Transcatheter Aortic Valve Implantation in Low-Risk Tricuspid or Bicuspid Aortic Stenosis: The NOTION-2 Trial.

BACKGROUND AND AIMS: Transcatheter aortic valve implantation (TAVI) has become the first choice to treat older patients with severe symptomatic aortic stenosis (AS). This study aimed to compare TAVI with surgery in low-risk patients ≤ 75 years of age, including both tricuspid and bicuspid AS. METHODS: The NOTION-2 trial enrolled and 1:1 randomized low-risk patients aged ≤ 75 years with severe symptomatic AS to TAVI or surgery. The primary endpoint was a composite of all-cause mortality, stroke or rehospitalization (related to the procedure, valve or heart failure) at 12 months. RESULTS: A total of 370 patients were enrolled with a mean age of 71.1 years and a median Society of Thoracic Surgeons risk score of 1.1%. A total of 100 patients had bicuspid AS. The 1-year incidence of the primary endpoint was 10.2% in the TAVI group and 7.1% in the surgery group (absolute risk difference 3.1%; 95% confidence interval [CI], -2.7% to 8.8%; hazard ratio (HR) 1.4, 95% CI: 0.7 to 2.9; p=0.3). Patients with TAVI, when compared to surgery, had lower risk of major bleeding and new-onset atrial fibrillation and higher risk of non-disabling stroke, permanent pacemaker implantation and moderate-or-greater paravalvular regurgitation. The risk of the primary composite endpoint was 8.7% and 8.3% in patients with tricuspid AS (HR 1.0, 95% CI: 0.5 to 2.3) and 14.3% and 3.9% in patients with bicuspid AS (HR 3.8, 95% CI: 0.8 to 18.5) treated with TAVI or surgery, respectively (P for interaction=0.1). CONCLUSIONS: Among low-risk patients aged ≤ 75 years with severe symptomatic AS, the rate of the composite of death, stroke, or rehospitalization at one year was similar between TAVI and surgery. TAVI outcomes in young bicuspid AS patients warrant caution and should be further investigated. (NOTION-2, ClinicalTrials.gov, NCT02825134).

Cohort Profile: the European Unified Registries On Heart care Evaluation and Randomised Trials (EuroHeart) - Acute Coronary Syndrome and Percutaneous Coronary Intervention.

AIMS: The European Unified Registries On Heart care Evaluation And Randomized Trials (EuroHeart) aims to improve the quality of care and clinical outcomes for patients with cardiovascular disease. The collaboration of acute coronary syndrome/percutaneous coronary intervention (ACS/PCI) registries is operational in seven vanguard European Society of Cardiology member countries. METHODS AND RESULTS: Adults admitted to hospitals with ST-elevation myocardial infarction (STEMI) and non-ST-elevation myocardial infarction (NSTEMI) are included, and individual patient-level data collected and aligned according to the internationally agreed EuroHeart data standards for ACS/PCI. The registries provide up to 155 variables spanning patient demographics and clinical characteristics, in-hospital care, in-hospital outcomes, and discharge medications. After performing statistical analyses on patient data, participating countries transfer aggregated data to EuroHeart for international reporting.Between 1st January 2022 and 31st December 2022, 40 021 admissions (STEMI 46.7%, NSTEMI 53.3%) were recorded from 192 hospitals in the seven vanguard countries: Estonia, Hungary, Iceland, Portugal, Romania, Singapore, and Sweden. The mean age for the cohort was 67.9 (standard deviation 12.6) years, and it included 12 628 (31.6%) women. CONCLUSION: The EuroHeart collaboration of ACS/PCI registries prospectively collects and analyses individual data for ACS and PCI at a national level, after which aggregated results are transferred to the EuroHeart Data Science Centre. The collaboration will expand to other countries and provide continuous insights into the provision of clinical care and outcomes for patients with ACS and undergoing PCI. It will serve as a unique international platform for quality improvement, observational research, and registry-based clinical trials.

[Management and revascularization of diabetics with coronary artery disease in Iceland].

