ARNI Pre-Operative Use and Vasoplegic Syndrome in Patients Undergoing Heart Transplantation or Left Ventricular Assist Device Surgery

Background: Vasoplegic syndrome after orthotopic heart transplantation (OHT) or left ventricular assist device (LVAD) implantation is a rare but highly lethal syndrome with complex etiologies. The objective of this study was to assess if the preoperative use of sacubitril-valsartan combination is associated with an increased vasoplegic syndrome (VS) frequency after OHT or LVAD implantation and its relationship with 30-day mortality. Methods: A retrospective review of perioperative data, between January 2016 and December 2017, from 73 consecutive OHT and LVAD surgery adult patients at our institution was performed. VS was defined as normal cardiac output with persistent low systemic resistance requiring a norepinephrine intravenous perfusion > 0.5 µg/kg/min and the absence of sepsis or hemorrhagic shock within 48 h after surgery. Patients were all followed-up for adverse events and all-cause mortality at 30 days. Results: In our cohort of 73 patients (median age 51.7 years, 65% male patients), 25 (34%) patients developed VS. Twenty-two (30.1%) patients were on ARNI at the time of surgery, 31 (42.5%) were on other RAS blockers, 12 (16.4%) were on norepinephrine and 8 (11%) had no pre-operative drug. The pre-operative use of any vasoactive agent, was not significantly associated with VS (OR = 1.36; IC95% [0.78; 2.35]; p = 0.38). The pre-operative use of an ARNI compared to all other groups was not significantly associated with VS (OR = 2.0; IC95% [0.71; 5.62]; p = 0.19). The pre-operative use of an ARNI compared to other RAS blockers was also not significantly associated with VS (OR = 1.25; IC95% [0.37; 4.26]; p = 0.72). At 30 days, 18 (24.7%) patients had died. The pre-operative treatment with ARNI, or other RAS inhibitors was associated with a significantly lower rate of death compared to the absence of treatment (HR = 0.11; IC95% [0.02; 0.55]; p = 0.009 for ARNI and HR = 0.20; IC95% [0.06; 0.69]; p = 0.011 for other RASi). Conclusions: Preoperative use of sacubitril-valsartan was not significantly associated with development of vasoplegic syndrome in patients undergoing OHT or LVAD surgery. Furthermore, our data suggests a significant 30-day survival benefit with efficient renin-angiotensin blockade before surgery.

Renin–Angiotensin–Aldosterone System and Immunomodulation: A State-of-the-Art Review

The renin–angiotensin system (RAS) has long been described in the field of cardiovascular physiology as the main player in blood pressure homeostasis. However, other effects have since been described, and include proliferation, fibrosis, and inflammation. To illustrate the immunomodulatory properties of the RAS, we chose three distinct fields in which RAS may play a critical role and be the subject of specific treatments. In oncology, RAS hyperactivation has been associated with tumor migration, survival, cell proliferation, and angiogenesis; preliminary data showed promise of the benefit of RAS blockers in patients treated for certain types of cancer. In intensive care medicine, vasoplegic shock has been associated with severe macro- and microcirculatory imbalance. A relative insufficiency in angiotensin II (AngII) was associated to lethal outcomes and synthetic AngII has been suggested as a specific treatment in these cases. Finally, in solid organ transplantation, both AngI and AngII have been associated with increased rejection events, with a regional specificity in the RAS activity. These elements emphasize the complexity of the direct and indirect interactions of RAS with immunomodulatory pathways and warrant further research in the field.

Biologia Futura: is ADAM 17 the reason for COVID-19 susceptibility in hyperglycemic and diabetic patients?

COVID-19 is a disease-causing current pandemic. It prevails in patients with pre-existing conditions such as diabetes and hypertension. Renin–angiotensin system was identified as a center of COVID-19 pathophysiology. There is a current controversy concerning the usage of ACE inhibitors and AR blockers in patients with COVID-19. Multiple clinical trials are on the way to determine the effect of RAS blockers in patients with COVID-19. ACE2 receptor is thought to be the point of entry utilized by a coronavirus. However, other factors have been identified which potentially facilitate SARS-CoV-2 entry into the cell. ADAM17 could facilitate viral entry in hyperglycemic and diabetic patients. Insulin is an ADAM17 inhibitor. Heme oxygenase (HO)-1 level is reduced in diabetic patients, contributing to the worst outcome for patients with poor glycemic control. The combined therapy of glycemic control and antioxidant response to oxidative stress could be explored in patients with COVID-19.

