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The Framingham Risk Score (FRS) and Pooled Cohort Equations (PCEs) overestimate risk in many contemporary cohorts.This study sought to determine if recalibration of these scores using contemporary population-level data improves risk stratification for statin therapy.Five-year FRS and PCEs were recalibrated using a cohort of Ontario residents alive January 1, 2011, who were 30 to 79 years of age without cardiovascular disease. Scores were externally validated in a primary care cohort of routinely collected electronic medical record data from January 1, 2010, to December 31, 2014. The relative difference in mean predicted and observed risk, number of statins avoided, and number needed to treat with statins to reduce a cardiovascular event at 5 years were reported.The FRS was recalibrated in 6,938,971 Ontario residents (51.6% women, mean age 48 years) and validated in 71,450 individuals (56.1% women, mean age 52 years). Recalibration reduced overestimation from 109% to 49% for women and 131% to 32% for men. The recalibrated FRS was estimated to reduce statin prescriptions in up to 26 per 1,000 low-risk women and 80 per 1,000 low-risk men, as well as reduce the number needed to treat from 61 to 47 in women and from 53 to 41 in men. In contrast, after recalibration of the PCEs, risk remained overestimated by 217% in women and 128% in men.Recalibration is a feasible solution to improve risk prediction but is dependent on the model being used. Recalibration of the FRS but not the PCEs reduced overestimation and may improve utilization of statins.

Background: Incremental low-density lipoprotein (LDL) cholesterol lowering with the proprotein convertase subtilisin kexin type 9 inhibitor evolocumab regresses coronary atherosclerosis in statin-treated patients. Objectives: The purpose of this study was to evaluate the effect of adding evolocumab to statin therapy on coronary plaque composition. Methods: A total of 968 statin-treated coronary artery disease patients underwent serial coronary intravascular ultrasound imaging at baseline and following 76 weeks of treatment with placebo or evolocumab 420 mg monthly. Plaque composition changes were determined in 331 patients with evaluable radiofrequency analysis of the ultrasound backscatter signal. Results: Compared with statin monotherapy, evolocumab further reduced LDL cholesterol (33.5 mg/dl vs. 89.9 mg/dl; p < 0.0001) and induced regression of percent atheroma volume (−1.2% vs. +0.17%; p < 0.0001) and total atheroma volume (−3.6 mm3 vs. −0.8 mm3; p = 0.04). No difference was observed between the evolocumab and placebo groups in changes in calcium (1.0 ± 0.3 mm3 vs. 0.6 ± 0.3 mm3; p = 0.49), fibrous (−3.0 ± 0.6 mm3 vs. −2.4 ± 0.6 mm3; p = 0.49), fibrofatty (−5.0 ± 1.0 mm3 vs. −3.0 ± 1.0 mm3; p = 0.49), and necrotic (−0.6 ± 0.5 mm3 vs. −0.1 ± 0.5 mm3; p = 0.49) volumes. An inverse correlation was observed between changes in LDL cholesterol and plaque calcification (r = −0.15; p < 0.001). Conclusions: The addition of evolocumab to a statin did not produce differential changes in plaque composition compared with statin monotherapy. This suggests that evaluation of plaque morphology using virtual histology imaging may provide no incremental information about the plaque effects of evolocumab beyond measurement of plaque burden. (GLobal Assessment of Plaque reGression With a PCSK9 antibOdy as Measured by intraVascular Ultrasound [GLAGOV]; NCT01813422)

Current guidelines recommend an evaluation for underlying heart disease and reversible conditions for patients with new-onset heart failure (HF). There are limited data on contemporary testing for coronary artery disease (CAD) in HF patients. We performed an analysis of the GWTG-HF registry linked

Chylopericardium is a rare cause of pericardial effusion secondary to lymphatic injury or obstruction, usually involving the thoracic duct. A 57 year-old female presented with acute dyspnea. She was hypotensive and tachycardic with a lactate of 3.2 mmol/L. She has a history of idiopathic VT with

A cardinal feature of heart failure (HF) is reduced exercise tolerance (peak oxygen uptake [Vo2]) that is associated with dyspnea and increased left ventricular (LV) filling pressure [(1)][1]. Elevated resting LV filling pressures in patients with HF have been shown to be associated with increased

