BACKGROUND: Hyperhomocyst(e)inemia is a risk factor for atherosclerosis and is prevalent in the elderly. The objective of this study was to determine whether hyperhomocyst(e)inemia is associated with impaired endothelium-dependent vasodilation in humans. METHODS AND RESULTS: High-resolution vascular ultrasonography was used to study endothelium-dependent and -independent vasodilation in a nonatherosclerotic peripheral conduit artery of 26 elderly hyperhomocyst(e)inemic subjects and 15 age- and sex-matched subjects with normal homocysteine levels. Flow-mediated, endothelium-dependent (nitric oxide-mediated) vasodilation was assessed by measuring the percent change in brachial artery diameter during reactive hyperemia. Endothelium-independent vasodilation was assessed after the administration of 0.4 mg sublingual nitroglycerin. Endothelium-dependent vasodilation was significantly impaired in the hyperhomocyst(e)inemic subjects compared with control subjects (3.7 +/- 0.6% versus 8.1 +/- 1.2%; P =.004), whereas endothelium-independent vasodilation was not different between the two groups (10.1 +/- 1.6% versus 9.3 +/- 1.5%; P = NS). In a linear regression analysis with serum homocysteine concentration, folic acid, age, sex, cholesterol (serum total, LDL, or HDL cholesterol), mean arterial blood pressure, use of antihypertensive medication, and baseline brachial artery diameter included as covariates, serum homocysteine concentration emerged as the only significant predictor of flow-mediated vasodilation. CONCLUSIONS: These data indicate that hyperhomocyst(e)inemia is associated with impaired endothelium-dependent vasodilation in humans and suggest that the bioavailability of nitric oxide is decreased in hyperhomocyst(e)inemic humans.

BACKGROUND: Fractional flow reserve (FFR), defined as the ratio of maximum flow in the presence of a stenosis to normal maximum flow, is a lesion-specific index of stenosis severity that can be calculated by simultaneous measurement of mean arterial, distal coronary, and central venous pressure (Pa, Pd, and Pv, respectively), during pharmacological vasodilation. The aims of this study were to define ranges of FFR values, whether associated with inducible ischemia or not, and to investigate FFR in normal coronary arteries. METHODS AND RESULTS: In 60 patients accepted for percutaneous transluminal coronary angioplasty (PTCA) of single-vessel disease, with a positive exercise test (ET)< 24 hours before PTCA, FFR was determined during adenosine-induced hyperemia just before and 15 minutes after angioplasty. Pa was measured by the guiding catheter, Pd by an 0.018-in fiber-optic pressure-monitoring wire, and Pv, by a multipurpose catheter. The ET was repeated after 5 to 7 days, and only if this second ET had reverted to normal was the pre-PTCA value of FFR definitely considered to be associated with inducible ischemia and the post-PTCA value not. Myocardial FFR (FFRmyo) increased from 0.53 +/- 0.15 before PTCA to 0.88 +/- 0.07 after PTCA. Coronary FFR increased from 0.38 +/- 0.19 to 0.83 +/- 0.12. In all patients, values of FFRmyo definitely associated with ischemia were < or = 0.74, whereas all except two values not associated with inducible ischemia exceeded 0.74. Moreover, FFRmyo in 18 coronary arteries in 5 normal patients equaled 0.98 +/- 0.03. CONCLUSIONS: A value of FFRmyo of 0.74 reliably discriminates coronary stenosis, whether associated with inducible ischemia or not. Therefore, FFRmyo is a useful index to determine the functional significance of an epicardial coronary stenosis and may facilitate clinical decision making in patients with an equivocal coronary stenosis.

OBJECTIVES: The purpose of this study was to evaluate whether transthoracic Doppler echocardiography (TTDE) can reliably measure coronary flow velocity (CFV) and coronary flow velocity reserve (CFVR) in the left anterior descending coronary artery (LAD) in the clinical setting. BACKGROUND: Coronary flow velocity measurement has provided useful clinical and physiologic information. Advancement in TTDE provides noninvasive measurement of CFV and CFVR in the distal LAD. METHODS: In 23 patients, CFV in the distal LAD was measured by TTDE (5 or 3.5 MHz) under the guidance of color Doppler flow mapping at the time of Doppler guide wire (DGW) examination. Coronary flow velocity in the distal LAD were measured at baseline and hyperemic conditions (intravenous administration of adenosine 0.14 mg/kg/min) by both TTDE and DGW techniques. Coronary flow velocity reserve was defined as the ratio of peak hyperemic to basal averaged peak velocity in the distal LAD. RESULTS: Clear envelopes of basal and hyperemic CFV in the distal LAD were obtained in 18 (78%) of 23 study patients by TTDE. There were excellent correlations between TTDE and DGW methods for the measurements of CFV (averaged peak velocity: r=0.97, y=0.94x + 0.40; averaged diastolic peak velocity: r=0.97, y=0.94x + 0.69; systolic peak velocities: r=0.97, y=0.91x + 0.87; diastolic peak velocity: r=0.98, y=0.95x + 1.10). Coronary flow velocity reserve from TTDE correlated highly with those from DGW examinations (r=0.94, y=0.95x + 0.21). CONCLUSIONS: Noninvasive measurement of CFV and CFVR in the distal LAD using TTDE accurately reflects invasive measurement of CFV and CFVR by DGW method.

