has shown some potential for integration into clinical practice. sST2 is produced by both cardiac fibroblasts and cardiomyocytes in response to myocardial stress. Other sources of sST2 are endothelial cells of the aorta and coronary arteries and immune cells such as T cells. Indeed, ST2 is also associated with inflammatory and immune processes. We aimed at reviewing the prognostic value of sST2 in both chronic and acute heart failure. In this setting, we also provide a flowchart about its potential use in clinical practice

Characterization of ANGPT2 mutations associated with primary lymphedema

Lymphedema can occur when tissue fluid cannot enter or leaks from the lymphatic system into surrounding tissues. Some genetic causes of primary lymphedema are known, but these currently explain a minority of cases. Previous studies have shown that dominant-negative mutations in angiopoietin 2 (ANGPT2), which is involved in lymphatic vessel formation and maturation, promote lymphangiogenesis in mice. Leppänen et al. now show that inactivating mutations in angiopoietin 2 associate with primary lymphedema in humans.Primary lymphedema is caused by developmental and functional defects of the lymphatic vascular system that result in accumulation of protein-rich fluid in tissues, resulting in edema. The 28 currently known genes causing primary lymphedema can explain <30% of cases. Angiopoietin 1 (ANGPT1) and ANGPT2 function via the TIE1-TIE2 (tyrosine kinase with immunoglobulin-like and epidermal growth factor–like domains 1 and 2) receptor complex and α5β1 integrin to form an endothelial cell signaling pathway that is critical for blood and lymphatic vessel formation and remodeling during embryonic development, as well as for homeostasis of the mature vasculature. By screening a cohort of 543 individuals affected by primary lymphedema, we identified one heterozygous de novo ANGPT2 whole-gene deletion and four heterozygous ANGPT2 missense mutations. Functional analyses revealed three missense mutations that resulted in decreased ANGPT2 secretion and inhibited the secretion of wild-type (WT)–ANGPT2, suggesting that they have a dominant-negative effect on ANGPT2 signaling. WT-ANGPT2 and soluble mutants T299M and N304K activated TIE1 and TIE2 in an autocrine assay in human lymphatic endothelial cells. Molecular modeling and biophysical studies showed that amino-terminally truncated ANGPT subunits formed asymmetrical homodimers that bound TIE2 in a 2:1 ratio. The T299M mutant, located in the dimerization interphase, showed reduced integrin α5 binding, and its expression in mouse skin promoted hyperplasia and dilation of cutaneous lymphatic vessels. These results demonstrate that primary lymphedema can be associated with ANGPT2 mutations and provide insights into TIE1 and TIE2 activation mechanisms.Peer reviewe