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1.
Diabetes Obes Metab ; 22(1): 30-38, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31468659

RESUMO

AIMS: The AleCardio trial aimed to characterize the efficacy and safety of peroxisome proliferator-activated receptor-αγ agonist aleglitazar in patients with type 2 diabetes mellitus and acute coronary syndrome. The trial terminated early because of futility and safety signals. We evaluated whether the safety signals could be attributed to increased exposure to aleglitazar. MATERIALS AND METHODS: The AleCardio trial enrolled 7226 patients to receive aleglitazar 150 µg or matching placebo on top of standard care. A population pharmacokinetic analysis was conducted in a pharmacokinetic substudy to identify covariates that explained interindividual variability in exposure. Subsequently, the effect of these covariates on surrogate and clinical outcomes was assessed in the full patient population. RESULTS: Concomitant administration of clopidogrel was identified as a covariate that influenced the apparent clearance of aleglitazar. Patients using clopidogrel had a mean predicted area under the plasma-concentration-time curve (AUC0-24 ) of 174.7 ng h/mL (SD: ±112.9 ng h/mL) versus 142.2 ng h/mL (SD: ±92.6 ng h/mL) in patients without clopidogrel. The effect of aleglitazar compared with placebo on HbA1c, haemoglobin, serum creatinine and adiponectin was modified by concomitant clopidogrel use (P for interaction 0.007, 0.002, <0.001 and < 0.001, respectively). CONCLUSIONS: Concomitant use of clopidogrel was identified as a covariate that explained interindividual variability in exposure to aleglitazar. Patients using clopidogrel showed an additional lowering of HbA1c, at the expense of an additional decrease in haemoglobin, and an increase in serum creatinine and adiponectin. Clopidogrel is a moderate inhibitor of CYP2C8. Because aleglitazar is metabolized by CYP2C8, a pharmacokinetic interaction could explain differences in exposure and response to aleglitazar.

2.
Eur J Prev Cardiol ; : 2047487319887578, 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31744333

RESUMO

AIM: Remnant cholesterol has been proposed to promote atherosclerotic cardiovascular disease independent of low-density lipoprotein cholesterol, yet the underlying mechanisms are not well understood. We aimed to study the association of remnant cholesterol with coronary atheroma progression and clinical events. METHODS: We analyzed data from 5754 patients with coronary artery disease undergoing serial intravascular ultrasonography who were enrolled in 10 trials examining various medical therapies. Remnant cholesterol was calculated as (non-high-density lipoprotein cholesterol - low-density lipoprotein cholesterol (estimated using the Hopkins-Martin equation)). Changes in percentage atheroma volume and 2-year major adverse cardiovascular events were compared across various levels of remnant cholesterol, and multivariable models were used to assess the independent relationship of remnant cholesterol with changes in percentage atheroma volume. RESULTS: The mean age was 58.1 ± 9.2 years, 28% were women and 96% received a statin. Percentage atheroma volume progression (changes in percentage atheroma volume > 0) occurred in a linear fashion at on-treatment remnant cholesterol levels of 25 mg/dL or greater. The highest on-treatment remnant cholesterol quartile demonstrated greater percentage atheroma volume progression (+0.53 ± 0.26 vs. -0.15 ± 0.25%, P < 0.001) and 2-year major adverse cardiovascular events (23% vs. 14%, log-rank P < 0.001) compared with the lowest. In multivariable analyses, changes in percentage atheroma volume significantly correlated with on-treatment remnant cholesterol (P < 0.001] independent of low-density lipoprotein cholesterol, apolipoprotein B, C-reactive protein, high-density lipoprotein cholesterol levels and clinical risk factors. Changes in percentage atheroma volume also significantly correlated with changes in remnant cholesterol following multivariable adjustment. CONCLUSIONS: In statin-treated patients with atherosclerotic cardiovascular disease, remnant cholesterol was associated with coronary atheroma progression regardless of conventional lipid parameters, C-reactive protein or clinical risk factors. Higher remnant cholesterol levels also correlated with higher major adverse cardiovascular events. These data support further investigations into remnant cholesterol-lowering interventions in statin-treated patients harboring residual atherosclerotic cardiovascular disease risk.

