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Assessment of resistance vessel function in human skeletal muscle: guidelines for experimental design, Doppler ultrasound, and pharmacology.
Limberg, JK, Casey, DP, Trinity, JD, Nicholson, WT, Wray, DW, Tschakovsky, ME, Green, DJ, Hellsten, Y, Fadel, PJ, Joyner, MJ, et al
American journal of physiology. Heart and circulatory physiology. 2020;(2):H301-H325
Abstract
The introduction of duplex Doppler ultrasound almost half a century ago signified a revolutionary advance in the ability to assess limb blood flow in humans. It is now widely used to assess blood flow under a variety of experimental conditions to study skeletal muscle resistance vessel function. Despite its pervasive adoption, there is substantial variability between studies in relation to experimental protocols, procedures for data analysis, and interpretation of findings. This guideline results from a collegial discussion among physiologists and pharmacologists, with the goal of providing general as well as specific recommendations regarding the conduct of human studies involving Doppler ultrasound-based measures of resistance vessel function in skeletal muscle. Indeed, the focus is on methods used to assess resistance vessel function and not upstream conduit artery function (i.e., macrovasculature), which has been expertly reviewed elsewhere. In particular, we address topics related to experimental design, data collection, and signal processing as well as review common procedures used to assess resistance vessel function, including postocclusive reactive hyperemia, passive limb movement, acute single limb exercise, and pharmacological interventions.
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Beta-Blockers, Calcium Channel Blockers, and Mortality in Stable Coronary Artery Disease.
Cruz Rodriguez, JB, Alkhateeb, H
Current cardiology reports. 2020;(3):12
Abstract
PURPOSE OF REVIEW To examine the current clinical evidence behind the use of calcium channel blockers (CCB) and beta-blockers (BB) for the treatment of patients with stable coronary artery disease (SCAD) and their effect on mortality. RECENT FINDINGS Current evidence suggests that BB use as a first line antianginal medication is associated with lower 5-year all-cause mortality only in patients who had MI within a year. This could be driven due to their effects reducing the sympathetic neuro-hormonal activation of more acutely ill patients. The use of CCB as an antianginal therapy, although proven effective in multiple trials both as monotherapy and combined with other agents, has not shown mortality benefit. Both BB and CCB are effective antianginals, and the selection among them depends on the patient clinical presentation and comorbidities. BB are the only ones that have shown survival benefit in SCAD, particularly the first year post-MI.
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Design of a prospective patient-level pooled analysis of two parallel trials of empagliflozin in patients with established heart failure.
Packer, M, Butler, J, Filippatos, G, Zannad, F, Ferreira, JP, Zeller, C, Brueckmann, M, Jamal, W, Pocock, SJ, Anker, SD, et al
European journal of heart failure. 2020;(12):2393-2398
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Abstract
AIM: The EMPEROR-Reduced trial demonstrated that empagliflozin reduced the combined risk of cardiovascular death or hospitalization for heart failure in patients with a reduced ejection fraction, and the EMPEROR-Preserved trial is currently evaluating the effect of the drug on the same endpoint in patients with an ejection fraction >40%. However, neither the trial was designed to have adequate statistical power to evaluate the effects of empagliflozin and dapagliflozin on major adverse renal outcomes or on mortality. Herein we describe the design of a prospective individual patient-level pooled analysis of two large-scale trials with empagliflozin (EMPEROR-Reduced and EMPEROR-Preserved) in patients with heart failure across the spectrum of ejection fraction. METHODS The trials were carried out in parallel using the same administrative structure and committees, randomization procedure, schedule of study visits and adjudication criteria and similar groups of investigators and case report forms. The two component trials specified the same primary and key secondary endpoints and used an identical hierarchical testing procedure, which included a pooled analysis of the two trials as a key component of the hierarchy. Consequently, the pooled analysis has been prospectively assigned a false positive error rate, which is conditional on one or both trials first achieving success on their primary and one or both key secondary endpoints. The pooled analysis has its own statistical plan with its own endpoints, and this plan was finalized before either trial had begun recruitment of patients into either study. The primary endpoint of the pooled analysis is a composite of serious adverse renal outcomes, defined by chronic dialysis, renal transplantation and a profound or sustained decrease in glomerular filtration rate. All-cause and cardiovascular mortality are specified as secondary endpoints. CONCLUSION The planned pooled analysis has an unusually high degree of statistical rigour that will allow it to address important questions that cannot be fully addressed by the individual trials.
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Sex Differences in Cardiovascular Medication Prescription in Primary Care: A Systematic Review and Meta-Analysis.
