Angiotensin-converting Enzyme Inhibitor Ramipril Research Articles

Blood pressure variability assessed by office, home, and ambulatory measurements before and during antihypertensive drug treatment: a sub-analysis of the REVERENT randomized trial.

Blood pressure (BP) variability (BPV) can be assessed using office (OBP), home (HBP), or ambulatory BP (ABP) measurements. This analysis investigated the association and agreement between OBP, HBP, and ABP measurements for BPV assessment at baseline and 10 weeks after initiating antihypertensive drug therapy. Untreated hypertensive patients with elevated BPV were randomized to receive an angiotensin-converting enzyme inhibitor (ramipril) or a calcium channel blocker (nifedipine GITS) in a 10-week, open-label, blinded-end point study. BPV was assessed using standard deviation (SD) and coefficient of variation (CV) (reading-to-reading analyses). Data from 146 participants from three research centers (Athens/Greece; Milan/Italy; Shanghai/China) were analyzed [mean age 53 ± 10 (SD) years, male individuals 60%, baseline systolic OBP, HBP, and 24 h ABP 144 ± 9, 138 ± 10, and 143 ± 10 mmHg, respectively]. Post-treatment minus pre-treatment systolic CV difference was: OBP: 0.3%, P = 0.28; HBP: -0.2%, P = 0.20; 24 h ABP: 1.1%, P < 0.001. Home and ambulatory (not office) BPV indices presented weak-to-moderate correlation, both before and during treatment (range of coefficients 0.04-0.33). The correlation coefficient between systolic HBP and awake ABP CV was 0.21 and 0.28 before and during treatment, respectively ( P < 0.05/< 0.001, respectively). Home and ambulatory (not office) BPV indices presented slight-to-fair agreement (range 64-73%) in detecting participants with high systolic BPV (top quartile of respective distributions) both before and during treatment (kappa range 0.04-0.27). These data showed a weak-to-moderate association between out-of-office (but not office) BPV indices both before and during BP-lowering treatment, with reasonable agreement in detecting individuals with high BPV. Out-of-office BP measurements provide more similar and consistent BPV information than office measurements.

Abstract 14399: Development of Heart Failure in High-Risk Post-Myocardial Infarction Patients: An Analysis of the Paradise-MI Trial

Objectives: The aims of this study were i) to examine the incidence, risk factors and subsequent mortality after high-risk acute myocardial infarction (AMI) and ii) compare the effects of sacubitril/valsartan with the ACE inhibitor ramipril across heart failure (HF) risk categories. Background: The contemporary risk of developing HF following AMI in the coronary reperfusion era is not well documented. Methods: We analyzed the 5661 patients enrolled in the PARADISE-MI trial which compared sacubitril-valsartan to ramipril after AMI. Patients were required to have acute pulmonary congestion and/or left ventricular systolic dysfunction at the time of AMI, but no history of HF. We analyzed a composite outcome of first occurrence of investigator-reported HF hospitalization or outpatient development of HF. Results: During a median follow up of 22 months, 734 patients (13%) developed a first episode of HF, of which 496 (68%) were a hospitalization and 238 (32%) an outpatient HF episode. Only 74 patients (10%) experienced another AMI prior to developing HF. Independent predictors for the development of HF were a lower baseline left ventricular ejection fraction (LVEF), pulmonary congestion, diabetes, older age, higher heart rate, previous MI, and renal dysfunction. A risk-score showed an exponential increased risk of developing HF with a higher score (Figure 1). The relative effect of sacubitril/valsartan compared to ramipril was similar across the HF risk spectrum (p-value for interaction=0.14). The hazard ratio for cardiovascular mortality after outpatient development of HF (in comparison to no event) was 3.9 (95% CI 2.5-6.2) and after an HF hospitalization was 10.0 (95% CI 7.8-12.8). Conclusion: New onset HF after high-risk AMI was common and resulted in a 10-fold higher cardiovascular mortality than no HF. Sacubitril/valsartan, compared to ramipril, showed similar efficacy across the HF risk spectrum.

Impact of concomitant cardiovascular medications on overall survival in patients with liver cirrhosis