Whether androgen deficiency increases the risk of cardiovascular (CV) events among men remains a subject of intense scientific interest. We examined the relationship between low baseline testosterone (T) levels and subsequent CV outcomes among male subjects in the AIM-HIGH Trial with low HDL-C and

Objectives This study sought to examine the relationship between niacin treatment, lipoproteins, and cardiovascular (CV) outcomes in this secondary analysis of the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes) trial. Background During a 3-year follow-up in 3,414 patients with established CV disease and low high-density lipoprotein cholesterol (HDL-C) levels, combined niacin + low-density lipoprotein cholesterol (LDL-C)–lowering therapy did not reduce CV events compared with LDL-C–lowering therapy alone. Methods Subjects taking simvastatin and/or ezetimibe were randomized to receive extended-release (ER) niacin 1,500 to 2,000 mg or minimal immediate-release niacin (≤150 mg) as placebo at bedtime. LDL-C levels in both groups were maintained from 40 to 80 mg/dl. Hazard ratios were estimated by using Cox proportional hazards models for relationships between lipoproteins and the composite endpoint of CV death, myocardial infarction, acute coronary syndrome, ischemic stroke, or symptom-driven revascularization. Results CV outcomes were not associated with ER niacin in any baseline lipoprotein tertile. In a subset of patients in both the highest triglyceride (≥198 mg/dl) and lowest HDL-C ( Conclusions Baseline lipoprotein tertiles did not predict differential benefit or harm with ER niacin added to LDL-C–lowering therapy, but a small dyslipidemic subgroup may benefit. ER niacin attenuated expected relationships of lipoprotein risk factors with CV events, raising the possibility that nonlipoprotein actions of niacin could affect risk. (Niacin Plus Statin to Prevent Vascular Events [AIM-HIGH]; NCT00120289 )

Percutaneous transluminal angioplasty of calcified peripheral artery lesions often results in suboptimal vessel expansion. Angioplasty of calcified lesions is often associated with acute loss of patency due to residual stenosis or dissection, often requiring stenting [(1,2)][1]. A high rate of

ObjectivesWe sought to determine whether patients with functional mitral regurgitation (FMR) would benefit from ventricular reshaping by the Coapsys device (Myocor, Inc., Maple Grove, Minnesota).BackgroundFMR occurs when ventricular remodeling impairs valve function. Coapsys is a ventricular shape change device placed without cardiopulmonary bypass to reduce FMR. It compresses the mitral annulus and reshapes the ventricle. We hypothesized that Coapsys for FMR would improve clinical outcomes compared with standard therapies.MethodsRESTOR-MV (Randomized Evaluation of a Surgical Treatment for Off-Pump Repair of the Mitral Valve) was a randomized, prospective, multicenter study of patients with FMR and coronary disease with core laboratory analysis. After enrollment, patients were stratified to the standard indicated surgery: either coronary artery bypass graft alone or coronary artery bypass graft with mitral valve repair. In each stratum, randomization was to either control (indicated surgery) or treatment (coronary artery bypass graft with Coapsys ventricular reshaping).ResultsThe study was terminated when the sponsor failed to secure ongoing funding; 165 patients were randomized. Control and Coapsys both produced decreases in left ventricular (LV) end-diastolic dimension and MR at 2 years (p < 0.001); Coapsys provided a greater decrease in LV end-diastolic dimension (p = 0.021). Control had lower MR grades during follow-up (p = 0.01). Coapsys showed a survival advantage compared with control at 2 years (87% vs. 77%) (hazard ratio: 0.421; 95% confidence interval: 0.200 to 0.886; stratified log-rank test; p = 0.038). Complication-free survival (including death, stroke, myocardial infarction, and valve reoperation) was significantly greater with Coapsys at 2 years (85% vs. 71%) (hazard ratio: 0.372; 95% confidence interval: 0.185 to 0.749; adjusted log-rank test; p = 0.019).ConclusionsAnalysis of RESTOR-MV indicates that patients with FMR requiring revascularization treated with ventricular reshaping rather than standard surgery had improved survival and a significant decrease in major adverse outcomes. This trial validates the concept of the ventricular reshaping strategy in this subset of patients with heart failure. (Randomized Evaluation of a Surgical Treatment for Off-Pump Repair of the Mitral Valve [RESTOR-MV]; NCT00120276)