BACKGROUND: The incidence of diabetes is growing, and diabetics have increased risk of atherosclerosis and diffuse coronary artery disease (CAD). Our aim was to assess the revascularization treatment of diabetics with CAD in Iceland from 2010-2020, changes in management and long-term survival of patients. METHODS: All patients in Iceland with diabetes and CAD on cardiac catheterization 2010-2020 were included in this retrospective, population-based study. We analyzed data from the SCAAR/SWEDEHEART database: patients' background information, findings of cardiac catheterization, planned treatment and results. The Kaplan-Meier method was used to estimate long-term survival and Cox-regression-analysis to adjust for predictor variables. RESULTS: Of 1905 cases (1485 patients), 1230 (65%) underwent PCI, 274 (14%) CABG and 401 (21%) had medical therapy only. The age distribution differed: The PCI group had the widest age bracket, the CABG group the narrowest, and the medical therapy group had the highest mean age. Most patients with STEMI or cardiogenic shock underwent PCI, while most patients with concomitant heart-valve disease underwent CABG. The proportion of patients undergoing CABG increased with more diffuse CAD. 41% of patients with left main- and three-vessel disease underwent CABG while only 2% of those with single-vessel disease. From 2010-2020 the proportion of patients that underwent PCI increased from 49% to 72%. There was no difference in survival between the PCI and CABG groups (p=1.00). CONCLUSION: Three quarters of patients with diabetes and obstructive CAD are now treated with PCI. The PCI and CABG groups had overall equal survival but the groups had different characteristics.

[Management of patients with left main stem stenosis in Iceland 2010-2020: PCI or CABG].

INTRODUCTION: Coronary artery bypass surgery (CABG) has been standard treatment for patients with left main coronary artery disease (LMCAD) but percutaneous coronary intervention (PCI) can be a good alternative. Our aim was to evaluate revascularization of LMCAD-patients in Iceland and treatment changes in recent years. We also assessed the impact of patient background factors on treatment choice and long-term survival. METHODS: This retrospective, population-based registry-study analyzed data from the SCAAR-SWEDEHEART database. Patients with significant LMCAD on coronary angiography in Iceland 2010-2020, without previous history of CABG or contraindication for surgery were enrolled. The Kaplan-Meier method was used to study long-term survival and COX-regression analysis to adjust for predictor variables. FINDINGS: Of 702 LMCAD patients, 195 were treated with PCI, 460 with CABG and 47 with medical therapy. The widest age-range was in the PCI group and the mean age was highest in the medical therapy group. Patients with LMCAD and concomitant three vessel disease or heart valve disese were mostly treated with CABG (76.1% and 84.4%). The majority of patients with LMCAD only were treated with PCI, as well as patients presenting with STEMI or in cardiogenic shock (67.1% and 70.0%). The proportion of patients treated with PCI increased from 19.8% in 2010-2015 to 42.7% in 2016-2020. There was no significant difference in survival between the PCI and CABG-groups (p=0.41). CONCLUSIONS: In patients with LMCAD the main factors determining treatment choice are age, anatomical complexity and acuteness. There has been a significant increase in LMCAD patients treated with PCI.

Long-term survival of Icelandic women following acute myocardial infarction.

Objective. To evaluate the impact of sex on treatment and survival after acute myocardial infarction (AMI) in Iceland. Methods. A retrospective, nationwide cohort study of patients with STEMI (2008-2018) and NSTEMI (2013-2018) and obstructive coronary artery disease. Patient and procedural information were obtained from a registry and electronic health records. Survival was estimated with Kaplan-Meier method and Cox regression analysis used to identify risk factors for long-term mortality. Excess mortality from the AMI episode was estimated by comparing the survival with age- and sex-matched population in Iceland at 30-day interval. Results. A total of 1345 STEMI-patients (24% women) and 1249 NSTEMI-patients (24% women) were evaluated. Women with STEMI (mean age: 71 ± 11 vs. 67 ± 12) and NSTEMI (mean age: 69 ± 13 vs. 62 ± 12) were older and less likely to have previous cardiovascular disease. There was neither sex difference in the extent of coronary artery disease nor treatment. Although crude one-year post-STEMI survival was lower for women (88.7% vs. 93.4%, p = .006), female sex was not an independent risk factor after adjusting for age and co-morbidities after STEMI and was protective for NSTEMI (HR 0.67, 95% CI: 0.46-0.97). There was excess 30-day mortality in both STEMI and NSTEMI for women compared with sex-, age- and inclusion year-matched Icelandic population, but thereafter the mortality rate was similar. Conclusion. Women and men with AMI in Iceland receive comparable treatment including revascularization and long-term survival appears similar. Prognosis after NSTEMI is better in women, whereas higher early mortality after STEMI may be caused by delays in presentation and diagnosis.

