Both high and low plasma levels of 25-hydroxy vitamin D increase blood pressure in a normal rat model.

The lower threshold plasma 25-hydroxy vitamin D (25(OH)D) level for optimal cardiovascular health is unclear, whereas the toxicity threshold is less clear. The aim of this study was to examine the cardiovascular-vitamin D dose-response curve in a normal rat model. Doses of cholecalciferol ranged from deficiency to toxic levels (equivalent to human doses of 0, 0·015, 0·25 and 3·75mg/d) for 4 weeks, and then cardiovascular health was examined using blood pressure telemetry and high-resolution ultrasound in normal male rats (n 16/group, 64 rats total). After 1 month, only the 0·25mg/d group had plasma 25(OH)D that was within current recommended range (100-125 nmol/l), and all groups failed to change plasma Ca or phosphate. Systolic blood pressure increased significantly (10-15 mmHg) in the rat groups with plasma 25(OH)D levels at both 30 and 561 nmol/l (groups fed 0 and 3·75mg/d) compared with the group fed the equivalent to 0·015mg/d (43 nmol/l 25(OH)D). Although not significant, the group fed the equivalent to 0·25mg/d (108 nmol/l 25(OH)D) also showed a 10 mmHg increase in systolic blood pressure. Carotid artery diameter was significantly smaller and wall thickness was larger, leading to higher peak carotid systolic blood velocity in these two groups. Despite these vascular changes, cardiac function did not differ among treatment groups. The key finding in this study is that arterial stiffness and systolic blood pressure both showed a U-shaped dose-response for vitamin D, with lowest values (best cardiovascular health) observed when plasma 25(OH)D levels were 43 nmol/l in normal male rats.

Recurrent upper extremity arterial thrombosis preceding a diagnosis of COVID-19.

Arterial thrombosis occurs when there is endothelial damage in the setting of hypercoagulability and arterial blood stasis. COVID-19 has been theorized to cause both endothelial damage and promote hypercoagulability by causing an imbalance of clotting factors. In many studies, there have been a large proportion of COVID-19 patients that suffered a thromboembolic event, in both the venous and arterial systems. Our patient, who did not have a significant past medical history, presented with a recurrent brachial artery occlusion despite medical and surgical management, and subsequently tested positive for COVID-19 late in his admission. In conclusion, there is high suspicion that there is a relationship between COVID-19 infection and recurrent arterial thrombosis.

Neprilysin Inhibitors in Heart Failure: The Science, Mechanism of Action, Clinical Studies, and Unanswered Questions.

This article provides a contemporary review and a new perspective on the role of neprilysin inhibition in heart failure (HF) in the context of recent clinical trials and addresses potential mechanisms and unanswered questions in certain HF patient populations. Neprilysin is an endopeptidase that cleaves a variety of peptides such as natriuretic peptides, bradykinin, adrenomedullin, substance P, angiotensin I and II, and endothelin. It has a broad role in cardiovascular, renal, pulmonary, gastrointestinal, endocrine, and neurologic functions. The combined angiotensin receptor and neprilysin inhibitor (ARNi) has been developed with an intent to increase vasodilatory natriuretic peptides and prevent counterregulatory activation of the angiotensin system. ARNi therapy is very effective in reducing the risks of death and hospitalization for HF in patients with HF and New York Heart Association functional class II to III symptoms, but studies failed to show any benefits with ARNi when compared with angiotensin-converting enzyme inhibitors or angiotensin receptor blocker in patients with advanced HF with reduced ejection fraction or in patients following myocardial infarction with left ventricular dysfunction but without HF. These raise the questions about whether the enzymatic breakdown of natriuretic peptides may not be a very effective solution in advanced HF patients when there is downstream blunting of the response to natriuretic peptides or among post-myocardial infarction patients in the absence of HF when there may not be a need for increased natriuretic peptide availability. Furthermore, there is a need for additional studies to determine the long-term effects of ARNi on albuminuria, obesity, glycemic control and lipid profile, blood pressure, and cognitive function in patients with HF.

Sarcopenia in the Cirrhotic Patient: Current Knowledge and Future Directions.