Evaluation of modifiable risk factors for peritoneal dialysis-related peritonitis: a single-center retrospective cohort study

Background Peritoneal dialysis (PD)-related peritonitis risk factors can be categorized as modifiable and uncorrectable. We aimed to identify modifiable risk factors for PD-related peritonitis in our facility to prevent PD-related peritonitis and continue quality improvement. Methods This retrospective, observational study included 90 patients who started receiving PD after 2008 and who were continued for over 1 year. Twenty-three patients experienced 40 episodes of peritonitis. Several clinical factors identified at peritonitis onset among patients with a peritonitis history were compared with those identified 1 year after PD initiation among patients without a peritonitis history, and a multivariate analysis was performed. Several serum parameter levels were evaluated as time-average concentrations (TACs; from PD initiation to 1 month before peritonitis onset or to 1 year later). The clinical factors to be investigated were selected based on previous studies. Results There were no significant between-group differences in baseline characteristics regarding uncorrectable factors and TAC values for serum parameters. Use of exchange devices was significantly higher (95.7% vs 71.6%; p = 0.054) whereas administration of renin-angiotensin-aldosterone system (RAS) blockers, calcium channel blockers (CCBs), or oral vitamin D was significantly lower (35.0% vs 65.7%, p = 0.002; 55.0% vs 74.6%, p = 0.036; and 55.0% vs 74.6%, p = 0.036, respectively) in the patients with history of peritonitis, although we did not find a factor independently associated with peritonitis in multivariable logistic regression. Conclusions Although hypokalemia, hypoalbuminemia, and exchange device use which are considered as risk factors did not affect peritonitis, administration of RAS blockers, CCBs, and oral vitamin D is significantly larger in patients without peritonitis.

Treatment of Resistant Hypertension in Real Clinical Settings

Background. Current guidelines describe in detail the approaches to the management of patients with resistant hypertension, however, in real clinical settings the number of non-rational and ineffective combinations of antihypertensive drugs used remains high.Aim. To analyze the distribution of different combinations of antihypertensive drugs for the treatment of resistant hypertension and to estimate the proportion of non-rational combinations.Methods. The retrospective analysis includes 117 outpatients with resistant hypertension. Resistant hypertension was defined as blood pressure that remains above goal despite concurrent use of three antihypertensive agents of different classes. Exclusion criteria was secondary hypertension. We defined rational combination as the standard combination (renin-angiotensin system [RAS] blocker + calcium-channel blocker [CCB] + diuretic) plus one of the group of reserve drugs (mineralocorticoid receptors antagonist [MRA], beta-blocker, alpha-blocker, agonist of imidazoline receptors [AIR]). Non-rational were considered combinations in which reserve drugs were used before the appointment of a triple combination of first-line drugs. Moreover, in a subgroup of non-rational therapy, situations were identified where such a combination was justified.Results. The proportion of rational combinations was 58.9%, reasonably non-rational - 15.5%, unreasonably non-rational - 25.6%. Unreasonably non-rational combinations are distributed as follows: non-appointment of CCB - 12%, non-appointment of RAS-blockers - 8%, non-appointment of diuretics - 6%, use of RAS-blockers for hyperkalemia - 6%, administration of MRA without non-potassium-sparing diuretics - 5%, double blockade of RAS - 3%, other combinations - 7%. In addition to first-line drugs, beta-blockers (93.2%), loop diuretics (22.2%), AIR (21.4) were the most prescribable, while the proportion of MRA is only 15.4% of the entire sample.Limitation: some patient's characteristics could be missed in case histories and some of the combinations could be falsely recognized as malpractice since the analysis was conducted retrospectively.Conclusion. The proportion of the non-rational combinations for the treatment of resistant hypertension is high. Among the drugs of the reserve, the frequent use of beta-blockers and moxonidine and the inadequate administration of spironolactone are noteworthy. The problem of treatment strategy choice remains relevant in real clinical practice.

MO626EFFECTS OF RAMIPRIL IN LUNG AND KIDNEY ANGIOTENSIN CONVERTING ENZYME 2 (ACE2) EXPRESSION IN A TYPE 2 DIABETIC MURINE MODEL: LESSONS FOR COVID-19 INFECTION

Background and Aims Angiotensin converting enzyme 2 (ACE2) is one of the components of the renin-angiotensin system (RAS) that mainly degrades angiotensin II to angiotensin-(1-7). ACE2 is predominantly expressed in the kidney and the heart, but it has been evidenced in type 2 alveolar lung cells, where it acts as a receptor for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this context, a controversy arose as to whether the use of RAS blockers could increase ACE2 lung expression and the risk infection by COVID-19. This study aimed to investigate the effect of an ACE inhibitor (Ramipril) on ACE2 expression in experimental diabetes. Method 12 weeks old diabetic db/db mice (n=7) were given ramipril (8 mg/Kg/day) during 8 weeks or the respective vehicle. db/m (n=7) vehicle-treated non-diabetic mice were included as controls. ACE2 mRNA expression and enzymatic activity were studied in kidney, heart and lung samples of these animals to identify if the diabetic condition or treatment with ramipril modulated ACE2 expression. Results In vehicle-treated diabetic db/db animals, ACE2 mRNA expression was significantly increased in the kidney (p<0.001) and ramipril treatment reversed this effect (p=0.026). In the heart, ACE2 expression decreased in db/db when compared to db/m littermates (p=0.035) and ramipril had no effect. We found no differences in ACE2 gene expression in the lung. Besides, ACE2 enzymatic activity was increased in the kidney (29%) and also in the lung (16%) of db/db mice when compared to controls. Ramipril treatment decreased ACE2 activity a 19% in the lung and had no effect in the kidney when compared to untreated db/db (see figure). In the heart, ACE2 activity tended to decrease in db/db mice (29%) when compared to db/m and ramipril increased ACE2 activity (18%) but did not exceed the cardiac ACE2 activity of the db/m. Conclusion ACE2 is increased in the kidney and the lung, and decreased in the heart of diabetic mice. Ramipril treatment restores ACE2 levels. The results suggest that ACE inhibitors do not increase ACE2 expression and the activity decrease exerted in the lung may be protective against COVID-19 infection.