Objectives The purpose of this study was to characterize interactions between normal pacing system operation and the initiating sequence of ventricular tachycardia (VT)/ventricular fibrillation (VF). Background Abrupt changes in ventricular cycle lengths (short-long-short, S-L-S) might initiate VT/VF. The S-L-S sequences might be passively permitted or actively facilitated by bradycardia pacing. Methods Initiating sequences of 1,356 VT/VF episodes in the PainFree Rx II (n = 634) and EnTrust Trial (n = 421) were analyzed with stored electrograms and by pacing mode (DDD/R, VVI/R, and Managed Ventricular Pacing [MVP]). Interactions between pacing and VT/VF initiation were classified as: non-pacing associated, pacing associated, pacing permitted, and pacing facilitated. Results Non-pacing associated (no pacing, no S-L-S) and pacing associated (ventricular pacing without S-L-S) onset accounted for 44.0% and 29.8% of all VT/VF, respectively. Pacing permitted (S-L-S sequences without ventricular pacing) episodes accounted for 6.4% (DDD/R), 20.0% (MVP), and 25.6% (VVI/R) of 1,356 VT/VF episodes. Pacing facilitated onset (S-L-S sequences actively facilitated by ventricular pacing including the terminal beat after a pause) accounted for 8.2% (MVP), 9.4% (VVI/R), and 14.8% (DDD/R) of 1,356 VT/VF episodes. Pacing facilitated S-L-S VT/VF occurred in 2.6% (MVP), 3.3% (VVI/R), and 5.2% (DDD/R) of patients with episodes and was the sole initiating sequence in approximately 1% of patients. Pause durations during pacing facilitated S-L-S differed between modes (DDD/R 793 ± 172 ms vs. MVP 865 ± 278 ms vs. VVI/R 1180 ± 414 ms, p = 0.002). The majority of these episodes were monomorphic VT. Conclusions Ventricular tachycardia/VF in some implantable cardioverter-defibrillator patients might be initiated by S-L-S sequences that are actively facilitated by bradycardia pacing operation and might constitute an important mechanism of ventricular proarrhythmia.

One hypothesis that may explain the apparent failure of recent trials of high-density lipoprotein (HDL)-raising therapy is based on the finding that HDL may become proatherogenic under certain circumstances [(1,2)][1], with the proposed result that raising HDL levels in these individuals would be

ObjectivesThe purpose of this research was to compare the Thrombolysis In Myocardial Infarction (TIMI) frame count (CTFC) with coronary flow velocity reserve (CFVR) in patients undergoing percutaneous coronary intervention (PCI).BackgroundThe relationship between CTFC and CFVR has not been adequately assessed in patients with coronary artery disease.MethodsWe studied 62 patients who underwent successful non-emergent PCI. All patients had Doppler evaluation of CFVR, CTFC, and quantitative coronary angiography. In an additional 17 patients, a frame count reserve was calculated as baseline CTFC/CTFC at peak hyperemia, induced by intracoronary adenosine after PCI.ResultsThe CTFC decreased from 27 ± 13 to 18 ± 8, and CFVR increased from 1.5 ± 0.4 to 2.6 ± 0.7 (both p < 0.0001). The pre-PCI CTFC and the CFVR were closely related to minimal lumen diameter (p < 0.0001). After PCI, there was no correlation between CFVR and CTFC. In addition, no relationship was observed between CFVR and the frame count reserve.ConclusionsThere was no significant correlation between CFVR and CTFC in patients undergoing coronary intervention. The relative utility of these measures in predicting outcomes in this setting requires further evaluation, but CTFC (or frame count reserve) does not appear to be an adequate surrogate measure of Doppler-derived CFVR.