Zhao, M, Woodward, M, Vaartjes, I, Millett, ERC, Klipstein-Grobusch, K, Hyun, K, Carcel, C, Peters, SAE
Journal of the American Heart Association. 2020;(11):e014742
Abstract
Background Sex differences in the management of cardiovascular disease have been reported in secondary care. We conducted a systematic review with meta-analysis of systematically investigated sex differences in cardiovascular medication prescription among patients at high risk or with established cardiovascular disease in primary care. Methods and Results PubMed and Embase were searched between 2000 and 2019 for observational studies reporting on the sex-specific prevalence of aspirin, statins, and antihypertensive medication prescription, including beta blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors, and diuretics, in primary care. Random effects meta-analysis was used to obtain pooled women-to-men prevalence ratios for each cardiovascular medication prescription. Metaregression models assessed the impact of age and year on the findings. A total of 43 studies were included, involving 2 264 600 participants (28% women) worldwide. Participants' mean age ranged from 51 to 76 years. The pooled prevalence of cardiovascular medication prescription for women was 41% for aspirin, 60% for statins, and 68% for any antihypertensive medications. Corresponding rates for men were 56%, 63%, and 69% respectively. The pooled women-to-men prevalence ratios were 0.81 (95% CI, 0.72-0.92) for aspirin, 0.90 (95% CI, 0.85-0.95) for statins, and 1.01 (95% CI, 0.95-1.08) for any antihypertensive medications. Women were less likely to be prescribed angiotensin-converting enzyme inhibitors (0.85; 95% CI, 0.81-0.89) but more likely with diuretics (1.27; 95% CI, 1.17-1.37). Mean age, mean age difference between the sexes, and year of study had no significant impact on findings. Conclusions Sex differences in the prescription of cardiovascular medication exist among patients at high risk or with established cardiovascular disease in primary care, with a lower prevalence of aspirin, statins, and angiotensin-converting enzyme inhibitors prescription in women and a lower prevalence of diuretics prescription in men.
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Association of Vascular Risk Factors With β-Amyloid Peptide and Tau Burdens in Cognitively Unimpaired Individuals and Its Interaction With Vascular Medication Use.
Köbe, T, Gonneaud, J, Pichet Binette, A, Meyer, PF, McSweeney, M, Rosa-Neto, P, Breitner, JCS, Poirier, J, Villeneuve, S, ,
JAMA network open. 2020;(2):e1920780
Abstract
IMPORTANCE Vascular risk factors are associated with increased risk of Alzheimer disease (AD), but it is unclear whether there is a direct association of these risk factors with AD pathogenesis. OBJECTIVES To assess the associations of vascular risk factors with AD pathogenesis in asymptomatic individuals, and to test whether this association is moderated among individuals who use vascular medications. DESIGN, SETTING, AND PARTICIPANTS This cross-sectional study used data from the Presymptomatic Evaluation of Experimental or Novel Treatments for Alzheimer Disease (PREVENT-AD) cohort of cognitively unimpaired individuals aged 55 to 82 years with a parental or multiple-sibling history of sporadic AD, who were recruited via advertisement from the greater Montreal, Quebec, Canada, metropolitan area. Participants were enrolled between September 9, 2011, to May, 3, 2017, and stratified by use vs no use of vascular medications. Data were analyzed July 1, 2018, to April 5, 2019. MAIN OUTCOMES AND MEASURES Principal analyses investigated associations of total, high-density lipoprotein, and low-density lipoprotein cholesterol levels, systolic and diastolic blood pressure, pulse pressure, and a combined vascular risk score (measured using the Framingham Coronary Risk Profile) with global β-amyloid peptide (Aβ) and entorhinal tau burden as measured by positron emission tomography (PET). Potential moderating associations of use of vascular medications with these associations were examined. Secondary similar analyses considered cerebrospinal fluid (CSF) Aβ1-42 and phosphorylated tau levels. RESULTS Among 215 participants (mean [SD] age, 62.3 [5.0] years; 161 [74.8%] women), 120 participants underwent PET, including 75 participants (62.5%) who were not using vascular medications, and 162 participants underwent CSF assessment, including 113 participants (69.8%) who were not using vascular medications. There was an overlap of 67 participants who underwent PET and CSF assessment. Interaction analyses showed that among participants not using vascular medications, higher Aβ deposition as measured by PET was associated with higher total cholesterol level (β = -0.002 [SE, 0.001]; P = .02), low-density lipoprotein cholesterol level (β = -0.002 [SE, 0.001]; P = .006), systolic blood pressure (β = -0.006 [SE, 0.002]; P = .02), pulse pressure (β = -0.007 [SE, 0.002]; P = .004), and Framingham Coronary Risk Profile score (β = -0.038 [SE, 0.011]; P = .001), but such associations were absent in participants who used vascular medications. Interactions were also found between vascular medication use and high-density lipoprotein cholesterol (β = -3.302 [SE, 1.540]; P = .03), low-density lipoprotein cholesterol (β = 1.546 [SE, 0.754]; P = .04), and Framingham Coronary Risk Profile score (β = 23.102 [SE, 10.993]; P = .04) on Aβ1-42 burden as measured in CSF. Higher Framingham Coronary Risk Profile scores were associated with reduced tau burden among participants using vascular medications but not among participants not using vascular medications (interaction, β = -0.010 [SE, 0.005]; P = .046). CONCLUSIONS AND RELEVANCE These findings corroborate previously reported associations of vascular risk factors with Aβ burden but not tau burden. However, these associations were found only among individuals who were not using vascular medications. These results suggest that medication use or other control of vascular risk factors should be considered in Alzheimer disease prevention trials.
