Protective Effects of Meldonium in Experimental Models of Cardiovascular Complications with a Potential Application in COVID-19.

Right ventricular (RV) and left ventricular (LV) dysfunction is common in a significant number of hospitalized coronavirus disease 2019 (COVID-19) patients. This study was conducted to assess whether the improved mitochondrial bioenergetics by cardiometabolic drug meldonium can attenuate the development of ventricular dysfunction in experimental RV and LV dysfunction models, which resemble ventricular dysfunction in COVID-19 patients. Effects of meldonium were assessed in rats with pulmonary hypertension-induced RV failure and in mice with inflammation-induced LV dysfunction. Rats with RV failure showed decreased RV fractional area change (RVFAC) and hypertrophy. Treatment with meldonium attenuated the development of RV hypertrophy and increased RVFAC by 50%. Mice with inflammation-induced LV dysfunction had decreased LV ejection fraction (LVEF) by 30%. Treatment with meldonium prevented the decrease in LVEF. A decrease in the mitochondrial fatty acid oxidation with a concomitant increase in pyruvate metabolism was noted in the cardiac fibers of the rats and mice with RV and LV failure, respectively. Meldonium treatment in both models restored mitochondrial bioenergetics. The results show that meldonium treatment prevents the development of RV and LV systolic dysfunction by enhancing mitochondrial function in experimental models of ventricular dysfunction that resembles cardiovascular complications in COVID-19 patients.

Beneficial Properties of Bromelain.

Bromelain is a major sulfhydryl proteolytic enzyme found in pineapple plants, having multiple activities in many areas of medicine. Due to its low toxicity, high efficiency, high availability, and relative simplicity of acquisition, it is the object of inexhaustible interest of scientists. This review summarizes scientific reports concerning the possible application of bromelain in treating cardiovascular diseases, blood coagulation and fibrinolysis disorders, infectious diseases, inflammation-associated diseases, and many types of cancer. However, for the proper application of such multi-action activities of bromelain, further exploration of the mechanism of its action is needed. It is supposed that the anti-viral, anti-inflammatory, cardioprotective and anti-coagulatory activity of bromelain may become a complementary therapy for COVID-19 and post-COVID-19 patients. During the irrepressible spread of novel variants of the SARS-CoV-2 virus, such beneficial properties of this biomolecule might help prevent escalation and the progression of the COVID-19 disease.

Endothelial Dysfunction as a Component of Severe Acute Respiratory Syndrome Coronavirus 2-Related Multisystem Inflammatory Syndrome in Children With Shock.

TRIAL REGISTRATION: NCT04420468. OBJECTIVES: Severe acute respiratory syndrome coronavirus 2-related multisystem inflammatory syndrome in children is frequently associated with shock; endothelial involvement may be one of the underlying mechanisms. We sought to describe endothelial dysfunction during multisystem inflammatory syndrome in children with shock and then assess the relationship between the degree of endothelial involvement and the severity of shock. DESIGN: Observational study. SETTING: A PICU in a tertiary hospital. PATIENTS: Patients aged under 18 (n = 28) with severe acute respiratory syndrome coronavirus 2-related multisystem inflammatory syndrome in children and shock, according to the Centers for Disease Control and Prevention criteria. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Correlations between endothelial marker levels and shock severity were assessed using Spearman coefficient. The median (interquartile range) age was 9 years (7.5-11.2 yr). Sixteen children presented with cardiogenic and distributive shock, 10 presented with cardiogenic shock only, and two presented with distributive shock only. The median left ventricular ejection fraction, troponin level, and lactate level were, respectively, 40% (35-45%), 261 ng/mL (131-390 ng/mL), and 3.2 mmol/L (2-4.2 mmol/L). Twenty-five children received inotropes and/or vasopressors; the median Vasoactive and Inotropic Score was 8 (5-28). Plasma levels of angiopoietin-2 (6,426 pg/mL [2,814-11,836 pg/mL]), sE-selectin (130,405 pg/mL [92,987-192,499 pg/mL]), von Willebrand factor antigen (344% [288-378%]), and the angiopoietin-2/angiopoietin-1 ratio (1.111 [0.472-1.524]) were elevated and significantly correlated with the Vasoactive and Inotropic Score (r = 0.45, p = 0.016; r = 0.53, p = 0.04; r = 0.46, p = 0.013; and r = 0.46, p = 0.012, respectively). CONCLUSIONS: Endothelial dysfunction is associated with severe acute respiratory syndrome coronavirus 2-related multisystem inflammatory syndrome in children with shock and may constitute one of the underlying mechanisms.

