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Journal of Cardiovascular Pharmacology... 2023Ventricular remodeling is a mal-adaptive process. Both angiotensin-converting enzyme inhibitors and sacubitril/valsartan have been shown to reverse remodeling in mostly...
Ventricular remodeling is a mal-adaptive process. Both angiotensin-converting enzyme inhibitors and sacubitril/valsartan have been shown to reverse remodeling in mostly uncontrolled observational studies. There is a lack of head-to-head studies. This cohort study compares the remodeling effects of angiotensin receptor blockers combined with a neprilysin inhibitor (ARNI) and perindopril in heart failure with reduced ejection fraction (HFrEF) patients between January 2017 and December 2020. Inclusion criteria: (i) age > 18 years, (ii) recent diagnosis of de-novo HFrEF (EF < 40%), (iii) baseline echocardiography performed not more than 2 months prior to treatment onset, and (iv) follow-up echocardiography performed not earlier than 6 months and not later than 18 months posttreatment onset. No prior treatment with renin-angiotensin-aldosterone system inhibitors was permitted in the ARNI group. Left ventricular ejection fraction (LVEF), left ventricular end-diastolic volume (LVEDV), and left ventricular end-systolic volume (LVESV) were analyzed. A two-way repeated measure ANOVA (for normally distributed) and generalized estimating equation test for nonnormally distributed interval dependent variables. Mean comparison between and within groups was performed using the Bonferroni test. Following an average treatment period of 9 months, LVEF improved from 24.9% to 36.4% for ARNI and from 28.7% to 40.5% for perindopril, increments of 11.5% and 11.8% resp. (Bonferroni test [ ≤ .05]). LVEDV was reduced by 8.4 mL and 3.2 mL, and LVESV by 17.9 mL and 10.8 mL for ARNI and perindopril resp. Only the reduction of LVESV for ARNI was statistically significant ( = .007). Both ARNI and perindopril yielded a significant improvement in the LVEF within 9 months. The remodeling effect of ARNI seems stronger because of the greater improvements in left ventricular volumes.
Topics: Humans; Adult; Middle Aged; Heart Failure; Stroke Volume; Cohort Studies; Perindopril; Ventricular Function, Left; Tetrazoles; Treatment Outcome; Valsartan; Angiotensin Receptor Antagonists; Drug Combinations
PubMed: 37635324
DOI: 10.1177/10742484231195019 -
Materia Socio-medica Mar 2020Perindopril is a tissue-specific ACE inhibitor with 24 hours long blood pressure-lowering effect, which protects blood vessels and decreases the variability of blood...
INTRODUCTION
Perindopril is a tissue-specific ACE inhibitor with 24 hours long blood pressure-lowering effect, which protects blood vessels and decreases the variability of blood pressure.
AIM
The aim of our study was to investigate the effectiveness and safety of perindopril in newly diagnosed or previously treated but uncontrolled adult hypertensive patients.
METHODS
This prospective cohort study included primary care patients with essential hypertension. Primary study outcomes were decreasing arterial blood pressure to normal levels (<140/90 mmHg), reducing systolic arterial blood pressure for 10 mmHg or more and reducing diastolic arterial blood pressure for 5 mmHg or more. Safety was evaluated by type and frequency of adverse events.
RESULTS
In the great majority of the study patients (more than 96%) perindopril was effective as monotherapy, achieving a significant reduction in both systolic and diastolic blood pressure, and in three-quarters of the study patients it normalized both systolic and diastolic blood pressure. The effectiveness of perindopril was shown in both patients with previously and newly diagnosed hypertension, adverse events were mild and rare, even hyperkalemia was encountered less often than before the onset of the therapy with perindopril.
CONCLUSIONS
Our study confirmed excellent effectiveness of perindopril in the treatment of essential hypertension and its remarkable safety. When used as monotherapy of hypertension, perindopril's doses should be carefully titrated until the achievement of full effect, which in some patients should be awaited for at least 6 months from onset of the therapy.
PubMed: 32410885
DOI: 10.5455/msm.2020.32.4-9 -
British Journal of Pharmacology Mar 2021Fibrosis is a hallmark of chronic kidney disease (CKD) that significantly contributes to renal dysfunction, and impairs the efficacy of stem cell-based therapies. This...