Objectives of the article Liver cirrhosis is the end-stage liver disease associated with poor prognosis and cardiovascular comorbidity could significantly impact mortality of cirrhotic patients. We conducted a large, retrospective study to investigate the survival impact of cardiovascular co-medications in patients with liver cirrhosis. Materials and methods A study-specific R package was processed on the local databases of partner institutions within the Observational Health Data Sciences and Informatics consortium, namely Columbia University, New York City (NYC), USA and Ajou University School of Medicine (AUSOM), South Korea. Patients with cirrhosis diagnosed between 2000 and 2020 were included. Final analysis of the anonymous survival data was performed at Medical Faculty Mannheim, Heidelberg University. Results We investigated a total of 32,366 patients with liver cirrhosis. Our data showed that administration of antiarrhythmics amiodarone or digoxin presented as a negative prognostic indicator (p = 0.000 in both cohorts). Improved survival was associated with angiotensin-converting enzyme inhibitor ramipril (p = 0.005 in NYC cohort, p = 0.075 in AUSOM cohort) and angiotensin II receptor blocker losartan (p = 0.000 in NYC cohort, p = 0.005 in AUSOM cohort). Non-selective beta blocker carvedilol was associated with a survival advantage in the NYC (p = 0.000) cohort but not in the AUSOM cohort (p = 0.142). Patients who took platelet inhibitor clopidogrel had a prolonged overall survival compared to those without (p = 0.000 in NYC cohort, p = 0.003 in AUSOM cohort). Conclusion Concomitant cardiovascular medications are associated with distinct survival difference in cirrhotic patients. Multidisciplinary management is needed for a judicious choice of proper cardiovascular co-medications in cirrhotic patients.

The membrane-associated protein 17 (MAP17) is up-regulated in response to empagliflozin on top of RAS blockade in experimental diabetic nephropathy.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have proven to delay diabetic kidney disease (DKD) progression on top of the standard of care with the renin-angiotensin system (RAS) blockade. The molecular mechanisms underlying the synergistic effect of SGLT2i and RAS blockers is poorly understood. We gave a SGLT2i (empagliflozin), an angiotensin-converting enzyme inhibitor (ramipril), or a combination of both drugs for 8 weeks to diabetic (db/db) mice. Vehicle-treated db/db and db/m mice were used as controls. At the end of the experiment, mice were killed, and the kidneys were saved to perform a differential high-throughput proteomic analysis by mass spectrometry using isobaric tandem mass tags (TMT labeling) that allow relative quantification of the identified proteins. The differential proteomic analysis revealed 203 proteins differentially expressed in one or more experimental groups (false discovery rate < 0.05 and Log2 fold change ≥ ±1). Fourteen were differentially expressed in the kidneys from the db/db mice treated with empagliflozin with ramipril. Among them, MAP17 was up-regulated. These findings were subsequently validated by Western blot. The combined therapy of empagliflozin and ramipril up-regulated MAP17 in the kidney of a diabetic mice model. MAP17 is a major scaffolding protein of the proximal tubular cells that places transporters together, namely SGLT2 and NHE3. Our results suggest that SGLT2i on top of RAS blockade may protect the kidney by boosting the inactivation of NHE3 via the up-regulation of key scaffolder proteins such as MAP17.

N-[2-(5-metoksi-1H-indol-3-il)]acetamid može da koriguje arterijsku hipertenziju kod ljudi koji imaju problema sa spavanjem

Introduction. Sleep disturbance is a frequent complaint of patients suffering from arterial hypertension (AH) for a long time. A hidden and uncontrolled increase in blood pressure (BP) makes the course of physiological processes more difficult, disrupts the regulation of biological rhythms, and increases the risk of cardiovascular complications even with a short duration of AH. At the same time, chronic sleep disorders contribute to the development of hypertension, defining the role of a new socially significant risk factor. An important role in the pathogenesis of insomnia is played by a deficiency in melatonin (MT) synthesis, which negatively affects the cardiovascular system (CVS). Aim. The aim of the paper was to study the features of central and vascular hemodynamics in patients with the 1st degree AH and to evaluate the clinical effectiveness of antihypertensive therapy with synthetic analog of prolonged-release MT at the onset of the disease. Methods. Instrumental examination included registration of an electrocardiogram, office measurement of blood pressure with an automatic tonometer, non-invasive automatic blood pressure monitoring for 24 hours. The severity of insomnia was assessed by somnological questionnaires. Representatives of the 1st group (n = 34) took monotherapy with the ACE inhibitor ramipril, participants of the 2nd group (n = 33) took the ACE inhibitor ramipril in combination with a synthetic analogue of melatonin. Results. The results of a randomized open prospective study including 78 participants reveal the activity of the renin-angiotensin-aldosterone system (RAAS), hypersympathicotonia at night and desynchronosis due to a possible deficiency in the MT secretion. Pharmacological antihypertensive therapy with the addition of prolonged release MT analog was accompanied by a significant improvement in the clinical condition of hypertensive patients. Positive dynamics of indicators of systemic hemodynamics and functional arterial parameters of stiffness was noted. Conclusion. The article describes the probable benefits of melatonin as part of combination antihypertensive therapy in patients with early-stage hypertension and insomnia. Additional introduction of MT at the onset of the AN as a physiological regulator of circadian biological rhythms is substantiated.