Cirrhosis predisposes to abnormalities in energy, hormonal, and immunological homeostasis. Disturbances in these metabolic processes create susceptibility to sarcopenia or pathological muscle wasting. Sarcopenia is prevalent in cirrhosis and its presence portends significant adverse outcomes including the length of hospital stay, infectious complications, and mortality. This highlights the importance of identification of at-risk individuals with early nutritional, therapeutic and physical therapy intervention. This manuscript summarizes literature relevant to sarcopenia in cirrhosis, describes current knowledge, and elucidates possible future directions.

Stroke Features, Risk Factors, and Pathophysiology in SARS-CoV-2-Infected Patients.

OBJECTIVE: To provide a comprehensive description of stroke characteristics, risk factors, laboratory parameters, and treatment in a series of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients admitted to Mayo Clinic hospitals in Rochester, Minnesota; Jacksonville, Florida; and Phoenix, Arizona, as well as the Mayo Clinic Health System. PATIENTS AND METHODS: We retrospectively identified hospitalized patients in whom stroke and SARS-CoV-2 infection were diagnosed within the same 3-month interval between September 8, 2019, and December 31, 2020. and extracted data on all available variables of interest. We further incorporated our findings into the existing body of basic science research to present a schematic model illustrating the proposed pathogenesis of ischemic stroke in SARS-CoV-2-infected patients. RESULTS: We identified 30 cases during the study period, yielding a 0.5% stroke rate across 6381 SARS-CoV-2-infected hospitalized patients. Strokes were ischemic in 26 of 30 individuals and hemorrhagic in 4 of 30. Traditional risk factors were common including hypertension (24 of 30), hyperlipidemia (18 of 30), smoking history (13 of 30), diabetes (11 of 30), and atrial fibrillation (8 of 30). The most common ischemic stroke mechanisms were cardioembolism (9 of 26) and cryptogenic (9 of 26). Intravenous alteplase and mechanical thrombectomy were administered to 2 of 26 and 1 of 26, respectively. The median (interquartile range) serum C-reactive protein, interleukin-6, D-dimer, fibrinogen, and ferritin levels were 66 (21-210) mg/L, 116 (8-400) pg/mL, 1267 (556-4510) ng/mL, 711 (263-772) mg/dL, and 407 (170-757) mcg/L, respectively, which were elevated in individuals with available results. CONCLUSION: The high prevalence of vascular risk factors and concurrent elevation of proinflammatory and procoagulation biomarkers suggest that there is an interplay between both factors in the pathogenesis of stroke in SARS-CoV-2-infected patients.

SARS-CoV-2 Infections, Impaired Tissue, and Metabolic Health: Pathophysiology and Potential Therapeutics.

The SARS-CoV-2 enters the human airways and comes into contact with the mucous membranes lining the mouth, nose, and eyes. The virus enters the healthy cells and uses cell machinery to make several copies itself. Critically ill patients infected with SARS-CoV-2 may have damaged lungs, air sacs, lining, and walls. Since COVID-19 causes cytokine storm, it damages the alveolar cells of the lungs and fills them with fluid, making it harder to exchange oxygen and carbon dioxide. The SARS-CoV-2 infection causes a range of complications, including mild to critical breathing difficulties. It has been observed that older people suffering from health conditions like cardiomyopathies, nephropathies, metabolic syndrome, and diabetes instigate severe symptoms. Many people who died due to COVID-19 had impaired metabolic health [IMH], characterized by hypertension, dyslipidemia, and hyperglycemia, i.e., diabetes, cardiovascular system, and renal diseases, making their retrieval challenging. Jeopardy stresses for increased mortality from COVID-19 include older age, COPD, ischemic heart disease, diabetes mellitus, and immunosuppression. However, no targeted therapies are available as of now. Almost two-thirds of diagnosed coronavirus patients had cardiovascular diseases and diabetes, out of which 37% were under 60. The NHS audit revealed that with a higher expression of ACE-2 receptors, viral particles could easily bind their protein spikes and get inside the cells, finally causing COVID-19 infection. Hence, people with IMH are more prone to COVID-19 and, ultimately, comorbidities. This review provides enormous information about tissue [lungs, heart, and kidneys] damage, pathophysiological changes, and impaired metabolic health of SARS-CoV-2 infected patients. Moreover, it also designates the possible therapeutic targets of COVID-19 and drugs which can be used against these targets.