Covid-19 and development of heart failure: mystery and truth.

Coronavirus disease 2019 (Covid-19) is a novel worldwide pandemic caused by a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). During Covid-19 pandemic, socioeconomic deprivation, social isolation, and reduced physical activities may induce heart failure (HF), destabilization, and cause more complications. HF appears as a potential hazard due to SARS-CoV-2 infection, chiefly in elderly patients with underlying comorbidities. In reality, the expression of cardiac ACE2 is implicated as a target point for SARS-CoV-2-induced acute cardiac injury. In SARS-CoV-2 infection, like other febrile illnesses, high blood viscosity, exaggerated pro-inflammatory response, multisystem inflammatory syndrome, and endothelial dysfunction-induced coagulation disorders may increase risk of HF development. Hypoxic respiratory failure, as in pulmonary edema, severe acute lung injury (ALI), and acute respiratory distress syndrome (ARDS) may affect heart hemodynamic stability due to the development of pulmonary hypertension. Indeed, Covid-19-induced HF could be through the development of cytokine storm, characterized by high proliferation pro-inflammatory cytokines. In cytokine storm-mediated cardiac dysfunction, there is a positive correlation between levels of pro-inflammatory cytokine and myocarditis-induced acute cardiac injury biomarkers. Therefore, Covid-19-induced HF is more complex and related from a molecular background in releasing pro-inflammatory cytokines to the neuro-metabolic derangements that together affect cardiomyocyte functions and development of HF. Anti-heart failure medications, mainly digoxin and carvedilol, have potent anti-SARS-CoV-2 and anti-inflammatory properties that may mitigate Covid-19 severity and development of HF. In conclusion, SARS-CoV-2 infection may lead to the development of HF due to direct acute cardiac injury or through the development of cytokine storms, which depress cardiomyocyte function and cardiac contractility. Anti-heart failure drugs, mainly digoxin and carvedilol, may attenuate severity of HF by reducing the infectivity of SARS-CoV-2 and prevent the development of cytokine storms in severely affected Covid-19 patients.

BET inhibition blocks inflammation-induced cardiac dysfunction and SARS-CoV-2 infection.

Cardiac injury and dysfunction occur in COVID-19 patients and increase the risk of mortality. Causes are ill defined but could be through direct cardiac infection and/or inflammation-induced dysfunction. To identify mechanisms and cardio-protective drugs, we use a state-of-the-art pipeline combining human cardiac organoids with phosphoproteomics and single nuclei RNA sequencing. We identify an inflammatory "cytokine-storm", a cocktail of interferon gamma, interleukin 1ß, and poly(I:C), induced diastolic dysfunction. Bromodomain-containing protein 4 is activated along with a viral response that is consistent in both human cardiac organoids (hCOs) and hearts of SARS-CoV-2-infected K18-hACE2 mice. Bromodomain and extraterminal family inhibitors (BETi) recover dysfunction in hCOs and completely prevent cardiac dysfunction and death in a mouse cytokine-storm model. Additionally, BETi decreases transcription of genes in the viral response, decreases ACE2 expression, and reduces SARS-CoV-2 infection of cardiomyocytes. Together, BETi, including the Food and Drug Administration (FDA) breakthrough designated drug, apabetalone, are promising candidates to prevent COVID-19 mediated cardiac damage.

SARS-CoV-2 infection in an infant with severe dilated cardiomyopathy.

A four- and a half-month-old girl with severe dilated cardiomyopathy due to neonatal enterovirus myocarditis, treated with diuretics and milrinone for the past 4 months, was infected with SARS-CoV-2. The disease course was characterised by high fever and gastrointestinal symptoms. Cardiac function, as measured by echocardiography, remained stable. The treatment focused on maintaining a normal heart rate and a stable fluid balance. In children with severe underlying cardiac disease, even a mild SARS-CoV-2 infection can require close monitoring and compound treatment.

Cardiometabolic vigilance in COVID-19 and resource husbandry in resource-challenged times: Clinical practice- based expert opinion.