5-Year Outcomes of PCI Guided by Measurement of Instantaneous Wave-Free Ratio Versus Fractional Flow Reserve.

BACKGROUND: Instantaneous wave-free ratio (iFR) is a coronary physiology index used to assess the severity of coronary artery stenosis to guide revascularization. iFR has previously demonstrated noninferior short-term outcome compared to fractional flow reserve (FFR), but data on longer-term outcome have been lacking. OBJECTIVES: The purpose of this study was to investigate the prespecified 5-year follow-up of the primary composite outcome of all-cause mortality, myocardial infarction, and unplanned revascularization of the iFR-SWEDEHEART trial comparing iFR vs FFR in patients with chronic and acute coronary syndromes. METHODS: iFR-SWEDEHEART was a multicenter, controlled, open-label, registry-based randomized clinical trial using the Swedish Coronary Angiography and Angioplasty Registry for enrollment. A total of 2,037 patients were randomized to undergo revascularization guided by iFR or FFR. RESULTS: No patients were lost to follow-up. At 5 years, the rate of the primary composite endpoint was 21.5% in the iFR group and 19.9% in the FFR group (HR: 1.09; 95% CI: 0.90-1.33). The rates of all-cause death (9.4% vs 7.9%; HR: 1.20; 95% CI: 0.89-1.62), nonfatal myocardial infarction (5.7% vs 5.8%; HR: 1.00; 95% CI: 0.70-1.44), and unplanned revascularization (11.6% vs 11.3%; HR: 1.02; 95% CI: 0.79-1.32) were also not different between the 2 groups. The outcomes were consistent across prespecified subgroups. CONCLUSIONS: In patients with chronic or acute coronary syndromes, an iFR-guided revascularization strategy was associated with no difference in the 5-year composite outcome of death, myocardial infarction, and unplanned revascularization compared with an FFR-guided revascularization strategy. (Evaluation of iFR vs FFR in Stable Angina or Acute Coronary Syndrome [iFR SWEDEHEART]; NCT02166736).

[Effects of the COVID-19 pandemic and associated non-pharmaceutical interventions on diagnosis of myocardial infarction and selected infections in Iceland 2020].

INTRODUCTON: Nonpharmaceutical interventions to contain the spread of COVID-19 infections in Iceland in 2020 were successful, but the effects of these measures on incidence and diagnosis of other diseases is unknown. The aim of this study was to evaluate the impact of the COVID-19 pandemic on the diagnosis of myocardial infarction (MI) and selected infections with different transmission routes. MATERIALS AND METHODS: Health records of individuals 18 years or older who were admitted to Landspitali University Hospital (LUH) in 2016-2020 with pneumonia or MI were extracted from the hospital registry. We acquired data from the clinical laboratories regarding diagnostic testing for Chlamydia trachomatis, influenza, HIV and blood cultures positive for Enterobacterales species. Standardized incidence ratio (SIR) for 2020 was calculated with 95% confidence intervals (95%CI) and compared to 2016-2019. RESULTS: Discharge diagnoses due to pneumonia decreased by 31% in 2020, excluding COVID-19 pneumonia (SIR 0.69 (95%CI 0.64-0.75)). Discharge diagnoses of MI decreased by 18% (SIR 0.82 (95%CI 0.75-0.90)), and emergency cardiac catheterizations due to acute coronary syndrome by 23% (SIR 0.77 (95%CI 0.71-0.83)), while there was a 15% increase in blood stream infections for Enterobacterales species (SIR 1.15 (95%CI 1.04-1.28)). Testing for Chlamydia trachomatis decreased by 14.8% and positive tests decreased by 16.3%. Tests for HIV were reduced by 10.9%, while samples positive for influenza decreased by 23.6% despite doubling of tests being performed. CONCLUSION: The number of pneumonia cases of other causes than COVID-19 requiring admission dropped by a quarter in 2020. MI, chlamydia and influensa diagnoses decreased notably. These results likely reflect a true decrease, probably due to altered behaviour during the pandemic.