PS-C12-8: BLOOD PRESSURE VARIABILITY IN PREVIOUSLY UNTREATED HYPERTENSIVE PATIENTS RANDOMIZED TO NIFEDIPINE GITS OR RAMIPRIL. REVERENT STUDY

Blood pressure (BP) variability (BPV) independently predicts adverse outcomes, making it a potential target for treatment. Preliminary data indicate that dihydropyridine calcium channel blockers (CCB) may reduce BPV more than other antihypertensives. Aim of Reverent: (Reducing blood pressure Variability in Essential hypertension with Ramipril vErsus Nifedipine GITS) Trial was to compare changes in either short-, mid- and long-term BPV in patients treated with a CCB (nifedipine GITS) or an ACE inhibitor (ramipril) in a randomised fashion. Methods: Untreated (treatment-naïve or after treatment washout) patients with mild to moderate essential hypertension and elevated basal BPV, were randomized to open label treatment with nifedipine GITS 30 mg or ramipril 10 mg once daily. BPV after 10 weeks and 12 months of treatment was assessed based on home (primary endpoint; validated AND UA-651BLE monitor), 24-hour ambulatory (A&amp;D TM 2430) and office (AND UA-651BLE) measurements and expressed as standard deviation [SD] of obtained readings. Results: 156 patients were included in the intention-to-treat analysis of the main study (10 weeks, primary analysis) and 138 of the extension study (12 months, exploratory analysis). No significant differences were observed between groups at baseline. Patient characteristics, BP and BPV values after 10 weeks of treatment are reported in the table. No significant differences between groups were observed in home and office BPV at the end of main study, also after adjusting for mean BP reduction. 24-hour weighted SD of systolic BP after 10 weeks of treatment was lower in the nifedipine GITS group (p = 0.032). Exploratory analysis also revealed lower office BPV after 12 months of treatment in nifedipine GITS group (7.15 ± 3.79 vs 9.00 ± 5.28 mmHg, p = 0.026). Conclusions: The study did not identify differences between nifedipine GITS and ramipril in reducing home BPV, while significant differences in favour of nifedipine GITS were observed in 24-hour BPV and in office BPV after 12 months. Clinical impact of these findings remains to be evaluated in outcome studies.

Enhanced Cardiorenal Protective Effects of Combining SGLT2 Inhibition, Endothelin Receptor Antagonism and RAS Blockade in Type 2 Diabetic Mice.

Treatments with sodium-glucose 2 cotransporter inhibitors (SGLT2i) or endothelin receptor antagonists (ERA) have shown cardiorenal protective effects. The present study aimed to evaluate the cardiorenal beneficial effects of the combination of SGLT2i and ERA on top of renin-angiotensin system (RAS) blockade. Type 2 diabetic mice (db/db) were treated with different combinations of an SGLT2i (empagliflozin), an ERA (atrasentan), and an angiotensin-converting enzyme inhibitor (ramipril) for 8 weeks. Vehicle-treated diabetic mice and non-diabetic mice were included as controls. Weight, blood glucose, blood pressure, and kidney and heart function were monitored during the study. Kidneys and heart were collected for histological examination and to study the intrarenal RAS. Treatment with empagliflozin alone or combined significantly decreased blood glucose compared to vehicle-treated db/db. The dual and triple therapies achieved significantly greater reductions in diastolic blood pressure than ramipril alone. Compared to vehicle-treated db/db, empagliflozin combined with ramipril or in triple therapy significantly prevented GFR increase, but only the triple combination exerted greater protection against podocyte loss. In the heart, empagliflozin alone or combined reduced cardiac isovolumetric relaxation time (IVRT) and left atrium (LA) diameter as compared to vehicle-treated db/db. However, only the triple therapy was able to reduce cardiomyocyte area. Importantly, the add-on triple therapy further enhanced the intrarenal ACE2/Ang(1-7)/Mas protective arm of the RAS. These data suggest that triple therapy with empagliflozin, atrasentan and ramipril show synergistic cardiorenal protective effects in a type 2 diabetic mouse model.

EFFECT OF NIFEDIPINE GITS OR RAMIPRIL ON BLOOD PRESSURE VARIABILITY IN PREVIOUSLY UNTREATED HYPERTENSIVE PATIENTS: RESULTS OF REVERENT RANDOMIZED TRIAL