BACKGROUND: Vascular tone is a determinant of conduit artery distensibility. The aim of this study was to establish whether endothelium-derived relaxing factor (EDRF) influences the distensibility of conduit arteries and whether endothelium-mediated increases in distensibility are impaired in chronic heart failure (CHF). METHODS AND RESULTS: Conduit artery distensibility was measured by two methods in healthy subjects and in nine patients with CHF caused by dilated cardiomyopathy. In the first method, pulse-wave velocity (PWV) was measured in the right common iliac artery at rest and during local infusions of acetylcholine (10(-7) to 10(-5) mol/L) or adenosine (2 x 10(-7) to 2 x 10(-5) mol/L), with correction for systemic effects. Acetylcholine induced concentration-dependent local reductions of PWV in healthy subjects (-5%,-15%, and -26%) but not in CHF patients (3%, 1%,-4%, P <.01), whereas adenosine induced similar reductions of PWV in healthy subjects and CHF patients. In the second method, brachial artery diameter, blood flow, and blood pressure were measured noninvasively by high-resolution ultrasound, continuous-wave Doppler, and photoplethysmography during reactive hyperemia in the hand and after sublingual glyceryl trinitrate (GTN, 400 micrograms). Hyperemic flow, similar in healthy subjects and CHF patients, was associated with increases in diameter and distensibility in healthy subjects (8.8% and 18.4%, respectively) but not in CHF patients (0.3% and -4.5%), whereas GTN induced similar effects in healthy subjects and CHF patients. CONCLUSIONS: These data indicate that conduit artery distensibility is increased by acetylcholine and increased blood flow in healthy subjects but not in CHF patients, whereas the effects of adenosine and GTN on distensibility are preserved in CHF patients. This implies that EDRF-mediated increases in distensibility are impaired in CHF patients, thus adding to cardiac work.

OBJECTIVES: The present study was designed to assess whether exercise training can enhance endothelium-dependent dilatation in healthy young men. BACKGROUND: Exercise has been shown to reduce cardiovascular morbidity and mortality, but the mechanisms for this benefit are unclear. Endothelial dysfunction is an early event in atherogenesis, and animal studies have shown that exercise training can enhance endothelial function. METHODS: We have examined the effect of a standardized, 10-week, aerobic and anaerobic exercise training program on arterial physiology in 25 healthy male military recruits, aged 17 to 24 (mean 20) years, of average fitness levels. Each subject was studied before starting, and after completing the exercise program. Baseline vascular reactivity was compared with that of 20 matched civilian controls. At each visit, the diameter of the right brachial artery was measured at rest, during reactive hyperemia (increased flow causing endothelium-dependent dilation) and after sublingual glyceryltrinitrate (GTN; an endothelium-independent dilator), using high-resolution external vascular ultrasound. RESULTS: At baseline, flow-mediated dilatation (FMD) and GTN-mediated dilatation were similar in the exercise and control groups (FMD 2.2+/-2.4% and 2.4+/-2.8%, respectively, p = 0.33; GTN 13.4+/-6.2 vs. 16.7+/-5.9, respectively, p = 0.53). In the military recruits, FMD improved from 2.2+/-2.4% to 3.9+/-2.5%(p = 0.01), with no change in the GTN-mediated dilation (13.4+/-6.2% vs. 13.9+/-5.8%, p = 0.31) following the exercise program. CONCLUSION: Exercise training enhances endothelium-dependent dilation in young men of average fitness. This may contribute to the benefit of regular exercise in preventing cardiovascular disease.

