Sex Differences in Cardiovascular Management: A Call for Better Acknowledgment-Part 1 Pharmacological Differences in Women and Men; How Relevant Are They?

BACKGROUND: Sex differences (SDs) in pharmacology of cardiovascular (CV) drugs have been described previously; however, paradoxically, there are scarce recommendations in therapy based on these differences. It is of utmost importance to identify whether these SDs determine a modified clinical response and the potential practical implications for this, to provide a base for personalized medicine. AREA OF UNCERTAINTY: The aim of this article was to outline the most important pharmacological drivers of cardiovascular drugs that differ between women and men, along with their implications and challenges in clinical practice. DATA SOURCES: A detailed assessment of English-written resources reflecting SDs impact in CV drug pharmacology was performed using PubMed and Embase databases. RESULTS: Despite large variations in CV drug pharmacokinetics and pharmacodynamics in individuals, correcting for height, weight, surface area, and body composition compensate for most "sex-dependent" differences. In addition, individual, cultural, and social factors significantly impact disease management in women versus men. Gender-biased prescribing patterns and gender-dependent adherence to therapy also influence outcomes. The development of sex-specific guidelines requires that they should reflect the SDs implications for the management of a disease and that the evidence should be carefully evaluated as to whether there is an adequate representation of both sexes and whether sex-disaggregated data are reported. CONCLUSIONS: Pharmacological drivers are under the influence of an impressive number of differences between women and men. However, to establish their significance in clinical practice, an adequate representation of women in studies and the reporting of distinct results is mandatory.

Mast cells: a novel therapeutic avenue for cardiovascular diseases?

Mast cells are tissue-resident immune cells strategically located in different compartments of the normal human heart (the myocardium, pericardium, aortic valve, and close to nerves) as well as in atherosclerotic plaques. Cardiac mast cells produce a broad spectrum of vasoactive and proinflammatory mediators, which have potential roles in inflammation, angiogenesis, lymphangiogenesis, tissue remodelling, and fibrosis. Mast cells release preformed mediators (e.g. histamine, tryptase, and chymase) and de novo synthesized mediators (e.g. cysteinyl leukotriene C4 and prostaglandin D2), as well as cytokines and chemokines, which can activate different resident immune cells (e.g. macrophages) and structural cells (e.g. fibroblasts and endothelial cells) in the human heart and aorta. The transcriptional profiles of various mast cell populations highlight their potential heterogeneity and distinct gene and proteome expression. Mast cell plasticity and heterogeneity enable these cells the potential for performing different, even opposite, functions in response to changing tissue contexts. Human cardiac mast cells display significant differences compared with mast cells isolated from other organs. These characteristics make cardiac mast cells intriguing, given their dichotomous potential roles of inducing or protecting against cardiovascular diseases. Identification of cardiac mast cell subpopulations represents a prerequisite for understanding their potential multifaceted roles in health and disease. Several new drugs specifically targeting human mast cell activation are under development or in clinical trials. Mast cells and/or their subpopulations can potentially represent novel therapeutic targets for cardiovascular disorders.

Sensitive "release-on-demand" fluorescent genosensors for probing DNA damage induced by commonly used cardiovascular drugs: Comparative study.

Cardiovascular drugs (CVDs) are agents working on the heart and the vascular system to treat many cardiovascular disorders. Such disorders represent the leading cause for morbidity and mortality worldwide. The treatment regimen includes different administered drugs on chronic basis. The cumulative drugs in human body coincides with exposure to electromagnetic radiations from different sources leading to drug-radiation interaction that may lead to drug photosensitization. Such photosensitization may lead to mutagenesis, cancer, and cell death due to molecular damage to DNA. This work involves the application of two bioluminescent genosensors; Terbium chloride and EvaGreen are utilized to investigate potential DNA damage caused by frequently used CVDs following UVA irradiation. A variety of CVDs are investigated. Ten drugs; Amiloride, Atorvastatin, Captopril, Enalapril, Felodipine, Hydrochlorothiazide, Indapamide, Losartan, Triamterene and Valsartan are studied. The study's findings showed that such drugs induced DNA damage following UVA irradiation. The induced DNA damage altered the fluorescence of terbium chloride and EvaGreen genosensors, proportionally. The results are confirmed by viscosity measurements reflecting the possible intercalation of CVDs with DNA. Also, the work is applied on calf thymus DNA to mimic the actual biological variability. The demonstrated bioluminescent genosensors provide automatic, simple and low-cost methods for assessing DNA-drug interactions.