Objective: Blood pressure (BP) variability (BPV) independently predicts adverse outcomes, making it a potential target for treatment. Preliminary data indicate that dihydropyridine calcium channel blockers (CCB) may reduce BPV more than other antihypertensives but data from ad hoc andomised trials are missing. Aim of REVERENT (Reducing blood pressure Variability in Essential hypertension with Ramipril andom Nifedipine GITS) Trial was to compare changes in short-, mid- and long-term BPV in patients treated with a CCB (nifedipine GITS) or an ACE inhibitor (ramipril). Design and method: Untreated (treatment-naïve or after treatment washout) patients with mild to moderate essential hypertension and elevated basal BPV (SD of home SBP&gt; 7 mmHg and/or SD of daytime ambulatory SBP&gt; 12 mmHg), were andomised to open label treatment with nifedipine GITS 30 mg or ramipril 10 mg once daily. BPV after 10 weeks and 12 months of treatment was assessed based on home (primary endpoint; validated A&amp;D UA-651BLE monitor), 24-hour ambulatory (A&amp;D TM 2430) and office (A&amp;D UA-651BLE) measurements and expressed as standard deviation (SD) of obtained readings. Results: 156 patients were included in the intention-to-treat analysis of the main study (10 weeks, primary analysis) and 138 of the extension study (12 months, exploratory analysis). No significant differences were observed between groups at baseline. Patient characteristics, BP and BPV values after 10 weeks of treatment are reported in the table (Table). No significant differences between groups were observed in home and office BPV at the end of main study, also after adjusting for mean BP reduction. 24-hour weighted SD of systolic BP after 10 weeks of treatment was lower in the nifedipine GITS group (p = 0.032) (Table). Exploratory analysis also revealed lower office systolic BPV after 12 months of treatment in nifedipine GITS group (7.2 ± 3.8 vs 9.0 ± 5.3 mmHg, p = 0.026). Conclusions: The study did not identify differences between nifedipine GITS and ramipril in their effect on home BPV, while significant differences in favour of nifedipine GITS were observed in 24-hour and office systolic BPV after 12 months. Clinical impact of these findings remains to be evaluated in outcome studies.

Comparative Efficacy of Antihypertensive Drugs in Dogs: A Systematic Review

Systemic arterial hypertension is a health condition causing target organ damage (TOD) in dogs. Early and effective treatment is essential to prevent hypertensive emergencies and to reduce the risk of TOD. This study investigated the diseases underlying hypertension and compared the short-term efficacy of antihypertensive drugs in dogs. We evaluated the medical records of client-owned dogs treated with antihypertensive drugs between 2017 and 2018. The study included 75 dogs diagnosed with systemic arterial hypertension (systolic blood pressure ≥150 mmHg). The dogs were classified based on treatment with the following antihypertensive drugs: calcium channel blocker amlodipine, angiotensin-converting enzyme inhibitor ramipril, and angiotensin receptor blocker telmisartan, either as monotherapy or combination therapy (telmisartan + amlodipine or ramipril + amlodipine). Systolic blood pressure was measured using an indirect Doppler method over 4 weeks. Naturally acquired hyperadrenocorticism was the most common disorder to be diagnosed in conjunction with systemic hypertension. In the telmisartan group, the systolic blood pressure decreased more rapidly for 3 weeks compared to ramipril. The combination of telmisartan and amlodipine showed the greatest decrease in systolic blood pressure throughout the 4-week treatment period. This study is meaningful as it suggests guidelines for the use of various antihypertensive drugs in dogs.

In-vitro NET-osis induced by COVID-19 sera is associated to severe clinical course in not vaccinated patients and immune-dysregulation in breakthrough infection

Since neutrophil extracellular traps formation (NET-osis) can be assessed indirectly by treating healthy neutrophils with blood-derived fluids from patients and then measuring the NETs response, we designed a pilot study to convey high-dimensional cytometry of peripheral blood immune cells and cytokines, combined with clinical features, to understand if NET-osis assessment could be included in the immune risk profiling to early prediction of clinical patterns, disease severity, and viral clearance at 28 days in COVID-19 patients. Immune cells composition of peripheral blood, cytokines concentration and in-vitro NETosis were detected in peripheral blood of 41 consecutive COVID-19 inpatients, including 21 mild breakthrough infections compared to 20 healthy donors, matched for sex and age. Major immune dysregulation in peripheral blood in not-vaccinated COVID-19 patients compared to healthy subjects included: a significant reduction of percentage of unswitched memory B-cells and transitional B-cells; loss of naïve CD3+CD4+CD45RA+ and CD3+CD8+CD45RA+ cells, increase of IL-1β, IL-17A and IFN-γ. Myeloid compartment was affected as well, due to the increase of classical (CD14++CD16−) and intermediate (CD14++CD16+) monocytes, overexpressing the activation marker CD64, negatively associated to the absolute counts of CD8+ CD45R0+ cells, IFN-γ and IL-6, and expansion of monocytic-like myeloid derived suppressor cells. In not-vaccinated patients who achieved viral clearance by 28 days we found at hospital admission lower absolute counts of effector cells, namely CD8+T cells, CD4+ T-cells and CD4+CD45RO+ T cells. Percentage of in-vitro NET-osis induced by patients’ sera and NET-osis density were progressively higher in moderate and severe COVID-19 patients than in mild disease and controls. The percentage of in-vitro induced NET-osis was positively associated to circulating cytokines IL-1β, IFN-γ and IL-6. In breakthrough COVID-19 infections, characterized by mild clinical course, we observed increased percentage of in-vitro NET-osis, higher CD4+ CD45RO+ and CD8+ CD45RO+ T cells healthy or mild-COVID-19 not-vaccinated patients, reduced by 24 h of treatment with ACE inhibitor ramipril. Taken together our data highlight the role of NETs in orchestrating the complex immune response to SARS-COV-2, that should be considered in a multi-target approach for COVID-19 treatment.

