Relation between C reactive protein concentrations and coronary microvascular endothelial function.

OBJECTIVE: To determine how C reactive protein (CRP), a sensitive marker of inflammation, is related to coronary endothelial function. DESIGN: Changes in quantitative coronary angiographic findings and Doppler flow velocity measurements in response to locally infused acetylcholine were assessed. SETTING: Tertiary cardiology centre. PATIENTS: 46 patients with angiographically normal coronary arteries were divided into groups with normal (< or = 3 mg/l) or increased (> 3 mg/l) CRP concentrations. INTERVENTIONS: Acetylcholine (3 and 30 microg/min) was infused into the left coronary ostium for two minutes. MAIN OUTCOME MEASURES: Percentage change in diameter of epicardial coronary arteries and coronary blood flow (CBF) in response to acetylcholine; and correlations between these parameters and serum CRP concentrations. RESULTS: 15 patients had increased CRP concentrations. The change in coronary artery diameter induced by acetylcholine infusion was similar between the groups but the increase in CBF induced by acetylcholine was smaller in patients with increased CRP concentrations (54.9% v 139.4% with acetylcholine 30 microg/min, p = 0.0030). Multivariate analysis identified increased CRP concentration as independently associated with attenuated CBF response to acetylcholine at 30 microg/min (p = 0.0078, R2 = 0.434). CONCLUSIONS: These findings suggest that inflammation appears to be associated with impaired coronary endothelial function in resistance but not conduit vessels. The data suggest a close relation between chronic vascular inflammation and endothelial dysfunction in atherosclerosis.

Tetrahydrobiopterin restores endothelial function of coronary arteries in patients with hypercholesterolaemia.

OBJECTIVE: To examine the effect of tetrahydrobiopterin (BH4), an essential cofactor for nitric oxide synthase, on coronary artery endothelial function in hypercholesterolaemic patients. DESIGN: Quantitative coronary angiography and Doppler flowmetry were used to examine the effects of intracoronary infusion of BH4 on vascular response to acetylcholine (ACh). SETTING: Tertiary cardiology centre. PATIENTS: 18 patients with angiographically normal coronary arteries, of whom nine had hypercholesterolaemia and nine had noromocholesterolaemia. INTERVENTIONS: ACh (3 and 30 microg/min) was infused for two minutes into the left coronary ostium. ACh was then simultaneously infused with BH4 (1 mg/min) before and after infusion of L-N(G)-monomethyl-L-arginine (L-NMMA) (40 micromol/min for five minutes). MAIN OUTCOME MEASURES: Diameter of the epicardial coronary arteries and coronary blood flow. RESULTS: In hypercholesterolaemic patients, BH4 attenuated the ACh induced decrease in coronary diameter (p < 0.05) and restored the ACh induced increase in coronary blood flow (p < 0.05). In normocholesterolaemic patients, BH4 did not affect the ACh induced changes in coronary diameter or coronary blood flow. In both groups, L-NMMA decreased the baseline coronary diameter (p < 0.05) and baseline coronary blood flow (p < 0.05). In hypercholesterolaemic patients, L-NMMA inhibited both the BH4 mediated attenuation of the ACh induced decrease in coronary diameter (p < 0.05) and the BH4 mediated enhancement of the ACh induced increase in coronary blood flow (p < 0.01). CONCLUSIONS: Intracoronary infusion of BH4 restores coronary endothelial function by improving the bioavailability of endothelium derived nitric oxide in hypercholesterolaemic patients.

Usefulness of flow-mediated dilation of the brachial artery and/or the intima-media thickness of the carotid artery in predicting coronary narrowing in patients suspected of having coronary artery disease.

It has been reported that flow-mediated dilation (FMD) of the brachial artery and the carotid intima-media thickness (IMT), markers of atherosclerosis, are altered in patients with coronary artery disease (CAD), but it is still not known if the presence of CAD can be detected using these markers. We examined whether the presence of CAD can be detected by FMD of the brachial artery and/or IMT. Eighty-one patients who underwent coronary angiography for the first time were enrolled. In each patient, brachial artery diameter responses to FMD and the administration of nitroglycerin spray, and carotid IMT were measured using high-resolution ultrasound (10 MHz) before coronary angiography. CAD was defined as >50% stenosis of a major coronary artery. Fifty-six patients had CAD. FMD was lower and IMT was greater in patients with CAD (FMD, 2.9 +/- 0.2% vs 9.4 +/- 0.5%; IMT, 1.09 +/- 0.05 vs 0.79 +/- 0.04 mm, both p <0.0001). Nitroglycerin-induced dilation did not differ in the 2 groups. Multivariate analysis showed that FMD was the only predictor of the presence of CAD (p = 0.0026). Receiver-operating characteristic analysis demonstrated that a cutoff value for FMD for detecting the presence of CAD was 6%, with a sensitivity of 0.93 (52 of 56) and a specificity of 0.88 (22 of 25). These findings suggest that FMD but not IMT may be used to detect the presence of CAD in patients with suspected CAD.