3.
J Am Heart Assoc ; 8(23): e013790, 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31752637

RESUMO

Background The failure of cholesteryl ester transfer protein inhibitor torcetrapib was associated with an off-target increase in plasma aldosterone. We sought to evaluate the impact of evacetrapib on plasma aldosterone level and determine the association between plasma aldosterone level and major adverse cardiovascular events among patients with stable high-risk vascular disease enrolled in the ACCELERATE (Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition With Evacetrapib in Patients at a High Risk for Vascular Outcomes) trial. Methods and Results We included all patients with a plasma aldosterone level (N=1624) and determined the impact of evacetrapib exposure compared with placebo on plasma aldosterone levels after 12 months of treatment. Using baseline and postexposure aldosterone levels, hazard ratios for major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, cerebrovascular accident, hospitalization for unstable angina, and revascularization) with increasing quartile of baseline and percentage change in plasma aldosterone level at follow-up were calculated. The average age was 65.2 years, 75.7% were men, 93.7% were hypertensive, 73.3% were diabetic, and 57.6% had a prior myocardial infarction. Baseline plasma aldosterone level (85.2 [43, 150] versus 86.8 [43, 155] pmol/L; P=0.81) and follow-up percentage change (13.6% [-29, 88] versus 17.9% [-24, 87]; P=0.23) were similar between those who received evacetrapib and placebo. During median follow-up of 28 months, major adverse cardiovascular events occurred in 263 patients (16.2%). The hazard ratios for increasing quartile of baseline or percentage change in plasma aldosterone level at follow-up were not significant for major adverse cardiovascular events. These findings remained consistent when adjusting for significant characteristics. Conclusions Exposure to evacetrapib did not result in significant change in plasma aldosterone levels compared with placebo. Among patients with stable high-risk vascular disease, plasma aldosterone levels were not a predictor for future cardiovascular events. Clinical Trial Registration URL: http://www.ClinicalTrials.gov. Unique identifier: NCT01687998.

4.
Heart Lung Circ ; 2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31564511

RESUMO

BACKGROUND: To compare computed tomography coronary angiography (CTCA) with intravascular ultrasound (IVUS) in quantitative and qualitative plaque assessment. METHODS: Patients who underwent IVUS and CTCA within 3 months for suspected coronary artery disease were retrospectively studied. Plaque volumes on CTCA were quantified manually and with automated-software and were compared to IVUS. High-risk plaque features were compared between CTCA and IVUS. RESULTS: There were 769 slices in 32 vessels (27 patients). Manual plaque quantification on CTCA was comparable to IVUS per slice (mean difference of 0.06±0.07, p=0.44; Bland-Altman 95% limits of agreement -2.19-2.08 mm3, bias of -0.06mm3) and per vessel (3.1mm3 ± -2.85mm3, p=0.92). In contrast, there was significant difference between automated-software and IVUS per slice (2.3±0.09mm3, p<0.001; 95% LoA -6.78 to 2.25mm3, bias of -2.2mm3) and per vessel (33.04±10.3 mm3, p<0.01). The sensitivity, specificity, positive and negative predictive value of CTCA to detect plaques that had features of echo-attenuation on IVUS was 93.3%, 99.6%, 93.3% and 99.6% respectively. The association of ≥2 high-risk plaque features on CTCA with echo attenuation (EA) plaque features on IVUS was excellent (86.7%, 99.6%, 92.9% and 99.2%). In comparison, the association of high-risk plaque features on CTCA and plaques with echo-lucency on IVUS was only modest. CONCLUSION: Plaque volume quantification by manual CTCA method is accurate when compared to IVUS. The presence of at least two high-risk plaque features on CTCA is associated with plaque features of echo attenuation on IVUS.

5.
Atherosclerosis ; 290: 59-65, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31568963

RESUMO

BACKGROUND AND AIMS: In patients with cardiovascular disease, considerable residual risk remains despite evidence-based secondary prevention measures. Alkaline phosphatase (ALP) has been suggested as a modifiable cardiovascular risk factor. We sought to determine whether cardiovascular risk reduction by the bromodomain and extra-terminal (BET) protein inhibitor apabetalone is associated with the concomitant lowering of serum ALP. METHODS: In a post-hoc analysis of 795 patients with established coronary heart disease and statin treatment, who participated in phase 2 placebo-controlled trials of apabetalone, we determined the effect of assigned treatment for up to 24 weeks on the incidence of major adverse cardiovascular events (MACE) and serum ALP. RESULTS: Baseline ALP (median 72 U/L) predicted MACE (death, non-fatal myocardial infarction, coronary revascularization, or hospitalization for cardiovascular causes), independent of high-sensitivity C-reactive protein (hsCRP), sex, age, race, study, cardiovascular risk factors, chronic kidney disease (CKD), liver function markers and treatment allocation (hazard ratio [HR] per standard deviation [SD] 1.6, 95% CI 1.19-2.16, p = 0.002). Mean placebo-corrected decreases in ALP from baseline were 9.2% (p < 0.001) after 12-14 weeks and 7.7% (p < 0.001) after 24-26 weeks of apabetalone treatment. In the apabetalone group, a 1-SD reduction in ALP was associated with a HR for MACE of 0.64 (95% CI 0.46-0.90, p = 0.009). CONCLUSIONS: Serum ALP predicts residual cardiovascular risk, independent of hsCRP, established cardiovascular risk factors and CKD, in patients with cardiovascular disease on statin treatment. Apabetalone lowers serum ALP, which was associated with a lower risk of cardiovascular events. Whether the beneficial cardiovascular effects of apabetalone are causally related to ALP reduction remains undetermined.

