Noninvasive study of coronary microcirculation response to a cold pressor test.

BACKGROUND: The aims of this study were to noninvasively (i) assess the coronary microcirculation changes in response to a cold pressor test (CPT) in control subjects, nondiabetic obese patients and patients with type 2 diabetes and (ii) investigate the response of the coronary microcirculation in patients with diabetes according to the presence or the absence of silent myocardial ischaemia (SMI), asymptomatic coronary stenosis (CS) and left ventricle hypertrophy (LVH). METHODS: The mean left anterior descending coronary flow velocity (mCFV) was measured using transthoracic Doppler before and after a CPT in 16 control subjects, 11 obese and 66 asymptomatic diabetic patients with a high cardiovascular risk. Patients with diabetes were screened for SMI using stress myocardial scintigraphy and/or echocardiography. A coronary angiography was performed in those with SMI. RESULTS: At baseline, pressure-rate product (PRP) was correlated with mCFV (r = 0.23; P < 0.05) and left ventricle mass (r = 0.26; P < 0.05) in the whole population. Changes in PRP and mCFV during CPT were correlated with controls (r = 0.58, P < 0.05), obese (r = 0.75, P < 0.01) and diabetic patients without CS (r = 0.56, P < 0.0001) or without LVH (r = 0.63, P < 0.05) but not in diabetic patients with CS or with LVH. In patients with diabetes, SMI was associated with mCFV changes, independent of other parameters (P < 0.05). CONCLUSION: Transthoracic coronary Doppler allows noninvasive study of changes in the coronary microcirculation during CPT. In asymptomatic patients with type 2 diabetes, this method showed that SMI was associated with mCFV changes during CPT and the presence of CS or LVH was associated with a mismatch between coronary microcirculation and myocardial oxygen demand.

Flow-mediated-paradoxical vasoconstriction is independently associated with asymptomatic myocardial ischemia and coronary artery disease in type 2 diabetic patients.

BACKGROUND: To investigate whether flow-mediated dilation (FMD) impairment, which precedes overt atherosclerosis, is associated with silent myocardial ischemia (SMI) and asymptomatic coronary artery disease (CAD) in type 2 diabetes. METHODS: Forearm FMD was measured by ultrasonography in 25 healthy control, 30 non-diabetic overweight or obese patients and 118 asymptomatic type 2 diabetic patients with a high cardiovascular risk profile. SMI (abnormal stress myocardial scintiscan and/or stress dobutamine echocardiogram) and CAD (coronary angiography in the patients with SMI) were assessed in the diabetic cohort. RESULTS: FMD was lower in diabetic patients (median 0.61% (upper limits of first and third quartiles -1.22;3.2)) than in healthy controls (3.95% (1.43;5.25), p < 0.01) and overweight/obese patients (4.25% (1.74;5.56), p < 0.01). SMI was present in 60 diabetic patients, including 21 subjects with CAD. FMD was lower in patients with SMI than in those without (0.12% (-2.3;1.58) vs 1.64% (0;3.69), p < 0.01), with a higher prevalence of paradoxical vasoconstriction (50.0% vs 29.3%, p < 0.05). FMD was also lower in patients with than without CAD (-1.22% (-2.5;1) vs 1.13% (-0.4;3.28), p < 0.01; paradoxical vasoconstriction 61.9% vs 34.4%, p < 0.05). Logistic regression analyses considering the parameters predicting SMI or CAD in univariate analyses with a p value <0.10 showed that paradoxical vasoconstriction (odds ratio 2.7 [95% confidence interval 1.2-5.9], p < 0.05) and nephropathy (OR 2.6 [1.2-5.7], p < 0.05) were independently associated with SMI; and only paradoxical vasoconstriction (OR 3.1 [1.2-8.2], p < 0.05) with CAD. The negative predictive value of paradoxical vasoconstriction to detect CAD was 88.7%. CONCLUSIONS: In diabetic patients, FMD was independently associated with SMI and asymptomatic CAD. TRIAL REGISTRATION: Trial registration number NCT00685984.

Subendocardial viability index is related to the diastolic/systolic time ratio and left ventricular filling pressure, not to aortic pressure: an invasive study in resting humans.

