Journal of Cardiovascular Pharmacology and Therapeutics最新文献

{"title":"The Role of Pyroptosis in Ischemic and Reperfusion Injury of the Heart.","authors":"Sergey V Popov,&nbsp;Leonid N Maslov,&nbsp;Natalia V Naryzhnaya,&nbsp;Alexandr V Mukhomezyanov,&nbsp;Andrey V Krylatov,&nbsp;Sergey Y Tsibulnikov,&nbsp;Vyacheslav V Ryabov,&nbsp;Michael V Cohen,&nbsp;James M Downey","doi":"10.1177/10742484211027405","DOIUrl":"https://doi.org/10.1177/10742484211027405","url":null,"abstract":"<p><p>While ischemia itself can kill heart muscle, much of the infarction after a transient period of coronary artery occlusion has been found to result from injury during reperfusion. Here we review the role of inflammation and possible pyroptosis in myocardial reperfusion injury. Current evidence suggests pyroptosis's contribution to infarction may be considerable. Pyroptosis occurs when inflammasomes activate caspases that in turn cleave off an N-terminal fragment of gasdermin D. This active fragment makes large pores in the cell membrane thus killing the cell. Inhibition of inflammation enhances cardiac tolerance to ischemia and reperfusion injury. Stimulation of the purinergic P2X7 receptor and the β-adrenergic receptor and activation of nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) by toll-like receptor (TLR) agonists are all known to contribute to ischemia/reperfusion (I/R) cardiac injury through inflammation, potentially by pyroptosis. In contrast, stimulation of the cannabinoid CB2 receptor reduces I/R cardiac injury and inhibits this pathway. MicroRNAs, Akt, the phosphate and tension homology deleted on chromosome 10 protein (PTEN), pyruvate dehydrogenase and sirtuin-1 reportedly modulate inflammation in cardiomyocytes during I/R. Cryopyrin and caspase-1/4 inhibitors are reported to increase cardiac tolerance to ischemic and reperfusion cardiac injury, presumably by suppressing inflammasome-dependent inflammation. The ambiguity surrounding the role of pyroptosis in reperfusion injury arises because caspase-1 also activates cytotoxic interleukins and proteolytically degrades a surprisingly large number of cytosolic enzymes in addition to activating gasdermin D.</p>","PeriodicalId":15281,"journal":{"name":"Journal of Cardiovascular Pharmacology and Therapeutics","volume":"26 6","pages":"562-574"},"PeriodicalIF":2.6,"publicationDate":"2021-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/10742484211027405","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39186480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Direct Oral Anticoagulants: A Delicate and Dynamic Balance.","authors":"Massimo Giordan","doi":"10.1177/10742484211037764","DOIUrl":"https://doi.org/10.1177/10742484211037764","url":null,"abstract":"I read with interest the article by Raccah et al, focusing on the impact of prescribing errors with direct oral anticoagulants (DOACs) on the risk of bleeding in patients with atrial fibrillation (AF). The prevalence of errors, consisting in either unjustified low dosage or inappropriate drugs combinations, with a consequent higher major bleeding risk, appears significantly high (33%), but not surprising, since adhering to clinical reality, as we similarly observe in our routine practice. We totally agree with the authors, who remark the importance of being aware of the potential negative impact of prescribing errors and regular follow-up. Moreover, a recent retrospective analysis conducted by Chaudhry et al, focusing on outcome of patients 80 years receiving low dose DOACs, evidenced in the low dose group a higher all-cause mortality rate, as long as higher rate of major bleeding, while the thromboembolic events were not significantly lower than the warfarin group. These results represent a mirror of clinical practice also in our daily experience. About these observations, I would like to stress some trends we commonly encounter with patients affected by AF taking DOACs, which we believe many of our colleagues will share:","PeriodicalId":15281,"journal":{"name":"Journal of Cardiovascular Pharmacology and Therapeutics","volume":"26 6","pages":"739-740"},"PeriodicalIF":2.6,"publicationDate":"2021-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/10742484211037764","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39286850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety and Efficacy of Triple Therapy With Ticagrelor or Prasugrel Versus Clopidogrel After Percutaneous Coronary Intervention for ST-Elevation Myocardial Infarction.","authors":"Kristina Gill,&nbsp;Nicholas Servati,&nbsp;Julie Flahive,&nbsp;Kyle Fraielli","doi":"10.1177/10742484211031436","DOIUrl":"https://doi.org/10.1177/10742484211031436","url":null,"abstract":"<p><strong>Background: </strong>Patients on dual antiplatelet therapy following percutaneous coronary intervention often have indications for concomitant oral anticoagulation, known as triple antithrombotic therapy. Majority of literature evaluating triple antithrombotic therapy fails to adequately represent patients with ST-elevation myocardial infarction and those prescribed potent P2Y12 inhibitors, ticagrelor or prasugrel. The purpose of this study was to evaluate the safety and efficacy of triple antithrombotic regimens containing ticagrelor or prasugrel versus clopidogrel after percutaneous coronary intervention in the setting of ST-elevation myocardial infarction.</p><p><strong>Methods: </strong>This was a single-center, retrospective cohort trial. The primary endpoint was net adverse clinical event, defined as the primary efficacy endpoint of death, myocardial infarction, or cerebrovascular accident and the primary safety endpoint of any bleeding event.</p><p><strong>Results: </strong>Between October 2017 and October 2019, a total of 65 patients with ST-elevation myocardial infarction were initiated on triple therapy. Forty-six patients were included in the primary analysis, of which 26 were discharged on triple antithrombotic therapy with clopidogrel and 20 discharged on potent P2Y12 inhibitors (ticagrelor or prasugrel). The primary endpoint occurred in 27% of the clopidogrel group and 40% of the potent P2Y12 inhibitor group (<i>P</i> = 0.35). Bleeding occurred in 23% of the clopidogrel group and 35% of the potent P2Y12 inhibitor group (<i>P</i> = 0.37).</p><p><strong>Conclusions: </strong>This small cohort study suggests, in patients with ST-elevation myocardial infarction undergoing percutaneous coronary intervention, the net adverse clinical event rate does not differ between clopidogrel and potent P2Y12 inhibitors in the setting of triple antithrombotic therapy. The results of this exploratory analysis warrant confirmation in a larger, randomized study.</p>","PeriodicalId":15281,"journal":{"name":"Journal of Cardiovascular Pharmacology and Therapeutics","volume":"26 6","pages":"625-629"},"PeriodicalIF":2.6,"publicationDate":"2021-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/10742484211031436","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39164179","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nitric Oxide-cGMP Pathway Modulation in an Experimental Model of Hypoxic Pulmonary Hypertension.","authors":"Melanie Reinero,&nbsp;Maurice Beghetti,&nbsp;Piergiorgio Tozzi,&nbsp;Ludwig K von Segesser,&nbsp;Michele Samaja,&nbsp;Giuseppina Milano","doi":"10.1177/10742484211014162","DOIUrl":"https://doi.org/10.1177/10742484211014162","url":null,"abstract":"<p><p>Manipulation of nitric oxide (NO) may enable control of progression and treatment of pulmonary hypertension (PH). Several approaches may modulate the NO-cGMP pathway in vivo. Here, we investigate the effectiveness of 3 modulatory sites: (i) the amount of l-arginine; (ii) the size of plasma NO stores that stimulate soluble guanylate cyclase; (iii) the conversion of cGMP into inactive 5'-GMP, with respect to hypoxia, to test the effectiveness of the treatments with respect to hypoxia-induced PH. Male rats (n = 80; 10/group) maintained in normoxic (21% O₂) or hypoxic chambers (10% O₂) for 14 days were subdivided in 4 sub-groups: placebo, l-arginine (20 mg/ml), the NO donor molsidomine (15 mg/kg in drinking water), and phoshodiesterase-5 inhibitor sildenafil (1.4 mg/kg in 0.3 ml saline, i.p.). Hypoxia depressed homeostasis and increased erythropoiesis, heart and right ventricle hypertrophy, myocardial fibrosis and apoptosis inducing pulmonary remodeling. Stimulating anyone of the 3 mechanisms that enhance the NO-cGMP pathway helped rescuing the functional and morphological changes in the cardiopulmonary system leading to improvement, sometimes normalization, of the pressures. None of the treatments affected the observed parameters in normoxia. Thus, the 3 modulatory sites are essentially similar in enhancing the NO-cGMP pathway, thereby attenuating the hypoxia-related effects that lead to pulmonary hypertension.