Gut commensal Coprococcus comes diminishes the blood pressure‐lowering effect of ester angiotensin‐converting enzyme inhibitors

IntroductionDrug resistant HTN (rHTN) affects around 15% to 20% of hypertensive (HTN) patients. The underlying mechanisms of resistance to treatment remain poorly understood. The majority of angiotensin‐converting enzyme inhibitors (ACEi) are esters, whereby we hypothesized that select gut microbiota hydrolyze ACEi rendering lower efficacy (Figure 1A). To test this hypothesis, we investigated if and which gut microbe modulates the effectiveness of ACEi.MethodsVancomycin, Meropenem and Omeprazole (VMO) were given to 16‐week‐old male Spontaneously Hypertensive Rats (SHR) at 50 mg/kg/day for five days. A single dose of 8mg/kg Quinapril was orally administered to both SHR and SHR+VMO, and blood pressure (BP) was recorded via radio‐telemetry. Liquid chromatography–mass spectrometry was used to measure the catabolism of quinapril. The hydrolysis of p‐nitro‐phenylbutyrate was used to measure the activity of bacterial esterase. 16S rRNA sequencing was used to study the microbial composition. At last, ester ACEi ramipril and non‐ester lisinopril were co‐administered with Coprococcus comes, respectively, to generalize the effect of C. comes on ACEi's effectiveness.ResultsCompared to the SHR, depletion of gut microbiota in the SHR+VMO group preserved the BP lowering effect of Quinapril, an ester ACEi (Figure 1B). The SHR+VMO group showed (1) reduced Coprococcus (Figure 1C); (2) lower esterase activity per gram of cecal microbiota to hydrolyze quinapril (Figure 1D); (3) a 50% lower reduction in quinapril quantity (nmol) after incubation with 1mg of cecal lysate for 3 hr (Figure 1E). C. comes,a species in Coprococcusgenus, catabolized quinapril in vitro and reduced its BP‐lowering effects in the SHR (Figure 2A‐B). Importantly, C. comes also reduced the BP‐lowering effects of ramipril (ester), but not lisinopril (non‐ester) in the SHR (Figure 2C‐D).ConclusionThese observations constitute the first report of an unrecognized role of a select gut microbe, C. comes, in reducing the effectiveness of ester ACEi. As such, this mechanistic study serves as the foundation for expanding clinical management of antihypertensive drug resistance via manipulation of gut microbiota.

A Neutralizing IL-11 Antibody Improves Renal Function and Increases Lifespan in a Mouse Model of Alport Syndrome.

Alport syndrome is a genetic disorder characterized by a defective glomerular basement membrane, tubulointerstitial fibrosis, inflammation, and progressive renal failure. IL-11 was recently implicated in fibrotic kidney disease, but its role in Alport syndrome is unknown. We determined IL-11 expression by molecular analyses and in an Alport syndrome mouse model. We assessed the effects of a neutralizing IL-11 antibody (×203) versus an IgG control in Col4a3-/- mice (lacking the gene encoding a type IV collagen component) on renal tubule damage, function, fibrosis, and inflammation. Effects of ×203, the IgG control, an angiotensin-converting enzyme (ACE) inhibitor (ramipril), or ramipril+X203 on lifespan were also studied. In Col4a3-/- mice, as kidney failure advanced, renal IL-11 levels increased, and IL-11 expression localized to tubular epithelial cells. The IL-11 receptor (IL-11RA1) is expressed in tubular epithelial cells and podocytes and is upregulated in tubular epithelial cells of Col4a3-/- mice. Administration of ×203 reduced albuminuria, improved renal function, and preserved podocyte numbers and levels of key podocyte proteins that are reduced in Col4a3-/- mice; these effects were accompanied by reduced fibrosis and inflammation, attenuation of epithelial-to-mesenchymal transition, and increased expression of regenerative markers. X203 attenuated pathogenic ERK and STAT3 pathways, which were activated in Col4a3-/- mice. The median lifespan of Col4a3-/- mice was prolonged 22% by ramipril, 44% with ×203, and 99% with ramipril+X203. In an Alport syndrome mouse model, renal IL-11 is upregulated, and neutralization of IL-11 reduces epithelial-to-mesenchymal transition, fibrosis, and inflammation while improving renal function. Anti-IL-11 combined with ACE inhibition synergistically extends lifespan. This suggests that a therapeutic approach targeting IL-11 holds promise for progressive kidney disease in Alport syndrome.