Rapeseed (canola) oil aggravates metabolic syndrome-like conditions in male but not in female stroke-prone spontaneously hypertensive rats (SHRSP).

This study was conducted to investigate whether or not there are sex differences in canola oil (CAN)-induced adverse events in the rat and to understand the involvement and the role of testosterone in those events, including life-shortening. Stroke-prone spontaneously hypertensive rats (SHRSP) of both sexes were fed a diet containing 10 wt/wt% soybean oil (SOY, control) or CAN as the sole dietary fat. The survival of the males fed the CAN diet was significantly shorter than that of those fed the SOY diet. In contrast, the survival of the females was not affected by CAN. The males fed the CAN diet showed elevated blood pressure, thrombopenia and insulin-tolerance, which are major symptoms of metabolic syndrome, whereas such changes by the CAN diet were not found in the females. Plasma testosterone was significantly lower in animals of both sexes fed the CAN diet than in those fed the SOY diet, but interestingly, the lowered testosterone was accompanied by a marked increase in plasma aldosterone only in the males. These results demonstrate significant sex differences in CAN-toxicity and suggest that those sex differences may be attributable to the increased aldosterone level, which triggers aggravation of the genetic diseases specific to SHRSP, that is, metabolic syndrome-like conditions, but only in the males. The present results also suggest that testosterone may negatively regulate aldosterone production in the physiology of the males, and the inhibition of that negative regulation caused by the CAN diet is one of the possible causes of the adverse events.

Cardiovascular complications in the Post-Acute COVID-19 syndrome (PACS).

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV 2) or coronavirus disease 2019 (COVID-19) initially surfaced in December 2019 from Wuhan, China, sweeping the world with various strains, forcing the WHO to declare a pandemic epidemic in March 2020. Furthermore, COVID-19 manifests with a wide array of presentations from fever and fatigue to severe respiratory and cardiovascular complications. Post-COVID-19 syndrome is poorly understood affecting COVID-19 survivors at all levels of disease severity. The disease is most associated with post-discharge dyspnea and fatigue. However, other persistent symptoms as chest pains, palpitations, smell, and taste dysfunctions. Patients with high concentrations of CRP and creatinine in the acute phase of Covid-19 are more prone to cardiac sequelae. Therefore, high levels of cardiac-sensitive troponin and hypokalaemia can also be used for risk stratification. Furthermore, Cardiac damage can manifest as myocarditis, pericarditis, rhythm abnormalities. The use of different diagnostic modalities like electrocardiogram (ECG), echocardiogram, and cardiac magnetic resonance imaging (MRI)(CMR) to evaluate the myocardial damage were studied. However, Cardiovascular complications are a common manifestation of PASC, classification of severity of cardiac symptoms and the emergence of CMR as a diagnostic tool needs more evidence.

Evolution of Mineralocorticoid Receptor Antagonists in the Treatment of Chronic Kidney Disease Associated with Type 2 Diabetes Mellitus.

Chronic kidney disease (CKD) is one of the most frequent complications associated with type 2 diabetes mellitus (T2DM) and is also an independent risk factor for cardiovascular disease. The mineralocorticoid receptor (MR) is a nuclear receptor expressed in many tissue types, including kidney and heart. Aberrant and long-term activation of MR by aldosterone in patients with T2DM triggers detrimental effects (eg, inflammation and fibrosis) in these tissues. The suppression of aldosterone at the early stage of T2DM has been a therapeutic strategy for patients with T2DM-associated CKD. Although patients have been treated with renin-angiotensin system (RAS) blockers for decades, RAS blockers alone are not sufficient to prevent CKD progression. Steroidal MR antagonists (MRAs) have been used in combination with RAS blockers; however, undesired adverse effects have restricted their usage, prompting the development of nonsteroidal MRAs with better target specificity and safety profiles. Recently conducted studies, Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) and Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD), have reported that finerenone, a nonsteroidal MRA, improves both renal and cardiovascular outcomes compared with placebo. In this article, we review the history of MRA development and discuss the possibility of its combination with other treatment options, such as sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and potassium binders for patients with T2DM-associated CKD.