1. The myocardial perfusion relative to left ventricular (LV) workload may be estimated by the subendocardial viability index (SVI). The SVI is a pressure-time integral ratio: the numerator is the area between aortic and LV pressures during diastolic time (DT) and the denominator is the area under the LV pressure curve during systolic time (ST). New non-invasive tonometric devices allow estimation of SVI but neglect LV end-diastolic pressure (LVEDP) in the calculation. The aim of the present study was to determine the haemodynamic correlates of SVI and to test the effects of neglecting LVEDP on SVI estimation. 2. High-fidelity pressures were recorded at rest at the aortic root and LV level in 38 subjects (33 men/five women; mean (+/-SD) age 47 +/- 14 years; nine controls and 29 patients with various cardiac diseases). The SVI (1.16 +/- 0.28) was positively correlated with the DT/ST ratio (1.71 +/- 0.35; r(2) = 0.81) and was negatively correlated with LVEDP (15 +/- 7 mmHg; multiple r(2) = 0.94). The SVI was not related to aortic pressure (mean, pulse, mean systolic, mean diastolic). In 17 patients with LVEDP > 14 mmHg, the SVI calculated assuming zero LVEDP was 33 +/- 15% higher (range 16-70%) than the actual SVI. 3. The DT/ST ratio was the main determinant of the myocardial perfusion relative to cardiac workload and accounted for 81% of SVI variability, whereas aortic pressure did not contribute. Although LVEDP accounted for only 13% of SVI variability, it should be taken into account in the non-invasive calculation of SVI in patients with known or suspected increases in LV filling pressure.

Subendocardial viability ratio estimated by arterial tonometry: a critical evaluation in elderly hypertensive patients with increased aortic stiffness.

1. Increased aortic stiffness predisposes to myocardial ischaemia by increasing the systolic tension-time index and by decreasing aortic pressure throughout diastole. The tonometric subendocardial viability ratio (SEVR) is a non-invasive estimate of myocardial perfusion relative to cardiac workload. The hypothesis that SEVR is impaired in elderly hypertensives with high aortic pulse pressure (PP) was tested in the present study. 2. The SEVR was calculated by radial applanation tonometry in 203 subjects. In addition, diastolic time (DT), systolic time (ST) and mean diastolic and systolic aortic pressures (Pd and Ps, respectively) were calculated. First, 60 subjects matched for age and gender were analysed (20 controls, 20 hypertensives with pulse pressure (PP) < or = 60 mmHg, 20 hypertensives with PP > 60 mmHg; mean (+/-SD) age 64 +/- 9 years; 24 women, 36 men). The remaining 143 subjects, aged 53 +/- 10 years, were analysed subsequently. 3. The SEVR was similar in the three elderly groups (1.39 +/- 0.34, 1.39 +/- 0.28 and 1.35 +/- 0.25, in controls and hypertensive patients with PP < or = 60 and > 60 mmHg, respectively). The SEVR was positively related to DT/ST (r(2) = 0.89) and to DT (r(2) = 0.73) and was negatively related to heart rate (r(2) = 0.56; P < 0.001 each). However, SEVR was not related to ST, PP, mean Pd or mean Ps. At a given DT/ST, SEVR tended to be lower in hypertensives with PP > 60 mmHg than in hypertensives with normal PP. The positive linear relationship between SEVR and DT/ST was confirmed in the remaining 143 subjects (r(2) = 0.90), with no influence of aortic pressure. 4. The tonometric SEVR was not impaired in elderly hypertensive patients with increased aortic stiffness. In resting elderly and middle-aged individuals, the tonometric SEVR was mainly related to DT/ST ratio, not to aortic pressure.

Impaired coronary endothelium-dependent vasodilation is associated with microalbuminuria in patients with type 2 diabetes and angiographically normal coronary arteries.