Ramipril Reduces Acylcarnitines and Distinctly Increases Angiotensin-Converting Enzyme 2 Expression in Lungs of Rats.

The angiotensin-converting enzyme 2 (ACE2) receptor has been identified as the entry receptor for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that is abundantly expressed in many organs. With respect to the role of circulating ACE2 and its receptor expression in the pathogenesis of the SARS-CoV-2 infection, it is still debated whether diseases such as hypertension or pharmacotherapies, including ACE inhibitors and angiotensin receptor blockers that affect ACE2 receptor expression, may modulate the severity and outcome of the coronavirus disease 2019 (COVID-19). We therefore tested the hypothesis that treatment with the ACE inhibitor Ramipril affects organ-specific ACE2 receptor mRNA and protein expression as well as the serum metabolome in BioBreeding (BB) rats. Twelve male BioBreeding rats were randomly divided into a Ramipril (10 mg/kg body weight) treatment group or a control group (N = 12; n = 6 per group) over a period of seven days. Ramipril treatment resulted in the reduction of acylcarnitines (C3–C6) out of 64 metabolites. Among the different organs studied, only in the lungs did Ramipril treatment significantly increase both Ace2 mRNA and ACE2 receptor membrane protein levels. Increased ACE2 receptor lung expression after Ramipril treatment was not associated with differences in ACE2 serum concentrations between experimental groups. Our data provide experimental in vivo evidence that the ACE inhibitor Ramipril selectively increases pulmonary ACE2 receptor mRNA and protein levels and reduces acylcarnitines.

Efficacy and Safety of Angiotensin Receptor Neprilysin Inhibitor versus Angiotensin Converting Enzyme Inhibitor in Heart Failure with Reduced Ejection Fraction- A Prospective Observational Study from a Major Tertiary Care Hospital, Assam, India

Introduction: Angiotensin Receptor Neprilysin Inhibitor (ARNI) has shown to reduce morbidity and mortality in comparison to Angiotensin Converting Enzyme Inhibitors (ACEI) inpatients of Heart Failure with Reduced Ejection Fraction (HFrEF). However, the use of ARNI in real-world practice is limited and has not been studied in North Eastern Indian population. Aim: To compare the efficacy and safety of ARNI with ACEI in the management of symptomatic chronic HFrEF in North Eastern Indian population. Materials and Methods: The prospective observational study was conducted in the Department of Cardiology at Gauhati Medical College, Guwahati, Assam, India, from April 2019 to October 2020. The study included patients with diagnosis of chronic HFrEF &lt;40%, on ACEI therapy and who had atleast one hospitalisation for Acute Decompensated Heart Failure (ADHF) in the last 6 months. A total of 63 patients were included in this study. Three patients were lost on follow-up. Out of the 60 patients who were included in the final analysis, 30 patients each were included in two groups i.e, ARNI group and ACEI group. As perdiscretion of the treating physician, the patients were started on ARNI 50 mg twice daily which consist of Sacubitril/Valsartan (24/26 mg), along with other anti-heart failure medications, and they were compared with the patients who continued on ACEI. Uptitration was considered with the aim to double the dose till the target dose was achieved at every 2-4 weeks at the treating physician’s discretion The endpoints included the rate of repeat HF hospitalisation, mortality, renal outcomes and quality of life. All statistical analyses were performed using Statistical Package for Social Sciences (SPSS, IBM) software version 20.0. Results: The demographics and clinical characteristics were comparable between the groups. The dose of ARNI was uptitrated to a maximum of 100 mg twice daily in 11 patients. ARNI significantly reduced HF hospitalisation (36.7% vs. 66.7%; p-value=0.039) and mortality (10% vs. 20%, p-value=0.038) compared to patients with ACEI. There was a significant improvement in the KCCQ score in the ARNI group as compared to the ACEI group (p-value=0.001). Treatment with ARNI was also associated with a significant improvement in the New York Heart Association (NYHA) functional class, serum creatinine, and estimated Glomerular Filtration Rate (eGFR) and a significant reduction in N-Terminal pro B-type Natriuretic Peptide (NT-proBNP) level. Conclusion: In patients with symptomatic HFrEF, shifting to ARNI from background therapy on ACE inhibitors in comparison with continuation of ACE inhibitors appeared to be safe and superior in reducing the risk of death and of hospitalisation, when initiated on outpatient basis. ARNI could not be uptitrated in two-third of patients, yet substantial benefits are evident even at low doses in comparison to ACE inhibitor ramipril.