Genetic variants associated with platelet count are predictive of human disease and physiological markers.

Platelets play an important role in hemostasis and other aspects of vascular biology. We conducted a meta-analysis of platelet count GWAS using data on 536,974 Europeans and identified 577 independent associations. To search for mechanisms through which these variants affect platelets, we applied cis-expression quantitative trait locus, DEPICT and IPA analyses and assessed genetic sharing between platelet count and various traits using polygenic risk scoring. We found genetic sharing between platelet count and counts of other blood cells (except red blood cells), in addition to several other quantitative traits, including markers of cardiovascular, liver and kidney functions, height, and weight. Platelet count polygenic risk score was predictive of myeloproliferative neoplasms, rheumatoid arthritis, ankylosing spondylitis, hypertension, and benign prostate hyperplasia. Taken together, these results advance understanding of diverse aspects of platelet biology and how they affect biological processes in health and disease.

Acute gastrointestinal bleeding among patients on antiplatelet and anticoagulant therapy after percutaneous coronary intervention.

BACKGROUND: Patients undergoing percutaneous coronary intervention (PCI) require dual antiplatelet therapy and some require additional anticoagulation. We aimed to investigate the incidence of acute gastrointestinal bleeding (AGIB) among PCI patients receiving antiplatelet and anticoagulant therapy. METHODS: A population-based study that included all patients undergoing PCI during 2008-2016 in Iceland. Data from the Icelandic Medicines Registry were obtained on all outpatient prescriptions 1 year after first PCI. Patients receiving single or dual-antiplatelet therapy with or without anticoagulation cotherapy were analyzed. Rehospitalization for AGIB and endoscopic data were obtained within the 12-month follow-up period. RESULTS: A total of 5166 patients (male 75%) underwent PCI during the study period. The incidence of AGIB was 1% (54/5166) per year. The mean age among non-bleeders 65 (±11) years was lower than among bleeders 69 (±9) years (p = .002). The proportion of acute upper GIB (AUGIB) was 56%, whereas lower GIB occurred in 44%. Overall, 41% with AUGIB had PPIs compared to 39% of non-bleeders (NS). The incidence of AGIB among patients on single antiplatelet therapy combined with an anticoagulant was 2.5% compared to 0.9% among those on single antiplatelet treatment alone (p = .028). The number needed to harm (NNH) for treatment with single antiplatelet therapy and anticoagulant therapy compared to single antiplatelet therapy was 62 but no deaths related to AGIB. CONCLUSIONS: The 1-year incidence of AGIB was low with no mortality. Bleeding risk was found to be higher among patients on single antiplatelet therapy combined with anticoagulant therapy compared to patients on single antiplatelet therapy alone.

Association Between Preoperative Opioid and Benzodiazepine Prescription Patterns and Mortality After Noncardiac Surgery.