</p>","PeriodicalId":15281,"journal":{"name":"Journal of Cardiovascular Pharmacology and Therapeutics","volume":"26 6","pages":"665-676"},"PeriodicalIF":2.6,"publicationDate":"2021-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/10742484211014162","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38966702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chronic Sildenafil Therapy in the ZSF1 Obese Rat Model of Metabolic Syndrome and Heart Failure With Preserved Ejection Fraction.","authors":"Sara Leite,&nbsp;Liliana Moreira-Costa,&nbsp;Rui Cerqueira,&nbsp;Cláudia Sousa-Mendes,&nbsp;António Angélico-Gonçalves,&nbsp;Dulce Fontoura,&nbsp;Francisco Vasques-Nóvoa,&nbsp;Adelino F Leite-Moreira,&nbsp;André P Lourenço","doi":"10.1177/10742484211034253","DOIUrl":"https://doi.org/10.1177/10742484211034253","url":null,"abstract":"<p><p>Although decreased protein kinase G (PKG) activity was proposed as potential therapeutic target in heart failure with preserved ejection fraction (HFpEF), randomized clinical trials (RCTs) with type-5 phosphodiesterase inhibitors (PDE5i) showed neutral results. Whether specific subgroups of HFpEF patients may benefit from PDE5i remains to be defined. Our aim was to test chronic sildenafil therapy in the young male ZSF1 obese rat model of HFpEF with severe hypertension and metabolic syndrome. Sixteen-week-old ZSF1 obese rats were randomly assigned to receive sildenafil 100 mg·Kg^-1·d^-1 dissolved in drinking water (ZSF1 Ob SIL, n = 8), or placebo (ZSF1 Ob PL, n = 8). A group of Wistar-Kyoto rats served as control (WKY, n = 8). Four weeks later animals underwent effort tests, glucose metabolism studies, hemodynamic evaluation, and samples were collected for aortic ring preparation, left ventricular (LV) myocardial adenosine triphosphate (ATP) quantification, immunoblotting and histology. ZSF1 Ob PL rats showed systemic hypertension, aortic stiffening, impaired LV relaxation and increased LV stiffness, with preserved ejection fraction and cardiac index. Their endurance capacity was decreased as assessed by maximum workload and peak oxygen consumption (V˙O₂) and respiratory quotient were increased, denoting more reliance on anaerobic metabolism. Additionally, ATP levels were decreased. Chronic sildenafil treatment attenuated hypertension and decreased LV stiffness, modestly enhancing effort tolerance with a concomitant increase in peak, ATP levels and VASP phosphorylation. Chronic sildenafil therapy in this model of HFpEF of the young male with extensive and poorly controlled comorbidities has beneficial cardiovascular effects which support RCTs in HFpEF patient subgroups with similar features.</p>","PeriodicalId":15281,"journal":{"name":"Journal of Cardiovascular Pharmacology and Therapeutics","volume":"26 6","pages":"690-701"},"PeriodicalIF":2.6,"publicationDate":"2021-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/10742484211034253","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39259995","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Treating Acute Myocardial Infarctions With Anti-Inflammatory Agents.","authors":"Robert A Kloner","doi":"10.1177/10742484211033711","DOIUrl":"https://doi.org/10.1177/10742484211033711","url":null,"abstract":"There is an unmet need to further reduce the size of acute myocardial infarctions above and beyond the current standard of care of early reperfusion therapy with primary percutaneous coronary intervention (angioplasty/stenting) and anti-platelet agents to keep the infarct related artery patent. Even a 5% reduction in myocardial infarct size may be clinically meaningful. It is known that the inflammatory process occurs early after coronary artery occlusion/reperfusion with very early influx of neutrophils. There has been concern that if the inflammatory response is too severe it could contribute to additional myocardial cells dying and lead to infarct extension with a larger