Computed tomography and coronary artery calcium score for screening of coronary artery disease and cardiovascular risk management in asymptomatic individuals.

Several risk prediction models exist to predict atherosclerotic cardiovascular disease in asymptomatic individuals, but systematic reviews have generally found these models to be of limited utility. The coronary artery calcium score (CACS) offers an improvement in risk prediction, yet its role remains contentious. Notably, its negative predictive value has a high ability to rule out clinically relevant atherosclerotic cardiovascular disease. Nonetheless, CACS 0 does not permanently reclassify to a lower cardiovascular risk and periodic reassessment every 5 to 10 years remains necessary. Conversely, elevated CACS (> 100 or > 75th percentile adjusted for age, sex and ethnicity) can reclassify intermediate-risk individuals to a high risk, benefiting from preventive medication. The forthcoming update to the Dutch cardiovascular risk management guideline intends to re-position CACS for cardiovascular risk assessment as such in asymptomatic individuals. Beyond CACS as a single number, several guidelines recommend coronary CT angiography (CCTA), which provides additional information about luminal stenosis and (high-risk) plaque composition, as the first choice of test in symptomatic patients and high-risk patients. Ongoing randomised studies will have to determine the value of atherosclerosis evaluation with CCTA for primary prevention in asymptomatic individuals.

Effects of icosapent ethyl according to baseline residual risk in patients with atherosclerotic cardiovascular disease: results from REDUCE-IT.

AIMS: Icosapent ethyl lowers triglycerides and significantly reduces major adverse cardiovascular events (MACE), though treatment effects may vary between individuals. This study aimed to determine the relative and absolute effects of icosapent ethyl on MACE according to baseline cardiovascular disease (CVD) risk in patients with atherosclerotic cardiovascular disease (ASCVD). METHODS AND RESULTS: Participants from the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) with ASCVD were included (n = 5785). The primary outcome was 3-point MACE, i.e. non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death. Baseline 5-year risk of MACE was estimated using the European Society of Cardiology (ESC) guideline-recommended SMART2 risk score. Modification of the relative treatment effects of icosapent ethyl by baseline risk was assessed using Cox proportional hazards models, including a treatment-by-risk interaction. Next, treatment effects were assessed stratified by quartiles of baseline risk. During a median follow-up of 4.8 years (interquartile range 3.2-5.3), MACE occurred in 361 vs. 489 patients in the icosapent ethyl vs. placebo group [95% confidence interval (CI)]; hazard ratio (HR) 0.72 (0.63-0.82), absolute risk reduction (ARR) 4.4% (2.6-6.2%), number needed to treat (NNT) 23 (16-38), and 5-year Kaplan-Meier estimated cumulative incidence reduction (CIR) 5.7% (3.5-7.9%). Icosapent ethyl significantly reduced MACE in all risk quartiles, with an HR (95% CI) of 0.62 (0.43-0.88), 0.66 (0.48-0.92), 0.69 (0.53-0.90), and 0.78 (0.63-0.96), respectively (P for treatment-by-risk interaction = 0.106). The ARR (95% CI) increased across risk quartiles, i.e. was 3.9% (1.0-6.8%), 4.3% (1.2-7.3%), 5.1% (1.4-8.7%), and 5.6% (1.3-10.0%), respectively. This translates to NNTs (95% CI) of 26 (15-98), 24 (14-84), 20 (11-70), and 18 (10-77). The 5-year CIR (95% CI) was 4.8% (1.3-8.2%), 5.0% (1.3-8.7%), 6.1% (1.7-10.5%), and 7.7% (2.3-13.2%), respectively. Consistent results were obtained for 5-point MACE, additionally including coronary revascularization and unstable angina. CONCLUSION: Among patients with ASCVD and elevated triglyceride levels, icosapent ethyl significantly reduces the risk of MACE irrespective of baseline CVD risk, though absolute benefits are largest for patients at the highest risk.

Unexpected gaps in knowledge of familial hypercholesterolaemia among Dutch general practitioners.