Importance: The number of patients prescribed long-term opioids and benzodiazepines and complications from their long-term use have increased. Information regarding the perioperative outcomes of patients prescribed these medications before surgery is limited. Objective: To determine whether patients prescribed opioids and/or benzodiazepines within 6 months preoperatively would have greater short- and long-term mortality and increased opioid consumption postoperatively. Design, Setting, and Participants: This retrospective, single-center, population-based cohort study included all patients 18 years or older, undergoing noncardiac surgical procedures at a national hospital in Iceland from December 12, 2005, to December 31, 2015, with follow-up through May 20, 2016. A propensity score-matched control cohort was generated using individuals from the group that received prescriptions for neither medication class within 6 months preoperatively. Data analysis was performed from April 10, 2018, to March 9, 2019. Exposures: Patients who filled prescriptions for opioids only, benzodiazepines only, both opioids and benzodiazepines, or neither medication within 6 months preoperatively. Main Outcomes and Measures: Long-term survival compared with propensity score-matched controls. Secondary outcomes were 30-day survival and persistent postoperative opioid consumption, defined as a prescription filled more than 3 months postoperatively. Results: Among 41 170 noncardiac surgical cases in 27 787 individuals (16 004 women [57.6%]; mean [SD] age, 56.3 [18.8] years), a preoperative prescription for opioids only was filled for 7460 cases (17.7%), benzodiazepines only for 3121 (7.4%), and both for 2633 (6.2%). Patients who filled preoperative prescriptions for either medication class had a greater comorbidity burden compared with patients receiving neither medication class (Elixhauser comorbidity index >0 for 16% of patients filling prescriptions for opioids only, 22% for benzodiazepines only, and 21% for both medications compared with 14% for patients filling neither). There was no difference in 30-day (opioids only: 1.3% vs 1.0%; P = .23; benzodiazepines only: 1.9% vs 1.5%; P = .32) or long-term (opioids only: hazard ratio [HR], 1.12 [95% CI, 1.01-1.24]; P = .03; benzodiazepines only: HR, 1.11 [95% CI, 0.98-1.26]; P = .11) survival among the patients receiving opioids or benzodiazepines only compared with controls. However, patients prescribed both opioids and benzodiazepines had greater 30-day mortality (3.2% vs 1.8%; P = .004) and a greater hazard of long-term mortality (HR, 1.41; 95% CI, 1.22-1.64; P < .001). The rate of persistent postoperative opioid consumption was higher for patients filling prescriptions for opioids only (43%), benzodiazepines only (23%), or both (66%) compared with patients filling neither (12%) (P < .001 for all). Conclusions and Relevance: The findings suggest that opioid and benzodiazepine prescription fills in the 6 months before surgery are associated with increased short-and long-term mortality and an increased rate of persistent postoperative opioid consumption. These patients should be considered for early referral to preoperative clinic and medication optimization to improve surgical outcomes.

Reclassification of Treatment Strategy With Instantaneous Wave-Free Ratio and Fractional Flow Reserve: A Substudy From the iFR-SWEDEHEART Trial.

OBJECTIVES: The authors sought to compare reclassification of treatment strategy following instantaneous wave-free ratio (iFR) and fractional flow reserve (FFR). BACKGROUND: iFR was noninferior to FFR in 2 large randomized controlled trials in guiding coronary revascularization. Reclassification of treatment strategy by FFR is well-studied, but similar reports on iFR are lacking. METHODS: The iFR-SWEDEHEART (Instantaneous Wave-Free Ratio Versus Fractional Flow Reserve in Patients With Stable Angina Pectoris or Acute Coronary Syndrome Trial) study randomized 2,037 participants with stable angina or acute coronary syndrome to treatment guided by iFR or FFR. Interventionalists entered the preferred treatment (optimal medical therapy [OMT], percutaneous coronary intervention [PCI], or coronary artery bypass grafting [CABG]) on the basis of coronary angiograms, and the final treatment decision was mandated by the iFR/FFR measurements. RESULTS: In the iFR/FFR (n = 1,009/n = 1,004) populations, angiogram-based treatment approaches were similar (p = 0.50) with respect to OMT (38%/35%), PCI of 1 (37%/39%), 2 (15%/16%), and 3 vessels (2%/2%) and CABG (8%/8%). iFR and FFR reclassified 40% and 41% of patients, respectively (p = 0.78). The majority of reclassifications were conversion of PCI to OMT in both the iFR/FFR groups (31.4%/29.0%). Reclassification increased with increasing number of lesions evaluated (odds ratio per evaluated lesion for FFR: 1.46 [95% confidence interval: 1.22 to 1.76] vs. iFR 1.37 [95% confidence interval: 1.18 to 1.59]). Reclassification rates for patients with 1, 2, and 3 assessed vessels were 36%, 52%, and 53% (p < 0.01). CONCLUSIONS: Reclassification of treatment strategy of intermediate lesions was common and occurred in 40% of patients with iFR or FFR. The most frequent reclassification was conversion from PCI to OMT regardless of physiology modality. Irrespective of the physiological index reclassification of angiogram-based treatment strategy increased with the number of lesions evaluated.

Acute kidney injury following coronary angiography: a nationwide study of incidence, risk factors and long-term outcomes.