OBJECTIVE: Microalbuminuria and impaired endothelium-dependent vasodilation are both predictors for cardiac events in patients with type 2 diabetes. The aim of the study was to evaluate whether microalbuminuria correlated with coronary endothelium-dependent vasodilation. RESEARCH DESIGN AND METHODS: We evaluated 84 patients (47 men, mean age 50.5 +/- 5.9 years) with type 2 diabetes for 9.4 +/- 3.4 years, without angiographic coronary stenosis and without major cardiovascular risk factors or other confounding factors, for endothelium investigation. Quantitative coronary angiography was used to assess coronary artery response to cold pressor testing, used to assess endothelium-dependent vasodilation, and to isosorbide dinitrate (endothelium-independent vasodilation). RESULTS: Endothelium-dependent vasodilation differed in the patients with and without microalbuminuria (changes in coronary artery diameter during cold pressor testing: -15.0 +/- 1.9% vs. -10.2 +/- 1.3%, respectively, P < 0.05) and correlated with urinary albumin excretion rate (r = -0.39, P = 0.003), diastolic blood pressure (r = 0.29, P < 0.01), and left ventricular mass index (r = -0.24, P < 0.05). Independent predictors for endothelium-dependent vasodilation were urinary albumin excretion rate (beta -0.04 [95% CI -0.07 to -0.01], P < 0.005) and left ventricular mass index (-0.26 [-0.49 to -0.05], P < 0.05). Endothelium-independent vasodilation was similar in both groups. CONCLUSIONS: Type 2 diabetic patients with microalbuminuria have a more severely impaired coronary endothelium-dependent vasodilation than those with normoalbuminuria. These data suggest a common pathophysiological process for both coronary vasomotor abnormalities and microalbuminuria.

[Microalbuminuria and urinary albumin excretion: clinical practice guidelines]. / Microalbuminurie et excrétion urinaire d'albumine: recommandations pour la pratique clinique.

Measurement of urinary albumin excretion (UAE) may be done on a morning urinary sample or on a 24 hours-urine sample. Values defining microalbuminuria are: 24 hour-urine sample: 30-300 mg/24 hours; morning urine sample: 20-200 mg/ml or 30-300 mg/g creatinine or 2.5-25 mg/mmol creatinine (men) or 3.5-35 mg/mol (women). Timed urine sample: 20-200 microg/min. The optimal use of semi-quantitative urine test-strip is not clearly defined. It is generally believed that microalbuminuria reflects a generalized impairment of the endothelium; however, no definite proof has been shown in humans. IN DIABETIC SUBJECTS: Microalbuminuria is a marker of increased risk of cardiovascular (CV) and renal morbidity and mortality in type 1 and type 2 diabetic subjects. The increase in UAE during follow-up is also a marker of CV and renal risk in type 1 and type 2 diabetic subjects; its decrease during follow-up is associated with lower risks. IN NO DIABETIC SUBJECTS: Microalbuminuria is a marker of increased risk for diabetes mellitus, deterioration of the renal function, CV morbidity and all-cause mortality. It is a marker of increased risk for the development of hypertension in normotensive subjects, and is associated with unfavorable outcome in patients with cancer and lymphoma. Persistence or elevation of UAE overtime is associated with deleterious outcome in some hypertensive subjects. Measurement of UAE may be recommended in hypertensive subjects with one or two CV risk factors in whom CV risk remains difficult to assess, and in those with refractory hypertension: microalbuminuria indicates a high CV risk and must lead to strict control of arterial pressure. Studies focused on microalbuminuria in non-diabetic non-hypertensive subjects are limited; most of them suggest that microalbuminuria predicts CV complications and deleterious outcome as it is in diabetic or hypertensive subjects. Subjects with a history of CV or cerebrovascular disease have an even greater CV risk if microalbuminuria is present than if it is not; however, in all cases, therapeutic intervention must be aggressive regardless of whether microalbuminuria is present or not. It is not recommended to measure UAE in non-diabetic non-hypertensive subjects in the absence of history of renal disease. Monitoring of renal function (UAE, serum creatinine and estimation of GFR) is annually recommended in all subjects with microalbuminuria. MANAGEMENT: In patients with microalbuminuria, weight reduction, sodium restriction (<6 g/day), smoking cessation, strict glucose control in diabetic subjects, strict arterial pressure control are necessary; in diabetic subjects: use of maximal doses of ACEI or ARB are recommended; ACEI/ARB and thiazides have synergistic actions on arterial pressure and reduction of UAE; in non diabetic subjects, any of the five classes of antihypertensive medications (ACEI, ARB, thiazides, calcium channel blockers or betablockers) can be used.