6.
Expert Rev Cardiovasc Ther ; 17(10): 707-716, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31592685

RESUMO

Introduction: In CKD subjects, atherosclerotic cardiovascular disease (ASCVD) is a major cause of their morbidity and mortality (1-3). Current therapeutic guidelines recommend lowering LDL-C level to prevent ASCVD (4, 5). However, it remains uncertain how this therapeutic approach effectively modifies atherosclerosis of CKD. These findings suggest the need to further understand pathophysiology of atherosclerosis. Given that intravascular imaging modalities have contributed to characterize the natural history of coronary atherosclerosis (13-23), the integration of plaque imaging is expected to help to elucidate targets associated with stabilizing atheroma.Areas covered: This review will outline atherogenic stimuli in patients with CKD. In addition, the characteristics of their coronary atheroma will be presented from finding in clinical studies using a variety of intravascular imaging modalities. The efficacy of current guideline recommended anti-atherosclerotic therapies in CKD patients will be also summarized. All related articles were searched through PubMed.Expert opinion: Integration of intravascular imaging has a great potential to establish effective therapies for slowing progression of atherosclerosis in subjects with CKD. More efforts toward searching therapeutic target associated with atherosclerosis of CKD are required. In particular, identifying drivers associated with plaque calcification will lead to the development of new agents which regress calcium accumulation.

7.
JAMA ; 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31475726

RESUMO

Importance: The relationship between exposure to lower low-density lipoprotein cholesterol (LDL-C) and lower systolic blood pressure (SBP) with the risk of cardiovascular disease has not been reliably quantified. Objective: To assess the association of lifetime exposure to the combination of both lower LDL-C and lower SBP with the lifetime risk of cardiovascular disease. Design, Setting, and Participants: Among 438 952 participants enrolled in the UK Biobank between 2006 and 2010 and followed up through 2018, genetic LDL-C and SBP scores were used as instruments to divide participants into groups with lifetime exposure to lower LDL-C, lower SBP, or both. Differences in plasma LDL-C, SBP, and cardiovascular event rates between the groups were compared to estimate associations with lifetime risk of cardiovascular disease. Exposures: Differences in plasma LDL-C and SBP compared with participants with both genetic scores below the median. Genetic risk scores higher than the median were associated with lower LDL-C and lower SBP. Main Outcomes and Measures: Odds ratio (OR) for major coronary events, defined as coronary death, nonfatal myocardial infarction, or coronary revascularization. Results: The mean age of the 438 952 participants was 65.2 years (range, 40.4-80.0 years), 54.1% were women, and 24 980 experienced a first major coronary event. Compared with the reference group, participants with LDL-C genetic scores higher than the median had 14.7-mg/dL lower LDL-C levels and an OR of 0.73 for major coronary events (95% CI, 0.70-0.75; P < .001). Participants with SBP genetic scores higher than the median had 2.9-mm Hg lower SBP and an OR of 0.82 for major coronary events (95% CI, 0.79-0.85, P < .001). Participants in the group with both genetic scores higher than the median had 13.9-mg/dL lower LDL-C, 3.1-mm Hg lower SBP, and an OR of 0.61 for major coronary events (95% CI, 0.59-0.64; P < .001). In a 4 × 4 factorial analysis, exposure to increasing genetic risk scores and lower LDL-C levels and SBP was associated with dose-dependent lower risks of major coronary events. In a meta-regression analysis, combined exposure to 38.67-mg/dL lower LDL-C and 10-mm Hg lower SBP was associated with an OR of 0.22 for major coronary events (95% CI, 0.17-0.26; P < .001), and 0.32 for cardiovascular death (95% CI, 0.25-0.40; P < .001). Conclusions and Relevance: Lifelong genetic exposure to lower levels of low-density lipoprotein cholesterol and lower systolic blood pressure was associated with lower cardiovascular risk. However, these findings cannot be assumed to represent the magnitude of benefit achievable from treatment of these risk factors.