Efficacy and Safety of Acoramidis in Transthyretin Amyloid Cardiomyopathy.

BACKGROUND: Transthyretin amyloid cardiomyopathy is characterized by the deposition of misfolded monomeric transthyretin (TTR) in the heart. Acoramidis is a high-affinity TTR stabilizer that acts to inhibit dissociation of tetrameric TTR and leads to more than 90% stabilization across the dosing interval as measured ex vivo. METHODS: In this phase 3, double-blind trial, we randomly assigned patients with transthyretin amyloid cardiomyopathy in a 2:1 ratio to receive acoramidis hydrochloride at a dose of 800 mg twice daily or matching placebo for 30 months. Efficacy was assessed in the patients who had an estimated glomerular filtration rate of at least 30 ml per minute per 1.73 m2 of body-surface area. The four-step primary hierarchical analysis included death from any cause, cardiovascular-related hospitalization, the change from baseline in the N-terminal pro-B-type natriuretic peptide (NT-proBNP) level, and the change from baseline in the 6-minute walk distance. We used the Finkelstein-Schoenfeld method to compare all potential pairs of patients within strata to generate a P value. Key secondary outcomes were death from any cause, the 6-minute walk distance, the score on the Kansas City Cardiomyopathy Questionnaire-Overall Summary, and the serum TTR level. RESULTS: A total of 632 patients underwent randomization. The primary analysis favored acoramidis over placebo (P<0.001); the corresponding win ratio was 1.8 (95% confidence interval [CI], 1.4 to 2.2), with 63.7% of pairwise comparisons favoring acoramidis and 35.9% favoring placebo. Together, death from any cause and cardiovascular-related hospitalization contributed more than half the wins and losses to the win ratio (58% of all pairwise comparisons); NT-proBNP pairwise comparisons yielded the highest ratio of wins to losses (23.3% vs. 7.0%). The overall incidence of adverse events was similar in the acoramidis group and the placebo group (98.1% and 97.6%, respectively); serious adverse events were reported in 54.6% and 64.9% of the patients. CONCLUSIONS: In patients with transthyretin amyloid cardiomyopathy, the receipt of acoramidis resulted in a significantly better four-step primary hierarchical outcome containing components of mortality, morbidity, and function than placebo. Adverse events were similar in the two groups. (Funded by BridgeBio Pharma; ATTRibute-CM ClinicalTrials.gov number, NCT03860935.).

The efficacy and safety of ivabradine hydrochloride in hemodialysis patients with chronic heart failure.

INTRODUCTION: There is little evidence for ivabradine hydrochloride in patients undergoing hemodialysis. METHODS: In this open-label prospective interventional trial of hemodialysis patients with chronic heart failure, during 12 weeks of treatment, changes in Heart rate (HR), frequency of dialysis-related hypotension were examined, and we investigated health-related quality of life (HR-QOL) and adverse effects. RESULTS: 18 patients from 6 facilities were enrolled in the study. HR significantly decreased over time, from 87 ± 12.61/min at baseline to 75.85 ± 8.91/min (p = 0.0003), and systolic blood pressure also increased significantly (p < 0.0001). The frequency of dialysis-related hypotension was markedly reduced (p = 0.0001). The HR-QOL survey showed significant improvements in Social Functioning among others (p = 0.0178). No specific adverse events occurred. CONCLUSION: Ivabradine hydrochloride improved dialysis-related hypotension. Furthermore, the HR-QOL improvement effect were suggested. These results demonstrated the safety and effectiveness of ivabradine hydrochloride.

[Antimicrobials discovery against Staphylococcus aureus by high throughput screening of drug library].