Influence of critical closing pressure on systemic vascular resistance and total arterial compliance: A clinical invasive study.

BACKGROUND: Systemic vascular resistance (SVR) and total arterial compliance (TAC) modulate systemic arterial load, and their product is the time constant (Tau) of the Windkessel. Previous studies have assumed that aortic pressure decays towards a pressure asymptote (P∞) close to 0mmHg, as right atrial pressure is considered the outflow pressure. Using these assumptions, aortic Tau values of ∼1.5seconds have been documented. However, a zero P∞ may not be physiological because of the high critical closing pressure previously documented in vivo. AIMS: To calculate precisely the Tau and P∞ of the Windkessel, and to determine the implications for the indices of systemic arterial load. METHODS: Aortic pressure decay was analysed using high-fidelity recordings in 16 subjects. Tau was calculated assuming P∞=0mmHg, and by two methods that make no assumptions regarding P∞ (the derivative and best-fit methods). RESULTS: Assuming P∞=0mmHg, we documented a Tau value of 1372±308ms, with only 29% of Windkessel function manifested by end-diastole. In contrast, Tau values of 306±109 and 353±106ms were found from the derivative and best-fit methods, with P∞ values of 75±12 and 71±12mmHg, and with ∼80% completion of Windkessel function. The "effective" resistance and compliance were ∼70% and ∼40% less than SVR and TAC (area method), respectively. CONCLUSION: We did not challenge the Windkessel model, but rather the estimation technique of model variables (Tau, SVR, TAC) that assumes P∞=0. The study favoured a shorter Tau of the Windkessel and a higher P∞ compared with previous studies. This calls for a reappraisal of the quantification of systemic arterial load.

Coronary microvascular adaptation to myocardial metabolic demand can be restored by inhibition of iron-catalyzed formation of oxygen free radicals in type 2 diabetic patients.

Dilation of coronary vessels is impaired in diabetic patients when myocardial metabolic demand is increased. Deferoxamine (DFX) restores a normal dilation of epicardial coronary arteries. To assess the effects of DFX on metabolic coronary microvascular dilation in type 2 diabetic patients, coronary blood flow was measured using intracoronary Doppler and quantitative angiography in 17 type 2 diabetic patients with normal coronary arteries and without any other coronary risk factors. Measurements were made at baseline and during a cold pressor test (CPT), before and after intravenous administration of DFX. With a similar rate-pressure product (RPP) increase during CPT before and after DFX (+21.1 +/- 8.7 vs. +20.5 +/- 8.9%, respectively), coronary blood flow increase was significantly enhanced after DFX (+31.8 +/- 16.7 vs. +6.3 +/- 12.9% before DFX, P < 0.001). Moreover, coronary resistance increased during CPT before DFX and decreased after DFX (+14.8 +/- 21.9 vs. -7.9 +/- 10.9%, respectively, P < 0.001). Lastly, the negative relationship between coronary blood flow and RPP before DFX (R = 0.546, P < 0.05) was changed in a positive relationship after DFX (R = 0.518, P < 0.05). In conclusion, in type 2 diabetic patients, inhibition of iron-catalyzed oxidative reactions by DFX restored dilation of the coronary microcirculation and a normal matching between myocardial metabolic demand and coronary blood flow.

Cardiovascular outcome of patients with abnormal coronary vasomotion and normal coronary arteriography is worse in type 2 diabetes mellitus than in arterial hypertension: a 10 year follow-up study.