8.
Am Heart J ; 217: 72-83, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31520897

RESUMO

After an acute coronary syndrome (ACS), patients with diabetes remain at high risk for additional cardiovascular events despite use of current therapies. Bromodomain and extra-terminal (BET) proteins are epigenetic modulators of inflammation, thrombogenesis, and lipoprotein metabolism implicated in atherothrombosis. The BETonMACE trial tests the hypothesis that treatment with apabetalone, a selective BET protein inhibitor, will improve cardiovascular outcomes in patients with diabetes after an ACS. DESIGN: Patients (n = 2425) with ACS in the preceding 7 to 90 days, with type 2 diabetes and low HDL cholesterol (≤40 mg/dl for men, ≤45 mg/dl for women), receiving intensive or maximum-tolerated therapy with atorvastatin or rosuvastatin, were assigned in double-blind fashion to receive apabetalone 100 mg orally twice daily or matching placebo. Baseline characteristics include female sex (25%), myocardial infarction as index ACS event (74%), coronary revascularization for index ACS (80%), treatment with dual anti-platelet therapy (87%) and renin-angiotensin system inhibitors (91%), median LDL cholesterol 65 mg per deciliter, and median HbA1c 7.3%. The primary efficacy measure is time to first occurrence of cardiovascular death, non-fatal myocardial infarction, or stroke. Assumptions include a primary event rate of 7% per annum in the placebo group and median follow-up of 1.5 years. Patients will be followed until at least 250 primary endpoint events have occurred, providing 80% power to detect a 30% reduction in the primary endpoint with apabetalone. SUMMARY: BETonMACE will determine whether the addition of the selective BET protein inhibitor apabetalone to contemporary standard of care for ACS reduces cardiovascular morbidity and mortality in patients with type 2 diabetes. Results are expected in 2019.

9.
Artigo em Inglês | MEDLINE | ID: mdl-31485851

RESUMO

Despite the widespread use of statins in the setting of high cardiovascular risk, many patients continue to experience clinical events. This highlights the need to identify additional therapeutic strategies for high-risk patients. Interest in the use of omega-3 polyunsaturated fatty acids to prevent cardiovascular disease has been high for several decades. Despite promising results from before the statin era, many clinical trials have produced disappointing findings regarding products containing conventional doses of omega-3 fatty acids. More recent clinical trials using high doses of omega-3 fatty acids in targeted populations have suggested potential benefit when targeting the risk driven by atherogenic dyslipidemia. We review the clinical implications of completed and ongoing trials.

10.
Am J Physiol Heart Circ Physiol ; 317(4): H811-H819, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31441693

RESUMO

A large body of evidence demonstrates an independent association between arterial stiffness and prospective risk of cardiovascular events. A reduction in coronary perfusion is presumed to underscore this association; however, studies confirming this are lacking. This study compared invasive measures of coronary blood flow (CBF) with cardiac magnetic resonance (CMR)-derived aortic distensibility (AD). Following coronary angiography, a Doppler FloWire and infusion microcatheter were advanced into the study vessel. Average peak velocity (APV) was acquired at baseline and following intracoronary adenosine to derive coronary flow velocity reserve (CFVR = hyperemic APV/resting APV) and CBF [π × (diameter)2 × APV × 0.125]. Following angiography, patients underwent CMR to evaluate distensibility at the ascending aorta (AA), proximal descending aorta (PDA) and distal descending aorta (DDA). Fifteen participants (53 ± 13 yr) with minor epicardial disease (maximum stenosis <30%) were enrolled. Resting CBF was 44.1 ± 11.9 mL/min, hyperemic CBF was 143.8 ± 37.4 mL/min, and CFVR was 3.15 ± 0.48. AD was 3.89 ± 1.72·10-3mmHg-1 at the AA, 4.08 ± 1.80·10-3mmHg-1 at the PDA, and 4.42 ± 1.67·10-3mmHg-1 at the DDA. All levels of distensibility correlated with resting CBF (R2 = 0.350-0.373, P < 0.05), hyperemic CBF (R2 = 0.453-0.464, P < 0.01), and CFVR (R2 = 0.442-0.511, P < 0.01). This study demonstrates that hyperemic and, to a lesser extent resting CBF, are significantly associated with measures of aortic stiffness in patients with only minor angiographic disease. These findings provide further in vivo support for the observed prognostic capacity of large artery function in cardiovascular event prediction.NEW & NOTEWORTHY Cardiac magnetic resonance-derived aortic distensibility is associated with invasive measures of coronary blood flow. Large artery function is more strongly correlated with hyperemic than resting blood flow. Increased stiffness may represent a potential target for novel antianginal medications.