BACKGROUND: A family history of premature coronary artery disease (CAD) in a first-degree relative is an independent risk factor for coronary disease. Both genetic and environmental influences are likely to be responsible and may interact, but their relative importance is unclear. METHODS AND RESULTS: We studied endothelial function in 50 first-degree relatives (31 men, 19 women; mean age, 25+/-8 years) of patients (men < or = 45 years, women < or = 55 years) with proven CAD. All subjects were well, lifelong nonsmokers, not diabetic, and not hypertensive and took no medications. Using high-resolution external vascular ultrasound, we measured brachial artery diameter at rest and in response to reactive hyperemia (with increased flow causing an endothelium-dependent vasodilatation) and to sublingual glyceryltrinitrate (GTN, an endothelium-independent dilator). Vascular responses were compared with those of 50 healthy control subjects matched for age and sex. Flow-mediated dilatation (FMD) was impaired in the family history group (4.9+/-4.6% versus 8.3+/-3.5% in control subjects, P<.005). In contrast, GTN caused dilatation in all subjects (family history, 17.1+/-8.8%; control subjects, 19.0+/-6.3%; P=NS), suggesting that reduced FMD was due to endothelial dysfunction. When the family history subjects were subdivided, those found to have a serum cholesterol > 4.2 mmol/L (group A, n=10) had mildly impaired FMD compared with control subjects (5.5+/-5.1% versus 8.3+/-3.5%). In others whose affected relative had coronary risk factors (group B, n=24), FMD was also only slightly reduced (6.2+/-4.8% versus 8.3+/-3.5%). In contrast, subjects with no risk factors and whose affected relative had a normal cardiovascular risk factor profile (group C, n=16) had markedly impaired FMD (2.9+/-3.7% versus 8.3+/-3.5%). Although ANOVA of the three family history subgroups did not reach statistical significance (F=2.55, P=.09), pairwise analysis showed that FMD in group C was significantly impaired compared with group B (P=.026). CONCLUSIONS: Healthy young adults with a family history of premature coronary disease may have impaired endothelium-dependent dilatation, even in the absence of other cardiovascular risk factors. Those subjects, who were free of risk factors and whose affected first-degree relative was free of risk factors, had the most impaired endothelial function, suggesting a genetic influence on early arterial physiology that may be relevant to later clinical disease.

OBJECTIVES: We sought to evaluate the long-term effects of alternative right ventricular pacing sites on myocardial function and perfusion. BACKGROUND: Previous studies have demonstrated that asynchronous ventricular activation due to right ventricular apical (RVA) pacing alters regional myocardial perfusion and functions. METHODS: We randomized 24 patients with complete atrioventricular block to undergo permanent ventricular stimulation either at the RVA (n = 12) or right ventricular outflow (RVOT)(n = 12). All patients underwent dipyridamole thallium myocardial scintigraphy and radionuclide ventriculography at 6 and 18 months after pacemaker implantation. RESULTS: After pacing, the mean QRS duration was significantly longer during RVA pacing than during RVOT pacing (151 +/- 6 vs. 134 +/- 4 ms, p = 0.03). At six months, the incidence of myocardial perfusion defects (50% vs. 25%) and regional wall motion abnormalities (42% vs. 25%) and the left ventricular ejection fraction (LVEF)(55 +/- 3% vs. 55 +/- 1%) were similar during RVA pacing and RVOT pacing (p > 0.05). However, at 18 months, the incidence of myocardial perfusion defects (83% vs. 33%) and regional wall motion abnormalities (75% vs. 33%) were higher and LVEF (47 +/- 3 vs. 56 +/- 1%) was lower during RVA pacing than during RVOT pacing (all p < 0.05). Patients with RVA pacing had a significant increase in the incidence of myocardial perfusion defects (p < 0.05) and a decrease in LVEF (p < 0.01) between 6 and 18 months, but patients with RVOT pacing did not (p > 0.05). CONCLUSIONS: This study demonstrates that preserved synchronous ventricular activation with RVOT pacing prevents the long-term deleterious effects of RVA pacing on myocardial perfusion and function in patients implanted with a permanent pacemaker.

OBJECTIVES: This study evaluates the impact of obesity on coronary endothelial function in patients with normal or mild coronary artery disease. BACKGROUND: The American Heart Association (AHA) has recently classified obesity as a modifiable risk factor for coronary heart disease. METHODS: A total of 397 consecutive patients with normal or mildly diseased coronary arteries at angiography underwent coronary vascular reactivity evaluation using intracoronary adenosine, acetylcholine and nitroglycerin. Patients were divided into three groups based on the body mass index (BMI): Group 1, patients with a BMI <25 (n = 117, normal weight); Group 2, patients with a BMI 25-30 (n = 149, overweight) and Group 3, patients with a BMI >30 (n = 131, obese). RESULTS: There were no significant differences among the groups in regard to other cardiovascular risk factors, except that overweight but not obese patients were significantly older than normal-weight patients (47 +/- 1 years in Group 1, 53 +/- 1 years in Group 2 and 50 +/- 1 years in Group 3, p < 0.001). The percent change of coronary blood flow to acetylcholine (%delta CBF Ach) was significantly lower in the obese patients than in the normal-weight group (85.2 +/- 12.0% in Group 1, 63.7 +/- 10.0% in Group 2 and 38.1 +/- 9.6% in Group 3, p = 0.009). By multivariate analysis, overweight (odds ratio, 1.55; 95% confidence interval, 1.2-2.0) and obesity (odds ratio, 2.41; 95% confidence interval, 1.5-4.0) status were independently associated with impaired coronary endothelial function. CONCLUSIONS: The study demonstrates that obesity is independently associated with coronary endothelial dysfunction in patients with normal or mildly diseased coronary arteries.