BACKGROUND AND PURPOSE
Fibrosis is a hallmark of chronic kidney disease (CKD) that significantly contributes to renal dysfunction, and impairs the efficacy of stem cell-based therapies. This study determined whether combining bone marrow-derived mesenchymal stem cells (BM-MSCs) with the renoprotective effects of recombinant human relaxin (serelaxin) could therapeutically reduce renal fibrosis in mice with one kidney/deoxycorticosterone acetate/salt (1K/DOCA/salt)-induced hypertension, compared with the effects of the ACE inhibitor, perindopril.
EXPERIMENTAL APPROACH
Adult male C57BL/6 mice were uni-nephrectomised and received deoxycorticosterone acetate and saline to drink (1K/DOCA/salt) for 21 days. Control mice were uni-nephrectomised but received water over the same time period. Sub-groups of 1K/DOCA/salt-injured mice (n = 5-8 per group) were treated with either serelaxin (0.5 mg·kg ·day ) or BM-MSCs (1 × 10 per mouse) alone; both treatments combined (with 0.5 × 10 or 1 × 10 BM-MSCs per mouse); or perindopril (2 mg·kg ·day ) from days 14-21.
KEY RESULTS
1K/DOCA/salt-injured mice developed elevated BP and hypertension-induced renal damage, inflammation and fibrosis. BM-MSCs alone reduced the injury-induced fibrosis and attenuated BP to a similar extent as perindopril. Serelaxin alone modestly reduced renal fibrosis and effectively reduced tubular injury. Strikingly, the combined effects of BM-MSCs (at both doses) with serelaxin significantly inhibited renal fibrosis and proximal tubular epithelial injury while restoring renal architecture, to a greater extent than either therapy alone, and over the effects of perindopril.
CONCLUSION AND IMPLICATIONS
Combining BM-MSCs and serelaxin provided broader renoprotection over either therapy alone or perindopril and might represent a novel treatment for hypertensive CKD.
Topics: Animals; Blood Pressure; Desoxycorticosterone; Desoxycorticosterone Acetate; Hypertension; Hypertension, Renal; Kidney; Male; Mesenchymal Stem Cells; Mice; Mice, Inbred C57BL
PubMed: 33450051
DOI: 10.1111/bph.15361 -
Current Oncology (Toronto, Ont.) Apr 2022Two anti-cancer agents, doxorubicin (DOX) and trastuzumab (TRZ), are commonly used in the management of breast cancer in women. Despite their efficacy in reducing the...
BACKGROUND
Two anti-cancer agents, doxorubicin (DOX) and trastuzumab (TRZ), are commonly used in the management of breast cancer in women. Despite their efficacy in reducing the morbidity and mortality of individuals with breast cancer, the use of these agents is limited by adverse cardiotoxic side effects. Both the nutraceutical agent flaxseed (FLX) and the pharmaceutical drug perindopril (PER) have been studied individually in the prevention of chemotherapy-mediated cardiac dysfunction. The objective of this study was to determine whether the prophylactic administration of FLX is comparable and/or synergistic with PER in preventing DOX + TRZ-induced cardiotoxicity.
METHODS
Over a six-week period, 81 wild-type C57Bl/6 female mice (8-12 weeks old) were randomized to receive regular chow (RC) or 10% FLX-supplemented diets with or without PER (3 mg/kg/week; oral gavage). Starting at week 4, mice were randomized to receive a weekly injection of saline or DOX (8 mg/kg) + TRZ (3 mg/kg). Serial echocardiography was conducted weekly and histological and biochemical analyses were performed at the end of the study.
RESULTS
In mice treated with RC + DOX + TRZ, left ventricular ejection (LVEF) decreased from 75 ± 2% at baseline to 37 ± 3% at week 6. However, prophylactic treatment with either FLX, PER, or FLX + PER partially preserved left ventricular systolic function with LVEF values of 61 ± 2%, 62 ± 2%, and 64 ± 2%, respectively. The administration of FLX, PER, or FLX + PER was also partially cardioprotective in preserving cardiomyocyte integrity and attenuating the expression of the inflammatory biomarker NF-κB due to DOX + TRZ administration.
CONCLUSION
FLX was equivalent to PER at preventing DOX + TRZ-induced cardiotoxicity in a chronic in vivo murine model.