BACKGROUND: Familial hypercholesterolaemia (FH) warrants early diagnosis to prevent premature atherosclerotic cardiovascular disease (CVD). However, underdiagnosis and undertreatment of FH persist. This study aimed to assess the knowledge and practice of FH care among general practitioners (GPs) in the Netherlands. METHODS: An internationally standardised, online questionnaire was sent to Dutch GPs between February 2021 and July 2022. The survey assessed knowledge and awareness of FH, encompassing general familiarity, awareness of management guidelines, inheritance, prevalence, CVD risk, and clinical practice related to FH. Comparative analysis was performed using data on primary care physicians from Western Australia, the Asia-Pacific region and the United Kingdom. RESULTS: Of the 221 participating GPs, 62.4% rated their familiarity with FH as above average (score > 4 on a 1-7 scale), with 91.4% considering themselves familiar with FH treatment and referral guidelines. Correct identification of the FH definition, typical lipid profile, inheritance pattern, prevalence and CVD risk was reported by 83.7%, 87.8%, 55.7%, 19.5%, and 13.6% of the respondents, respectively. Of the participants, 58.4% answered fewer than half of the 8 knowledge questions correctly. Dutch GPs reported greater FH familiarity and guideline awareness compared with their international counterparts but exhibited similar low performance on FH knowledge questions. CONCLUSION: Despite the Netherlands' relatively high FH detection rate, substantial knowledge gaps regarding FH persist among Dutch GPs, mirroring global trends. Enhanced FH education and awareness in primary care are imperative to improve FH detection and ensure adequate treatment. Targeting the global suboptimal understanding of FH might require international efforts.

PCSK9 inhibition with orally administered NNC0385-0434 in hypercholesterolaemia: a randomised, double-blind, placebo-controlled and active-controlled phase 2 trial.

BACKGROUND: Currently available injectable drugs that target proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce serum LDL cholesterol and improve cardiovascular outcomes. This phase 2 study assessed NNC0385-0434, an oral PCSK9 inhibitor, in individuals receiving oral lipid-lowering therapy. METHODS: In this randomised, double-blind, placebo-controlled and active-controlled trial, 42 research sites across seven countries (Belgium, Germany, Greece, Japan, the Netherlands, Poland, and the USA) recruited individuals with established atherosclerotic cardiovascular disease (aged ≥40 years) or at high risk of atherosclerotic cardiovascular disease (aged >50 years), who had LDL cholesterol concentration of at least 1·8 mmol/L and were receiving maximum tolerated statins and stable lipid-lowering therapy. The study randomly allocated participants (3:1) with an interactive web response system to receive either NNC0385-0434 (15 mg, 40 mg, or 100 mg) once a day co-formulated with the oral absorption enhancer sodium N-[8-(2-hydroxybenzoyl)amino] caprylate (500 mg); placebo; or open-label evolocumab (140 mg) every 2 weeks administered subcutaneously. Blinding was performed within each dose level. The primary endpoint was percentage change from baseline in LDL cholesterol measured by ß quantification at week 12. All randomly assigned participants received at least one dose of treatment and were included in both safety and efficacy analyses. The trial was registered on ClinicalTrials.gov, NCT04992065, and is completed. FINDINGS: Between Aug 16, 2021, and Jan 28, 2022, we randomly assigned 267 patients to one of the three NNC0385-0434 dose cohorts (n=53 per cohort), matching placebo (n=54), or open-label evolocumab (n=54). The study population comprised 82 (31%) women and 185 (69%) men; mean age was 64·3 years (SD 9·0). Baseline mean LDL cholesterol concentration was 2·7 mmol/L (SD 0·8). Treatment with NNC0385-0434 resulted in reductions in LDL cholesterol from baseline to week 12, of 32·0 percentage points (95% CI 20·9 to 43·0) in the 15 mg cohort, 44·9 percentage points (33·8 to 56·0) in the 40 mg cohort, and 61·8 percentage points (50·7 to 72·9) in the 100 mg cohort, compared with the placebo group (p<0·0001 for each). Patients treated with evolocumab had similar LDL cholesterol reductions (59·6% [SE 4·1] decrease from baseline) to patients receiving NNC0385-0434 100 mg (56·2% [4·0]). The estimated treatment difference between NNC0385-0434 100 mg and evolocumab 140 mg was 3·4 percentage points [95% CI -7·8 to 14·7]. The most frequently reported adverse event was COVID-19, which affected 31 (12%) of 267 patients, with similar numbers across treatment groups. Investigative sites reported gastrointestinal disorders as the most frequent treatment-related adverse event (26 patients and 35 events total in the three NNC0385 cohorts and one patient and one event each in the placebo and evolocumab cohorts). No deaths or treatment-related serious adverse events occurred. INTERPRETATION: This study showed excellent 12-week LDL cholesterol lowering efficacy and good patient tolerance of an oral PCSK9 inhibitor, NNC0835-0434, similar to an injectable drug. However, the sponsor chose to discontinue further development of NNC0835-0434 due to portfolio considerations. FUNDING: Novo Nordisk.