infarct size. On the other hand, the early inflammatory response is the first step in the healing phase of myocardial infarction. Experimental studies from the 1980s suggested that certain anti-inflammatory medicines, such as steroids and non-steroidal anti-inflammatory agents, such as ibuprofen, administered early during infarction would reduce the size of myocardial infarction. There was considerable excitement about this possibility and clinical studies were planned and some were carried out. However, there was underlying concern that inhibiting the inflammatory cascade early after occlusion might then inhibit the healing phase of acute myocardial infarction. In a series of studies from the early 1980s our research group assessed the effects of methylprednisolone, ibuprofen, and indomethacin on the healing phase of myocardial infarctions. Methylprednisolone was shown to enhance “mummification” of the myocardium whereby large sheets of necrotic, but architecturally preserved muscle fibers remained in the center of the myocardial infarction during the healing phase. Steroids clearly suppressed the process whereby necrotic debris is removed from the infarct and delayed the shrinkage of the scar. Short term administration of methylprednisolone resulted in thinner scars and reduced left ventricular function. Nonsteroidal anti-inflammatory drugs including ibuprofen and indomethacin when administered early and acutely after myocardial infarction contributed to an increase in myocardial infarct expansion, that phenomenon whereby necrotic myocytes thin, stretch, slip by each other resulting in a thin and elongated infarct, thinned scar, regional ventricular dilatation and then global dilatation. This phenomenon of adverse left ventricular remodeling is known to occur in patients, especially those with large infarcts and can contribute to heart failure, myocardial rupture and death. There were a few clinical studies that examined the effect of steroids on myocardial infarct size in which the results were negative; although one meta-analysis suggested corticosteroids did no harm and perhaps improved survival. Clinical trials that tried to impede the function of neutrophils, including their ability to adhere to the walls of blood vessels and trials of anticomplement strategies were neg","PeriodicalId":15281,"journal":{"name":"Journal of Cardiovascular Pharmacology and Therapeutics","volume":"26 6","pages":"736-738"},"PeriodicalIF":2.6,"publicationDate":"2021-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/10742484211033711","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39259996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prescribing Errors With Direct Oral Anticoagulants and Their Impact on the Risk of Bleeding in Patients With Atrial Fibrillation.","authors":"Bruria Hirsh Raccah, Yevgeni Erlichman, Arthur Pollak, Ilan Matok, Mordechai Muszkat","doi":"10.1177/10742484211019657","DOIUrl":"10.1177/10742484211019657","url":null,"abstract":"<p><strong>Introduction: </strong>Anticoagulants are associated with significant harm when used in error, but there are limited data on potential harm of inappropriate treatment with direct oral anticoagulants (DOACs). We conducted a matched case-control study among atrial fibrillation (AF) patients admitting the hospital with a chronic treatment with DOACs, in order to assess factors associated with the risk of major bleeding.</p><p><strong>Methods: </strong>Patient data were documented using hospital's computerized provider order entry system. Patients identified with major bleeding were defined as cases and were matched with controls based on the duration of treatment with DOACs and number of chronic medications. Appropriateness of prescribing was assessed based on the relevant clinical guidelines. Conditional logistic regression was used to evaluate the potential impact of safety-relevant prescribing errors with DOACs on major bleeding.</p><p><strong>Results: </strong>A total number of 509 eligible admissions were detected during the study period, including 64 cases of major bleeding and 445 controls. The prevalence of prescribing errors with DOACs was 33%. Most prevalent prescribing errors with DOACs were \"drug dose too low\" (16%) and \"non-recommended combination of drugs\" (11%). Safety-relevant prescribing errors with DOACs were associated with major bleeding [adjusted odds ratio (aOR) 2.17, 95% confidence interval (CI) 1.14-4.12].