Topics: Animals; Breast Neoplasms; Cardiotoxicity; Doxorubicin; Female; Flax; Humans; Mice; Mice, Inbred C57BL; Perindopril; Trastuzumab
PubMed: 35621631
DOI: 10.3390/curroncol29050241 -
Journal of Clinical Hypertension... Aug 2023Studies have shown that angiotensin converting enzyme inhibitors (ACEIs) are superior in primary and secondary prevention for cardiac mortality and morbidity to... (Meta-Analysis)
Meta-Analysis
Studies have shown that angiotensin converting enzyme inhibitors (ACEIs) are superior in primary and secondary prevention for cardiac mortality and morbidity to angiotensin receptor blocker (ARBs). One of the common side effects from ACEI is dry cough. The aims of this systematic review, and network meta-analysis are to rank the risk of cough induced by different ACEIs and between ACEI and placebo, ARB or calcium channel blockers (CCB). We performed a systematic review, and network meta-analysis of randomized controlled trials to rank the risk of cough induced by each ACEI and between ACEI and placebo, ARB or CCB. A total of 135 RCTs with 45,420 patients treated with eleven ACEIs were included in the analyses. The pooled estimated relative risk (RR) between ACEI and placebo was 2.21 (95% CI: 2.05-2.39). ACEI had more incidences of cough than ARB (RR 3.2; 95% CI: 2.91, 3.51), and pooled estimated of RR between ACEI and CCB was 5.30 (95% CI: 4.32-6.50) Moexipril ranked as number one for inducing cough (SUCRA 80.4%) and spirapril ranked the least (SUCRA 12.3%). The order for the rest of the ACEIs are as follows: ramipril (SUCRA 76.4%), fosinopril (SUCRA 72.5%), lisinopril (SUCRA 64.7%), benazepril (SUCRA 58.6%), quinapril (SUCRA 56.5%), perindopril (SUCRA 54.1%), enalapril (SUCRA 49.7%), trandolapril (SUCRA 44.6%) and, captopril (SUCRA 13.7%). All ACEI has the similar risk of developing a cough. ACEI should be avoided in patients who have risk of developing cough, and an ARB or CCB is an alternative based on the patient's comorbidity.
Topics: Humans; Antihypertensive Agents; Angiotensin-Converting Enzyme Inhibitors; Angiotensin Receptor Antagonists; Network Meta-Analysis; Cough; Hypertension; Calcium Channel Blockers
PubMed: 37417783
DOI: 10.1111/jch.14695 -
Journal of Hypertension Mar 2023The aim of this study was to assess the reduction in all-cause death and cardiovascular outcomes associated with the administration of the thiazide-like diuretic... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
The aim of this study was to assess the reduction in all-cause death and cardiovascular outcomes associated with the administration of the thiazide-like diuretic indapamide monotherapy or in combination with perindopril as a blood pressure lowering drug in randomized controlled trials (RCTs).
METHOD
Aggregate data from four published RCTs conducted versus matching placebo were pooled: PATS, a 2-year study (indapamide), and PROGRESS, a 4-year study (indapamide and perindopril), both in patients with a history of stroke or transient ischemic attack; ADVANCE, a 4-year study in patients with type 2 diabetes and cardiovascular risk factor (single-pill combination perindopril/indapamide) and HYVET, a 2-year study in very elderly hypertensive individuals (indapamide and an option of perindopril). The pooled effect (fixed and random) estimate (hazard ratio) was reported with corresponding 95% confidence intervals and P values. Treatment discontinuations were also analysed to assess the net benefit of the treatment.
RESULTS
The population involved 24 194 patients (active: 12 113, placebo: 12 081). The fixed-effects meta-analysis of the three mortality endpoints found low statistical heterogeneity ( I2 = 0). Statistically significant risk reductions in the indapamide with or without perindopril-treated patients as compared to placebo were observed for all-cause death (-15%), cardiovascular death (-21%), fatal stroke (-36%) and all strokes (-27%). Other cardiovascular outcomes were improved (risk reduction, 22 to 36%). As expected, discontinuation rates for safety (two studies) were higher in the active group (6.4 vs. 3.9%), while they were similar when discontinuation for any reason is concerned (18.4 vs. 18.0%).