Effects of a stepwise, structured LDL-C lowering strategy in patients post-acute coronary syndrome.

OBJECTIVE: Low-density lipoprotein cholesterol (LDL-C) lowering constitutes a cornerstone of secondary prevention of atherosclerotic cardiovascular disease (ASCVD), yet a considerable number of patients do not achieve guideline-recommended LDL­C targets. The 2016 European guidelines recommended titration of LDL­C lowering medication in a set number of steps, starting with oral medication. We aimed to investigate the effects of this stepwise approach in post-acute coronary syndrome (ACS) patients. METHODS: In a multicentre, prospective, non-randomised trial, we evaluated a three-step strategy aiming to reduce LDL­C to ≤ 1.8 mmol/l in post-ACS patients with prior ASCVD and/or diabetes mellitus. Steps, undertaken every 4-6 weeks, included: 1) start high-intensity statin (HIST); 2) addition of ezetimibe; 3) addition of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i). The primary outcome was the proportion of patients achieving LDL-C ≤ 1.8 mmol/l after Steps 1 and 2 (using oral medications alone). Secondary outcomes examined the prevalence of meeting the target throughout all steps ( https://onderzoekmetmensen.nl/nl/trial/21157 ). RESULTS: Out of 999 patients, 84% (95% confidence intervals (CI): 81-86) achieved the LDL­C target using only statin and/or ezetimibe. In an intention-to-treat analysis, the percentages of patients meeting the LDL­C target after each step were 69% (95% CI: 67-72), 84% (95% CI: 81-86), and 87% (95% CI: 85-89), respectively. There were protocol deviations for 23, 38 and 23 patients at each respective step. CONCLUSION: Through stepwise intensification of lipid-lowering therapy, 84% of very high-risk post-ACS patients achieved an LDL­C target of ≤ 1.8 mmol/l with oral medications alone. Addition of PCSK9i further increased this rate to 87% (95% CI: 85-89).

Individual lifetime benefit from low-dose colchicine in patients with chronic coronary artery disease.

AIMS: Low-dose colchicine reduces cardiovascular risk in patients with coronary artery disease (CAD), but absolute benefits may vary between individuals. This study aimed to assess the range of individual absolute benefits from low-dose colchicine according to patient risk profile. METHODS AND RESULTS: The European Society of Cardiology (ESC) guideline-recommended SMART-REACH model was combined with the relative treatment effect of low-dose colchicine and applied to patients with CAD from the Low-Dose Colchicine 2 (LoDoCo2) trial and the Utrecht Cardiovascular Cohort-Second Manifestations of ARTerial disease (UCC-SMART) study (n = 10 830). Individual treatment benefits were expressed as 10-year absolute risk reductions (ARRs) for myocardial infarction, stroke, or cardiovascular death (MACE), and MACE-free life-years gained. Predictions were also performed for MACE plus coronary revascularization (MACE+), using a new lifetime model derived in the REduction of Atherothrombosis for Continued Health (REACH) registry. Colchicine was compared with other ESC guideline-recommended intensified (Step 2) prevention strategies, i.e. LDL cholesterol (LDL-c) reduction to 1.4 mmol/L and systolic blood pressure (SBP) reduction to 130 mmHg. The generalizability to other populations was assessed in patients with CAD from REACH North America and Western Europe (n = 25 812). The median 10-year ARR from low-dose colchicine was 4.6% [interquartile range (IQR) 3.6-6.0%] for MACE and 8.6% (IQR 7.6-9.8%) for MACE+. Lifetime benefit was 2.0 (IQR 1.6-2.5) MACE-free years, and 3.4 (IQR 2.6-4.2) MACE+-free life-years gained. For LDL-c and SBP reduction, respectively, the median 10-year ARR for MACE was 3.0% (IQR 1.5-5.1%) and 1.7% (IQR 0.0-5.7%), and the lifetime benefit was 1.2 (IQR 0.6-2.1) and 0.7 (IQR 0.0-2.3) MACE-free life-years gained. Similar results were obtained for MACE+ and in American and European patients from REACH. CONCLUSION: The absolute benefits of low-dose colchicine vary between individual patients with chronic CAD. They may be expected to be of at least similar magnitude to those of intensified LDL-c and SBP reduction in a majority of patients already on conventional lipid-lowering and blood pressure-lowering therapy.