Ефективність та безпечність триметазидину (Карметадину) в комплексному лікуванні хворих на ішемічну хворобу серця та хронічну серцеву недостатність

Метою дослідження було вивчення ефективності та безпечності триметазидину (Карметадин, компанія World Medicine) в комплексному лікуванні пацієнтів з ішемічною хворобою серця та хронічною серцевою недостатністю. 80 включеним у дослідження хворим з ішемічною хворобою серця (стабільна стенокардія напруження II–III функціонального класу) та хронічною серцевою недостатністю (II–III функціональний клас за класифікацією NYHA) проводили стандартне загальноклінічне обстеження, лабораторні (загальні аналізи крові та сечі, ліпідний, печінковий, нирковий комплекси, коагулограма, глюкоза крові) та інструментальні (електрокардіографія, ехокардіографія, добове моніторування електрокардіограми) дослідження. Пацієнти були розділені на дві групи. У контрольну групу увійшли 40 хворих, яким було призначено комплексне лікування: антитромботична терапія (аспірин 100 мг на добу), бета-адреноблокатор (бісопролол 5–10 мг на добу залежно від початкової частоти серцевих скорочень та рівня артеріального тиску за умови попередньої титрації дози), інгібітор ангіотензинперетворюючого ферменту (раміприл 5–10 мг на добу залежно від початкового рівня артеріального тиску за умови попередньої титрації дози), статин (розувастатин 20 мг на добу), при необхідності були рекомендовані нітрати та діуретики. 40 пацієнтів основної групи на фоні вищезазначеної базисної терапії приймали Карметадин (35 мг 2 рази на добу, таблетки з модифікованим вивільненням препарату). Період спостереження становив 6 місяців. Застосування Карметадину в складі комплексного лікування хворих на ішемічну хворобу серця та хронічну серцеву недостатність асоціювалося з поліпшенням якості життя пацієнтів, суттєвим зменшенням кількості та тривалості ангінозних атак, зниженням потреби в короткодіючих нітратах, поліпшенням функціонального класу серцевої недостатності, збільшенням фракції викиду лівого шлуночка; не призводило до розвитку побічних ефектів, що потребували би відміни препарату.

An ACE inhibitor reduces bactericidal activity of human neutrophils in vitro and impairs mouse neutrophil activity in vivo.

Angiotensin-converting enzyme inhibitors (ACEIs) are used by millions of patients to treat hypertension, diabetic kidney disease, and heart failure. However, these patients are often at increased risk of infection. To evaluate the impact of ACEIs on immune responses to infection, we compared the effect of an ACEI versus an angiotensin receptor blocker (ARB) on neutrophil antibacterial activity. ACEI exposure reduced the ability of murine neutrophils to kill methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, and Klebsiella pneumoniae in vitro. In vivo, ACEI-treated mice infected with MRSA had increased bacteremia and tissue bacteria counts compared to mice treated with an ARB or with no drug. Similarly, ACEIs, but not ARBs, increased the incidence of MRSA-induced infective endocarditis in mice with aortic valve injury. Neutrophils from ACE knockout (KO) mice or mice treated with an ACEI produced less leukotriene B4 (LTB4) upon stimulation with MRSA or lipopolysaccharide, whereas neutrophils overexpressing ACE produced more LTB4 compared to wild-type neutrophils. As a result of reduced LTB4 production, ACE KO neutrophils showed decreased survival signaling and increased apoptosis. In contrast, neutrophils overexpressing ACE had an enhanced survival phenotype. Last, in a cohort of human volunteers receiving the ACEI ramipril for 1 week, ACEI administration reduced neutrophil superoxide and reactive oxygen species production and neutrophils isolated from volunteers during ramipril treatment had reduced bactericidal activity. Together, these data demonstrate that ACEI treatment, but not ARB treatment, can reduce the bacterial killing ability of neutrophils.

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 AimsAngiotensin 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.Method12 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.ResultsIn 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.MO626 Figure: ACE2 mRNA expression and activity. ACE2 mRNA expression in the kidney (A), lung (B) and heart (C). ACE2 enzymatic activity in the kidney (A), lung (E) and heart (F).ConclusionACE2 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.

ANALYSIS OF THE USE OF VARIOUS ANTIHYPERTENSIVE AGENTS IN PATIENTS WITH ARTERIAL HYPERTENSION, CONCOMITANT TYPE 2 DIABETES MELLITUS AND OBESITY (LITERATURE REVIEW AND OWN DATA)

Treatment of patients with arterial hypertension with diabetes and obesity requires taking into account the individual risk of complications and the use of appropriate differentiated tactics, and therefore the appointment of complex treatment with drugs that inhibit excessive activation of the renin-angiotensin-aldosterone system, in particular angiotensin converting enzyme inhibitors and angiotensin II receptor blockers, is the most appropriate and justified. Thus, a comparative analysis of the use of various treatment regimens in patients with arterial hypertension, concomitant type 2 diabetes mellitus and obesity was carried out using the angiotensinconverting enzyme inhibitor ramipril and the angiotensin II receptor blocker telmisartan. The inclusion of ramipril or telmisartan in standard therapy has been shown to have a positive effect on the structural and functional parameters of the left ventricle and ejection fractions. Also, at the same time, the neutral effect of these drugs on carbohydrate and improvement of some components of lipid metabolism in the examined category of patients was determined.