</p><p><strong>Conclusion: </strong>Prescribers should be aware of the potential negative impact of prescribing errors with DOACs and understand the importance of proper prescribing and regular follow-up.</p>","PeriodicalId":15281,"journal":{"name":"Journal of Cardiovascular Pharmacology and Therapeutics","volume":"26 6","pages":"601-610"},"PeriodicalIF":2.5,"publicationDate":"2021-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/1b/c9/10.1177_10742484211019657.PMC8547237.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38969885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of a Novel Oral Testosterone Undecanoate on Ambulatory Blood Pressure in Hypogonadal Men.","authors":"William B White,&nbsp;Adrian Dobs,&nbsp;Culley Carson,&nbsp;Anthony DelConte,&nbsp;Mohit Khera,&nbsp;Martin Miner,&nbsp;Muhammad Shahid,&nbsp;Kilyoung Kim,&nbsp;Nachiappan Chidambaram","doi":"10.1177/10742484211027394","DOIUrl":"https://doi.org/10.1177/10742484211027394","url":null,"abstract":"<p><strong>Background: </strong>Testosterone replacement therapies may increase blood pressure (BP) with chronic use but the mechanism is not clear. TLANDO™ is a new oral testosterone undecanoate (TU) under development for the treatment of male hypogonadism.</p><p><strong>Methods: </strong>We studied the effects of the TU at 225 mg twice daily on ambulatory BP (ABP) and heart rate, in 138 men with hypogonadism (mean age, 54 years, 79% white, 48% with hypertension). Ambulatory BP and heart rate and hematologic assessments were obtained at baseline and following 4-months of therapy.</p><p><strong>Results: </strong>Changes from baseline in ambulatory 24-hour, awake, and sleep systolic BP (SBP) of 3.8 (<i>P</i> < 0.001), 5.2 (<i>P</i> < 0.001), and 4.3 mmHg (<i>P</i> = 0.004) were observed post-treatment, respectively. Lesser changes in the diastolic BP (DBP) were observed (1.2 (<i>P</i> = 0.009), 1.7 (<i>P</i> = 0.004), and 1.7 mmHg (<i>P</i> = 0.011) for 24-hour, awake, and sleep, respectively). Hematocrit and hemoglobin were increased by 3.2% and 0.9 g/dL (<i>P</i> < 0.001), respectively. In those men in the top quartile of changes in hematocrit (range of 6% to 14%), the largest increases in ambulatory SBP (mean, 8.3 mmHg) were observed, whereas the changes in ambulatory SBP in the lower 3 quartiles were smaller (mean, 1.9, 3.3, and 2.1 mmHg in 1st, 2nd and 3 rd quartiles, respectively).</p><p><strong>Conclusion: </strong>These data demonstrate that small increases in ABP occurred following 4 months of the oral TU. For those men whose hematocrit rose by >6%, BP increases were of greater clinical relevance. Hence, hematocrit may aid in predicting the development of BP increases on testosterone therapy.</p><p><strong>Clinicaltrials.gov identifier: </strong>NCT03868059.</p>","PeriodicalId":15281,"journal":{"name":"Journal of Cardiovascular Pharmacology and Therapeutics","volume":"26 6","pages":"630-637"},"PeriodicalIF":2.6,"publicationDate":"2021-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/10742484211027394","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39123301","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hydrochlorothiazide Reduces Cardiac Hypertrophy, Fibrosis and Rho-Kinase Activation in DOCA-Salt Induced Hypertension.","authors":"David Mondaca-Ruff,&nbsp;Patricio Araos,&nbsp;Cristián E Yañez,&nbsp;Ulises F Novoa,&nbsp;Italo G Mora,&nbsp;María Paz Ocaranza,&nbsp;Jorge E Jalil","doi":"10.1177/10742484211053109","DOIUrl":"https://doi.org/10.1177/10742484211053109","url":null,"abstract":"<p><strong>Background: </strong>Thiazides are one of the most common antihypertensive drugs used for hypertension treatment and hydrochlorothiazide (HCTZ) is the most frequently used diuretic for hypertension treatment. The Rho/Rho-kinase (ROCK) path plays a key function in cardiovascular remodeling. We hypothesized that in preclinical hypertension HCTZ reduces myocardial ROCK activation and consequent myocardial remodeling.