Endothelial dysfunction is an independent factor responsible for vasospastic angina.

In order to evaluate peripheral endothelial function in patients with vasospastic angina (VSA), we measured flow-mediated dilation (FMD) of the brachial artery in patients with VSA and compared it with FMD in patients without VSA. Endothelial dysfunction is considered one of the mechanisms underlying VSA. However, its exact role remains to be clarified. The study included 30 patients with positive spasm-provocational test results without evidence of significant coronary stenosis (VSA group) and 30 patients with negative spasm-provocational test results without evidence of significant coronary stenosis (control group). In each patient, brachial artery diameter responses to hyperemic flow and glyceryl trinitrate spray were measured using high-resolution ultrasound. The carotid intima-media thickness was also measured as a marker of systemic atherosclerosis. FMD was lower in the VSA group (4.8+/-0.5%) compared with the control group (9.4+/-0.7%, P<0.0001). In the VSA group, FMD was not affected by coronary risk factors or the presence of atherosclerotic changes on coronary angiography. Glyceryl trinitrate-induced dilation did not differ between the two groups. The intima-media thickness was comparable between the VSA (0.85+/-0.04 mm) and control groups (0.81+/-0.05 mm). These findings indicated that peripheral endothelial function is impaired only in the VSA group, whereas the atherosclerotic changes were similar in the two groups. We conclude that endothelial dysfunction may be an independent factor responsible for the development of VSA.

Magnesium causes nitric oxide independent coronary artery vasodilation in humans.

OBJECTIVE: To determine how magnesium affects human coronary arteries and whether endothelium derived nitric oxide (EDNO) is involved in the coronary arterial response to magnesium. DESIGN: Quantitative coronary angiography and Doppler flow velocity measurements were used to determine the effects of the nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA) on magnesium induced dilation of the epicardial and resistance coronary arteries. SETTING: Hiroshima University Hospital a tertiary cardiology centre. PATIENTS: 17 patients with angiographically normal coronary arteries. INTERVENTIONS: Magnesium sulfate (MgSO(4)) (0.02 mmol/min and 0.2 mmol/min) was infused for two minutes into the left coronary ostium before and after intracoronary infusion of L-NMMA. MAIN OUTCOME MEASURES: Diameter of the proximal and distal segments of the epicardial coronary arteries and coronary blood flow. RESULTS: At a dose of 0.02 mmol/min, MgSO(4) did not affect the coronary arteries. At a dose of 0.2 mmol/min, MgSO(4) caused coronary artery dilation (mean (SEM) proximal diameter 3.00 (0.09) to 3.11 (0.09) mm; distal 1.64 (0.06) to 1.77 (0.07) mm) and increased coronary blood flow (79.3 (7.5) to 101.4 (9.9) ml/min, p < 0.001 v baseline for all). MgSO(4) increased the changes in these parameters after the infusion of L-NMMA (p < 0.001 v baseline). CONCLUSIONS: Magnesium dilates both the epicardial and resistance coronary arteries in humans. Furthermore, the coronary arterial response to magnesium is dose dependent and independent of EDNO.

The preventive effect of magnesium on coronary spasm in patients with vasospastic angina.

STUDY OBJECTIVES: Previous studies have reported that magnesium (Mg) deficiency is associated with coronary spasm. However, little is known about the preventive effect of Mg on coronary spasm. The present study investigated whether Mg prevents coronary spasm in patients with vasospastic angina (VSA). DESIGN: Effectiveness trial. SETTING: University medical center. PATIENTS: Twenty-two patients with VSA. INTERVENTION: Coronary spasm was induced with an intracoronary infusion of acetylcholine (Ach). After spontaneous relief of the coronary spasm, Mg sulfate (0.27 mmol/kg body weight) was infused IV over 20 min in 14 patients and isotonic glucose was infused in 8 patients as control subjects. Intracoronary infusion of Ach was then repeated, and the diameter of the coronary arteries was measured quantitatively. MEASUREMENTS AND RESULTS: Mg infusion caused coronary artery dilatation at baseline in both the spastic (5. 9 +/- 2.3%) and nonspastic segments (5.5 +/- 1.5%). Mg infusion reduced the severity of chest pain and ST-segment deviations during coronary spasm. After the Mg infusion, the percent change in the diameter of the spastic segments improved from - 62.8 +/- 2.6% to - 43.7 +/- 4.7% during coronary spasm. Overall, 10 of 14 patients (71%) responded favorably to Mg infusion. Isotonic glucose infusion did not elicit changes in chest pain severity, ST-segment deviations, or the diameter of the coronary arteries during spasm. CONCLUSIONS: Mg infusion produces nonsite-specific basal coronary dilatation and suppresses Ach-induced coronary spasm in patients with VSA.

The role of nitric oxide in bradykinin-induced dilation of coronary resistance vessels in patients with hypercholesterolemia.