BACKGROUND: We studied the incidence and risk factors of acute kidney injury (AKI) following coronary angiography (CA) and examined short- and long-term outcomes of patients who developed AKI, including progression of chronic kidney disease (CKD). METHODS: This was a retrospective study of all patients undergoing CA in Iceland from 2008 to 2015, with or without percutaneous coronary intervention. All procedures were performed with iso-osmolar contrast. AKI was defined according to the SCr component of the KDIGO criteria. Patients without post-procedural SCr were assumed to be free of AKI. Incident CKD was defined as 90-day sustained estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2, and progression of CKD as worsening at least one stage sustained over 90 days. RESULTS: AKI was detected in 231 of 13,561 cases (1.7%). There was an interaction between contrast dose and preexisting kidney function, where the risk for AKI was only significant at a dose > 150 mL in patients with baseline eGFR < 45 mL/min/1.73 m2 (OR 5.3, 95% CI 2.1-14.2). The AKI patients had worse short-and long-term survival, as well as elevated hazard of both new-onset CKD (HR 3.7, 95% CI 2.7-5.0) and progression of preexisting CKD (HR 2.0, 95% CI 1.5-2.6) over a median follow-up of 3.3 years (range 0.1-8.4 years), compared to a propensity score-matched control group. CONCLUSIONS: For iso-osmolar contrast, the risk of AKI related to contrast dose was evident for higher amount of contrast in patients with baseline eGFR < 45 mL/min/1.73 m2. In addition to association with adverse short- and long-term survival AKI had a strong association with new-onset or progression of CKD when patients were followed longitudinally.

Instantaneous Wave-free Ratio versus Fractional Flow Reserve to Guide PCI.

BACKGROUND: The instantaneous wave-free ratio (iFR) is an index used to assess the severity of coronary-artery stenosis. The index has been tested against fractional flow reserve (FFR) in small trials, and the two measures have been found to have similar diagnostic accuracy. However, studies of clinical outcomes associated with the use of iFR are lacking. We aimed to evaluate whether iFR is noninferior to FFR with respect to the rate of subsequent major adverse cardiac events. METHODS: We conducted a multicenter, randomized, controlled, open-label clinical trial using the Swedish Coronary Angiography and Angioplasty Registry for enrollment. A total of 2037 participants with stable angina or an acute coronary syndrome who had an indication for physiologically guided assessment of coronary-artery stenosis were randomly assigned to undergo revascularization guided by either iFR or FFR. The primary end point was the rate of a composite of death from any cause, nonfatal myocardial infarction, or unplanned revascularization within 12 months after the procedure. RESULTS: A primary end-point event occurred in 68 of 1012 patients (6.7%) in the iFR group and in 61 of 1007 (6.1%) in the FFR group (difference in event rates, 0.7 percentage points; 95% confidence interval [CI], -1.5 to 2.8; P=0.007 for noninferiority; hazard ratio, 1.12; 95% CI, 0.79 to 1.58; P=0.53); the upper limit of the 95% confidence interval for the difference in event rates fell within the prespecified noninferiority margin of 3.2 percentage points. The results were similar among major subgroups. The rates of myocardial infarction, target-lesion revascularization, restenosis, and stent thrombosis did not differ significantly between the two groups. A significantly higher proportion of patients in the FFR group than in the iFR group reported chest discomfort during the procedure. CONCLUSIONS: Among patients with stable angina or an acute coronary syndrome, an iFR-guided revascularization strategy was noninferior to an FFR-guided revascularization strategy with respect to the rate of major adverse cardiac events at 12 months. (Funded by Philips Volcano; iFR SWEDEHEART ClinicalTrials.gov number, NCT02166736 .).

Variants with large effects on blood lipids and the role of cholesterol and triglycerides in coronary disease.

Sequence variants affecting blood lipids and coronary artery disease (CAD) may enhance understanding of the atherogenicity of lipid fractions. Using a large resource of whole-genome sequence data, we examined rare and low-frequency variants for association with non-HDL cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides in up to 119,146 Icelanders. We discovered 13 variants with large effects (within ANGPTL3, APOB, ABCA1, NR1H3, APOA1, LIPC, CETP, LDLR, and APOC1) and replicated 14 variants. Five variants within PCSK9, APOA1, ANGPTL4, and LDLR associate with CAD (33,090 cases and 236,254 controls). We used genetic risk scores for the lipid fractions to examine their causal relationship with CAD. The non-HDL cholesterol genetic risk score associates most strongly with CAD (P = 2.7 × 10(-28)), and no other genetic risk score associates with CAD after accounting for non-HDL cholesterol. The genetic risk score for non-HDL cholesterol confers CAD risk beyond that of LDL cholesterol (P = 5.5 × 10(-8)), suggesting that targeting atherogenic remnant cholesterol may reduce cardiovascular risk.