CONCLUSION
Across medium to high cardiovascular risk population, long-term indapamide, mostly combined with perindopril-based treatment, provided evidence of benefit on mortality and morbidity.
Topics: Humans; Aged; Perindopril; Indapamide; Antihypertensive Agents; Hypertension; Stroke; Drug Combinations; Blood Pressure; Randomized Controlled Trials as Topic
PubMed: 36633311
DOI: 10.1097/HJH.0000000000003368 -
Journal of Physiology and Pharmacology... Jun 2023Thrombotic events are highly prevalent in coronavirus disease 2019 (COVID-19), especially in patients presenting with risk factors of adverse outcomes such as obesity....
Thrombotic events are highly prevalent in coronavirus disease 2019 (COVID-19), especially in patients presenting with risk factors of adverse outcomes such as obesity. Recently, the associations between the angiotensin converting enzyme 2 (ACE2) pathway and thrombosis have been reported. Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARBs) are widely used cardiovascular pharmacologic agents that upregulate ACE2 levels. An observation of the alterations in pro-coagulation factors after exposure to ACEIs and ARBs may provide valuable insight into the thrombosis mechanism and how it may relate to ACE2. This study use adipose tissue harvested from an obese male donor was isolated and exposed to perindopril, losartan, and ACE2 recombinant as binding assay, following exposure with 10 nm of SARS-CoV-2 S1 spike protein. After 48 hours, tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1) as pro-coagulation factors as well as ACE2 levels and binding evaluated. The results shows TF level was significantly reduced in Perindopril group compared to control (4.834; p=0.005), while a non-significant reduction was observed in Losartan group (5.624; p=0.111). However, Losartan group showed a better reduction of PAI-1 levels (2.633; p≤0.001) than Perindopril group (3.484; p=0.001). These findings were consistent with the observations in ACE2 recombinant group, suggesting that both drugs lowered the bindings of ACE2 and SARS-CoV-2 spike proteins. This study indicated that both perindopril and losartan may attenuate pro-coagulation factors in human adipocytes exposed to SARS-CoV-2 spike proteins, and therefore showcased a potential role of ACE2 in the mechanism of COVID-19-related thrombosis. Further investigation in non-COVID-19 populations should commence and may be of value to expanding this potential in general cardiovascular diseases.
Topics: Humans; Male; Perindopril; Spike Glycoprotein, Coronavirus; Losartan; Plasminogen Activator Inhibitor 1; Angiotensin-Converting Enzyme 2; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; COVID-19; SARS-CoV-2; Blood Coagulation Factors; Adipocytes; Thromboplastin; Cardiovascular Agents; Obesity
PubMed: 37661180
DOI: 10.26402/jpp.2023.3.03 -
Evidence-based Complementary and... 2021Excessive activation of the nod-like receptor family pyrin domain containing 3(NLRP3) inflammasome plays a significant role in the progression of cardiac injury. In...
BACKGROUND
Excessive activation of the nod-like receptor family pyrin domain containing 3(NLRP3) inflammasome plays a significant role in the progression of cardiac injury. In China, it has been well recognized that Chinese herbal medicine is markedly effective in treating cardiovascular diseases (CVDs). LuQi Formula (LQF) has been used clinically for more than 10 years and confirmed to be effective in improving cardiac function and inhibiting apoptosis. However, the specific mechanisms underlying its efficacy are mostly unknown. This study aimed to evaluate whether LQF could alleviate cardiac injury and apoptosis by regulating the NLRP3 inflammasome and the caspase-3/Bax pathway.
PURPOSE
In this study, we investigated the effects of LQF on cardiac remodeling in a mouse model of myocardial infarction (MI) in vivo.
METHODS
Forty male C57BL/6 mice were randomly divided into four groups: the sham group, the model group, the LQF group, and the perindopril group, with a sample size () of 10 mice in each group. Except the sham group, the other groups received left anterior descending (LAD) coronary artery ligation to induce MI and then treated with LQF, perindopril, or saline. Six weeks after MI, echocardiography was used to evaluate cardiac structure and function. Myocardial tissue morphology was observed by haematoxylin and eosin (H&E) staining, and heart samples were stained with Masson's trichrome to analyse myocardial fibrosis. Myocardial hypertrophy was observed by fluorescent wheat germ agglutinin (WGA) staining. The expressions of NLRP3, ASC, Cle-caspase-1, IL-1, TXNIP, Cle-caspase-3, Bcl-2, and Bax in heart tissues were assessed by western blot analysis. mRNA expressions of ANP and BNP in heart tissues were measured by RT-PCR. The expression of reactive oxygen species in myocardial tissue was detected by using a DCFH-DA probe.