The long-term benefits of treatment with low-dose colchicine were estimated for 36 642 individuals with coronary heart disease, and compared with those of lipid- and blood pressure­lowering therapy. On average, low-dose colchicine was estimated to lower the risk of cardiovascular disease in the next 10 years from 17.8 to 13.2% (a reduction of 4.6% points) and to afford 2.0 additional years of life without cardiovascular disease.Low-dose colchicine was estimated to be the most effective treatment in 49%, intensive blood pressure­lowering therapy in 28%, and intensive lipid-lowering therapy in 23% of patients.

[The PROMINENT trial: swan song of the fibrates]. / De PROMINENT-studie: zwanenzang van de fibraten.

Post hoc analyses of previous fibrate trials have suggested that individuals with type 2 diabetes mellitus with high triglyceride levels and low HDL-cholesterol levels benefit from fibrate therapy even when the overall trial results were neutral. However the PROMINENT (Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes) trial seems to close the door for fibrates. The trial found that fibrates do not reduce the risk of cardiovascular disease among individuals with type 2 diabetes and high triglyceride levels and low HDL cholesterol levels, despite triglyceride lowering. The results of PROMINENT suggest that triglyceride lowering without decreases in the plasma concentration of atherogenic lipoproteins are unlikely to decrease the risk of cardiovascular disease. These results also highlight the importance of rigorously confirmation of post hoc findings before implementation in clinical practice.

Unexploited potential of risk factor treatment in patients with atherosclerotic cardiovascular disease.

BACKGROUND: Most patients with atherosclerotic cardiovascular disease remain at (very) high risk for recurrent events due to suboptimal risk factor control. AIMS: This study aimed to quantify the potential of maximal risk factor treatment on 10-year and lifetime risk of recurrent atherosclerotic cardiovascular events in patients 1 year after a coronary event. METHODS AND RESULTS: Pooled data from six studies are as follows: RESPONSE 1, RESPONSE 2, OPTICARE, EUROASPIRE IV, EUROASPIRE V, and HELIUS. Patients aged ≥45 years at ≥6 months after coronary event were included. The SMART-REACH score was used to estimate 10-year and lifetime risk of recurrent atherosclerotic cardiovascular events with current treatment and potential risk reduction and gains in event-free years with maximal treatment (lifestyle and pharmacological). In 3230 atherosclerotic cardiovascular disease patients (24% women), at median interquartile range (IQR) 1.1 years (1.0-1.8) after index event, 10-year risk was median (IQR) 20% (15-27%) and lifetime risk 54% (47-63%). Whereas 70% used conventional medication, 82% had ≥1 drug-modifiable risk factor not on target. Furthermore, 91% had ≥1 lifestyle-related risk factor not on target. Maximizing therapy was associated with a potential reduction of median (IQR) 10-year risk to 6% (4-8%) and of lifetime risk to 20% (15-27%) and a median (IQR) gain of 7.3 (5.4-10.4) atherosclerotic cardiovascular disease event-free years. CONCLUSIONS: Amongst patients with atherosclerotic cardiovascular disease, maximizing current, guideline-based preventive therapy has the potential to mitigate a large part of their risk of recurrent events and to add a clinically important number of event-free years to their lifetime.