Hypertension, a Moving Target in COVID-19

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) associates with a considerable high rate of mortality and represents currently the most important concern in global health. The risk of more severe clinical manifestation of COVID-19 is higher in males and steeply raised with age but also increased by the presence of chronic comorbidities. Among the latter, early reports suggested that arterial hypertension associates with higher susceptibility to SARS-CoV-2 infection, more severe course and increased COVID-19–related deaths. Furthermore, experimental studies suggested that key pathophysiological hypertension mechanisms, such as activation of the renin-angiotensin system (RAS), may play a role in COVID-19. In fact, ACE2 (angiotensin-converting-enzyme 2) is the pivotal receptor for SARS-CoV-2 to enter host cells and provides thus a link between COVID-19 and RAS. It was thus anticipated that drugs modulating the RAS including an upregulation of ACE2 may increase the risk for infection with SARS-CoV-2 and poorer outcomes in COVID-19. Since the use of RAS-blockers, ACE inhibitors or angiotensin receptor blockers, represents the backbone of recommended antihypertensive therapy and intense debate about their use in the COVID-19 pandemic has developed. Currently, a direct role of hypertension, independent of age and other comorbidities, as a risk factor for the SARS-COV-2 infection and COVID-19 outcome, particularly death, has not been established. Similarly, both current experimental and clinical studies do not support an unfavorable effect of RAS-blockers or other classes of first line blood pressure lowering drugs in COVID-19. Here, we review available data on the role of hypertension and its management on COVID-19. Conversely, some aspects as to how the COVID-19 affects hypertension management and impacts on future developments are also briefly discussed. COVID-19 has and continues to proof the critical importance of hypertension research to address questions that are important for global health.

SARS-CoV-2 – the Hidden Agonist of the Pressor Arm Within the Renin-Angiotensin System: Considerations for Statins and Propionate Derivatives

"Coronavirus disease 2019 (COVID-19) has become a serious healthcare problem, causing more than 2 million fatalities worldwide. Several treatments used for the management of chronic diseases such as hypertension, cardiovascular disease, diabetes and arthritis were shown to increase the expression of the receptor exploited by the virus, the angiotensin-converting enzyme 2 (ACE2), in vitro. This raises concerns on the safety of continuing such drugs or switching to other classes that don’t interfere with the receptor exploited by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here we emphasize the mechanisms behind the regulation of ACE2 expression by several widely used drugs with possible interactions with COVID-19. Moreover, we discuss how the physiological mechanisms of attenuating inflammation and fibrosis can lead to increased expression of the receptor exploited by the virus and how this expression is further influenced be statins, propionate derivative nonsteroidal antiinflamatory drugs (NSAIDs) and renin-angiotensin system (RAS) blockers."

Use of Population-Based Health Informatics Research to Improve Care for Patients with Cardiovascular Diseases

There are common clinical scenarios in chronic heart disease where no randomized controlled data exist to guide management, and it is likely that well-designed observational studies will have to be used to inform clinical practice. Showing the clinical applicability of this type of study design, using record linkage of population electronic health records, we have provided key observational evidence that use of renin–angiotensin-system (RAS) blockers is associated with better outcomes in patients with aortic stenosis and that metformin could be used safely as an antiglycemic drug in patients with diabetes and heart failure. Each of these pieces of underpinning research has made a major contribution to relevant international clinical practice guidelines, helped the Food and Drug Administration in their decision making and changed prescribing practice.

Modeling the Molecular Impact of SARS-CoV-2 Infection on the Renin-Angiotensin System

SARS-CoV-2 infection is mediated by the binding of its spike protein to the angiotensin-converting enzyme 2 (ACE2), which plays a pivotal role in the renin-angiotensin system (RAS). The study of RAS dysregulation due to SARS-CoV-2 infection is fundamentally important for a better understanding of the pathogenic mechanisms and risk factors associated with COVID-19 coronavirus disease and to design effective therapeutic strategies. In this context, we developed a mathematical model of RAS based on data regarding protein and peptide concentrations; the model was tested on clinical data from healthy normotensive and hypertensive individuals. We used our model to analyze the impact of SARS-CoV-2 infection on RAS, which we modeled through a downregulation of ACE2 as a function of viral load. We also used it to predict the effect of RAS-targeting drugs, such as RAS-blockers, human recombinant ACE2, and angiotensin 1–7 peptide, on COVID-19 patients; the model predicted an improvement of the clinical outcome for some drugs and a worsening for others. Our model and its predictions constitute a valuable framework for in silico testing of hypotheses about the COVID-19 pathogenic mechanisms and the effect of drugs aiming to restore RAS functionality.