Administration Of Angiotensin-converting Enzyme Inhibitors Research Articles

Association of SLCO1B1 gene variants with angiotensin-converting enzyme inhibitor-induced cough in a Pakistani hypertensive cohort.

Angiotensin-converting enzyme inhibitors (ACEIs) are prescribed for individuals with high cardiovascular (CV) risk; however, persistent cough limits the use of ACEIs in a large number of patients. The current study aimed to identify the genetic variants in the SLCO1B1 gene that might be associated with ACEI-related cough in a Pakistani hypertensive population. A prospective cohort study was conducted at a tertiary care hospital in Pakistan. A total of 74 patients who had been treated with ACEIs were recruited through a convenient sampling method. The study was approved by the Institutional Review Board & Ethics Committee of the Shifa International Hospital, Islamabad. Patients provided 2ml of blood for sequencing after signing informed consent. Partial gene sequencing of SLCO1B1 was carried out to find single nucleotide polymorphisms (SNPs) and haplotypes. It was found, through a structured questionnaire, that thirty-eight (38) patients experienced cough within 2weeks of ACEI administration and were considered as a case group (cough), and thirty-six (36) patients were considered as a control group (no cough). The incidence of cough was 51%. We found six different SNPs and 9 haplotypes in the partial gene sequences of SLCO1B1. Haplotype H4 was associated significantly with cough after adjusting for sex and smoking status. Other SNPs and haplotypes were not significantly associated with ACE-Is-induced cough. These findings emphasize the significance of SLCO1B1 genetic variants, specifically H4, as a potential predictor of ACEI-induced cough. It could be included in clinical practice as a possible risk factor for ACEI-induced cough once confirmed in larger clinical trials with bigger sample sizes. The replication of these findings in larger and more diverse populations is likely to contribute to the therapeutic use of ACEIs by predicting ACEI-induced cough.

Effects of Cardioprotective Drugs on 90-Day Mortality or Heart Transplantation in Patients With Fulminant Myocarditis.

Cardioprotective drugs have not been previously shown to improve the prognosis in patients with fulminant myocarditis presentation (FMP). We aimed to investigate whether cardioprotective drugs, including angiotensin-converting enzyme inhibitor (ACEI)/angiotensin II receptor blocker (ARB) and β-blocker, administered during hospitalization improved the prognosis in patients with FMP. This multicenter cohort study conducted in Japan included 755 patients with clinically diagnosed FMP. Those who died within 14 days of admission were excluded, and 588 patients (median age 53 [37-65] years and 40% female) were evaluated. The primary outcome was the composite of 90-day mortality or heart transplantation. The patients were divided into 4 groups according to whether they were administered ACEI/ARB or β-blocker during hospitalization. Administration of ACEI/ARB without β-blocker improved the overall patient outcomes (log-rank test [vs. ACEI/ARB - and β-blocker -]: ACEI/ARB + and β-blocker -, P<0.001; ACEI/ARB - and β-blocker +, P=0.256). Subsequently, a matched cohort of 146 patient pairs was generated for patients with or without ACEI/ARB administration during hospitalization. The outcome-free survival at 90 days was significantly higher in the ACEI/ARB administration group than in the non-administration group (hazard ratio 0.37; 95% confidence interval 0.19-0.71). Administration of ACEI or ARB during hospitalization was associated with favorable outcomes in terms of 90-day mortality and heart transplantation events in patients with clinically diagnosed FMP.

Prevention of Anthracyclines and HER2 Inhibitor-Induced Cardiotoxicity: A Systematic Review and Meta-Analysis.

This meta-analysis and systematic review aim to consolidate evidence on cardiotoxicity prevention and treatment strategies in patients receiving anthracyclines or HER2 receptor inhibitors, vital treatments for breast cancer and hematologic malignancies. By synthesizing existing research, the goal is to provide impactful insights that enhance patient care and outcomes. Comprehensive research across PubMed, Scopus, EMBASE, and the Cochrane Central Register for Controlled Trials was conducted, selecting clinical trials focusing on cardioprotection in anthracyclines or HER2 inhibitor-treated individuals. Effect sizes were computed using OpenMeta (Analyst), with leave-out meta-analysis to assess potential small study effects. Meta-regression explored treatment duration and sample size effects. Evidence quality for primary outcomes was evaluated using ROB, Robins 2, and Newcastle-Ottawa tools. Twenty -three studies involving a total of 14,652 patients (13,221 adults and 1431 kids) were included in the current systematic review and meta-analysis. The risk of bias and methodological quality of the included studies suggested good and moderate quality. Patients prescribed β-blockers demonstrated a 74% lower likelihood of exhibiting cardiotoxicity symptoms (OR 1.736). Similarly, the use of dexrazoxane was linked to a threefold decrease in cardiac abnormalities risk (OR 2.989), and ACE inhibitor administration showed half the risk compared with the control group (OR 1.956). Through this systematic review and meta-analysis, it was shown that there is a reduction in cardiotoxicity from either anthracyclines or HER2 inhibitors in patients receiving pharmacoprophylaxis.