To develop antimicrobials against Staphylococcus aureus by high throughput screening of drug library. The type of this study is experimental research. The clinical isolates of S. aureus were collected from the sputum samples of respiratory inpatient department of the Third Xiangya Hospital of Central South University. The anti-planktonic cells growth inhibition activity of FDA-approved drugs library (including 1 573 molecules) was assessed by building a planktonic cells screening platform; The biofilm inhibitory effect of the FDA-approved drugs was detected by building a biofilm screening platform combined with crystal violet staining; Minimal inhibitory concentrations of the selected hits were determined by broth microdilution assay. Finally, the cytotoxicity of the selected hits was detected by CCK-8 assay. The results showed that 218 hits were exhibited effective growth inhibitory effects against S. aureus by setting the concentrations of the molecules in the FDA-approved library to 100 µmol/L. These selected molecules are mainly anti-infective drugs, accounting for 118 hits; Followed by anti-cancer drugs, anti-inflammatory/-immune drugs, neurological drugs, cardiovascular drugs, endocrine drugs, and metabolic disease drugs, which accounts for 40, 19, 12, 9, 8, and 3 hits; Other unclassified drugs accounts for 9 hits. The top 10 hits exhibiting anti-planktonic cells activity against S. aureus were mainly including antitumor drugs, followed by neurological drugs and unclassified drugs like vitamin K3 with the inhibition rate of 99.65%-100%. Similarly, the top 10 hits showing biofilm inhibitory effects against S. aureus were also mainly including antitumor drugs, followed by neurological drugs and anti-inflammatory/-immune drugs with the inhibition rate of 50.22%-92.95%. The minimal inhibitory concentration (MIC) of the 51 hits by second round screening was determined by micro-dilution assay, which mainly include the antitumor drugs, cardiovascular drugs, endocrine drugs, anti-inflammatory/-immune drugs, metabolic disease drugs, neurological drugs and other unclassified drugs accounted for 22, 5, 3, 9, 2, 5 and 5 hits, respectively, with the MICs of 1.56-50 µmol/L, 6.25-25 µmol/L, 6.25-25 µmol/L, 0.2-50 µmol/L, 25-50 µmol/L, 1.56-50 µmol/L and 0.1-12.5 µmol/L, respectively. In conclusion, the minimum inhibitory concentrations of small molecules screened through high-throughput assay are at the level of micromolar with strong drug development potential and high modifiability. The high effective anti-planktonic cells and anti-biofilm activity by these molecules are expected to provide new ideas for the development of new antimicrobials against S. aureus.

Real-time monitoring of the contractile properties of H9C2 cardiomyocytes by double resonator piezoelectric cytometry.

Testing the mechanical properties of cardiomyocytes plays an important role in the study of the physiological and pathological processes of constant contraction and diastole of the cardiovascular system. However, there is currently no satisfactory and dynamic technology to measure the mechanical properties of cardiomyocytes in a sustained manner, greatly affecting their practical application in clinical diagnosis and treatment evaluation. Herein, a double resonator piezoelectric cytometry (DRPC) technique was employed for dynamic monitoring of H9C2 cardiomyocyte adhesion and the effects of two cardiovascular drugs on the contractile properties of H9C2 cardiomyocytes, i.e., isoprenaline (ISO, a positive inotropic agent) and verapamil (VRP, a negative inotropic agent). Specifically, we used 9 MHz AT and BT-cut bare gold and transparent ITO electrodes and compared their dynamic adhesion to the two electrodes modified with RGD and gelatin respectively versus unmodified to measure the cell generated stress (ΔS) exerted on the quartz crystal surface by a population of cells and the cell viscoelastic index (CVI). We found that the DRPC technique can quantitatively measure the magnitude and direction of the generated forces during the adhesion process of the cells and under the effect of drugs. In conclusion, the technique presented in this study can be used for the simultaneous measurement of cell adhesion, traction force and viscoelasticity of living cells in a noninvasive, dynamic and continuous way, making it an ideal tool for assessing the population contractility of cardiomyocytes and evaluating the efficacy and toxicity of cardiovascular drugs.

Investigation of the Effects of Some Cardiovascular Drugs on Angiogenesis by Transgenic Zebrafish.