Diabetes and arterial hypertension are major cardiovascular risk factors. Coronary endothelial dysfunction is frequently observed in diabetic and hypertensive patients. This study was designed to compare cardiovascular outcome of hypertensive (HT) and type 2 diabetic patients (D2) with angiographically normal coronary arteries on the basis of their epicardial coronary endothelial function. Coronary reactivity assessment by cold-pressor test (CPT) using quantitative coronary angiography was achieved in 65 HT (45 males, 20 females) aged 51.9+/-7.6 years, and in 59 D2 (32 males, 27 females) aged 48.9+/-7.3 years, with angiographically normal coronary arteries and without other major coronary risk factor. Cardiovascular events (CVE) were recorded with a mean follow-up of 108+/-15 months in HT, and 113+/-10 months in D2. During CPT, in HT coronary artery dilation occurred in 10.8% of the patients, no change in 21.5%, and constriction in 67.7%. In D2, dilation occurred in 3.4% of the patients, no change in 18.6%, and constriction in 78.0%. During follow-up, in HT there were nine CVE in 6/65 patients (9.2%), all in the 6/44 (13.6%) patients with coronary artery constriction. In D2, there were 18 CVE in 16/59 patients (27.1%, P<0.01 versus HT), with 17 CVE in the 15/46 patients with coronary artery constriction, and one CVE in the 1/13 patients without constriction (32.6% versus 7.7%). In patients with coronary artery constriction, CVE were more frequent in D2 than in HT (P<0.05). Last, CVE were more severe and occurred earlier in D2 than in HT. In conclusion, epicardial coronary endothelial dysfunction is predictive of long-term CVE in HT and D2 with angiographically normal coronary arteries. Cardiovascular outcome of patients with coronary constriction is worse in D2 than in HT. At the opposite, patients without constriction have good cardiovascular prognosis in both subgroups.

Mean aortic pressure is the geometric mean of systolic and diastolic aortic pressure in resting humans.

The aim of our study was twofold: 1) to establish a mathematical link between mean aortic pressure (MAP) and systolic (SAP) and diastolic aortic pressures (DAP) by testing the hypothesis that either the geometric mean or the harmonic mean of SAP and DAP were reliable MAP estimates; and 2) to critically evaluate three empirical formulas recently proposed to estimate MAP. High-fidelity pressures were recorded at rest at the aortic root level in controls (n = 31) and in subjects with various forms of cardiovascular diseases (n = 108). The time-averaged MAP and the pulse pressure (PP = SAP - DAP) were calculated. The MAP ranged from 66 to 160 mmHg [mean = 107.9 mmHg (SD 18.2)]. The geometric mean, i.e., the square root of the product of SAP and DAP, furnished a reliable estimate of MAP [mean bias = 0.3 mmHg (SD 2.7)]. The harmonic mean was inaccurate. The following MAP formulas were also tested: DAP + 0.412 PP (Meaney E, Alva F, Meaney A, Alva J, and Webel R. Heart 84: 64, 2000), DAP + 0.33 PP + 5 mmHg [Chemla D, Hébert JL, Aptecar E, Mazoit JX, Zamani K, Frank R, Fontaine G, Nitenberg A, and Lecarpentier Y. Clin Sci (Lond) 103: 7-13, 2002], and DAP + [0.33 + (heart rate x 0.0012)] PP (Razminia M, Trivedi A, Molnar J, Elbzour M, Guerrero M, Salem Y, Ahmed A, Khosla S, Lubell DL. Catheter Cardiovasc Interv 63: 419-425, 2004). They all provided accurate and precise estimates of MAP [mean bias = -0.2 (SD 2.9), -0.3 (SD 2.7), and 0.1 mmHg (SD 2.9), respectively]. The implications of the geometric mean pressure strictly pertained to the central (not peripheral) level. It was demonstrated that the fractional systolic (SAP/MAP) and diastolic (DAP/MAP) pressures were reciprocal estimates of aortic pulsatility and that the SAP times DAP product matched the total peripheral resistance times cardiac power product. In conclusion, although the previously described thumb-rules applied, the "geometric MAP" appears more valuable as it established a simple mathematical link between the steady and pulsatile component of aortic pressure.

Prognostic value of epicardial coronary artery constriction to the cold pressor test in type 2 diabetic patients with angiographically normal coronary arteries and no other major coronary risk factors.