Sickle cell nephropathy; exploring epidemiology, diagnostic challenges, and precision medicine advances

Sickle cell nephropathy (SCN) poses an important challenge in the realm of sickle cell disease (SCD) and sickle cell trait (SCT), especially impacting the pediatric population and progressing to chronic kidney disease (CKD) in adulthood. This review navigates through the epidemiology of SCN, emphasizing its variable clinical course and the age-related dynamics of onset. The intricate challenges in diagnosis are explored, highlighting the evolving landscape of early detection and treatment strategies. The prevalence of SCN is intricately linked to the global distribution of SCD and SCT, with higher incidences in regions where these conditions prevail. Diagnosing SCN presents significant challenges due to its variable clinical course, necessitating advanced imaging techniques and novel biomarkers. Promising biomarkers such as KIM-1 and MCP-1 show potential for early detection and intervention, addressing the limitations of conventional diagnostic methods. Precision medicine, focusing on genetic profiling, emerges as a crucial approach for risk stratification and personalized treatment plans. The multifaceted clinical manifestations of SCN, including hematuria, proteinuria, and hypertension, underscore the importance of timely intervention. Treatment strategies involve the administration of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, hydroxyurea for preventing chronic organ damage, and kidney transplantation for end-stage renal disease. Early diagnosis and intervention are critical to mitigate the progression of SCN and its associated complications, emphasizing the need for collaborative efforts in research and precision medicine to improve outcomes for individuals with SCN.

P798 Study of the concordance between the enzymatic activity of Thiopurine S-methyltransferase and polymorphisms in the TPMT gene in patients with Inflammatory Bowel Disease

Abstract Background Thiopurine therapy is associated with an increased risk of serious adverse events in patients with Inflammatory Bowel Disease (IBD). Thiopurine S-methyltransferase (TPMT) is the enzyme responsible for metabolism, and its determination helps identify patients at risk of toxicity. This study aims to explore the level of correspondence between the TPMT genotype and enzymatic activity (phenotype) with the objective of preventing adverse events prior to the commencement of thiopurine therapy. Methods Consecutive patients with IBD, Crohn’s Disease (CD) or Ulcerative Colitis (UC), were included. Genotype was conducted for the most prevalent TPMT variants (TPMT*2, TPMT*3B, TPMT*3C), TPMT enzymatic activity assessment, and quantification of 6-thioguanine nucleotide (6-TGN) levels. Adverse effects were documented, along with the administration of biologics, mesalazine, ACE inhibitors or allopurinol. The primary objective was to evaluate the concordance between TPMT genotype and phenotype. Secondary objectives included determining the prevalence of genotype and phenotype within our patient cohort, 6-TGN serum levels, the prevalence of adverse events and identifying potential pharmacological inducers of the phenotype. Results A total of 218 patients were included (131 with CD and 81 with UC). Thirteen patients did not initiate thiopurines, and 34.63% (71/205) had discontinued treatment. The most observed adverse events were myelotoxicity (15.12%), gastrointestinal toxicity (12.20%), and hepatic toxicity (5.37%). TPMT activity exhibited a trimodal distribution, with 87.61% (191/218) having normal activity, 11.47% having intermediate activity, and 1% having low activity. Genotypically, 90.83% (198/218) had a wild-type genotype, 8.72% (18/218) had a heterozygous genotype, and 0.5% (1/218) had a homozygous genotype. The concordance index between phenotype and genotype was calculated at 0.57. Significantly, myelotoxicity was associated with the presence of genotypic variants (p=0.004). 6-TGN levels did not correlate with TPMT activity and concurrent medications did not affect TPMT activity . Conclusion The proactive assessment of TPMT (phenotype or genotype) before initiating thiopurine therapy effectively mitigates the occurrence of myelotoxicity in IBD patients. Importantly, the level of concordance between TPMT activity and genotype is moderate, with genotyping serving as the more reliable approach for preselecting patients susceptible to myelotoxic reactions.