Introduction: Angiogenesis contributes to the pathophysiology of cardiovascular disease (CVD). Some cardiovascular drugs used in the treatment of CVD have an effect on the process of angiogenesis. Methods: Transgenic Tg (flk1: EGFP) zebrafish embryos were used to identify the effects of some cardiovascular drugs on angiogenesis during vertebral development in vivo. Zebrafish embryos at a one-cell stage or two-cell stage were cultured with embryo medium containing cardiovascular drugs at a final solvent concentration of 0.5% (V/V) dimethyl sulfoxide (DMSO) for 24 hours in 24-well plates. Results: We found that 6 drugs including isosorbide mononitrate, amlodipine, bisoprolol fumarate, carvedilol, irbesartan, and rosuvastatin calcium may affect angiogenesis by vascular endothelial growth factor (VEGF) signaling pathway. Conclusion: These new findings of some cardiovascular drugs should improve the treatment of cardiovascular diseases.

Time to benefit of heart rate reduction with ivabradine in patients with heart failure and reduced ejection fraction.

AIMS: In the SHIFT (Systolic Heart failure treatment with the If inhibitor ivabradine Trial, ISRCTN70429960) study, ivabradine reduced cardiovascular death or heart failure (HF) hospitalizations in patients with HF and reduced ejection fraction (HFrEF) in sinus rhythm and with a heart rate (HR) ≥70 bpm. In this study, we sought to determine the clinical significance of the time durations of HR reduction and the significant treatment effect on outcomes among patients with HFrEF. METHODS AND RESULTS: The time to statistically significant reduction of the primary outcome (HF hospitalization and cardiovascular death) and its components, all-cause death, and HF death, were assessed in a post-hoc analysis of the SHIFT trial in the overall population (HR ≥70 bpm) and at HR ≥75 bpm, representing the approved label in many countries. Compared to placebo, the primary outcome and HF hospitalizations were significantly reduced at 102 days, while there was no effect on cardiovascular death, all-cause death, and HF death at HR ≥70 bpm. In the population with a baseline HR ≥75 bpm, a reduction of the primary outcome occurred after 67 days, HF hospitalization after 78 days, cardiovascular death after 169 days, death from HF after 157 days and all-cause death after 169 days. CONCLUSION: Treatment with ivabradine should not be deferred in patients in sinus rhythm with a HR of ≥70 bpm to reduce the primary outcome and HF hospitalizations, in particular in patients with HR ≥75 bpm. At HR ≥75 bpm, the time to risk reduction was shorter for reduction of hospitalization and mortality outcomes in patients with HFrEF after initiation of guideline-directed medication, including beta-blockers at maximally tolerated doses.

Perhexiline: Old Drug, New Tricks? A Summary of Its Anti-Cancer Effects.

Cancer metabolic plasticity, including changes in fatty acid metabolism utilisation, is now widely appreciated as a key driver for cancer cell growth, survival and malignancy. Hence, cancer metabolic pathways have been the focus of much recent drug development. Perhexiline is a prophylactic antianginal drug known to act by inhibiting carnitine palmitoyltransferase 1 (CPT1) and 2 (CPT2), mitochondrial enzymes critical for fatty acid metabolism. In this review, we discuss the growing evidence that perhexiline has potent anti-cancer properties when tested as a monotherapy or in combination with traditional chemotherapeutics. We review the CPT1/2 dependent and independent mechanisms of its anti-cancer activities. Finally, we speculate on the clinical feasibility and utility of repurposing perhexiline as an anti-cancer agent, its limitations including known side effects and its potential added benefit of limiting cardiotoxicity induced by other chemotherapeutics.

[Clinical observation of Qiliqiangxin capsule combined with recombinant human brain natriuretic peptide in patients with acute heart failure].