11.
Arterioscler Thromb Vasc Biol ; 39(10): 1902-1910, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31462089

RESUMO

Vascular calcification (VC) is strongly associated with all-cause mortality and is an independent predictor of cardiovascular events. Resulting from its complex, multifaceted nature, targeted treatments for VC have not yet been developed. Lipoproteins are well characterized in the pathogenesis of atherosclerotic plaques, leading to the development of plaque regressing therapeutics. Although their roles in plaque progression are well documented, their roles in VC, and calcification of a plaque, are not well understood. In this review, early in vitro data and clinical correlations suggest an inhibitory role for HDL (high-density lipoproteins) in VC, a stimulatory role for LDL (low-density lipoprotein) and VLDL (very low-density lipoprotein) and a potentially causal role for Lp(a) (lipoprotein [a]). Additionally, after treatment with a statin or PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor, plaque calcification is observed to increase. With the notion that differing morphologies of plaque calcification associate with either a more stable or unstable plaque phenotype, uncovering the mechanisms of lipoprotein-artery wall interactions could produce targeted therapeutic options for VC.

12.
Lancet ; 394(10199): 697-708, 2019 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-31448741

RESUMO

Atherosclerosis and its clinical manifestation as ischaemic heart disease remains a considerable health burden. Given that many factors contribute to ischaemic heart disease, a multifactorial approach to prevention is recommended, starting with lifestyle advice, smoking cessation, and control of known cardiovascular risk factors, such as blood pressure and lipids. Within the lipid profile, the principal target is lowering LDL cholesterol, firstly with lifestyle interventions and subsequently with pharmacological therapy. Statins are the recommended first-line pharmacological treatment. Some individuals might require further lowering of LDL cholesterol or be unable to tolerate statins. Additional therapies targeting different pathways in cholesterol metabolism are now available, ranging from small molecules taken orally, to injectable therapies. Examples include ezetimibe, which targets Niemann-Pick C1-like protein, and monoclonal antibodies that target PCSK9. Phase 3 trials have also been completed for bempedoic acid (targeting ATP-citrate lyase) and inclisiran (an interference RNA-based therapeutic targeting hepatic PCSK9 synthesis). In addition to LDL cholesterol, mendelian randomisation studies support a causal role for lipoprotein(a) and triglycerides in ischaemic heart disease. In this Series paper, we appraise currently available and emerging therapies for lowering LDL cholesterol, lipoprotein(a), and triglycerides for prevention of ischaemic heart disease.


Assuntos
Anticorpos Monoclonais/farmacologia , Anticolesterolemiantes/farmacologia , LDL-Colesterol/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Lipoproteínas/efeitos dos fármacos , Isquemia Miocárdica/prevenção & controle , LDL-Colesterol/sangue , Humanos , Lipoproteínas/sangue , Isquemia Miocárdica/tratamento farmacológico , Pró-Proteína Convertase 9 , Fatores de Risco , Triglicerídeos/sangue
13.
Sci Rep ; 9(1): 7286, 2019 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-31086203

RESUMO

The cellular origins of vasa vasorum are ill-defined and may involve circulating or local progenitor cells. We previously discovered that murine aortic adventitia contains Sca-1+CD45+ progenitors that produce macrophages. Here we investigated whether they are also vasculogenic. In aortas of C57BL/6 mice, Sca-1+CD45+ cells were localised to adventitia and lacked surface expression of endothelial markers (<1% for CD31, CD144, TIE-2). In contrast, they did show expression of CD31, CD144, TIE-2 and VEGFR2 in atherosclerotic ApoE-/- aortas. Although Sca-1+CD45+ cells from C57BL/6 aorta did not express CD31, they formed CD31+ colonies in endothelial differentiation media and produced interconnecting vascular-like cords in Matrigel that contained both endothelial cells and a small population of macrophages, which were located at branch points. Transfer of aortic Sca-1+CD45+ cells generated endothelial cells and neovessels de novo in a hindlimb model of ischaemia and resulted in a 50% increase in perfusion compared to cell-free control. Similarly, their injection into the carotid adventitia of ApoE-/- mice produced donor-derived adventitial and peri-adventitial microvessels after atherogenic diet, suggestive of newly formed vasa vasorum. These findings show that beyond its content of macrophage progenitors, adventitial Sca-1+CD45+ cells are also vasculogenic and may be a source of vasa vasorum during atherogenesis.