Patients with heart disease are at high risk of new cardiac events. This study amongst 3230 patients who had a heart attack or received a stent or bypass surgery shows missed potential for healthy life after a heart attack. The average age of study patients was 61 years, and 24% were women. At 1 year after the cardiac event, nearly one in three (30%) continued smoking, 79% were overweight, 45% reported insufficient physical activity, 40% had high blood pressure, and 65% had a too high LDL ('bad') cholesterol. We calculated that adherence to lifestyle advice and medications could on average halve the risk for another heart attack and add over 7 healthy years of life after a heart attack. This highlights the importance of healthy lifestyle and medication adherence after a heart attack. Key finding:• adherence to lifestyle advice and medications could add over 7 healthy years of life after a heart attack.

Prevention of Cardiovascular Events and Mortality With Icosapent Ethyl in Patients With Prior Myocardial Infarction.

BACKGROUND: REDUCE-IT was a double-blind trial that randomized 8,179 statin-treated patients with controlled low-density lipoprotein cholesterol and moderately elevated triglycerides to icosapent ethyl (IPE) or placebo. There was a significant reduction in the primary endpoint, including death from cardiovascular (CV) causes. The specific impact of IPE among patients with prior myocardial infarction (MI) was unknown. OBJECTIVES: Our goal was to examine the benefit of IPE on ischemic events among patients with prior MI in REDUCE-IT. METHODS: We performed post hoc analyses of patients with prior MI. The primary endpoint was CV death, MI, stroke, coronary revascularization, or hospitalization for unstable angina. The key secondary endpoint was CV death, MI, or stroke. RESULTS: A total of 3,693 patients had a history of prior MI. The primary endpoint was reduced from 26.1% to 20.2% with IPE vs placebo; HR: 0.74 (95% CI: 0.65-0.85; P = 0.00001). The key secondary endpoint was reduced from 18.0% to 13.3%; HR: 0.71 (95% CI: 0.61-0.84; P = 0.00006). There was also a significant 35% relative risk reduction in total ischemic events (P = 0.0000001), a 34% reduction in MI (P = 0.00009), a 30% reduction in CV death (P = 0.01), and a 20% lower rate of all-cause mortality (P = 0.054), although there was a slight increase in atrial fibrillation. Sudden cardiac death and cardiac arrest were also significantly reduced by 40% and 56%, respectively. CONCLUSIONS: Patients with a history of prior MI in REDUCE-IT treated with IPE demonstrated large and significant relative and absolute risk reductions in ischemic events, including CV death. (A Study of AMR101 to Evaluate Its Ability to Reduce Cardiovascular Events in High Risk Patients With Hypertriglyceridemia and on Statin. The Primary Objective is to Evaluate the Effect of 4 g/Day AMR101 for Preventing the Occurrence of a First Major Cardiovascular Event. [REDUCE-IT]; NCT01492361).

Carotid arterial stiffness is marginally higher in the metabolic syndrome and markedly higher in type 2 diabetes mellitus in patients with manifestations of arterial disease.