Objective: To observe the clinical effect of Qiliqiangxin capsule combined with recombinant human brain natriuretic peptide in acute left heart failure patients 7 days after onset as well as the effects of plasma MDA and ET-1. Methods: In total, 240 hospitalized patients with acute left heart failure from October 2017 to May 2021 were selected from the Department of Emergency and Critical Care Center of Beijing Anzhen Hospital, Capital Medical University and the Department of Cardiology of the Jilin Provincial People's Hospital. They were randomly divided into routine treatment group and combined treatment group, with 120 cases in each group. The routine treatment group was treated with vasodilation, diuresis, cardiotonic and recombinant human brain natriuretic peptide. The combined treatment group was treated with Qiliqiangxin capsules based on the routine treatment group. One week later, the changes in clinical efficacy, ejection fraction, left ventricular commoid diameter, and plasma BNP, MDA, and ET-1 were compared between the two groups before and after treatment. SPSS 11.5 statistical software was used. The measurement data was expressed in x¯±s, the independent sample t-test was used for comparison between groups, and the paired t-test was used for comparison before and after treatment within groups. Counting data was expressed as case (%), and the rank sum test was used for inter-group comparison. Result: In terms of clinical efficacy, the total effective rate of the combined treatment group was significantly higher than that of the conventional treatment group, and the difference was statistically significant (P<0.05). Compared with the routine treatment group, the left ventricular ejection fraction in the combined treatment group was significantly increased (P<0.05). The levels of plasma BNP, MDA and ET-1 were significantly decreased (P<0.05). Conclusion: Qiliqiangxin capsule combined with rhBNP treatment can effectively improve the clinical symptoms of acute heart failure, as well as reduce the lipid peroxidation product MDA content and endothetin ET-1 level in blood. The clinical application value of the Qiliqiangxin capsule needs to be further confirmed by further trials.

RAAS inhibition and beyond-cardiovascular medications in patients at risk of or affected by COVID-19.

The COVID-19 pandemic led to an enormous burden on healthcare systems worldwide. Causal therapy is still in its infancy. Contrary to initial views that the use of angiotensin-converting enzyme inhibitors (ACEi)/angiotensin II receptor blockers (ARBs) may increase the risk for a deleterious disease course, it has been shown that these agents may actually be beneficial for patients affected by COVID-19. In this article, we provide an overview of the three most commonly used classes of drugs in cardiovascular disease (ACEi/ARB, statins, beta-blockers) and their potential role in COVID-19 therapy. More results from randomized clinical trials are necessary to identify patients that can benefit most from the use of the respective drugs.

Ranolazine exhibits anti-inflammatory and antioxidant activities in H9c2 cardiomyocytes.

OBJECTIVE: The aim of this study was to evaluate the effectiveness of ranolazine on hypoxia-inducible factor-1α (HIF-1α) and oxidative stress in H9c2 cardiomyocyte cells. MATERIALS AND METHODS: We have assessed the effects of increasing concentrations of methotrexate (MTX) and ranolazine on proliferation of H9c2 rat cardiomyocyte cells by MTT assay. Malondialdehyde (MDA) protein oxidation [advanced oxidation protein products (AOPPs)], lipid hydroperoxide (LOOH) and xanthine oxidase (XO) activity as oxidative stress markers and HIF-1α levels increased and total thiol (T-SH), catalase (CAT) activity and total antioxidant capacity (TAC) antioxidant capacity markers decreased in MTX-treated cells compared to control cells. RESULTS: Oxidative stress markers decreased, and antioxidant capacity markers increased in cells treated with ranolazine alone compared to control cells. For all parameters, we showed that the levels of oxidant, antioxidant markers and HIF-1α in cells treated with MTX and ranolazine together reached the level of the control group, and ranolazine reversed the oxidative damage caused by MTX. CONCLUSIONS: The cell viability increased the levels of oxidant and prooxidant markers and decreased the levels of antioxidant markers decreased in H9c2 cardiomyocytes induced by oxidative stress. These results suggest that ranolazine may protect the cardiomyocytes from MTX-induced oxidative damage. The effects of ranolazine could result from its antioxidant properties.

Metabolomic profiling and antianginal activity of the bark of Sterculia setigera from Mali.

The present work focuses on the phytochemical characterization and evaluation of antianginal activity of the bark of Sterculia setigera. It was collected and authenticated in the African region of Mali, where the local population largely employs this plant for the treatment of several diseases. In the context of traditional or folk medicine and recent progresses in alternative medicine practices, it is essential to expand the knowledge about the chemical composition of such medicinal plants. In this research, a direct-Mass Spectrometry (MS) technique, known as Rapid Evaporative Ionization Mass Spectrometry (REIMS) was used for the identification of the main constituents of the Sterculia setigera bark. The REIMS source is here coupled with an electroknife as sampling device, so that the dried and pulverized bark was directly cut through the electroknife to generate a vapor, which was online transferred to the source via a Venture tube. In this way, an ambient MS approach was realized, which avoids any sample preparation procedure or pretreatment; the sample was analyzed in its native state according to a time-saving analytical process. A quadrupole-time of flight MS/MS analyzer was exploited for the identification process, based on mass accuracy data and MS/MS experiments for structure elucidation purposes. Lipids, including triterpenes, fatty acids, γ-sitosterol and α-tocopherol, and phenolic compounds were identified, some of them reported for the first time in a plant of the Sterculia genus and further confirmed through a gas chromatography-mass spectrometry analysis. The obtained metabolomic profile was successfully correlated to the antianginal activity of this plant.