Clinical Implications, Evaluation, and Management of Hyponatremia in Cirrhosis.

Hyponatremia is the most common electrolyte abnormality in patients with decompensated cirrhosis on Liver Transplantation (LT) waiting list. Most of these patients have dilutional or hypervolemic hyponatremia secondary to splanchnic vasodilatation. Excessive secretion of the antidiuretic hormone also plays an important role. Hypervolemic hyponatremia is commonly associated with refractory ascites, spontaneous bacterial peritonitis, and hepatic encephalopathy. Although uncommon, the use of diuretics and laxatives can cause hypovolemic hyponatremia that is characterized by the striking absence of ascites or pedal edema. Clinical features are often nonspecific and depend on the acuity of onset rather than the absolute value of serum sodium. Symptoms may be subtle, including nausea, lethargy, weakness, or anorexia. However, rarely patients may present with confusion, seizures, psychosis, or coma. Treatment includes discontinuation of diuretics, beta-blockers, and albumin infusion. Hypertonic saline (3%) infusion may be used in patients with very low serum sodium (<110 mmol/L) or when patients present with seizures or coma. Short-term use of Vasopressin (V2) receptor antagonists may also be used to normalize sodium levels prior to LT. However, all these measures may be futile, and LT remains the definite treatment in these patients to improve survival. In this review, we describe the classification, pathogenesis of hyponatremia, and its clinical implications in patients with cirrhosis. Approach to these patients along with management will also be discussed briefly.

STOP-HF Trial: Higher Endogenous BNP and Cardiovascular Protection in Subjects at Risk for Heart Failure.

B-type natriuretic peptide (BNP) possesses blood-pressure-lowering, antifibrotic, and aldosterone-suppressing properties. In Stage A and B heart failure, the carriers of the minor C allele of the BNP genetic variant rs198389 have higher circulating levels of BNP and are at decreased risk of hypertension, new-onset left ventricular systolic dysfunction, and hospitalization for major adverse cardiovascular events. Future studies are warranted to investigate the role of BNP genetic testing and BNP-based therapy in the prevention of heart failure.

Trends in kidney failure and kidney replacement therapy in people with diabetes in Hong Kong, 2002-2015: A retrospective cohort study.

BACKGROUND: There are limited population-wide trend data on kidney failure and kidney replacement therapy (KRT) in people with diabetes. We conducted a retrospective cohort study to report incidence trends of kidney failure and KRT and related mortality in people with diabetes in Hong Kong between 2002 and 2015. METHODS: We used territory-wide electronic medical records including laboratory, diagnostic and procedural data to identify people with kidney failure and KRT. We used Joinpoint regression models to estimate the average annual percent change (AAPC) of kidney failure and KRT incidence for entire study period, and annual percent change (APC) for each linear trend segment, along with 1-year and 5-year mortality rates. FINDINGS: During 4.9 million person-years of follow-up of 712,222 people with diabetes, 31,425 developed kidney failure, among whom 23.0% (n=7,233) received KRT. The incidence of kidney failure declined by 46.8% from 2002 to 2007 (APC: -11.6, 95% CI: -16.3, -6.7), then flattened from 2007 to 2015 (APC: -0.9, 95% CI: -3.1, 1.3). The incidence of KRT remained constant (AAPC: -1.6, 95% CI: -4.4, 1.2). The 1-year mortality rates declined statistically significantly after both kidney failure and KRT. The 5-year mortality rates declined after kidney failure but the decline was not statistically significant after KRT. INTERPRETATION: The findings of our study highlight the importance of developing new strategies to prevent a looming epidemic of kidney failure in people with diabetes in Hong Kong. FUNDING: Asia Diabetes Foundation.

Antisense Inhibition of Angiotensinogen With IONIS-AGT-LRx: Results of Phase 1 and Phase 2 Studies.