OBJECTIVE: Endothelium-dependent coronary dilation is impaired in diabetic patients and has been found to independently predict cardiovascular events (CVEs) in patients with multiple coronary risk factors. The aim of this study was to evaluate the outcome of type 2 diabetic patients on the basis of epicardial coronary dysfunction. RESEARCH DESIGN AND METHODS: We examined 56 control subjects (aged 51.7 +/- 6.4 years) using coronary artery response to the cold pressor test (quantitative coronary angiography) and compared them with 72 type 2 diabetic patients (aged 50.3 +/- 8.5 years) without other major coronary risk factors. RESULTS: Average diameter change was 17.2 +/- 10.4% in the control subjects, dilation occurred in 91.1% of subjects, no change occurred in 8.9%, and there was no constriction. Average diameter change was -14.4 +/- 12.1% in diabetic patients (P < 0.001 vs. control subjects), constriction occurred in 73.6%, no change occurred in 26.4%, and there was no dilation. CVEs were recorded with a mean follow-up of 45 +/- 19 months. There was 1 CVE in the control group and 26 CVEs in 18 of 72 diabetic patients (P < 0.001 vs. control subjects), with 23 events in 16 of 53 diabetic patients with coronary artery constriction (P < 0.001 vs. control subjects), and 3 events in 2 of 19 diabetic patients with no diameter change (NS vs. control subjects). CONCLUSIONS: In type 2 diabetic patients without other major coronary risk factors, constriction of angiographically normal coronary arteries to the cold pressor test is predictive of long-term CVEs.

Epicardial coronary artery constriction to cold pressor test is predictive of cardiovascular events in hypertensive patients with angiographically normal coronary arteries and without other major coronary risk factor.

Epicardial coronary endothelial dysfunction independently predicts cardiovascular events in patients with coronary risk factors. This study was designed to evaluate outcome of hypertensive patients on the basis of their epicardial coronary function assessed by cold pressor test (CPT). Control subjects (n = 68, 48.8 +/- 7.6 years) and hypertensive patients (n = 83, 51.3 +/- 7.9 years) with angiographically normal coronary arteries and without other major coronary risk factor underwent epicardial coronary reactivity assessment to CPT using quantitative angiography. Cardiovascular events were recorded with a mean follow-up of 115 months (range 84-132). In control subjects, dilation occurred in 88.2%, no change in 11.8% (mean diameter change: +14.6 +/- 9.3%). In hypertensive patients, dilation occurred in 13.3%, no change in 25.3% (mean diameter change for both: +10.9 +/- 11.2%), and constriction in 61.4% (mean diameter change: -12.7 +/- 3.4%). Endothelium-independent dilation was normal in control subjects and hypertensive patients. In control subjects, there were three cardiovascular events in two subjects (2.9%). In hypertensive patients, there were 17 cardiovascular events in 12 patients (14.5%, P < 0.01 versus control subjects), with 15 cardiovascular events in the 10/51 patients (19.6%) with coronary artery constriction, and two cardiovascular events in the 2/32 patients (6.3%) with no change or dilation (P < 0.05). In conclusion, in hypertensive patients with angiographically normal coronary arteries and without other major coronary risk factors, epicardial coronary artery dysfunction assessed by the cold pressor test is predictive of long-term cardiovascular events.

Should flow-volume loop be monitored in sleep apnea patients treated with continuous positive airway pressure?

Nasal continuous positive airway pressure (nCPAP) has been widely established in the treatment of obstructive sleep apnea syndrome (OSAS). However, only few studies have evaluated long-term effects of this treatment on lung function. This study assesses the effect of nCPAP on lung function parameters and response to bronchodilators in 50 OSAS patients. Spirometry and arterial blood gas measurements were performed before starting nCPAP and after 16.8 +/- 8 months of treatment. Of the 50 study patients (55 +/- 12 years, with an apnea/hypopnea index of 47 +/- 34h(-1)), 15 had asthma, 13 had chronic obstructive pulmonary disease (COPD) and 22 had no obstructive airway disease (NOAD). In the entire population, significant decreases in FEF50 (from 69 +/- 38% to 61 +/- 30%, P < 0.005), FEF25 (from 53 +/- 34% to 46 +/- 28%, P < 0.05) and FEF25-75 (from 65 +/- 33% to 57 +/- 27%, P < 0.005) were observed after treatment. No impairment of lung function was found in COPD and asthmatic patients. In contrast, lung function was changed in the NOAD group where FEF50, FEF25 and FEF25-75 as well as FEV1 and FEV1/VC ratio were significantly reduced. Moreover, bronchial hyperresponsiveness occurred in five of 22 patients of this group. These results suggest that tolerance of nCPAP should be handled by long-term follow-up of flow-volume loops.