14.
Heart Lung Circ ; 28(10): 1571-1579, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31104887

RESUMO

Proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies (mAb) have progressed from showing marked low density lipoprotein cholesterol lowering in early phase trials through to reducing cardiovascular events in large clinical outcome trials. Recently in Australia, the indication for evolocumab has been expanded to include both heterozygous and homozygous familial hypercholesterolaemia under the Pharmaceutical Benefits Scheme (PBS). With prices remaining high currently their use in non-familial hypercholesterolaemia in Australia remains by private prescription only at this stage. This manuscript summarises the major outcomes trials of the PCSK9 mAbs and the secondary analyses that have assessed their benefits in high risk patient groups, and describes the consensus of authors on which patients would most likely benefit from PCSK9 mAb therapy.

15.
Diab Vasc Dis Res ; 16(2): 171-177, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-31014095

RESUMO

BACKGROUND: Despite optimal treatment, type II diabetes mellitus remains associated with an increased risk for future cardiovascular events. We sought to determine the association between baseline fasting plasma insulin levels and major adverse cardiovascular outcomes in patients with type II diabetes mellitus and high-risk vascular disease enrolled in the ACCELERATE (Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition with Evacetrapib in Patients at a High Risk for Vascular Outcomes) trial. METHODS: We included all patients with type II diabetes mellitus who had a central laboratory measured fasting plasma insulin level drawn at baseline as part of the study protocol. Hazard ratios were generated for the risk of major adverse cardiovascular outcomes (composite of cardiovascular death, non-fatal myocardial infarction, stroke, hospitalization for unstable angina and coronary revascularization) with increasing quartile of baseline fasting plasma insulin level. We then performed a multivariable regression adjusting for significant baseline characteristics. RESULTS: Among 12,092 patients in ACCELERATE, 2042 patients with type II diabetes mellitus had a baseline fasting plasma insulin level drawn. Median follow-up was 28 months. The study population had a mean age of 66.6 years, 79.2% male and 96.2% had established coronary artery disease. During follow-up, major adverse cardiovascular outcomes occurred in 238 patients (11.6%); of these events, 177 were coronary revascularization (8.7%). We observed a statistically significant relationship between rates of revascularization and rising quartile of baseline fasting plasma insulin level which was not noted for the other individual components of major adverse cardiovascular outcomes. Patients with type II diabetes mellitus who underwent revascularization were noted to have significantly higher baseline fasting plasma insulin levels (27.7 vs 21.4 mU/L, p-value = 0.009) although baseline haemoglobin A1c (6.63% vs 6.55%), body mass index (31.5 vs 31.1 kg/m2) and medical therapy were otherwise similar to the group not undergoing revascularization. Following multivariable regression adjusting for significant characteristics including exposure to evacetrapib, the log of baseline fasting plasma insulin level was found to be an independent predictor for major adverse cardiovascular outcomes (hazard ratio = 1.36, 95% confidence interval = 1.09-1.69, p-value = 0.007); this was driven by need for future revascularization (hazard ratio = 1.56, 95% confidence interval = 1.21-2.00, p-value = 0.001). CONCLUSION: In a contemporary population of patients with type II diabetes mellitus and high-risk vascular disease on optimum medical therapy, baseline hyperinsulinaemia was an independent predictor for major adverse cardiovascular outcomes and need of future coronary revascularization. These results suggest a pathophysiological link between hyperinsulinaemia and progression of atherosclerotic vascular disease among diabetics.


Assuntos
Doenças Cardiovasculares/etiologia , Diabetes Mellitus Tipo 2/sangue , Jejum/sangue , Hiperinsulinismo/sangue , Insulina/sangue , Idoso , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/terapia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/mortalidade , Diabetes Mellitus Tipo 2/terapia , Feminino , Humanos , Hiperinsulinismo/complicações , Hiperinsulinismo/mortalidade , Hiperinsulinismo/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Fatores de Risco , Fatores de Tempo
16.
JAMA Cardiol ; 4(5): 437-443, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30969323