Objectives The study was done to determine whether eptifibatide, a platelet glycoprotein (GP) IIb/IIIa antagonist, prevents ischemic complications following percutaneous coronary interventions (PCIs) in women as well as in men. Background Eptifibatide reduces ischemic complications after nonurgent coronary stent interventions. Methods We compared outcomes in women (n = 562) and men (n = 1,502) enrolled in the Enhanced Suppression of the Platelet GP IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial of double-bolus eptifibatide during PCI. Results Women in the ESPRIT trial were older, and more frequently had hypertension, diabetes mellitus, or acute coronary syndromes, but were less likely to have prior PCI or coronary artery bypass graft surgery. The primary end point, a composite at 48 h of death, myocardial infarction (MI), urgent target vessel revascularization (TVR), and unplanned GP IIb/IIIa use, occurred in 10.5% of women and 7.9% of men (p = 0.082). The composite of death, MI, or TVR after one year occurred in 24.5% of women compared with 18% of men (p = 0.0008). At 48 h, eptifibatide reduced the composite of death, MI, and TVR from 14.5% to 6.0% in women versus 9.0% to 6.8% in men. At one year, these differences persisted: 28.9% versus 20.0% for women and 19.5% versus 16.6% for men. No statistical interaction existed between treatment and gender at either 48 h (p = 0.063) or one year (p = 0.2). Bleeding occurred more commonly in women (5.5% vs. 2.6%, p = 0.002), and was more common in eptifibatide-treated women. After adjustment for age, weight, and hypertension, no interaction between treatment and gender was present. Conclusions Eptifibatide is effective to prevent ischemic complications of PCI in women and may eliminate gender-related differences in PCI outcomes.

Endothelial function is thought to be an important factor in the pathogenesis of atherosclerosis, hypertension and heart failure. In the 1990s, high-frequency ultrasonographic imaging of the brachial artery to assess endothelium-dependent flow-mediated vasodilation (FMD) was developed. The technique provokes the release of nitric oxide, resulting in vasodilation that can be quantitated as an index of vasomotor function. The noninvasive nature of the technique allows repeated measurements over time to study the effectiveness of various interventions that may affect vascular health. However, despite its widespread use, there are technical and interpretive limitations of this technique. State-of-the-art information is presented and insights are provided into the strengths and limitations of high-resolution ultrasonography of the brachial artery to evaluate vasomotor function, with guidelines for its research application in the study of endothelial physiology.

Background: Coronary artery calcification presents multiple challenges to percutaneous revascularization and is associated with suboptimal results and adverse long-term clinical outcomes. Lithoplasty treatment is a balloon-based therapy deploying circumferential lithotripsy to disrupt intimal and

To the Editor: Noninvasive monitoring of cardiac gene therapy is critical to fully understand the biology of gene therapy in living subjects. We and others have monitored reporter gene expression in the myocardium of small ([1][1]) and large ([2][2]) animals (reviewed in reference [3][3]). However

Objectives.The relation between endothelium-dependent vasodilator function in the brachial and coronary arteries was determined in the same subjects.Background.Coronary artery endothelial dysfunction precedes the development of overt atherosclerosis and is important in its pathogenesis. A noninvasive assessment of endothelial function in a peripheral conduit vessel, the brachial artery, was recently described, but the relation between brachial artery function and coronary artery vasodilator function has not been explored.Methods.In 50 patients referred to the catheterization laboratory for the evaluation of coronary artery disease (mean age ± SD 56 ± 10 years), the coronary vasomotor response to serial intracoronary infusions of the endothelium-dependent agonist acetylcholine (10−8to 10−6mol/liter), was studied. Endotheliumdependent vasodilation was also assessed in the brachial artery by measuring the change in brachial artery diameter in response to reactive hyperemia.Results.Patients with coronary artery endothelial dysfunction manifested as vasoconstriction in response to acetylcholine had significantly impaired flow-mediated vasodilation in the brachial artery compared with that of patients with normal coronary endothelial function (4.8 ± 5.5% vs. 10.8 ± 7.6%, p < 0.01). Patients with coronary artery disease also had an attenuated brachial artery vasodilator response compared with that of patients with angiographically smooth coronary arteries (4.5 ± 4.6% vs. 9.7 ± 8.1%, p < 0.02). By multivariate analysis, the strongest predictors of reduced brachial dilator responses to flow were baseline brachial artery diameter (p < 0.001), coronary endothelial dysfunction (p = 0.003), the presence of coronary artery disease (p = 0.007) and cigarette smoking (p = 0.016). The brachial artery vasodilator response to sublingual nitroglycerin was independent of coronary endothelial responses or the presence of coronary artery disease. The positive predictive value of abnormal brachial dilation (