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Optimizing heart failure treatment following cardiac resynchronization therapy.
Jorsal, A, Pryds, K, McMurray, JJV, Wiggers, H, Sommer, A, Nielsen, JC, Nielsen, RR
Clinical research in cardiology : official journal of the German Cardiac Society. 2020;(5):638-645
Abstract
BACKGROUND Device therapy in addition to medical treatment improves prognosis in a subset of patients with heart failure and reduced ejection fraction. However, some patients remain symptomatic or their heart failure even progresses despite cardiac resynchronization therapy (CRT). The aim of the study was to evaluate the proportion of patients who could benefit from optimization of medical therapy using sacubitril/valsartan, ivabradine, or both following CRT implantation. METHODS We conducted a post hoc analysis of a single-centre, patient and outcome-assessor blinded, randomized-controlled trial, in which patients scheduled for CRT were randomized to empiric (n = 93) or imaging-guided left-ventricular lead placement (n = 89). All patients underwent clinical evaluation and blood sampling at baseline and 6 months following CRT implantation. The proportion of patients meeting the indication for sacubitril/valsartan (irrespective of angiotensin-converting enzyme inhibitor or angiotensin 2 receptor blocker dosage) and/or ivabradine according to current guidelines was evaluated at baseline and after 6 months. RESULTS Of 182 patients with an indication for CRT, 146 (80%) also had an indication for optimization of medical therapy at baseline by adding sacubitril/valsartan, ivabradine, or both. Of the 179 survivors at 6 months, 136 (76%) were still symptomatic after device implantation; of these, 51 (38%) patients had an indication for optimization of medical therapy: sacubitril/valsartan in 37 (27%), ivabradine in 7 (5%), and both drugs in 7 (5%) patients. Seven (18%) patients without indication at baseline developed an indication for medical optimization 6 months after CRT implantation. CONCLUSION In the present study, 38% of those who remained symptomatic 6 months after CRT implantation were eligible for optimization of medical therapy with sacubitril/valsartan, ivabradine, or both. Patients with CRT may benefit from systematic follow-up including evaluation of medical treatment.
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Ivabradine: a new frontier in the treatment of stable coronary artery disease and chronic heart failure.
Gammone, MA, Riccioni, G, D'Orazio, N
La Clinica terapeutica. 2020;(5):e449-e453
Abstract
Ivabradine (IVA) is an inhibitor of the If channel, the main determinant of the pacemaker function of the sinus node. This pure heart rate-lowering agent possesses well-documented antianginal and anti-ischemic properties comparable to well-established antianginal agents, such as β-blockers and calcium channel blockers. IVA lowers heart rate (HR) without affecting contractility or vascular tone and it is licensed for HR control in chronic heart diseases. The heart rate reduction is beneficial in patients with coronary artery disease (CAD), chronic stable angina pectoris, and chronic heart failure (CHF). Published trials documented not only pharmacodynamic and pharmacokinetic properties but also acceptable tolerance and safety profile of IVA, compared to other currently used cardiovascular drugs, including betablockers. The aim of this review is to describe recent evidences with IVA an interesting medicament, able to lower HR by selective inhibition of the If current, and to describe its applications.
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Prediction of Residual Risk by Ceramide-Phospholipid Score in Patients With Stable Coronary Heart Disease on Optimal Medical Therapy.