Targeting angiotensinogen (AGT) may provide a novel approach to more optimally inhibit the renin-angiotensin-aldosterone system pathway. Double-blind, placebo-controlled clinical trials were performed in subjects with hypertension as monotherapy or as an add-on to angiotensin-converting enzyme inhibitors/angiotensin receptor blockers with IONIS-AGT-LRx versus placebo up to 2 months. IONIS-AGT-LRx was well tolerated with no significant changes in platelet count, potassium levels, or liver and renal function. IONIS-AGT-LRx significantly reduced AGT levels compared with placebo in all 3 studies. Although not powered for this endpoint, trends were noted in blood pressure reduction. In conclusion, IONIS-AGT-LRx significantly reduces AGT with a favorable safety, tolerability, and on-target profile. (A Study to Assess the Safety, Tolerability and Efficacy of IONIS-AGT-LRx; NCT04083222; A Study to Assess the Safety, Tolerability and Efficacy of IONIS-AGT-LRx, an Antisense Inhibitor Administered Subcutaneously to Hypertensive Subjects With Controlled Blood Pressure; NCT03714776; Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Ionis AGT-LRx in Healthy Volunteers; NCT03101878).

Effects and clinical implications of sacubitril/valsartan on left ventricular reverse remodeling in patients affected by chronic heart failure: A 24-month follow-up.

BACKGROUND: Compared to angiotensin inhibition, angiotensin-neprilysin "blockade" improves mortality and reduces hospitalizations in patients with heart failure (HF) with reduced ejection fraction (EF). Sacubitril/valsartan is known to influence left ventricular (LV) reverse remodeling with systolic function improvement, although underlying mechanisms remain partially unclear. Our objectives were to evaluate whether sacubitril/valsartan promotes LV remodeling and improves LV ejection fraction (LVEF) (above the 35% threshold by echocardiographic evaluation) and to identify predictors of reverse remodeling in a real-world setting. METHODS: New York Heart Association (NYHA) class II-III patients with EF ≤ 35% were consecutively enrolled. All patients were on optimal medical therapy on the initiation of sacubitril/valsartan therapy. Full clinical and multi-parametric echocardiographic evaluation, electrocardiogram, and laboratory tests were performed at baseline and after 3, 6, 12, and 24 months. RESULTS: In total, 69 patients were recruited from July 2016 to August 2018. Reverse remodeling was observed in 57.7% (30/52) of patients, occurring within 3, 6, 12, and 24 months in 2, 11, 13, and 4 patients, respectively. Twenty-four (46%) patients showed LVEF improvement above the threshold of 35% during follow-up, occurring in 1, 10, 9, and 4 patients within 3, 6, 12, and 24 months, respectively. Primitive dilated cardiomyopathy and female gender were identified as significant predictors of reverse remodeling. NYHA class was improved in both remodeling and non-remodeling patients. CONCLUSION: Sacubitril/valsartan promotes favorable cardiac remodeling and significantly improves LVEF in a significant proportion of HF patients within 24 months, both in NYHA class II and III patients with HF.

Renal Outcomes in Patients with Systolic Heart Failure Treated With Sacubitril-Valsartan or Angiotensin Converting Enzyme Inhibitor/Angiotensin Receptor Blocker.