The treatment of calcified peripheral lesions remains a challenge as evidenced from multiple studies targeting this patient population. Calcified peripheral artery disease (PAD) is associated with vascular complications, high stent use and poor outcomes. This study sought to investigate the acute

This study tested the hypothesis that there is preferential recovery of subepicardial wall thickening after nontransmural myocardial infarction.Previous studies have demonstrated gradual recovery of mechanical function after reperfusion in acute myocardial infarction. Because myocardial necrosis is primarily subendocardial, it was hypothesized that recovery of mechanical function would occur primarily in the subepicardial layers.Eleven mongrel dogs were instrumented with ultrasonic crystals to measure transmural and outer wall thickening. Animals performed treadmill exercise before and 8 days after nontransmural infarction produced by coronary occlusion for 90 min.Coronary artery occlusion reduced myocardial blood flow to inner layers more than that to outer wall layers (mean [+/- SD] 0.19 +/- 0.35 vs. 0.38 +/- 0.38 ml/g per min, p0.05). Infarct size (% of risk region) was also greater in subendocardial layers (33.3 +/- 24.3% inner vs. 8.3 +/- 9.7% outer). Rest transmural wall thickening was 22.4 +/- 7.5% versus 14.4 +/- 6.3% for outer wall layers. During coronary artery occlusion, transmural and outer wall thickening decreased similarly (3.2 +/- 7.7% vs. 0.2 +/- 5.9%). Eight days after reperfusion, thickening of the entire wall recovered to 7.5 +/- 4.7%; however, outer wall thickening had only recovered to 0.0 +/- 5.8%. Myocardial blood flow was abnormal during exercise 8 days after reperfusion, with markedly reduced subendocardial perfusion. However, thickening of the inner and outer layers was similar, with transmural thickening of 8.5 +/- 9.3% and outer wall thickening of 1.6 +/- 6.2%.Despite preferential blood flow and less necrosis, thickening of the outer layer is not preserved 8 days after subendocardial infarction. The severity of subendocardial injury appears to be the major determinant of regional function after nontransmural infarction.

Patients with accessory pathway-mediated supraventricular tachycardia have typically been treated with drugs or surgery. Although catheter ablation using high voltage direct current shocks has been used to treat patients with drug-refractory supraventricular tachycardia, there are associated disadvantages, including damage due to barotrauma as well as the need for general anesthesia. Recently, transcatheter radiofrequency energy has evolved as an alternative to direct current shock or surgery to ablate accessory pathways.Percutaneous catheter ablation of 109 accessory pathways with use of radiofrequency energy was attempted in 100 consecutive patients. Patient age ranged from 3 to 67 years. The patients had been treated for recurrent tachycardia with a mean of 2.7 ± 0.2 antiarrhythmic agents that either proved ineffective or caused unacceptable side effects. In seven patients previous attempts at accessory pathway ablation with use of direct current shock had been unsuccessful. Forty-five (41%) of the pathways were left free wall, 43 (40%) were septal and 21 (19%) were right free wall.Eighty-nine (89%) of the 100 patients had successful radiofrequency ablation at the time of hospital discharge. In all but 12 patients the ablation was accomplished in a single session. Complications attributable to the procedure, but not to the ablation itself, occurred in four patients (4%). No patient developed atrioventricular block or other cardiac arrhythmias. Over a mean follow-up period of 10 months, nine patients had some return of accessory pathway conduction; a repeat ablation procedure was successful in all five patients in whom it was attempted.It is concluded that a catheter ablation procedure using radiofrequency energy can be performed on accessory pathways in all locations. The procedure is effective and safer, less costly and more convenient than cardiac surgery and can be considered as an alternative to lifelong medical therapy in any patient with symptomatic accessory pathway-mediated tachycardia.