BACKGROUND AND AIMS: The ongoing pandemic of coronavirus disease 2019 (COVID-19) is rapidly evolving, thereby posing a profound challenge to the global healthcare system. Cardiometabolic disorders are associated with poor clinical outcomes in persons with COVID-19. Healthcare challenges during the COVID-19 pandemic are linked to resource constraints including shortage of Personal Protective Equipment's (PPE), laboratory tests and medication. In this context, a group of clinical experts discussed the endocrine and cardiology vigilance required in times of COVID-19. Further, the group proposed certain resource husbandry recommendations to be followed during the pandemic to overcome the constraints. METHOD: The clinical experts discussed and provided their inputs virtually. The expert panel included clinical experts comprising endocrinologists, Consultant Physicians and cardiologists from India. The panel thoroughly reviewed existing literature on the subject and proposed expert opinion. RESULTS: The expert panel put forward clinical practice-based opinion for the management of cardiometabolic conditions including diabetes mellitus and hypertension. As these conditions are associated with poor clinical outcomes, the expert panel recommends that these persons be extra-cautious and take necessary precautions during the ongoing pandemic. Further, experts also provided appropriate, affordable, available and accessible solution to the resource constraint situations in times of COVID-19 pandemic. CONCLUSION: The clinical expert opinion put forward in this article will serve as a reference for clinicians treating diabetes and cardiovascular disease during the COVID-19 pandemic.

Is there an association between metformin use and clinical outcomes in diabetes patients with COVID-19?

AIM: Previous studies have reported inconsistent results regarding the association between metformin use and clinical outcomes in diabetes mellitus (DM) patients with coronavirus disease 2019 (COVID-19). This study aimed to evaluate the association between metformin use and clinical outcomes in DM patients with COVID-19. METHODS: This retrospective study was based on claims data. All diseases, including COVID-19, were defined using International Classification of Diseases 10th Revision (ICD-10) codes. Patients were divided into three groups depending on metformin use: CON (those not taking DM medication); N-MFOM (those taking DM medications other than metformin); and MFOM (those taking metformin for DM). Ultimately, 1865 patients were included; CON, N-MFOM and MFOM groups comprised 1301, 95 and 469 patients, respectively. RESULTS: Kaplan-Meier analyses showed that MFOM patients had poorer survival rates than those in the CON group, but there were no significant differences in survival rates between MFOM and N-MFOM groups. Multivariate Cox regression analyses revealed more favourable survival in CON than in N-MFOM patients, but there was no statistically significant difference in MFOM vs the other groups. Also, there were no significant differences in rates of use of inotropes, extracorporeal membrane oxygenation, conventional oxygen therapy, high-flow nasal cannulas or mechanical ventilators, nor in the rates of acute kidney injury or cardiac events across all study groups. CONCLUSION: No definite association could be found between metformin use and clinical outcomes, including survival. However, given the disproportionate participant numbers in our groups and small number of events, further studies are needed to determine whether the use of metformin has favourable or unfavourable effects in DM patients with COVID-19.

Sacubitril/Valsartan in Advanced Heart Failure With Reduced Ejection Fraction: Rationale and Design of the LIFE Trial.

The PARADIGM-HF (Prospective Comparison of Angiotensin II Receptor Blocker Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial reported that sacubitril/valsartan (S/V), an angiotensin receptor-neprilysin inhibitor, significantly reduced mortality and heart failure (HF) hospitalization in HF patients with a reduced ejection fraction (HFrEF). However, fewer than 1% of patients in the PARADIGM-HF study had New York Heart Association (NYHA) functional class IV symptoms. Accordingly, data that informed the use of S/V among patients with advanced HF were limited. The LIFE (LCZ696 in Hospitalized Advanced Heart Failure) study was a 24-week prospective, multicenter, double-blinded, double-dummy, active comparator trial that compared the safety, efficacy, and tolerability of S/V with those of valsartan in patients with advanced HFrEF. The trial planned to randomize 400 patients ≥18 years of age with advanced HF, defined as an EF ≤35%, New York Heart Association functional class IV symptoms, elevated natriuretic peptide concentration (B-type natriuretic peptide [BNP] ≥250 pg/ml or N-terminal pro-B-type natriuretic peptide [NT-proBNP] ≥800 pg/ml), and ≥1 objective finding of advanced HF. Following a 3- to 7-day open label run-in period with S/V (24 mg/26 mg twice daily), patients were randomized 1:1 to S/V titrated to 97 mg/103 mg twice daily versus 160 mg of V twice daily. The primary endpoint was the proportional change from baseline in the area under the curve for NT-proBNP levels measured through week 24. Secondary and tertiary endpoints included clinical outcomes and safety and tolerability. Because of the COVID-19 pandemic, enrollment in the LIFE trial was stopped prematurely to ensure patient safety and data integrity. The primary analysis consists of the first 335 randomized patients whose clinical follow-up examination results were not severely impacted by COVID-19. (Entresto [LCZ696] in Advanced Heart Failure [LIFE STUDY] [HFN-LIFE]; NCT02816736).