OBJECTIVE: To assess 4 adverse renal outcomes in a heterogeneous cohort of patients with systolic heart failure (HF) who were prescribed sacubitril-valsartan vs angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEi/ARB). PATIENTS AND METHODS: The OptumLabs Database Warehouse, which contains linked administrative claims and laboratory results, was used to identify patients with systolic HF who were prescribed sacubitril-valsartan or ACEi/ARB between July 1, 2015, and September 30, 2019. One-to-one propensity score matching and inverse probability of treatment weighting was used to balance baseline variables. Cox proportional hazards modeling was performed to compare renal outcomes in both medication groups, including 30% or more decline in estimated glomerular filtration rate (eGFR), doubling of serum creatinine, acute kidney injury (AKI), and kidney failure (eGFR < 15 mL/min per 1.73 m2, kidney transplant, or dialysis initiation). RESULTS: A total of 4667 matched pairs receiving sacubitril-valsartan or ACEi/ARB were included; the mean follow-up period was 7.8±7.8 months. The mean age was 69.4±11 years; 35% were female, 19% black, and 15% Hispanic. The cumulative risk at 1 year was 6% for 30% or more decline in eGFR, 2% for doubling of serum creatinine, 3% for AKI, and 2% to 3% for kidney failure. Furthermore, no significant differences in risk were observed with sacubitril-valsartan compared with ACEi/ARB for a 30% or more decline in eGFR (hazard ratio [HR], 0.96; 95% CI, 0.79 to 1.10), doubling of serum creatinine (HR, 0.94; 95% CI, 0.69 to 1.27); AKI (HR, 0.80; 95% CI, 0.63 to 1.03), and kidney failure (HR 0.80; 95% CI, 0.59 to 1.08). CONCLUSION: Among patients with systolic HF, the risk of adverse renal outcomes was similar between patients prescribed sacubitril-valsartan and those prescribed ACEi/ARB.

Relationship of Nonalcoholic Fatty Liver Disease and Heart Failure With Preserved Ejection Fraction.

Although there is an established bidirectional relationship between heart failure with reduced ejection fraction and liver disease, the association between heart failure with preserved ejection fraction (HFpEF) and liver diseases, such as nonalcoholic fatty liver disease (NAFLD), has not been well explored. In this paper, the authors provide an in-depth review of the relationship between HFpEF and NAFLD and propose 3 NAFLD-related HFpEF phenotypes (obstructive HFpEF, metabolic HFpEF, and advanced liver fibrosis HFpEF). The authors also discuss diagnostic challenges related to the concurrent presence of NAFLD and HFpEF and offer several treatment options for NAFLD-related HFpEF phenotypes. The authors propose that NAFLD-related HFpEF should be recognized as a distinct HFpEF phenotype.

Controlled underdilation using novel VIATORR® controlled expansion stents improves survival after transjugular intrahepatic portosystemic shunt implantation.

BACKGROUND & AIMS: Smaller 8-mm diameter transjugular intrahepatic portosystemic shunts (TIPS) appear to be more beneficial than larger 10-mm TIPS stent-grafts, but lack the ability for secondary dilation in cases of clinical ineffectiveness. Underdilated VIATORR® TIPS stent grafts (VTS) expand passively, whereas novel VIATORR Controlled Expansion (VCX) stent grafts do not. This study evaluated the impact on survival of underdilated VCX compared with VTS in patients with decompensated cirrhosis. METHODS: This was a prospective case-control study including patients with cirrhosis receiving TIPS using 10-mm VCX underdilated to 8 mm. Patients with cirrhosis receiving 10-mm VTS underdilated to 8 mm were matched for age, sex, indication for TIPS, and liver function. RESULTS: A total of 114 patients (47 VCX, 47 VTS, and 20 fully dilated VCX/VTS) were included. After TIPS implantation, underdilated VCX diameter was 8.0 (7.8-9.2) mm at a median time of 359 (87-450) days, compared with VTS at 9.9 (9.7-10.0) mm (p <0.001). The portosystemic pressure gradient immediately after TIPS procedure and after 7 days did not change significantly in VCX [mean 9.4 (± 0.8) vs. 10.4 (± 0.7) mmHg, p = 0.115). Hospital readmission rates for hepatic encephalopathy were 23% (n = 11) vs 51% (n = 24) for VCX and VTS (p <0.001), respectively. Patients with VCX had significantly lower rates of large-volume paracentesis (n = 5 [11%] vs. n = 10 [21%], p = 0.017) and heart failure (n = 1 [2%] vs. n = 7 [15%], p = 0.015). One-year mortality for underdilated VCX and VTS was 15% (n = 7) and 30% (n = 14) and, for fully dilated VCX/VTS, was 45% (n = 9) (log-rank p = 0.008), respectively. CONCLUSIONS: This study demonstrated that VCX stent grafts underdilated to 8 mm do not passively expand to nominal diameter and suggests reduced hospital readmissions because of hepatic encephalopathy, uncontrolled ascites, and heart failure, and improved 1-year survival compared with underdilated VTS. LAY SUMMARY: Transjugular intrahepatic portosystemic shunt (TIPS) improves survival in selected patients with liver cirrhosis and acute variceal bleeding or refractory ascites. Smaller 8-mm diameter TIPS stent grafts appear to improve patient outcome compared with larger 10-mm diameter stent grafts. Novel VIATORR® Controlled Expansion (VCX) stent grafts facilitate safe and stable underdilation to 8 mm of large 10-mm diameter stent grafts with improved patient outcome (survival, hepatic encephalopathy, ascites and heart failure) compared with legacy VIATORR TIPS stent graft (VTS). Thus, the use of underdilated VCX could preserve heart function. CLINICAL TRIALS REGISTRATION: The study is registered at Clinicaltrials.govNCT03628807.