Studying the Roles of the Renin-Angiotensin System in Accelerating the Disease of High-Fat-Diet-Induced Diabetic Nephropathy in a db/db and ACE2 Double-Gene-Knockout Mouse Model.

Diabetic nephropathy (DN) is a crucial metabolic health problem. The renin-angiotensin system (RAS) is well known to play an important role in DN. Abnormal RAS activity can cause the over-accumulation of angiotensin II (Ang II). Angiotensin-converting enzyme inhibitor (ACEI) administration has been proposed as a therapy, but previous studies have also indicated that chymase, the enzyme that hydrolyzes angiotensin I to Ang II in an ACE-independent pathway, may play an important role in the progression of DN. Therefore, this study established a model of severe DN progression in a db/db and ACE2 KO mouse model (db and ACE2 double-gene-knockout mice) to explore the roles of RAS factors in DNA and changes in their activity after short-term (only 4 weeks) feeding of a high-fat diet (HFD) to 8-week-old mice. The results indicate that FD-fed db/db and ACE2 KO mice fed an HFD represent a good model for investigating the role of RAS in DN. An HFD promotes the activation of MAPK, including p-JNK and p-p38, as well as the RAS signaling pathway, leading to renal damage in mice. Blocking Ang II/AT1R could alleviate the progression of DN after administration of ACEI or chymase inhibitor (CI). Both ACE and chymase are highly involved in Ang II generation in HFD-induced DN; therefore, ACEI and CI are potential treatments for DN.

Forms of Hereditary Angioedema That Are Independent of Kallikrein and Factor XIIa System

Hereditary angioedema (HAE) is an inherited disorder characterized by recurrent episodes of severe soft tissue swelling involving skin and mucous membranes. In most cases, edema is caused by excessive formation of the vasoactive nanopeptide bradykinin (BK) due to dysregulation of the plasma kallikrein-kinin system (KKS). The KKS consists of the zymogens prekallikrein (PK) and factor XII (FXII) and the cofactor/substrate high-molecular-weight kininogen (HK). PK and FXII reciprocally convert each other to the proteases plasma kallikrein (PKa) and FXIIa. PKa cleaves HK after Lys362 and Arg371 to release bradykinin. In most cases of HAE, increased KKS activation is due to low plasma activity of C1-Inhibitor (C1-INH), the main regulator of PKa and FXIIa. However, ~10% of HAE patients have normal C1-INH activity (HAEnC1). A relationship between fibrinolysis and kinin formation was first described in 1971. The fibrinolytic protease plasmin activates FXII and cleaves HK, although it is unclear that this results in significant bradykinin generation. Recently mutations in the PLG gene encoding plasminogen (Lys311Glu) and the KNG1 gene encoding HK and the related protein low-molecular-weight kininogen (LK, Met361Lys) were identified in patients with HAEnC1. Here we describe how the fibrinolytic system contributes to angioedema in patients with these mutations. Human Glu-plasminogen (Plg), HK and LK were expressed in HEK293 cells. Lys311 in plasminogen was changed to glutamic acid, and Met361 in HK and LK were changed to lysine, by site directed mutagenesis. Wild type (Plg-Lys311) and variant (Plg-Glu311) plasminogen were converted to plasmin (Plm-Lys311 and Plm-Glu311) with urokinase. The capacity of plasmin to cleave HK and LK were studied with SDS-PAGE, western blots and kinin ELISA. Cleavage of wild type HK-Met361 and LK-Met361 and variant HK-Lys361 and LK-Lys361 by PKa and plasmin were assessed in a similar manner. The types of kinin released during reactions were determined by mass spectroscopy. Normal plasma was supplemented with Plg-Lys311 or Plg-Glu311, and tPA was added to generate plasmin. Bradykinin release was substantially greater with Plm-Glu311 than Plm-Lys311. This held when reactions were run in plasma lacking FXII or PK, indicating activation of the KKS was not responsible for kinin production. Using plasma-derived proteins, PKa released bradykinin 100-fold faster from HK than LK, and released bradykinin from HK ~50-fold faster than did plasmin. PKa and plasmin released bradykinin at comparable relatively slow rates from LK. Plm-Glu311 released bradykinin from HK 10-fold faster, and from LK 3-fold faster, than in reactions with Plm-Lys311. In experiments in which kininogen deficient plasma was supplemented with either HK or LK to a physiologic concentration, the majority of bradykinin released by Plm-Glu311 was from LK. PKa-catalyzed release of bradykinin from wild type HK-Met361 and variant HK-Lys361 comparably. The same held for LK-Met361 and LK-Lys361. However, plasmin released kinin from HK-Lys361 and LK-Lys361 3.3-fold and 13-fold faster than from HK-Met361 and LK-Met361. While the kinin released from HK-Met361 and LK-Met361 was bradykinin, plasmin released the decapeptide Lys-bradykinin (kallidin) from HK-Lys361 and LK-Lys36. Our studies indicate that angioedema in some patients with HAEnC1 may be due to fibrinolytic activity, and not to KKS activity. Both HK and LK may be substrates in such patients. As the plasma LK concentration is ~4-fold higher than HK, it may be the main pathologic kinin source. The plasmin Lys311Glu substitution converts the protease into a more efficient kininogenase. Fibrinolytic activity is normally brisk in the mouth, perhaps explaining why patients with the Lys311Glu mutation primarily suffer from oral-lingual angioedema. The findings raise the possibility that oral-lingual edema after tPA infusion or ACE inhibitor administration may also be due to plasmin-mediated cleavage of LK and HK. The Met361Lys substitution in HK and LK introduces a novel protease cleavage site immediately upstream from a normal PKa cleavage site. The novel site is preferred over the normal site by plasmin, but not PKa. Several treatments for HAE directed at neutralizing PKa or FXIIa activity have been developed. Our results suggest that such drugs may be less effective in patients with HAEnC1 in which disease mechanisms operate independently of the KKS.