Cardiovascular Damage in COVID-19: Therapeutic Approaches Targeting the Renin-Angiotensin-Aldosterone System.

Coronavirus disease 2019 (COVID-19) is usually more severe and associated with worst outcomes in individuals with pre-existing cardiovascular pathologies, including hypertension or atherothrombosis. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) can differentially infect multiple tissues (i.e., lung, vessel, heart, liver) in different stages of disease, and in an age- and sex-dependent manner. In particular, cardiovascular (CV) cells (e.g., endothelial cells, cardiomyocytes) could be directly infected and indirectly disturbed by systemic alterations, leading to hyperinflammatory, apoptotic, thrombotic, and vasoconstrictive responses. Until now, hundreds of clinical trials are testing antivirals and immunomodulators to decrease SARS-CoV-2 infection or related systemic anomalies. However, new therapies targeting the CV system might reduce the severity and lethality of disease. In this line, activation of the non-canonical pathway of the renin-angiotensin-aldosterone system (RAAS) could improve CV homeostasis under COVID-19. In particular, treatments with angiotensin-converting enzyme inhibitors (ACEi) and angiotensin-receptor blockers (ARB) may help to reduce hyperinflammation and viral propagation, while infusion of soluble ACE2 may trap plasma viral particles and increase cardioprotective Ang-(1-9) and Ang-(1-7) peptides. The association of specific ACE2 polymorphisms with increased susceptibility of infection and related CV pathologies suggests potential genetic therapies. Moreover, specific agonists of Ang-(1-7) receptor could counter-regulate the hypertensive, hyperinflammatory, and hypercoagulable responses. Interestingly, sex hormones could also regulate all these RAAS components. Therefore, while waiting for an efficient vaccine, we suggest further investigations on the non-canonical RAAS pathway to reduce cardiovascular damage and mortality in COVID-19 patients.

Reverse takotsubo cardiomyopathy in fulminant COVID-19 associated with cytokine release syndrome and resolution following therapeutic plasma exchange: a case-report.

BACKGROUND: Fulminant (life-threatening) COVID-19 can be associated with acute respiratory failure (ARF), multi-system organ failure and cytokine release syndrome (CRS). We present a rare case of fulminant COVID-19 associated with reverse-takotsubo-cardiomyopathy (RTCC) that improved with therapeutic plasma exchange (TPE). CASE PRESENTATION: A 40 year old previous healthy male presented in the emergency room with 4 days of dry cough, chest pain, myalgias and fatigue. He progressed to ARF requiring high-flow-nasal-cannula (flow: 60 L/minute, fraction of inspired oxygen: 40%). Real-Time-Polymerase-Chain-Reaction (RT-PCR) assay confirmed COVID-19 and chest X-ray showed interstitial infiltrates. Biochemistry suggested CRS: increased C-reactive protein, lactate dehydrogenase, ferritin and interleukin-6. Renal function was normal but lactate levels were elevated. Electrocardiogram demonstrated non-specific changes and troponin-I levels were slightly elevated. Echocardiography revealed left ventricular (LV) basal and midventricular akinesia with apex sparing (LV ejection fraction: 30%) and depressed cardiac output (2.8 L/min) consistent with a rare variant of stress-related cardiomyopathy: RTCC. His ratio of partial arterial pressure of oxygen to fractional inspired concentration of oxygen was < 120. He was admitted to the intensive care unit (ICU) for mechanical ventilation and vasopressors, plus antivirals (lopinavir/ritonavir), and prophylactic anticoagulation. Infusion of milrinone failed to improve his cardiogenic shock (day-1). Thus, rescue TPE was performed using the Spectra Optia™ Apheresis System equipped with the Depuro D2000 Adsorption Cartridge (Terumo BCT Inc., USA) without protective antibodies. Over 5 days he received daily TPE (each lasting 4 hours). His lactate levels, oxygenation, and LV function normalized and he was weaned off vasopressors. His inflammation markers improved, and he was extubated on day-7. RT-PCR was negative on day-17. He was discharged to home isolation in good condition. CONCLUSION: Stress-cardiomyopathy may complicate the course of fulminant COVID-19 with associated CRS. If inotropic therapy fails, TPE without protective antibodies may help rescue the critically ill patient.