INTRODUCTION: Insulin resistance is generally considered to be of major importance in the pathophysiology of the metabolic syndrome and type 2 diabetes mellitus, both high-risk conditions for cardiovascular complications. Carotid artery stiffness is increasingly recognized as an important predictor of cardiovascular morbidity and mortality. Therefore, in the present study we determined whether the metabolic syndrome (MetSyn) and type 2 diabetes mellitus (DM2) are associated with carotid artery stiffness in patients with already clinical manifestations of arterial disease. METHODS AND RESULTS: A cross-sectional study in 2105 patients with manifest arterial disease (cerebral, coronary or peripheral artery disease, renal artery stenosis or an aneurysm of the abdominal aorta) was performed. The difference in carotid stiffness between patients with and without MetSyn and with and without DM2 was studied with linear regression analysis. Compared to patients without DM2 (N=1112), patients with DM2 (N=301) had significantly higher arterial stiffness (distension -18.5 (-35.1;-1.9) 95% CI/distensibility -1.8 (-2.2;-1.4) 95% CI). Generally, there was a trend of higher carotid stiffness in patients with MetSyn (N=922) compared to patients without (N=1112) MetSyn (distension -9.6 (-21.5;2.3) 95% CI/distensibility -2.0 (-2.6;-1.4) 95% CI). Excluding the patients with also DM2 (N=230) from the MetSyn-group diminished this relation (distension -5.7 (-18.8;7.4) 95% CI/distensibility -1.1 (-1.6;-0.6) 95% CI). Furthermore, in the population as a whole, carotid artery stiffness increased with increasing number of components of the metabolic syndrome (p=0.08 for distension/p< or =0.001 for distensibility). In addition, this association was not as clear after exclusion of the patients with DM2 from the MetSyn-group (p=0.24 for distension/p<0.001 for distensibility). From all the components of the MetSyn only high blood pressure and high fasting glucose influenced the carotid artery stiffness. CONCLUSIONS: We concluded that (increasing number of components of) the metabolic syndrome were associated with marginally higher carotid artery stiffness, while type 2 diabetes was associated with a marked increase in carotid artery stiffness, in patients with already clinical manifestations of arterial disease.

The operative risk factors in the metabolic syndrome: is it lipids and high BP or are there direct vascular effects of insulin resistance and obesity.

Increase in patients with central obesity and insulin resistance is an important cause for the worldwide increased incidence of type 2 diabetes. Several risk factors such as glucose intolerance, hyperinsulinemia, obesity, dyslipidemia, and hypertension, but also endothelial dysfunction and inflammation, have been found to cluster and often precede type 2 diabetes mellitus. Seeing the importance of early identification, the US National Cholesterol Education Program created a readily applicable definition of the metabolic syndrome for daily clinical practice. It is assumed that the cardiovascular risk for patients belonging to the metabolic syndrome can just be calculated out of the sum of the separate cardiovascular risk factors dyslipidemia and hypertension. However, there are also data pointing toward a higher risk than expected from these separate cardiovascular risk factors because of possible direct vascular effects of insulin resistance and obesity. Awareness of the underlying disorders of insulin resistance and its associated (non-) traditional risk factors such as endothelial dysfunction and inflammation is important for understanding the pathophysiology and thus coherent treatment.

TNF-alpha induces endothelial dysfunction in diabetic adults, an effect reversible by the PPAR-gamma agonist pioglitazone.

AIMS: Inflammation contributes to the pathogenesis of cardiovascular disease. Tumour necrosis factor (TNF)-alpha, in particular, is a key mediator of inflammation and vascular dysfunction and progression of atherosclerotic disease. Pioglitazone, a peroxisome proliferator-activated receptor-gamma agonist, not only improves insulin sensitivity, but may also have anti-inflammatory effects. The aims of this study were to investigate the acute effects of local intra-arterial infusion with low-dose TNF-alpha on resistance vessel endothelial function in type 2 diabetes and to determine whether short-term pioglitazone treatment protects against vascular dysfunction induced by this inflammatory stimulus. METHODS AND RESULTS: A randomized, parallel, placebo-controlled, double blind trial with 30 mg pioglitazone once daily for 4 weeks was performed in 16 male patients with recently diagnosed type 2 diabetes. Forearm plethysmography (FBF) was used to evaluate the effect on resistance vessel responses of intra-arterial administration of serotonin (NO-dependent vasodilation) and nitroprusside (endothelium-independent vasodilation) followed by another FBF-measurement during the second hour of intra-arterial infusion with TNF-alpha (10 ng/100 mL forearm volume/min for 2 h). Endothelial-dependent FBF of type 2 diabetic patients was significantly impaired (25.4%) by intra-arterial TNF-alpha infusion (P = 0.01), whereas nitroprusside-induced vasodilation did not change. Treatment with pioglitazone for 4 weeks completely blocked TNF-alpha-induced impairment of endothelial-dependent FBF compared with placebo. No significant changes in plasma concentrations of TNF-alpha, interleukin-6, soluble TNF-alpha-receptors, or CD40L were observed. CONCLUSION: Pioglitazone treatment can convey direct protection against cytokine (TNF-alpha)-induced endothelial dysfunction in humans with an increased cardiovascular risk due to type 2 diabetes.