Phase 3 Trial of Sotatercept for Treatment of Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary arterial hypertension is a progressive disease involving proliferative remodeling of the pulmonary vessels. Despite therapeutic advances, the disease-associated morbidity and mortality remain high. Sotatercept is a fusion protein that traps activins and growth differentiation factors involved in pulmonary arterial hypertension. METHODS: We conducted a multicenter, double-blind, phase 3 trial in which adults with pulmonary arterial hypertension (World Health Organization [WHO] functional class II or III) who were receiving stable background therapy were randomly assigned in a 1:1 ratio to receive subcutaneous sotatercept (starting dose, 0.3 mg per kilogram of body weight; target dose, 0.7 mg per kilogram) or placebo every 3 weeks. The primary end point was the change from baseline at week 24 in the 6-minute walk distance. Nine secondary end points, tested hierarchically in the following order, were multicomponent improvement, change in pulmonary vascular resistance, change in N-terminal pro-B-type natriuretic peptide level, improvement in WHO functional class, time to death or clinical worsening, French risk score, and changes in the Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT) Physical Impacts, Cardiopulmonary Symptoms, and Cognitive/Emotional Impacts domain scores; all were assessed at week 24 except time to death or clinical worsening, which was assessed when the last patient completed the week 24 visit. RESULTS: A total of 163 patients were assigned to receive sotatercept and 160 to receive placebo. The median change from baseline at week 24 in the 6-minute walk distance was 34.4 m (95% confidence interval [CI], 33.0 to 35.5) in the sotatercept group and 1.0 m (95% CI, -0.3 to 3.5) in the placebo group. The Hodges-Lehmann estimate of the difference between the sotatercept and placebo groups in the change from baseline at week 24 in the 6-minute walk distance was 40.8 m (95% CI, 27.5 to 54.1; P<0.001). The first eight secondary end points were significantly improved with sotatercept as compared with placebo, whereas the PAH-SYMPACT Cognitive/Emotional Impacts domain score was not. Adverse events that occurred more frequently with sotatercept than with placebo included epistaxis, dizziness, telangiectasia, increased hemoglobin levels, thrombocytopenia, and increased blood pressure. CONCLUSIONS: In patients with pulmonary arterial hypertension who were receiving stable background therapy, sotatercept resulted in a greater improvement in exercise capacity (as assessed by the 6-minute walk test) than placebo. (Funded by Acceleron Pharma, a subsidiary of MSD; STELLAR ClinicalTrials.gov number, NCT04576988.).

Breakthrough: a first-in-class virtual simulator for dose optimization of ACE inhibitors in translational cardiovascular medicine.

The renin-angiotensin-aldosterone-systems (RAAS) play a central role in the pathophysiology of congestive heart failure (CHF), justifying the use of angiotensin converting enzyme inhibitors (ACEi) in dogs and humans with cardiac diseases. Seminal studies in canine CHF had suggested that the pharmacological action of benazepril was relatively independent of doses greater than 0.25 mg/kg P.O, thereby providing a rationale for the European labeled dose of benazepril in dogs with CHF. However, most of these earlier studies relied on measures of ACE activity, a sub-optimal endpoint to characterize the effect of ACEi on the RAAS. The objectives of this study were (i) to expand on previous mathematical modeling efforts of the dose-exposure-response relationship of benazepril on biomarkers of the RAAS which are relevant to CHF pathophysiology and disease prognosis; and (ii) to develop a software implementation capable of simulating clinical trials in benazepril in dogs bedside dose optimization. Our results suggest that 0.5 mg/kg PO q12h of benazepril produces the most robust reduction in angiotensin II and upregulation of RAAS alternative pathway biomarkers. This model will eventually be expanded to include relevant clinical endpoints, which will be evaluated in an upcoming prospective trial in canine patients with CHF.