Myocardial injury and related mortality in hospitalized patients with COVID-19 during the Omicron pandemic: new perspectives and insights

Myocardial injury is one of the most common comorbidity in SARS-CoV-2 infected patients, and has poor prognosis. However, the incidence of myocardial injury in patients with SARS-CoV-2 infection has not been sufficiently investigated during the Omicron wave. We conducted a retrospective study of 2690 patients with confirmed SARS-CoV-2 Omicron infection from Tongji Hospital. The results indicated that the myocardial injury accounted for 30.8% of the total patients with SARS-CoV-2 infection and was associated with higher in-hospital mortality than those without injury before and after propensity score matching (PSM) [adjusted hazard ratio (HR), 10.61; 95% confidence interval (CI), 7.76–14.51; P ​< ​0.001; adjusted HR, 2.70; 95% CI, 1.86–3.93; P ​< ​0.001; respectively]. Further, the levels of cytokines (IL-1β, IL-6, IL-10, and TNF-α) in patients with myocardial injury were higher than those without injury, and the higher levels of cytokines in the myocardial injury group were associated with increased mortality. Administration of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACEI/ARB) could significantly reduce the mortality in patients with myocardial injury (adjusted HR, 0.52; 95% CI, 0.38–0.71; P ​< ​0.001). Additionally, the level of angiotensin II increased in patients with SARS-CoV-2 infection was even higher in myocardial injury group compared to those without injury. Collectively, the study summarized the clinical characteristic and outcome of SARS-CoV-2 infected patients with myocardial injury during the Omicron wave in China, and validated the protective role of ACEI/ARB in improving the survival of those with myocardial injury.

Sarkopenia pada Lanjut Usia: Patogenesis, Diagnosis dan Tata Laksana

‘Sarcopenia’ involves a progressive age-related loss of muscle mass and associated muscle weakness that renders frail elders susceptible to serious injury from sudden falls and fractures and losing their functional independence. This disease has a complex multifactorial pathogenesis, which involves not only age-related changes in neuromuscular function, muscle protein turnover, and hormone levels and sensitivity, but also a chronic pro-inflammatory state, oxidative stress, and behavioral factors – in particular, nutritional status and degree of physical activity. In the previous definition by the European Working Group on Sarcopenia in Older People (EWGSOP) in 2010, the diagnosis of sarcopenia requires the presence of both low muscle mass and low muscle function. Since the 2010 definition is difficult to be translated to clinical practice, the EWGSOP uses low muscle strength as the primary parameter of sarcopenia in the 2018 definition; sarcopenia is probable when low muscle strength is detected. A sarcopenia diagnosis is confirmed by the presence of low muscle quantity or quality. When low muscle strength, low muscle quantity/quality and low physical performance are all detected, sarcopenia is considered severe. According to the pathophysiological factors involved in the pathogenesis of sarcopenia, different treatment strategies against sarcopenia are resistance exercise training, increase essential amino acids intake, vitamin D supplementation for those with vitamin D deficiency, polyunsaturated fatty acids (PUFAs) supplementation, testosterone supplementation, angiotensin-converting enzyme inhibitor administration.