OBJECTIVE: To determine the prevalence of systemic sclerosis associated pulmonary arterial hypertension (SScPAH), evaluate outcome, and identify predictors of mortality in a large patient cohort. METHODS: A prospective four year follow up study of 794 patients (722 from our own unit and 72 referrals). All patients screened for PAH using a combination of echocardiography, lung function testing, and clinical assessment. Patients with suspected raised pulmonary artery systolic pressures of >35 mm Hg, carbon monoxide transfer factor (TLCO)<50% predicted, or a precipitous fall in TLCO >20% over a one year period with no pulmonary fibrosis, and patients with SSc with breathlessness with no pulmonary fibrosis found were investigated with right heart catheterisation. All patients with SScPAH were treated in accordance with current best practice. RESULTS: The prevalence of PAH was 12%(89/722) by right heart catheter. The survival was 81%, 63%, and 56% at 1, 2, and 3 years from the diagnosis (in 89 patients from our own cohort and 59/72 referrals). Haemodynamic indices of right ventricular failure--raised mRAP (hazard ratio 21), raised mPAP (hazard ratio 20), and low CI (hazard ratio 11) predicted an adverse outcome There was no significant difference in survival between patients with SScPAH with (n=40) and without (n=108) pulmonary fibrosis (p=0.3). CONCLUSIONS: The prevalence of SScPAH in this cohort was similar to that of other catheter based studies and lower than that of previous echo based studies. The 148 patients with SScPAH actively treated had comparable outcomes to those of the cohorts with primary pulmonary hypertension. A high mRAP was the strongest haemodynamic predictor of mortality. To improve prognosis, future treatments need to be implemented at an earlier disease stage to prevent right ventricular decompensation.

OBJECTIVES: The purpose of this study was to evaluate a myocardial perfusion reserve index (MPRI) derived from a quantitative magnetic resonance imaging (MRI) technique in normal human volunteers and patients with coronary artery disease and to relate MPRI to coronary artery stenosis severity measured with quantitative arteriography. BACKGROUND: Magnetic resonance imaging could be a useful noninvasive tool in the investigation of ischemic heart disease. However, there have been few studies in humans to quantify myocardial perfusion and myocardial perfusion reserve using MRI and none in patients with coronary disease. METHODS: Twenty patients with angiographically proven coronary artery disease and five normal volunteers underwent both resting and stress (adenosine 140 microg/kg(-1)/min(-1)) first-pass contrast-enhanced MRI examinations (using 0.05 mmol/kg 1 of gadopentetate dimeglumine. Using a tracer kinetic model, the unidirectional transfer constant (K(i)), a perfusion marker for the myocardial uptake of contrast, was computed in each coronary arterial territory. The ratio of K(i) for the rest and stress scans was used to calculate the MPRI. Percent reduction in luminal diameter of coronary lesions was measured using an automated edge-detection algorithm. RESULTS: Myocardial perfusion reserve index was significantly reduced in patients compared with normal subjects (2.02+/-0.7 vs. 4.21+/-1.16, p < 0.02). For regions supplied by individual vessels, there was a significant negative correlation of MPRI with percent diameter stenosis (r =-0.81, p < 0.01). Importantly, regions supplied by vessels with <40% diameter stenosis (non-flow limiting) had a significantly higher MPRI than regions supplied by stenoses of "intermediate" severity, that is,>40% to 59% diameter stenosis (2.80+/-0.77 and 1.93+/-0.38, respectively, p < 0.02). However, even regions supplied by vessels with <40% diameter stenosis had a significantly lower MPRI than volunteers (p < 0.01). CONCLUSIONS: A myocardial perfusion reserve index derived from first-pass MRI studies can distinguish between normal subjects and patients with coronary artery disease. Furthermore, it provides useful functional information on coronary lesions, particularly where the physiologic significance cannot be predicted accurately from the angiogram.