Seven of 120 consecutive patients with inducible sustained ventricular tachycardia (from September 1, 1988 to January 1, 1991) had bundle branch reentrant tachycardia and underwent percutaneous radiofrequency ablation of the right bundle branch. The seven patients had been unsuccessfully treated with a mean of 3 ± 1 drugs. Four patients presented with syncope and three with aborted sudden death. The baseline electrocardiogram revealed a left bundle branch block pattern in three patients and an intraventricular conduction defect in four.The baseline HV interval was prolonged in each case (79 ± 2 ms). With use of programmed ventricular extrastimuli, sustained bundle branch reentrant tachycardia was inducible in all patients at a mean cycle length of 283 ± 17 ms (range 230 to 350). Bundle branch reentrant tachycardia characteristics included atrioventricular dissociation, a His deflection that preceded each QRS complex and spontaneous His to His variation that preceded changes in ventricular tachycardia cycle length.A quadripolar catheter was positioned across the tricuspid valve with the distal electrode tip of the catheter near the right bundle branch. One to three applications of continuous unmodulated radiofrequency current at 300 kHz between the distal electrode and a large posterior skin patch resulted in complete right bundle branch block in all patients, after which none had inducible bundle branch reentrant tachycardia on restudy. On restudy, three of the seven patients had ventricular tachycardia of myocardial origin (not bundle branch reentry). One patient required no therapy; drug or defibrillator therapy was used in the others. After a mean follow-up interval of 12 ± 3 months (range 6 to 29) complete right bundle branch block persisted, there were no spontaneous episodes of ventricular tachycardia and no patient required a permanent pacemaker.Radiofrequency catheter ablation of the right bundle branch is easily performed and is a safe and effective treatment for bundle branch reentrant tachycardia. It is probably the procedure of choice for these highly symptomatic patients.

Ventricular fibrillation refractory to cardiopulmonary resuscitation including multiple transthoracic defibrillations occurred in four patients during 1,215 consecutive ventricular tachycardia induction studies. A technique of emergency intracardiac defibrillation for management of refractory ventricular fibrillation is described. In four patients, stable monomorphic ventricular tachycardia (320 to 570 ms cycle length) was induced during the study and overdrive ventricular pacing resulted in ventricular fibrillation.These patients did not respond to prompt transthoracic defibrillations (5 to 15 attempts/patient) and cardiopulmonary resuscitation, including antiarrhythmic therapy. As a last resort, intracardiac defibrillation was performed with use of a previously inserted standard right ventricular quadripolar catheter as cathode and a posterior skin patch as anode. High energy intracardiac defibrillation pulses (100 to 500 J) delivered from a standard defibrillator successfully terminated each arrhythmia.Intracardiac defibrillation is technically simple and appears effective in terminating refractory ventricular fibrillation in the electrophysiology laboratory. However, further research is necessary to determine the safety and efficacy of this technique, as well as potential applications in other emergency settings.

The vascular endothelium has long been recognized as a key modulator of the detrimental effects of cardiovascular risk factors. Through the release of vasoactive substances, including nitric oxide (NO), a healthy endothelium is cardioprotective. In response to perturbations imposed by enhanced