RESUMO

Importance: Visit-to-visit blood pressure variability (BPV) is associated with cardiovascular events, but mechanisms and therapeutic implications underlying this association are not well understood. Objective: To examine the association of intraindividual BPV, coronary atheroma progression, and clinical outcomes using serial intravascular ultrasonography. Design, Setting, and Participants: Post hoc patient-level analysis of 7 randomized clinical trials conducted from 2004 to 2016 involving 3912 patients in multicenter, international, clinic-based primary and tertiary care centers. Adult patients with coronary artery disease who underwent serial intravascular ultrasonography in the setting of a range of medical therapies were included. Data were analyzed between November 2017 and March 2019. Exposures: Visit-to-visit BPV measured using intraindividual standard deviation over 3, 6, 12, 18, and 24 months. Main Outcomes and Measures: Percent atheroma volume (PAV) progression and major adverse cardiovascular events (defined as death, myocardial infarction, stroke, urgent revascularization for acute coronary syndrome, and hospitalization for unstable angina). Results: Of 3912 patients, the mean (SD) age was 58 (9) years, 1093 (28%) were women, and 3633 (93%) were white . Continuous change in PAV was significantly associated with systolic BPV (ß, .049; 95% CI, 0.021-0.078; P = .001), diastolic BPV (ß, .031; 95% CI, 0.002-0.059; P = .03), and pulse pressure variability (ß, .036; 95% CI, 0.006-0.067; P = .02), without a signal for differential effect greater than or less than a mean BP of 140/90 mm Hg. The PAV progression as a binary outcome was significantly associated with systolic BPV (odds ratio, 1.09; 95% CI, 1.01-1.17; P = .02) but not diastolic BPV (odds ratio, 1.04; 95% CI, 0.97-1.11; P = .30) or pulse pressure variability (odds ratio, 1.03; 95% CI, 0.96-1.10; P = .47). Survival curves revealed a significant stepwise association between cumulative major adverse cardiovascular events and increasing quartiles of systolic BPV (Kaplan-Meier estimates for quartiles 1-4: 6.1% vs 8.5% vs 10.1% vs 12.0%, respectively; log-rank P <.001). These distinct stepwise associations were not seen with diastolic BPV or pulse pressure variability. Conclusions and Relevance: Greater BPV, particularly systolic BPV, is significantly associated with coronary atheroma progression and adverse clinical outcomes. These data suggest maintaining stable blood pressure levels may be important to further improve outcomes in patients with coronary disease.

17.
J Am Coll Cardiol ; 73(22): 2819-2828, 2019 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-30898608

RESUMO

BACKGROUND: The efficacy of ticagrelor in the long-term post-ST-segment elevation myocardial infarction (STEMI) treated with fibrinolytic therapy remains uncertain. OBJECTIVES: The purpose of this study was to evaluate the efficacy of ticagrelor when compared with clopidogrel in STEMI patients treated with fibrinolytic therapy. METHODS: This international, multicenter, randomized, open-label with blinded endpoint adjudication trial enrolled 3,799 patients (age <75 years) with STEMI receiving fibrinolytic therapy. Patients were randomized to ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) or clopidogrel (300- to 600-mg loading dose, 75 mg daily thereafter). The key outcomes were cardiovascular mortality, myocardial infarction, or stroke, and the same composite outcome with the addition of severe recurrent ischemia, transient ischemic attack, or other arterial thrombotic events at 12 months. RESULTS: The combined outcome of cardiovascular mortality, myocardial infarction, or stroke occurred in 129 of 1,913 patients (6.7%) receiving ticagrelor and in 137 of 1,886 patients (7.3%) receiving clopidogrel (hazard ratio: 0.93; 95% confidence interval: 0.73 to 1.18; p = 0.53). The composite of cardiovascular mortality, myocardial infarction, stroke, severe recurrent ischemia, transient ischemic attack, or other arterial thrombotic events occurred in 153 of 1,913 patients (8.0%) treated with ticagrelor and in 171 of 1,886 patients (9.1%) receiving clopidogrel (hazard ratio: 0.88; 95% confidence interval: 0.71 to 1.09; p = 0.25). The rates of major, fatal, and intracranial bleeding were similar between the ticagrelor and clopidogrel groups. CONCLUSION: Among patients age <75 years with STEMI, administration of ticagrelor after fibrinolytic therapy did not significantly reduce the frequency of cardiovascular events when compared with clopidogrel. (Ticagrelor in Patients With ST Elevation Myocardial Infarction Treated With Pharmacological Thrombolysis [TREAT]; NCT02298088).