Novel Diabetic Nephropathy-Based Hypertension Treatment for Type-2 Diabetes Mellitus and CKD Patients: A Mini Review

Diabetes mellitus is known to result in persistent renal impairment among individuals with the condition and is presently the primary aetiology of terminal-stage renal disease, with more than fifty percent of dialysis patients being affected. The prevalence of diabetes continues to rise, resulting in a decline in individuals' health status and imposing significant financial burdens on healthcare systems. Accurately distinguishing between the various types of diabetes is crucial in order to provide appropriate treatment that mitigates the severity of associated complications and their significant consequences. The co-occurrence of diabetes and renal disease has been found to be linked with a significant fourfold rise in both the frequency and fatality of cardiovascular disease. Pharmacological interventions aimed at reducing blood pressure have been a crucial component in the management of diabetic nephropathy for several decades. The past decade has witnessed a decline in the occurrence of end-stage renal disease, owing to enhanced care measures such as the administration of hypertension medication. It is assumed in clinical practice recommendations that angiotensin-converting enzyme inhibitors and angiotensin-receptor antagonists hold an equivalent status. The efficacy of low doses of ACEI and ARB in reducing proteinuria was found to be superior to that of high doses. The co-administration of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) has been observed to elicit a more pronounced reduction in 24-hour proteinuria and urinary albumin excretion rate (UAER) in comparison to the singular administration of either ACEI or ARB.

Effect of Angiotensin-Converting Enzyme Inhibitors/Angiotensin Receptor Blockers on In-Hospital Outcomes Based on Renal Function Among Critically Ill Patients: Findings From the Medical Information Mart for Intensive Care IV Database.

Renal dysfunction is associated with increased mortality and length of hospital stay in critically ill patients. However, it remains unclear whether the early administration of an angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) for intensive care unit patients with renal dysfunction is associated with reduced in-hospital mortality. We conducted a retrospective analysis of critically ill patients who received early administration of an ACEI/ARB within 72hours after being hospitalized. Patients were selected from the Medical Information Mart for Intensive Care IV database. We included 18,986 critically ill patients in our analysis. After propensity score matching, our final study cohort of 4974 patients consisted of patients who received early administration of an ACEI/ARB (n=2487) and nonusers (n=2487). Results of logistic regression showed that early administration of an ACEI/ARB was associated with reduced risk of in-hospital mortality (odds ratio, 0.64; 95% confidence interval, 0.53-0.77; P<.001) and intensive care unit death (odds ratio, 0.56; 95% confidence interval, 0.45-0.70; P<.001) when compared to nonusers. There was no meaningful interaction for early administration of an ACEI/ARB versus nonusers across estimated glomerular filtration rate in outcomes. Sensitivity analysis showed there was no difference in the outcomes between early administration of ACEI and that of ARB. In this study, we found that early administration of an ACEI/ARB was associated with a reduced risk of in-hospital adverse outcomes based on renal function among critically ill patients. There was no interaction between early administration of an ACEI/ARB and in-hospital adverse outcomes across estimated glomerular filtration rate.

#4590 A PROSPECTIVE STUDY OF EPLERENONE IN THE TREATMENT OF PATIENTS WITH GLOMERULONEPHRITIS

Abstract Background and Aims Clinical evidence suggests that high aldosterone plasma levels contributes to progressive kidney disease. Although administration of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin type 1 receptor blockers (ARB) can delay kidney disease progression, plasma aldosterone levels may increase to a significant extent even after the initiation of such treatment. Thus, administration of mineralocorticoid receptor antagonists such as spironolactone, on top of treatment with ACEi or ARBs has been shown to reduce albuminuria and slow down kidney function deterioration. Nevertheless, there is scanty evidence on the effect of eplerenone in patients with kidney disease due to glomerulonephritis. Method In this prospective open-label study, we evaluated the effects of eplerenone in patients with biopsy proven glomerulonephritis already treated with ACEi or ARBs. Patients were divided in the active treatment arm, who received 25 mg of eplerenone daily besides ACEi or ARBs, and a control group that received only standard treatment. Protein excretion in 24 h urine, eGFR, blood pressure and serum K+ levels were measured at 3, 6 and 12 months after study initiation. Results Out of 83 patients who were screened, 62 patients were included in the final analysis. Twenty-six received eplerenone and 36 were treated with ACEi (25) or ARBs (9) alone (controls). After 1 year of treatment with eplerenone, proteinuria decreased from 1597 to 1145 mg/24 h while it did not alter in controls. Eplerenone reduced proteinuria especially in those with baseline proteinuria of &amp;gt;1000 mg/24 h. Kidney function remained stable in patients treated with eplerenone (from eGFR: 82.51±22.6 to 84.68±31.7 ml/min/1.73 m2, p = 0.8) and showed a non significant deterioration in controls (from eGFR: 68.39±26.2 to 66.63±29.8 ml/min/1.73 m2, p = 0.08). Systolic blood pressure was significantly reduced in the active treatment arm (from 128.1±17.5 to 126.3±10.93 mmHg, p = 0.03), whereas eplerenone did not increase serum K+ levels or had any other significant adverse effect. Conclusion Administration of eplerenone at a dose of 25 mg/day, on top of treatment with ACEi or ARBs, can further reduce proteinuria and systolic blood pressure in patients with chronic glomerulonephritis.