The study was done to determine whether eptifibatide, a platelet glycoprotein (GP) IIb/IIIa antagonist, prevents ischemic complications following percutaneous coronary interventions (PCIs) in women as well as in men.Eptifibatide reduces ischemic complications after nonurgent coronary stent interventions.We compared outcomes in women (n = 562) and men (n = 1,502) enrolled in the Enhanced Suppression of the Platelet GP IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial of double-bolus eptifibatide during PCI.Women in the ESPRIT trial were older, and more frequently had hypertension, diabetes mellitus, or acute coronary syndromes, but were less likely to have prior PCI or coronary artery bypass graft surgery. The primary end point, a composite at 48 h of death, myocardial infarction (MI), urgent target vessel revascularization (TVR), and unplanned GP IIb/IIIa use, occurred in 10.5% of women and 7.9% of men (p = 0.082). The composite of death, MI, or TVR after one year occurred in 24.5% of women compared with 18% of men (p = 0.0008). At 48 h, eptifibatide reduced the composite of death, MI, and TVR from 14.5% to 6.0% in women versus 9.0% to 6.8% in men. At one year, these differences persisted: 28.9% versus 20.0% for women and 19.5% versus 16.6% for men. No statistical interaction existed between treatment and gender at either 48 h (p = 0.063) or one year (p = 0.2). Bleeding occurred more commonly in women (5.5% vs. 2.6%, p = 0.002), and was more common in eptifibatide-treated women. After adjustment for age, weight, and hypertension, no interaction between treatment and gender was present.Eptifibatide is effective to prevent ischemic complications of PCI in women and may eliminate gender-related differences in PCI outcomes.

Endothelial function is thought to be an important factor in the pathogenesis of atherosclerosis, hypertension and heart failure. In the 1990s, high-frequency ultrasonographic imaging of the brachial artery to assess endothelium-dependent flow-mediated vasodilation (FMD) was developed. The technique provokes the release of nitric oxide, resulting in vasodilation that can be quantitated as an index of vasomotor function. The noninvasive nature of the technique allows repeated measurements over time to study the effectiveness of various interventions that may affect vascular health. However, despite its widespread use, there are technical and interpretive limitations of this technique. State-of-the-art information is presented and insights are provided into the strengths and limitations of high-resolution ultrasonography of the brachial artery to evaluate vasomotor function, with guidelines for its research application in the study of endothelial physiology.

OBJECTIVES This study was designed to assess the effect of metformin on impaired endothelial function in type 2 diabetes mellitus. BACKGROUND Abnormalities in vascular endothelial function are well recognized among patients with type 2 (insulin-resistant) diabetes mellitus. Insulin resistance itself may be central to the pathogenesis of endothelial dysfunction. The effects of metformin, an antidiabetic agent that improves insulin sensitivity, on endothelial function have not been reported. METHODS Subjects with diet-treated type 2 diabetes but without the confounding collection of cardiovascular risk factors seen in the metabolic syndrome were treated with metformin 500 mg twice daily (n = 29) or placebo (n = 15) for 12 weeks. Before and after treatment, blood flow responses to intraarterial administration of endothelium-dependent (acetylcholine), endothelium-independent (sodium nitroprusside) and nitrate-independent (verapamil) vasodilators were measured using forearm plethysmography. Whole-body insulin resistance was assessed on both occasions using the homeostasis model (HOMA-IR). RESULTS Subjects who received metformin demonstrated statistically significant improvement in acetylcholine-stimulated flows compared with those treated with placebo (p = 0.0027 by 2-way analysis of variance), whereas no significant effect was seen on nitroprusside-stimulated (p = 0.27) or verapamil-stimulated (p = 0.40) flows. There was a significant improvement in insulin resistance with metformin (32.5% reduction in HOMA-IR, p = 0.01), and by stepwise multivariate analysis insulin resistance was the sole predictor of endothelium-dependent blood flow following treatment (r = -0.659, p = 0.0012). CONCLUSIONS Metformin treatment improved both insulin resistance and endothelial function, with a strong statistical link between these variables. This supports the concept of the central role of insulin resistance in the pathogenesis of endothelial dysfunction in type 2 diabetes mellitus. This has important implications for the investigation and treatment of vascular disease in patients with type 2 diabetes mellitus.