</p><p><strong>Methods: </strong>The preclinical model of deoxycorticosterone (DOCA)-salt hypertension was used (Sprague-Dawley male rats). After 3 weeks, in 3 different groups: HCTZ, the ROCK inhibitor fasudil or spironolactone was added (3 weeks). After 6 weeks myocardial hypertrophy and fibrosis, cardiac levels of profibrotic proteins, mRNA levels (RT PCR) of pro remodeling and pro oxidative molecules and ROCK activity were determined.</p><p><strong>Results: </strong>Blood pressure, myocardial hypertrophy and fibrosis were reduced significantly by HCTZ, fasudil and spironolactone. In the heart, increased levels of the pro-fibrotic proteins Col-I, Col-III and TGF-β1 and gene expression of pro-remodeling molecules TGF-β1, CTGF, MCP-1 and PAI-1 and the pro-oxidative molecules gp91phox and p22phox were significantly reduced by HCTZ, fasudil and spironolactone. ROCK activity in the myocardium was increased by 54% (<i>P</i> < 0.05) as related to the sham group and HCTZ, spironolactone and fasudil, reduced ROCK activation to control levels.</p><p><strong>Conclusions: </strong>HCTZ reduced pathologic LVH by controlling blood pressure, hypertrophy and myocardial fibrosis and by decreasing myocardial ROCK activation, expression of pro remodeling, pro fibrotic and pro oxidative genes. In hypertension, the observed effects of HCTZ on the myocardium might explain preventive outcomes of thiazides in hypertension, specifically on LVH regression and incident heart failure.</p>","PeriodicalId":15281,"journal":{"name":"Journal of Cardiovascular Pharmacology and Therapeutics","volume":"26 6","pages":"724-735"},"PeriodicalIF":2.6,"publicationDate":"2021-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39498173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Testosterone Deficiency, Long-Term Testosterone Therapy, and Inflammation.","authors":"Xiao Zhang,&nbsp;Hongwei Zhao,&nbsp;Jennifer Horney,&nbsp;Natalie Johnson,&nbsp;Farid Saad,&nbsp;Karim Sultan Haider,&nbsp;Ahmad Haider,&nbsp;Xiaohui Xu","doi":"10.1177/10742484211032402","DOIUrl":"https://doi.org/10.1177/10742484211032402","url":null,"abstract":"<p><strong>Objectives: </strong>We aimed to evaluate the association of testosterone deficiency with inflammation and how long-term testosterone therapy affects inflammation biomarkers over time.</p><p><strong>Methods: </strong>We conducted a 2-component study. First, we conducted a cross-sectional study using the recently released 2015-2016 National Health and Nutrition Examination Survey (NHANES) data to examine the association between testosterone deficiency and inflammation biomarkers including high sensitivity C-reactive protein (hsCRP), liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the US general population. Then we conducted a longitudinal study to investigate the longitudinal effect of testosterone therapy on inflammation biomarkers and the risk of cardiovascular events, using data from 776 hypogonadal men based on a registry study in Germany with up to 11 years' follow-up.</p><p><strong>Results: </strong>The adjusted odds ratios (ORs) describing the associations between testosterone deficiency and hsCRP ≥ 3mg/L, ALT > 40U/L, and AST > 40U/L were 1.81 (<i>P</i>-value < 0.001), 1.46 (<i>P</i>-value = 0.009), and 0.99 (<i>P</i>-value = 0.971), respectively. In the control group, CRP, ALT, and AST levels increased by 0.003 (95%CI: -0.001, 0.007) mg/L, 0.157 U/L (95%CI: 0.145, 0.170), and 0.147 (95%CI: 0.136, 0.159) U/L per month, while in the treatment group, CRP, ALT, and AST levels decreased by 0.05 (95%CI: -0.055, -0.046) mg/L, 0.142 U/L (95%CI: -0.154, -0.130), and 0.148 (95%CI: -0.158, -0.137) U/L per month.</p><p><strong>Conclusion: </strong>Testosterone deficiency was associated with an increased level of inflammation; long-term testosterone therapy alleviated inflammation among hypogonadal men, which may contribute to the reduced cardiovascular risk. Future large trials are warranted to confirm our observational study findings.</p>","PeriodicalId":15281,"journal":{"name":"Journal of Cardiovascular Pharmacology and Therapeutics","volume":"26 6","pages":"638-647"},"PeriodicalIF":2.6,"publicationDate":"2021-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/10742484211032402","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39172356","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}