Association polymorphism of guanine nucleotide-binding protein β3 subunit (GNB3) C825T and insertion/deletion of the angiotensin-converting enzyme (ACE) gene with peripartum cardiomyopathy.

Peripartum cardiomyopathy (PPCM) is a potentially life-threatening pregnancy-related heart disease. Genetic roles such as gene polymorphisms may relate to the etiology of PPCM. This study analyzes the association between single nucleotide gene polymorphism (SNP) guanine nucleotide-binding protein beta-3 subunit (GNB3) C825T and insertion/deletion (I/D) of the angiotensin-converting enzyme (ACE) gene with the incidence of PPCM. An analytic observational study with a case-control design was conducted at the Integrated Cardiac Service Center of Dr. Soetomo General Hospital, Surabaya, Indonesia. PPCM patients of the case and control groups were enrolled. Baseline characteristic data were collected and blood samples were analyzed for SNP in the GNB3 C825T gene and for I/D in the ACE gene by using the polymerase chain reaction, restriction fragment length polymorphism, and Sanger sequencing. We also assessed ACE levels among different ACE genotypes using a sandwich-ELISA test. A total of 100 patients were included in this study, with 34 PPCM cases and 66 controls. There were significant differences in GNB3 TT and TC genotypes in the case group compared with that in the control group (TT: 35.3% vs. 10.6%, p = 0.003; TC: 41.2% vs. 62.5%, p = 0.022). The TT genotype increased the risk of PPCM by 4.6-fold. There was also a significant difference in the ACE DD genotype in the case group compared with that in the control group (26.5% vs. 9.1%, p = 0.021). DD genotypes increased the risk of PPCM by 3.6-fold. ACE levels were significantly higher in the DD genotype group than in the ID and II genotype groups (4,356.88 ± 232.44 pg/mL vs. 3,980.91 ± 77.79 pg/mL vs. 3,679.94 ± 325.77 pg/mL, p < 0.001). The TT genotype of GNB3 and the DD genotype of the ACE are likely to increase the risk of PPCM. Therefore, these polymorphisms may be predisposing risk factors for PPCM incidence. ACE levels were significantly higher in the DD genotype group, which certainly had clinical implications for the management of PPCM patients in the administration of ACE inhibitors as one of the therapy options.

Post-Stroke Pneumonia in Real-World Practice: Background, Microbiological Examination, and Treatment.

Post-stroke pneumonia (PSP) has an impact on acute ischemic stroke (AIS). Although predictive scores for PSP have been developed, it is occasionally difficult to predict. Clarifying how PSP was treated after its onset in clinical practice is important. Admitted patients with AIS over a 2-year period were retrospectively reviewed. Of 281 patients with AIS, 24 (8.5%) developed PSP. The integer-based pneumonia risk score was higher in patients with PSP. The onset of PSP was frequently seen up to the 4th day of hospitalization. Of patients with PSP, sputum examination yielded Geckler 4 or 5 in only 8.3%. Angiotensin-converting enzyme inhibitor (ACE-I) was more frequently administered to patients with PSP; however, all these cases were started with ACE-I following PSP onset. Nasogastric tubes (NGTs) were inserted in 16 of the patients with PSP, of whom 11 were inserted following PSP onset. Multivariate analysis showed that PSP onset was a poor prognostic factor independent of the female sex, urinary tract infection, and National Institutes of Health Stroke Scale. PSP treatment would benefit from the administration of antimicrobials and ACE-I, as well as NGT insertion. To select effective agents for PSP and evaluate the indications for NGT insertion, further case studies are needed.

The complete reversal effect following angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and beta-blockers after the primary diagnosis of dilated cardiomyopathy.