OBJECTIVESTo determine the effect of angiotensin-converting enzyme (ACE) inhibition on brachial flow-mediated vasodilation.BACKGROUNDQuinapril, an ACE inhibitor with high affinity, has been shown to improve coronary endothelial dysfunction in patients with coronary artery disease. The effectiveness of different vasoactive agents to improve human endothelial function is unknown.METHODSHigh resolution ultrasound was used to assess endothelium-dependent brachial artery flow-mediated vasodilation (FMD) in patients with coronary disease. We studied 80 patients (mean age 58 ± 0.9 years) in a partial-block, cross-over design trial. Patients were randomized to one of four different drug sequences to receive quinapril 20 mg, enalapril 10 mg, losartan 50 mg or amlodipine 5 mg daily. Each patient received three drugs with a two-week washout period between treatments. The primary end point was the absolute difference in FMD after eight weeks of each study drug compared with their respective baselines analyzed in a blinded fashion.RESULTSThere was mild impairment of FMD at baseline (7.3 ± 0.6%). The change in FMD from baseline was significant only for quinapril (1.8 ± 1%, p < 0.02). No change was seen with losartan (0.8 ± 1.1%, p = 0.57), amlodipine (0.3 ± 0.9%, p = 0.97) or enalapril (−0.2 ± 0.8%, p = 0.84). No significant change in nitroglycerin-induced dilation occurred with drug therapy. The improvement in quinapril response was not seen in those with the DD ACE genotype (0.5 ± 2.1%) but was seen in those with the ID and II genotype (3.3 ± 1.2 and 3.2 ± 1.9%, respectively, p = 0.03).CONCLUSIONOnly quinapril was associated with significant improvement in FMD, and this response is related to the presence of the insertion allele of the ACE genotype.

Background: We previously reported the results of the WAVE 1 trial for Renal Sympathetic Denervation in twenty-four patients with refractory hypertension using the Kona Surround Sound System. Six month results demonstrated a 27mmHg reduction in systolic blood pressure in the study. This technology utilizes external focused ultrasound navigated by a targeting catheter in the renal artery. The WAVE 1 protocol involved making 18 focused lesions over 12.6 minutes on each side. This study (WAVE II) is evaluating the safety and efficacy of an optimized treatment protocol in which 14 focused lesions produced over 2.8 min on each side were utilized to create sympathetic denervation. Methods: Thirteen patients (8 men and 5 women; median age: 60 years), with resistant arterial hypertension underwent bilateral externally focused ultrasound utilizing a 5F intravascular catheter for targeting and tracking. Patients were on a minimum of three antihypertensive medications. All treatments were performed in patients under deep analgesic-sedation. The procedure was performed using the 2.8 min protocol for each side and targeting was directed to just proximal to the bifurcation of the renal artery. Results: During and after the procedure no serious complications were observed. Unlike the WAVE I trial, only one of 13 patients complained of back pain following the index procedure and this resolved within 4 days. To date, Eight patients reached the 6-week follow up time point and Systolic BP decreased by 18 mmHg and diastolic BP was unchanged.

Objectives. This study was designed to determine whether enhanced sensitivity to exogenous nitrovasodilators is present in the coronary arteries of patients with impaired endothelium-dependent dilation.Background. Animal studies have demonstrated that the dilator response to exogenous nitrovasodilators is exaggerated in the setting of endothelial dysfunction (diminished nitric oxide activity). Whether such relative hyperresponsiveness to exogenous nitrates occurs and is important in humans is unknown.Methods. We assessed coronary vasomotion in 110 patients (mean [±SD] age 56 ± 10 years) by serial intracoronary infusions of acetylcholine (10−8 to 10−6 mol/liter) to test endogenous nitric oxide and nitroglycerin (40 μg) to test responses to exogenous nitrovasodilators.Results. The vasomotor response to 10−6 mol/liter of acetylcholine differed between patients with (n = 95) and those without (n = 15) normal endothelial dysfunction (−21 ± 14% vs. 12 ± 8% respectively, p < 0.001). However, neither the dilator response to nitroglycerin (21 ± 14% vs. 18 ± 13%) nor the baseline diameter differed between those with endothelial dysfunction and normal function, respectively. There was no correlation between the magnitude of the dilator response to nitroglycerin and acetylcholine. The response to nitroglycerin was decreased with increasing age (r = −0.21, p = 0.03) but was not related to any other demographic factors or to the angiographic appearance of the vessel.Conclusions. The coronary vasodilator response to nitroglycerin is not significantly enhanced in patients with impaired endothelium-dependent dilation but decreases with increasing age. This finding provides indirect evidence that basal coronary tone is not increased in patients with endothelial dysfunction and that supersensitivity to exogenous nitrates is not clinically important in humans.