Vascular PAR-1: activity and antagonism.

Despite major advances in antiplatelet therapies, recurrent cardiovascular events remain high after acute coronary syndrome. Furthermore, incremental benefits achieved in the reduction of atherothrombotic events have almost always been at the expense of hemorrhagic side effects. Thrombin is the most potent platelet activating factor known and it makes important interactions with the endothelium and vascular smooth muscle with proinflammatory, proatherogenic effects. Distinct from its activity within the coagulation cascade, thrombin mediates these effects via protease-activated receptor type 1 (PAR-1) in man. This review discusses the role of PAR-1 in the vasculature and the development of novel PAR-1 antagonists. These drugs may provide important antiatherothrombotic effects without attendant bleeding complications and could represent a major breakthrough for the treatment of cardiovascular diseases.

Marked impairment of protease-activated receptor type 1-mediated vasodilation and fibrinolysis in cigarette smokers: smoking, thrombin, and vascular responses in vivo.

OBJECTIVES: We sought to test the hypothesis that cigarette smoking adversely alters protease-activated receptor type 1 (PAR-1)-mediated vascular effects in vivo in humans. BACKGROUND: Distinct from its role in the coagulation cascade, thrombin exerts its major cellular and cardiovascular actions via PAR-1. The activation of PAR-1 causes endothelium-dependent arterial vasodilation and the release of endogenous fibrinolytic factors. METHODS: Forearm blood flow was measured with venous occlusion plethysmography in 12 cigarette smokers and 12 age- and gender-matched nonsmokers during intrabrachial infusions of PAR-1-activating-peptide (SFLLRN; 5 to 50 nmol/min), bradykinin (100 to 1,000 pmol/min), and sodium nitroprusside (2 to 8 mug/min). Plasma tissue plasminogen activator (t-PA) and plasminogen-activator inhibitor 1 antigen and activity concentrations were measured throughout the experiment. RESULTS: All agonists caused dose-dependent increases in forearm blood flow (p < 0.0001 for all). Although bradykinin and sodium nitroprusside caused similar vasodilation, SFLLRN-induced vasodilation was attenuated in smokers (p = 0.04). Smokers had modest reductions in bradykinin-induced active t-PA release (reduced by 37%, p = 0.03) and had a marked impairment of SFLLRN-induced t-PA antigen (p = 0.02) and activity (p = 0.006) release, with a 96% reduction in overall net t-PA antigen release. The use of SFLLRN also caused similar (p = NS) increases in inactive plasminogen-activator inhibitor 1 in both smokers and nonsmokers (p

Role of the endothelium in the vascular effects of the thrombin receptor (protease-activated receptor type 1) in humans.

OBJECTIVES: The purpose of this study was to determine the role of the endothelium in the vascular actions of protease-activated receptor type 1 (PAR-1) activation in vivo in man. BACKGROUND: Thrombin is central to the pathophysiology of atherothrombosis. Its cellular actions are mediated via PAR-1. Protease-activated receptor type 1 activation causes arterial vasodilation, venoconstriction, platelet activation, and tissue-type plasminogen activator release in man. METHODS: Dorsal hand vein diameter was measured in 6 healthy volunteers before and after endothelial denudation. Forearm arterial blood flow, plasma fibrinolytic factors, and platelet activation were measured in 24 healthy volunteers during venous occlusion plethysmography. The effects of inhibition of prostacyclin, nitric oxide (NO), and endothelium-derived hyperpolarizing factor on PAR-1 responses were assessed during coadministration of aspirin, the "NO clamp" (L-N(G)-monomethyl arginine and sodium nitroprusside), and tetraethylammonium ion, respectively. RESULTS: Endothelial denudation did not affect PAR-1-evoked venoconstriction (SFLLRN; 0.05 to 15 nmol/min). Although aspirin had no effect, SFLLRN-induced vasodilation (5 to 50 nmol/min) was attenuated by the NO clamp (p < 0.0001) and tetraethylammonium ion (p < 0.05) and abolished by their combination (p < 0.01). The NO clamp augmented SFLLRN-induced tissue-type plasminogen activator and plasminogen activator inhibitor type 1 antigen (p < 0.0001) release, but tetraethylammonium ion and aspirin had no effect. SFLLRN-induced platelet activation was unaffected by NO or prostacyclin inhibition. CONCLUSIONS: Acting via PAR-1, thrombin causes contrasting effects in the human vasculature and has a major interaction with the endothelium. This highlights the critical importance of endothelial function during acute arterial injury and intravascular thrombosis, as occurs in cardiovascular events including myocardial infarction and stroke.