COVID-19 infection in left ventricular assist device patients.

We describe two cases of favorable and unexpected recovery in positive patients with coronavirus disease 2019, suffering from multiorgan comorbidity and already assisted with the left ventricular assist device. We have observed that, although in the presence of more comorbidities, when the maintenance of a valid support of the cardiovascular function is guaranteed, the possibility of successfully overcoming the severe acute respiratory syndrome coronavirus 2 infection is still alive.

Haemodynamic monitoring and management in COVID-19 intensive care patients: an International survey.

PURPOSE: To survey haemodynamic monitoring and management practices in intensive care patients with the coronavirus disease 2019 (COVID-19). METHODS: A questionnaire was shared on social networks or via email by the authors and by Anaesthesia and/or Critical Care societies from France, Switzerland, Belgium, Brazil, and Portugal. Intensivists and anaesthetists involved in COVID-19 ICU care were invited to answer 14 questions about haemodynamic monitoring and management. RESULTS: Globally, 1000 questionnaires were available for analysis. Responses came mainly from Europe (n = 460) and America (n = 434). According to a majority of respondents, COVID-19 ICU patients frequently or very frequently received continuous vasopressor support (56%) and had an echocardiography performed (54%). Echocardiography revealed a normal cardiac function, a hyperdynamic state (43%), hypovolaemia (22%), a left ventricular dysfunction (21%) and a right ventricular dilation (20%). Fluid responsiveness was frequently assessed (84%), mainly using echo (62%), and cardiac output was measured in 69%, mostly with echo as well (53%). Venous oxygen saturation was frequently measured (79%), mostly from a CVC blood sample (94%). Tissue perfusion was assessed biologically (93%) and clinically (63%). Pulmonary oedema was detected and quantified mainly using echo (67%) and chest X-ray (61%). CONCLUSION: Our survey confirms that vasopressor support is not uncommon in COVID-19 ICU patients and suggests that different haemodynamic phenotypes may be observed. Ultrasounds were used by many respondents, to assess cardiac function but also to predict fluid responsiveness and quantify pulmonary oedema. Although we observed regional differences, current international guidelines were followed by most respondents.

Spironolactone may provide protection from SARS-CoV-2: Targeting androgens, angiotensin converting enzyme 2 (ACE2), and renin-angiotensin-aldosterone system (RAAS).

In coronavirus disease-19 (COVID-19), four major factors have been correlated with worse prognosis: aging, hypertension, obesity, and exposure to androgen hormones. Angiotensin-converting enzyme-2 (ACE2) receptor, regulation of the renin-angiotensin-aldosterone system (RAAS), and transmembrane serine protease 2 (TMPRSS2) action are critical for the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) cell entry and infectivity. ACE2 expression and RAAS are abnormal in hypertension and obesity, while TMPRSS2 is overexpressed when exposed to androgens, which may justify why these factors are overrepresented in COVID-19. Among therapeutic targets for SARS-CoV-2, we hypothesized that spironolactone, a long used and safe mineralocorticoid and androgen receptors antagonist, with effective anti-hypertensive, cardioprotective, nephroprotective, and anti-androgenic properties may offer pleiotropic actions in different sites to protect from COVID-19. Current data shows that spironolactone may concurrently mitigate abnormal ACE2 expression, correct the balances membrane-attached and free circulating ACE2 and between angiotensin II and Angiotensin-(1-7) (Ang-(1-7)), suppress androgen-mediated TMPRSS2 activity, and inhibit obesity-related RAAS dysfunctions, with consequent decrease of viral priming. Hence, spironolactone may provide protection from SARS-CoV-2, and has sufficient plausibility to be clinically tested, particularly in the early stages of COVID-19.