Short-term pioglitazone treatment improves vascular function irrespective of metabolic changes in patients with type 2 diabetes.

To determine whether pioglitazone influences endothelial function directly, we examined in a randomized, crossover, placebo-controlled, double-blind trial the effects of 4 weeks of pioglitazone treatment in 20 male type 2 diabetic patients. We conclude that short-term pioglitazone treatment ameliorates endothelial dysfunction in conduit arteries irrespective of significant beneficial changes in plasma levels of insulin, FFA, adiponectin, or CRP in type 2 patients with diabetes. Pioglitazone, a PPARgamma agonist, not only improves insulin resistance and glycemic control but may also have additional beneficial vascular effects in patients with type 2 diabetes. Low-grade inflammation, free fatty acids, and adiponectin may play a role in modulation of vascular function. We studied the effect of 4 weeks of pioglitazone treatment on endothelial function, metabolic changes, and C-reactive protein in patients with type 2 diabetes. A randomized, crossover, placebo-controlled, double-blind trial was performed in which pioglitazone 30 mg once daily was administered to 20 patients with type 2 diabetes on oral antihyperglycemic agents for 4 weeks. Shear stress-induced flow-mediated dilation (FMD) of the brachial artery was used as outcome parameter for vascular function. Brachial artery endothelial function was significantly increased by pioglitazone treatment compared with placebo (FMD 5.4 +/- 0.5% versus 3.1 +/- 0.5%, P = 0.001). Endothelium-independent vasodilation was not different between the 2 study periods. Pioglitazone treatment reduced insulin, FFA, and C-reactive protein concentrations compared with placebo (18.3 +/- 2.4 versus 14.8 +/- 2.1 mU/L, P = 0.03; 641 +/- 46 versus 542 +/- 33 mumol/L, P = 0.04; and 3.5 +/- 0.6 mg/L versus 2.6 +/- 0.5 mg/L, P = 0.01; respectively). A significant increase in plasma adiponectin concentration (3.95 +/- 0.57 microg/mL versus 7.59 +/- 0.95 microg/mL, P = 0.002) was also observed. No correlations were found between these metabolic changes and the improvement of conduit artery endothelial function. Short-term pioglitazone treatment ameliorates endothelial dysfunction in conduit arteries irrespective of changes in insulin, FFA, adiponectin, or CRP in type 2 patients with diabetes.

Signaling of angiotensin II-induced vascular protein synthesis in conduit and resistance arteries in vivo.

BACKGROUND: From in vitro studies, it has become clear that several signaling cascades are involved in angiotensin II-induced cellular hypertrophy. The aim of the present study was to determine some of the signaling pathways mediating angiotensin II (Ang II)-induced protein synthesis in vivo in large and small arteries. METHODS: Newly synthesized proteins were labeled during 4 hours with tritiated leucine in conscious control animals, or animals infused for 24 hours with angiotensin II (400 ng/kg/min). Hemodynamic parameters were measure simultaneously. Pharmacological agents affecting signaling cascades were injected 5 hours before the end of Ang II infusion. RESULTS: Angiotensin II nearly doubled the protein synthesis rate in the aorta and small mesenteric arteries, without affecting arterial pressure. The AT1 receptor antagonist Irbesartan antagonized the actions of Ang II. The Ang II-induced protein synthesis was associated with increased extracellular signal-regulated kinases (ERK)1/2 phosphorylation in aortic, but not in mesenteric vessels. Systemic administration of PD98059, an inhibitor of the ERK-1/2 pathway, produced a significant reduction of protein synthesis rate in the aorta, and only a modest decrease in mesenteric arteries. Rapamycin, which influences protein synthesis by alternative signaling, had a significant effect in both vessel types. Rapamycin and PD98059 did not alter basal protein synthesis and had minimal effects on arterial pressure. CONCLUSION: ERK1/2 and rapamycin-sensitive pathways are involved in pressure-independent angiotensin II-induced vascular protein synthesis in vivo. However, their relative contribution may vary depending on the nature of the artery under investigation.

Metabolic and additional vascular effects of thiazolidinediones.