Inhibition of Lysine 63 Ubiquitination Prevents the Progression of Renal Fibrosis in Diabetic DBA/2J Mice.

Diabetic nephropathy (DN) is the most frequent cause of end-stage renal disease. Tubulointerstitial accumulation of lysine 63 (K63)-ubiquitinated (Ub) proteins is involved in the progression of DN fibrosis and correlates with urinary miR-27b-3p downregulation. We explored the renoprotective effect of an inhibitor of K63-Ub (NSC697923), alone or in combination with the ACE-inhibitor ramipril, in vitro and in vivo. Proximal tubular epithelial cells and diabetic DBA/2J mice were treated with NSC697923 and/or ramipril. K63-Ub protein accumulation along with α-SMA, collagen I and III, FSP-1, vimentin, p16INK4A expression, SA-α Gal staining, Sirius Red, and PAS staining were measured. Finally, we measured the urinary albumin to creatinine ratio (uACR), and urinary miR-27b-3p expression in mice. NSC697923, both alone and in association with ramipril, in vitro and in vivo inhibited hyperglycemia-induced epithelial to mesenchymal transition by significantly reducing K63-Ub proteins, α-SMA, collagen I, vimentin, FSP-1 expression, and collagen III along with tubulointerstitial and glomerular fibrosis. Treated mice also showed recovery of urinary miR-27b-3p and restored expression of p16INK4A. Moreover, NSC697923 in combination with ramipril demonstrated a trend in the reduction of uACR. In conclusion, we suggest that selective inhibition of K63-Ub, when combined with the conventional treatment with ACE inhibitors, might represent a novel treatment strategy to prevent the progression of fibrosis and proteinuria in diabetic nephropathy and we propose miR-27b-3p as a biomarker of treatment efficacy.

CHANGES THE LEVELS OF ANGIOTENSIN 1-7 DEPENDING ON TREATMENT WITH BLOCKERS OF RENIN-ANGIOTENSIN SISTEM IN PATIENTS WITH HYPERTENSION AND TYPE 2 DIABETES

Objective: The leading pathogenetic role in development of hypertension plays the renin-angiotensin system (RAS). The angiotensin 1–7 is the novel part of RAS, the metabolic product of angiotensin-II and the important protective cardiovascular factor. The aim of this study was to evaluate the effect of combined treatment with such blockers of RAS as angiotensin-II receptor blocker (ARB) olmesartan or angiotensin-converting enzyme inhibitor (ACEi) ramipril on the blood levels of angiotensin 1–7 in patients with hypertension and type 2 diabetes (T2D). Design and method: The study involved 76 patients with hypertension grades 2–3 and T2D (37 men and 39 women) aged 43 to 70. Depending on antihypertensive treatment, the patients randomized into two groups: patients treated with ARB olmesartan (20–40 mg/day) and calcium channel blocker lercanidipine (10–20 mg/day) (n = 38) and patients received ACEi ramipril (5–10 mg/day) with lercanidipine (10–20 mg/day) (n = 38). All patients treated with lipid-lowering therapy (atorvastatin 20–40 mg/day) and antidiabetic therapy (metformin 1000–2000 mg/day) additionally. The angiotensin 1–7 levels determined by ELISA at baseline and after 12 months of therapy. Results: Both groups did not differ significantly by angiotensin 1–7 levels at baseline. In the olmesartan group the levels of angiotensin 1–7 were 108,39(92,32;121,17) ng/l and in the ramipril group were 104,37(87,16;122,83) ng/l (p &gt; 0,05). After 12 months from the start of the treatment in both groups there was powerful antihypertensive effect. Targeted blood pressure levels were reached in 84.2% of patients (n = 32) treated with olmesartan and in 81.6% of patients (n = 31) treated with ramipril (p &gt; 0.05 - intergroup). In the end of the treatment the levels of angiotensin 1–7 were differed significantly only in patients treated with olmesartan - there was increasing in its concentration by 20.3% (from 108.39(92.32;121.17) ng/l to (130.43(124.42;138.37) ng/l, p &lt; 0.01). In patients treated with ramipril the levels of angiotensin 1–7 were 112.09(104.3;115.33) ng/l, which were not significantly different from basal levels (p &gt; 0.05). Conclusions: The using of ARB olmesartan, unlike ACEi ramipril, significantly increased angiotensin 1–7 blood levels in patients with hypertension and T2D. The increasing the levels of angiotensin 1–7 may have additional cardioprotective value of ARB olmesartan, which requires further study.