18.
Atherosclerosis ; 284: 24-30, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30870704

RESUMO

BACKGROUND AND AIMS: There remains a substantial residual risk of ischaemic heart disease (IHD) despite optimal low-density lipoprotein cholesterol (LDLC) reduction. Part of this risk may be attributable to remnant cholesterol, which is carried in triglyceride-rich lipoproteins. We evaluated the relationship between remnant cholesterol and coronary atherosclerotic plaque burden assessed non-invasively by computed tomography coronary angiography (CTCA) in patients with suspected coronary artery disease (CAD). METHODS AND RESULTS: This was a multicentre study of 587 patients who had a CTCA and fasting lipid profile within 3 months. Calculated remnant cholesterol was total cholesterol minus LDLC minus high-density lipoprotein cholesterol (HDLC). Significant coronary atherosclerotic burden was defined as CT-Leaman score >5 (CT-LeSc), an established predictor of cardiac events. Mean age was 61 ±â€¯12 years and mean pretest probability of CAD was 23.2 ±â€¯19.8%. LDLC levels were <1.8 mmol/L in 134 patients (23%), of whom 82% were statin-treated. Patients with CT-LeSc >5 had higher mean remnant cholesterol than those with CT-LeSc ≤5 (0.76 ±â€¯0.36 mmol/L vs. 0.58 ±â€¯0.33 mmol/L, p = 0.01). On univariable analysis, remnant cholesterol (p = 0.01), LDLC (p = 0.002) and HDLC (p < 0.001) levels predicted CT-LeSc >5, whilst triglycerides (p = 0.79) had no association with CT-LeSc >5. On multivariable analysis in the subset of patients with optimal LDLC levels, remnant cholesterol levels remained predictive of CT-LeSc >5 (OR 3.87, 95% confidence interval 1.34-7.55, p = 0.004), adjusted for HDLC and traditional risk factors. CONCLUSIONS: Remnant cholesterol levels are associated with significant coronary atherosclerotic burden as assessed by CTCA, even in patients with optimal LDLC levels. Future studies examining whether lowering of remnant cholesterol can reduce residual IHD risk are warranted.

19.
N Engl J Med ; 380(11): 1033-1042, 2019 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-30865797

RESUMO

BACKGROUND: ATP citrate lyase is an enzyme in the cholesterol-biosynthesis pathway upstream of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), the target of statins. Whether the genetic inhibition of ATP citrate lyase is associated with deleterious outcomes and whether it has the same effect, per unit decrease in the low-density lipoprotein (LDL) cholesterol level, as the genetic inhibition of HMGCR is unclear. METHODS: We constructed genetic scores composed of independently inherited variants in the genes encoding ATP citrate lyase (ACLY) and HMGCR to create instruments that mimic the effect of ATP citrate lyase inhibitors and HMGCR inhibitors (statins), respectively. We then compared the associations of these genetic scores with plasma lipid levels, lipoprotein levels, and the risk of cardiovascular events and cancer. RESULTS: A total of 654,783 participants, including 105,429 participants who had major cardiovascular events, were included in the study. The ACLY and HMGCR scores were associated with similar patterns of changes in plasma lipid and lipoprotein levels and with similar effects on the risk of cardiovascular events per decrease of 10 mg per deciliter in the LDL cholesterol level: odds ratio for cardiovascular events, 0.823 (95% confidence interval [CI], 0.78 to 0.87; P = 4.0×10-14) for the ACLY score and 0.836 (95% CI, 0.81 to 0.87; P = 3.9×10-19) for the HMGCR score. Neither lifelong genetic inhibition of ATP citrate lyase nor lifelong genetic inhibition of HMGCR was associated with an increased risk of cancer. CONCLUSIONS: Genetic variants that mimic the effect of ATP citrate lyase inhibitors and statins appeared to lower plasma LDL cholesterol levels by the same mechanism of action and were associated with similar effects on the risk of cardiovascular disease per unit decrease in the LDL cholesterol level. (Funded by Esperion Therapeutics and others.).


Assuntos
ATP Citrato (pro-S)-Liase/genética , Doenças Cardiovasculares/genética , LDL-Colesterol/sangue , Predisposição Genética para Doença , Hidroximetilglutaril-CoA Redutases/genética , Análise da Randomização Mendeliana , ATP Citrato (pro-S)-Liase/antagonistas & inibidores , Diabetes Mellitus/genética , Ácidos Dicarboxílicos/farmacologia , Ácidos Dicarboxílicos/uso terapêutico , Ácidos Graxos/farmacologia , Ácidos Graxos/uso terapêutico , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Hipolipemiantes/farmacologia , Hipolipemiantes/uso terapêutico , Lipoproteínas/sangue , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Neoplasias/genética , Razão de Chances , Risco , Triglicerídeos/sangue
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