Hilvo, M, Wallentin, L, Ghukasyan Lakic, T, Held, C, Kauhanen, D, Jylhä, A, Lindbäck, J, Siegbahn, A, Granger, CB, Koenig, W, et al
Journal of the American Heart Association. 2020;(10):e015258
Abstract
Background Identification of patients with stable coronary heart disease who are at significant residual risk could be helpful for targeted prevention. Our aim was to determine the prognostic value of the recently introduced ceramide- and phospholipid-based risk score, the Cardiovascular Event Risk Test (CERT2), in patients with stable coronary heart disease on optimal medical therapy and to identify biological processes that contribute to the CERT2 score. Methods and Results Plasma samples (n=11 222) obtained from the STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) trial were analyzed using a tandem liquid chromatography-mass spectrometry method. STABILITY was a trial in patients with stable coronary heart disease randomized to the lipoprotein-associated phospholipase A2 inhibitor darapladib or placebo on optimized medical therapy at baseline, with a median follow-up of 3.7 years. Hazard ratios per SD for the CERT2 risk score were 1.32 (95% CI, 1.25-1.39) for major adverse cardiovascular event, 1.47 (95% CI, 1.35-1.59) for cardiovascular death, 1.32 (95% CI, 1.16-1.49) for stroke, 1.23 (95% CI, 1.14-1.33) for myocardial infarction, and 1.56 (95% CI, 1.39-1.76) for hospitalization due to heart failure, when adjusted for traditional cardiovascular risk factors. CERT2 showed correlation (P<0.001, r>0.2) with inflammatory markers high-sensitivity C-reactive protein, interleukin 6, the heart failure marker N-terminal pro-B-type natriuretic peptide, and low-density lipoprotein cholesterol. After also adjusting for levels of other prognostic biomarkers, the CERT2 score was still independently related to the risk of cardiovascular death but not to nonfatal events. Conclusions The CERT2 risk score can detect residual risk in patients with stable coronary heart disease and is associated with biomarkers indicating inflammation, myocardial necrosis, myocardial dysfunction, renal dysfunction, and dyslipidemia. REGISTRATION URL https://www.clinicaltrials.gov. Unique identifier: NCT00799903.
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The Sweet Spot: Heart Failure Prevention with SGLT2 Inhibitors.
Vardeny, O
The American journal of medicine. 2020;(2):182-185
Abstract
Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a novel class of medications that reduce plasma glucose concentrations through an insulin-independent mechanism of increased urinary glucose excretion, with concomitant natriuresis and diuresis. Clinical outcomes trials with SGLT2 inhibitors revealed a cardioprotective benefit among patients with diabetes mellitus, with a consistent reduction in hospitalization for heart failure. As such, the 2018 updated US and European treatment guidelines for diabetes mellitus incorporated SGLT2 inhibitors as second-line glucose-lowering agents after metformin. Although well tolerated, there are known adverse effects with SGLT2 inhibitors that require clinical monitoring, such as genital mycotic infections, diabetic ketoacidosis, volume depletion particularly in the setting of concomitant diuretic use, and lower limb amputations with canagliflozin. Ongoing clinical trials will uncover the potential benefit of SGLT2 inhibitors in patients with prevalent heart failure with or without diabetes mellitus.
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Control of cardiovascular risk factors and health behaviors in patients post acute coronary syndromes eligible for protein convertase subtilisin/kexin-9 inhibitors.
Butty, A, Gencer, B, Koskinas, KC, Carballo, D, Räber, L, Klingenberg, R, Matter, CM, Lüscher, TF, Windecker, S, Muller, O, et al
International journal of cardiology. 2020;:289-295
Abstract
BACKGROUND We aimed to examine cardiovascular risk factors and health behaviors in patients with acute coronary syndromes (ACS) according to potential extension of eligibility criteria for protein convertase subtilisin/kexin-9 inhibitors (PCSK9i) to all patients with low-density lipoprotein cholesterol (LDL-c) equal or above 1.8 mmol/l. METHODS In this prospective cross-sectional study, patients with ACS between 2009 and 2016 and with available LDL-c at one year were considered. We defined three mutually exclusive groups of patients according to eligibility for PCSK9i: "not eligible", "currently eligible", and "newly eligible". We explored the control of cardiovascular risk factors and health behaviors. RESULTS Out of 3025 patients who had an ACS one year ago, 1071 (35.4%) were not eligible for PCSK9i, 415 (13.7%) were currently eligible, and 1539 (50.9%) were newly eligible. The proportion of patients with uncontrolled hypertension in the not eligible group was lower than in the group currently eligible (27.6% vs 33.6%, p = 0.02), but similar to the group newly eligible (27.6% vs 28.2%, p = 0.73). The proportion of smokers in the not eligible group was lower than in the group currently eligible (21.2% vs 28.0%, p = 0.02), but similar to the group newly eligible (21.2% vs 22.5%, p = 0.51). CONCLUSIONS More than half of patients with ACS would be additionally eligible for PCSK9i if prescription is extended from current guidelines to all patients with LDL-c equal or above 1.8 mmol/l. Patients currently eligible for PCSK9i one year after an ACS had a worst control of cardiovascular risk factors than patients potentially newly eligible.