Several cardiovascular risk factors (dyslipidaemia, hypertension, glucose intolerance, hypercoagulability, obesity, hyperinsulinaemia and low-grade inflammation) cluster in the insulin resistance syndrome. Treatment of these individual risk factors reduces cardiovascular complications. However, targeting the underlying pathophysiological mechanisms of the insulin resistance syndrome is a more rational treatment strategy to further improve cardiovascular outcome. Our understanding of the so-called cardiovascular dysmetabolic syndrome has been improved by the discovery of nuclear peroxisome proliferator-activated receptors (PPARs). PPARs are ligand-activated transcription factors belonging to the nuclear receptor superfamily. As transcription factors, PPARs regulate the expression of numerous genes and affect glycaemic control, lipid metabolism, vascular tone and inflammation. Activation of the subtype PPAR-gamma improves insulin sensitivity. Expression of PPAR-gamma is present in several cell types involved in the process of atherosclerosis. Thus, modulation of PPAR-gamma activity is an interesting therapeutic approach to reduce cardiovascular events. Thiazolidinediones are PPAR-gamma agonists and constitute a new class of pharmacological agents for the treatment of type 2 (non-insulin-dependent) diabetes mellitus. Two such compounds are currently available for clinical use: rosiglitazone and pioglitazone. Thiazolidinediones improve insulin sensitivity and glycaemic control in patients with type 2 diabetes. In addition, improvement in endothelial function, a decrease in inflammatory conditions, a decrease in plasma levels of free fatty acids and lower blood pressure have been observed, which may have important beneficial effects on the vasculature. Several questions remain to be answered about PPAR-gamma agonists, particularly with respect to the role of PPAR-gamma in vascular pathophysiology. More needs to be known about the adverse effects of thiazolidinediones, such as hepatotoxicity, increased low-density lipoprotein cholesterol levels and increased oedema. The paradox of adipocyte differentiation with weight gain concurring with the insulin-sensitising effect of thiazolidinediones is not completely understood. The decrease in blood pressure induced by thiazolidinedione treatment seems incompatible with an increase in the plasma volume, and the discrepancy between the stimulation of the expression of CD36 and the antiatherogenic effects of the thiazolidinediones also needs further explanation. Long-term clinical trials of thiazolidinediones with cardiovascular endpoints are currently in progress. In conclusion, studying the effects of thiazolidinediones may shed more light on the mechanisms involved in the insulin resistance syndrome. Furthermore, thiazolidinediones could have specific, direct effects on processes involved in the development of vascular abnormalities.

Vessel-specific stimulation of protein synthesis by nitric oxide synthase inhibition: role of extracellular signal-regulated kinases 1/2.

Although conduit arteries develop hypertrophy after chronic NO synthesis blockade, resistance arteries remodel without hypertrophy under the same conditions. Similar findings have been described in essential hypertension. We postulated that this regional difference may be related to a heterogeneous effect of endogenous NO on proliferation along the vascular tree. Newly synthesized proteins were radiolabeled in vivo with [(3)H]L-leucine in basal conditions and during NO synthase inhibition, with or without PD98059 (inhibitor of the extracellular signal-regulated kinases [ERK] 1/2). Blocking the generation of NO by 3 different L-arginine analogues increased protein synthesis by an average of 75% in the aorta, in association with enhanced ERK 1/2 phosphorylation. PD98059 significantly reduced L-arginine analogue-induced protein synthesis and ERK 1/2 phosphorylation, confirming the involvement of ERK 1/2 as an important signaling element. In small arteries, L-arginine analogues did not influence the extent of protein synthesis, although phosphorylation of ERK 1/2 was also enhanced. To determine the role of NO in a condition of enhanced protein synthesis, angiotensin II was infused for 24 hours. Angiotensin II augmented protein synthesis in mesenteric arteries and the aorta, and was additive to NO synthase blockade in the aorta. In conclusion, endogenous NO exerts a tonic inhibitory influence on aortic growth, with limited impact on small arteries in basal and hypertrophic conditions. This heterogeneous role of NO on vascular growth may explain the heterogeneity of vascular remodeling observed in essential hypertension, a condition associated with endothelial dysfunction.