Whether combination administration of angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and beta-blockers (BBs) has a "reversal" effect on cardiac structure and function for first-diagnosed idiopathic dilated cardiomyopathy (FSIDCM) patients with unclear etiologies and inducements is unknown. We studied the effect of the protocol on FSIDCM patients. The effect was investigated in 26 FSIDCM patients. The criteria of "complete reversal" included left ventricular end-diastolic diameter (LVEDD) ≤50 mm for females or ≤55 mm for males and left ventricular ejection fraction (LVEF) ≥45%; the criteria of "partial reversal" was the decreased rate of LVEDD (ΔLVEDD) >10% or the increase rate of LVEF (ΔLVEF) >10%; the criteria of "no reversal" included LVEDD >50 mm for females or >55 mm for males and ΔLVEDD <10%, and LVEF <45% and ΔLVEF <10%. Within the follow-up period, nine patients showed "complete reversal," eight "partial reversal," and nine "no reversal." Improvements in echocardiogram parameters were the most significant in "complete reversal" patients (P < 0.001), followed by "partial reversal" and "no reversal" patients (P < 0.05). The QRS (Q wave, R wave, S wave) duration and symptoms duration in "complete reversal" patients were the shortest, followed by "partial reversal" and "no reversal" patients. ACEIs or ARBs and BBs have a "complete reversal" effect on the left ventricular size and function of some FSIDCM patients. Patients with a narrow QRS and short symptom duration may have a good response.

Intravital imaging of hemodynamic glomerular effects of enalapril or/and empagliflozin in STZ-diabetic mice.

Background: Diabetic kidney disease is the leading cause of end-stage renal disease. Administration of ACE inhibitors or/and SGLT2 inhibitors show renoprotective effects in diabetic and other kidney diseases. The underlying renoprotective mechanisms of SGLT2 inhibition, especially in combination with ACE inhibition, are incompletely understood. We used longitudinal intravital microscopy to directly elucidate glomerular hemodynamics on a single nephron level in response to the ACE inhibitor enalapril or/and the SGLT2 inhibitor empagliflozin. Methods: Five weeks after the induction of diabetes by streptozotocin, male C57BL/6 mice were treated with enalapril, empagliflozin, enalapril/empagliflozin or placebo for 3 days. To identify hemodynamic regulation mechanisms, longitudinal intravital multiphoton microscopy was employed to measure single nephron glomerular filtration rate (snGFR) and afferent/efferent arteriole width. Results: Diabetic mice presented a significant hyperfiltration. Compared to placebo treatment, snGFR was reduced in response to enalapril, empagliflozin, or enalapril/empagliflozin administration under diabetic conditions. While enalapril treatment caused significant dilation of the efferent arteriole (12.55 ± 1.46 µm vs. control 11.92 ± 1.04 µm, p < 0.05), empagliflozin led to a decreased afferent arteriole diameter (11.19 ± 2.55 µm vs. control 12.35 ± 1.32 µm, p < 0.05) in diabetic mice. Unexpectedly under diabetic conditions, the combined treatment with enalapril/empagliflozin had no effects on both afferent and efferent arteriole diameter change. Conclusion: SGLT2 inhibition, besides ACE inhibition, is an essential hemodynamic regulator of glomerular filtration during diabetes mellitus. Nevertheless, additional mechanisms—independent from hemodynamic regulation—are involved in the nephroprotective effects especially of the combination therapy and should be further explored in future studies.

Sartans and ACE Inhibitors: Mortality in Patients Hospitalized with COVID-19. Retrospective Study in Patients on Long-Term Treatment Who Died in the Italian Hospitals of Area Vasta n.5-Marche Region.

Introduction: During the 2019 Coronavirus pandemic (COVID-19), a concern emerged regarding a possible correlation between the severe form of SARS-CoV-2 infection and administration of ACE-Inhibitors (ACE-I) and Sartans (ARB), since long-term use of these drugs may potentially result in an adaptive response with up-regulation of the ACE 2 receptor. Given the crucial role of ACE2, being the main target for virus entry into the cell, the potential consequences of ACE2 up-regulation have been a source of debate. The aim of this retrospective cohort study on COVID-19-positive patients who died is to investigate whether previous long-term exposure to ACE-I and/or ARB was associated with higher mortality due to COVID-19 infection, compared to all other types of drug treatment. Methods: We analysed the clinical and demographic data of 615 patients hospitalized for COVID-19 at the two hospitals of the Vasta Area n.5, between March 2020 and April 2021. Among them, 86 patients, treated with ACE-Is and/0 ARBs for about 12 months, died during hospitalization following a diagnosis of acute respiratory failure. Several quantitative and qualitative variables were recorded for all patients by reading their medical records. Results: The logistic model showed that the variables that increase mortality are age and comorbid diseases. There were no demonstrable mortality effects with ACE-I and ARB intake. Conclusions: The apparent increase in morbidity in patients with COVID-19 who received long-term treatment with ACE-I or ARB is not due to the drugs themselves, but to the conditions associated with their use.