RAAS, ACE2 and COVID-19; a mechanistic review.

The use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in coronavirus disease 2019 (COVID-19) patients has been claimed as associated with the risk of COVID-19 infection and its subsequent morbidities and mortalities. These claims were resulting from the possibility of upregulating the expression of angiotensin-converting enzyme 2 (ACE2), facilitation of SARS-CoV-2 entry, and increasing the susceptibility of infection in such treated cardiovascular patients. ACE2 and renin-angiotensin-aldosterone system (RAAS) products have a critical function in controlling the severity of lung injury, fibrosis, and failure following the initiation of the disease. This review is to clarify the mechanisms beyond the possible deleterious effects of angiotensin II (Ang II), and the potential protective role of angiotensin 1-7 (Ang 1-7) against pulmonary fibrosis, with a subsequent discussion of the latest updates on ACEIs/ARBs use and COVID-19 susceptibility in the light of these mechanisms and biochemical explanation.

Treatment Targets for Right Ventricular Dysfunction in Pulmonary Arterial Hypertension.

Right ventricle (RV) dysfunction is the strongest predictor of mortality in pulmonary arterial hypertension (PAH), but, at present, there are no therapies directly targeting the failing RV. Although there are shared molecular mechanisms in both RV and left ventricle (LV) dysfunction, there are important differences between the 2 ventricles that may allow for the development of RV-enhancing or RV-directed therapies. In this review, we discuss the current understandings of the dysregulated pathways that promote RV dysfunction, highlight RV-enriched or RV-specific pathways that may be of particular therapeutic value, and summarize recent and ongoing clinical trials that are investigating RV function in PAH. It is hoped that development of RV-targeted therapies will improve quality of life and enhance survival for this deadly disease.

Indian National Association for the Study of the Liver Consensus Statement on Acute Liver Failure (Part 1): Epidemiology, Pathogenesis, Presentation and Prognosis.

Acute liver failure (ALF) is an infrequent, unpredictable, potentially fatal complication of acute liver injury (ALI) consequent to varied etiologies. Etiologies of ALF as reported in the literature have regional differences, which affects the clinical presentation and natural course. In this part of the consensus article designed to reflect the clinical practices in India, disease burden, epidemiology, clinical presentation, monitoring, and prognostication have been discussed. In India, viral hepatitis is the most frequent cause of ALF, with drug-induced hepatitis due to antituberculosis drugs being the second most frequent cause. The clinical presentation of ALF is characterized by jaundice, coagulopathy, and encephalopathy. It is important to differentiate ALF from other causes of liver failure, including acute on chronic liver failure, subacute liver failure, as well as certain tropical infections which can mimic this presentation. The disease often has a fulminant clinical course with high short-term mortality. Death is usually attributable to cerebral complications, infections, and resultant multiorgan failure. Timely liver transplantation (LT) can change the outcome, and hence, it is vital to provide intensive care to patients until LT can be arranged. It is equally important to assess prognosis to select patients who are suitable for LT. Several prognostic scores have been proposed, and their comparisons show that indigenously developed dynamic scores have an edge over scores described from the Western world. Management of ALF will be described in part 2 of this document.