RESULTS
Echocardiographic analysis showed that compared with the model group, the left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) in the LQF and perindopril group were increased ( < 0.05), left ventricular internal diameter end diastole (LVIDd) and left ventricular internal diameter end-systole (LVIDs) were reduced ( < 0.05), and H&E and Masson's trichrome staining of cardiac tissues showed that LQF and perindopril could partially reverse ventricular remodeling and alleviate myocardial fibrosis ( < 0.05). WGA fluorescence results showed that compared with the model group, myocardial hypertrophy was significantly reduced in the LQF and perindopril group. We also found that LQF and perindopril reduce the oxidative stress response in the heart of MI mice. The protein expression of NLRP3, ASC, Cle-caspase-1, IL-1, TXNIP, Cle-caspase-3, and Bax was downregulated in the LHF and perindopril treatment group, and Bcl-2 expression was upregulated.
CONCLUSION
LQF and perindopril significantly attenuated cardiac injury and apoptosis in the MI model. In addition, we found that LQF effectively inhibited the activation of the NLRP3/ASC/caspase-1/IL-1 cascade, decreased inflammatory infiltration, delayed ventricular remodeling, and downregulated caspase-3/Bax signaling, which can effectively reduce the apoptosis of cardiomyocytes. Perindopril showed the same mechanism.
PubMed: 34257682
DOI: 10.1155/2021/5518083 -
European Heart Journal. Cardiovascular... Feb 2022An improved understanding of the pathophysiology of trastuzumab-mediated cardiotoxicity is required to improve outcomes of patients with human epidermal growth factor... (Randomized Controlled Trial)
Randomized Controlled Trial
AIMS
An improved understanding of the pathophysiology of trastuzumab-mediated cardiotoxicity is required to improve outcomes of patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. We aimed to characterize the cardiac and cardiometabolic phenotype of trastuzumab-mediated toxicity and potential interactions with cardiac pharmacotherapy.
METHODS AND RESULTS
This study was an analysis of serial magnetic resonance imaging (MRI) and circulating biomarker data acquired from patients with HER2-positive early-stage breast cancer participating in a randomized-controlled clinical trial for the pharmaco-prevention of trastuzumab-associated cardiotoxicity. Circulating biomarkers (B-type natriuretic peptide, troponin I, MMP-2 and -9, GDF-15, neuregulin-1, and IGF-1) and MRI of cardiac structure and function and abdominal fat distribution were acquired prior to trastuzumab, post-cycle 4 and post-cycle 17. Ninety-four participants (51 ± 8 years) completed the study with 30 on placebo, 33 on perindopril, and 31 on bisoprolol. Post-cycle 4, global longitudinal strain deteriorated from baseline in both placebo (+2.0 ± 2.7%, P = 0.002) and perindopril (+0.9 ± 2.5%, P = 0.04), but not with bisoprolol (-0.2 ± 2.1%, P = 0.55). In all groups combined, extracellular volume fraction and GDF-15 increased post-cycle 4 (+1.3 ± 4.4%, P = 0.004; +130 ± 150%, P ≤ 0.001, respectively). However, no significant change in troponin I was detected throughout trastuzumab. In all groups combined, visceral and intermuscular fat volume increased post-cycle 4 (+7 ± 17%, P = 0.02, +8 ± 23%, P = 0.02, respectively), while muscle volume and IGF-1 decreased from post-cycle 4 to 17 (-2 ± 10%, P = 0.008, -18 ± 28%, P < 0.001, respectively).
CONCLUSION
Trastuzumab results in impaired cardiac function and early myocardial inflammation. Trastuzumab is also associated with deleterious changes to the cardiometabolic phenotype which may contribute to the increased cardiovascular risk in this population.
Topics: Breast Neoplasms; Cardiotoxicity; Female; Humans; Natriuretic Peptide, Brain; Trastuzumab; Troponin I
PubMed: 33605416
DOI: 10.1093/ehjcvp/pvab016