The divergent protective effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on clinical outcomes of coronavirus disease 2019 (COVID-19): a systematic review and meta-analysis.

Some studies have speculated that patients on angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) are more susceptible to adverse outcomes of coronavirus disease 2019 (COVID-19). Here, we performed a systematic review and meta-analysis to evaluate the safety and efficacy of administering ACEIs and ARBs to patients with COVID-19. Studies of COVID-19 were collected from the PubMed, Embase, medRxiv and BioRxiv databases. The pooled relative risk odds ratio (OR) and 95% confidence interval (95% CI) were calculated. Subgroup analyses were conducted by medication (ACEIs and ARBs) and geographical location (China and outside China). Inter-study heterogeneity was assessed using meta-regression. Begg's test, Egger's test and funnel plots were adopted to evaluate possible publication bias. Thirty studies containing 10,434 adult patients were included in our meta-analysis. The pooled result indicated that the administration of ACEIs or ARBs reduced the risk of severe/death outcomes for COVID-19 patients. Meanwhile, a significant reduction in the risk of severe/death outcomes was observed to be associated with the administration of ACEIs or ARBs among COVID-19 patients in China, but this association was weaker for studies outside China. Furthermore, ACEI therapy was found to carry a significantly lower risk of an adverse clinical outcome. Our systematic review and meta-analysis found that neither ACEIs nor ARBs worsen the clinical outcomes of COVID-19 patients. On the contrary, we found that patients treated with ACEIs or ARBs have a reduced risk of severe/death outcomes, especially in Asia. Furthermore, ACEIs may reduce the risk of severe/death outcomes. Therefore, treatment interruption of ACEI or ARB therapy during COVID-19 infection is not recommended.

Why not change the therapy of hypertension in patients with COVID-19. Dual role of angiotensin-converting enzyme 2

Despite many organizational and medical efforts, the COVID-19 epidemic continues and is taking a lethal toll. Preliminary reports have already reported that the mortality associated with this disease is much higher in people with comorbidities, including hypertension. SARS-CoV-2 virus enters the body through the receptor which is the angiotensin converting enzyme 2 (ACE2). The administration of angiotensin converting enzyme inhibitors or sartans increases the activity of this enzyme. Therefore, there was a suspicion that patients treated with these preparations become more easily infected, and the infection itself is more severe and is associated with greater mortality. On the other hand, the ACE2 enzyme is known to reduce the risk of lung damage. The paper presents current reports describing the frequency of SARS-CoV-2 virus infection in patients with hypertension, the course of infection and the effect of administration of ACE inhibitors and sartans on the mortality of these patients. The presented data indicate that the use of angiotensin converting enzyme inhibitors and sartans in patients with COVID-19 does not worsen the course of the disease, and according to some authors this treatment even reduces the mortality of this infection.

Prognostic value of postural hypotension in hospitalized patients with heart failure

Although postural hypotension (PH) is reportedly associated with mortality in the general population, the prognostic value for heart failure is unclear. This was a post-hoc analysis of FRAGILE-HF, a prospective multicenter observational study focusing on frailty in elderly patients with heart failure. Overall, 730 patients aged ≥ 65 years who were hospitalized with heart failure were enrolled. PH was defined by evaluating seated PH, and was defined as a fall of ≥ 20 mmHg in systolic and/or ≥ 10 mmHg in diastolic blood pressure within 3 min after transition from a supine to sitting position. The study endpoints were all-cause death and heart failure readmission at 1 year. Predictive variables for the presence of PH were also evaluated. PH was observed in 160 patients (21.9%). Patients with PH were more likely than those without PH to be male with a New York Heart Association classification of III/IV. Logistic regression analysis showed that male sex, severe heart failure symptoms, and lack of administration of angiotensin-converting enzyme inhibitors were independently associated with PH. PH was not associated with 1-year mortality, but was associated with a lower incidence of readmission after discharge after adjustment for other covariates. In conclusion, PH was associated with reduced risk of heart failure readmission but not with 1-year mortality in older patients with heart failure.