Direct vascular effects of protease-activated receptor type 1 agonism in vivo in humans.

BACKGROUND: Protease-activated receptor type 1 (PAR-1) has been proposed as the principal thrombin receptor in humans, although its actions in vivo have not been defined. The aim of the present study was to determine the direct vascular actions of PAR-1 agonism in humans. METHODS AND RESULTS: Dorsal hand vein diameter was measured by the Aellig technique in 14 healthy volunteers during local intravenous SFLLRN (PAR-1 agonist; 0.05 to 15 nmol/min) and SLIGKV (PAR-2 agonist; 1.6 to 160 nmol/min) infusions. The venous effects of SFLLRN were further assessed in the presence or absence of norepinephrine or the glycoprotein IIb/IIIa antagonist tirofiban. Forearm blood flow was measured by venous occlusion plethysmography in 16 volunteers during infusion of SFLLRN (1 to 50 nmol/min), SLIGKV (160 to 800 nmol/min), and the endothelium-dependent vasodilator bradykinin (100 to 1000 pmol/min). Platelet-monocyte binding (a sensitive measure of platelet activation) and plasma tissue plasminogen activator (tPA), plasminogen-activator inhibitor 1, and von Willebrand factor concentrations were measured at intervals throughout the study. SFLLRN caused dose-dependent venoconstriction (P<0.001) that was unaffected by norepinephrine or tirofiban co-infusion. In forearm resistance vessels, SFLLRN increased forearm blood flow (P<0.001), tPA release (P<0.001), and platelet-monocyte binding (P<0.0001) without affecting plasma plasminogen-activator inhibitor 1 or von Willebrand factor concentrations. SLIGKV caused venous (P<0.001) and arterial (P<0.01) dilatation without tPA release. CONCLUSIONS: We have demonstrated that PAR-1 agonism causes platelet activation, venous constriction, arterial dilatation, and tPA release in vivo in humans. These unique and contrasting effects provide important insights into the physiological and pathophysiological role of thrombin in the human venous and arterial circulations.

Sildenafil potentiates nitric oxide mediated inhibition of human platelet aggregation.

Nitric oxide (NO) inhibits platelet aggregation primarily via a cyclic 3'5'-guanosine monophosphate (cGMP)-dependent process. Sildenafil is a phosphodiesterase type 5 (PDE5) inhibitor that potentiates NO action by reducing cGMP breakdown. We hypothesised that sildenafil would augment the inhibitory effects of NO on in vitro platelet aggregation. After incubation with sildenafil or the soluble guanylate cyclase inhibitor H-(1,2,4)oxadiazolo(4,3-a)quinoxallin-1-one (ODQ), collagen-mediated human platelet aggregation was assessed in the presence of two NO donors, the cGMP-dependent sodium nitroprusside (SNP) and the cGMP-independent diethylamine diazeniumdiolate (DEA/NO). SNP and DEA/NO caused a concentration-dependent inhibition of platelet aggregation. ODQ inhibited and sildenafil augmented the effect of SNP, and to a lesser extent the effect of DEA/NO. We conclude that sildenafil potentiates NO-mediated inhibition of platelet aggregation through blockade of cGMP metabolism and that PDE5 inhibitors may have important antiplatelet actions relevant to the prevention of cardiovascular disease.