OBJECT: In hypercholesterolemic patients, acetylcholine- and substance P-mediated endothelium-dependent dilation of the coronary resistance vessels is impaired due to decreased nitric oxide production. However, it is not clear if bradykinin-induced coronary vasodilation is impaired in these patients. We investigated whether the endothelium-dependent dilation of coronary resistance vessels mediated by bradykinin is impaired in patients with hypercholesterolemia and, if so, whether this impairment is caused by a decreased production of nitric oxide. METHODS: We examined the coronary vascular responses to acetylcholine and bradykinin. The vascular responses to bradykinin were also assessed after N(G)-monomethyl-L-arginine was infused to inhibit nitric oxide production. Drugs were infused into the left coronary ostium and coronary blood flow (CBF) and coronary vascular resistance were evaluated by quantitative angiography and Doppler flow velocity measurements. PATIENTS: Twelve hypercholesterolemic patients and 11 control patients with angiographically normal coronary arteries were studied. RESULTS: The vasodilator responses to acetylcholine and bradykinin were reduced in hypercholesterolemic patients compared with control patients (p<0.005 and p<0.04, respectively, by two-way analysis of variance (ANOVA)). The CBF responses to acetylcholine and bradykinin were significantly correlated (r=0.56; p<0.01). Bradykinin-induced dilation was similar in hypercholesterolemic patients and control patients after inhibition of nitric oxide. CONCLUSION: These results suggest that the bradykinin-mediated endothelium-dependent dilation of coronary resistance vessels may be impaired due to depressed nitric oxide production in patients with hypercholesterolemia.

Adenosine 5'-triphosphate induced dilation of human coronary microvessels in vivo.

OBJECT: This study was performed to compare the coronary microvascular response to adenosine 5'-triphosphate (ATP) with the response to adenosine in humans. METHODS: Coronary blood flow velocity was determined using a Doppler flow wire. After intracoronary nitroglycerin infusion, intracoronary bolus injections of adenosine (20 microg) and ATP (20 microg) were performed to induce reactive hyperemia. PATIENTS: Twenty-nine patients (23 men and 6 women, mean age: 63+/-9 years) with coronary artery disease and risk factors for coronary atherosclerosis were studied. RESULTS: Coronary flow reserve in response to ATP was similar to that for adenosine (2.7+/-0.7 vs. 2.7+/-0.7). However, the duration of ATP-induced vasodilation was longer than that of adenosine-induced dilation (39+/-25 seconds vs. 26+/-12 seconds, p<0.0001). The coronary flow reserve obtained with either ATP or adenosine was significantly reduced in the interventioned arteries compared with non-stenosed arteries. The coronary flow reserve obtained with ATP was similar to that obtained with adenosine in both artery groups. The duration of the vasodilator effect of ATP was significantly greater than that of adenosine in both artery groups. CONCLUSION: These results suggest that ATP induces maximal dilation of coronary microvessels, most likely through an endothelium-independent mechanism. The degradation of ATP to adenosine 5'-monophosphate (AMP) and adenosine, as well as the direct action of ATP on A2-adenosine receptors may be responsible for the dilation. We conclude that coronary flow reserve can be determined safely with intracoronary ATP administration.

Idiopathic verapamil-sensitive left ventricular tachycardia complicated by right ventricular outflow tract ventricular tachycardia and ventricular fibrillation.

Idiopathic ventricular tachycardias (VTs) are generally divided into those arising from the right ventricle and those arising from the left ventricle. There has been few reports of two morphologically distinct VT occurring in patients with no apparent structural heart disease. We report a patient with verapamil-sensitive left VT with a right bundle branch block pattern that spontaneously changed to VT with a left bundle branch block pattern. Ventricular fibrillation was induced by the application of programmed stimulation. Although it is unclear if our patient with pleomorphic VT has ventricular vulnerability, it is necessary to investigate further and follow him carefully.

Assessment of the severity of coronary artery stenosis by the ratio of the regional washout rate determined by adenosine triphosphate stress Tl-201 SPECT.

BACKGROUND: Adenosine triphosphate stress thallium-201 single-photon emission computed tomography (ATP SPECT) is useful for diagnosis of coronary artery disease, but its usefulness for evaluating the severity of coronary artery stenosis has not been established. METHODS AND RESULTS: We performed region-of-interest analysis of short-axis images obtained by ATP SPECT in 31 patients with single-vessel disease (>50% stenosis of the luminal diameter). We selected the lowest and highest washout rates (WR) among the anterior, lateral, and inferior WRs and calculated the ratio of the lowest WR to the highest WR (WR ratio = 0.925+/-0.027 in 14 control subjects). ATP SPECT showed positive results in 29 (94%) of 31 patients. The severity of coronary artery stenosis was inversely correlated with the WR ratio (r = -0.703, P < .0001). The sensitivity and specificity of a WR ratio < or = 0.660 for the diagnosis of severe coronary stenosis (> or =80% stenosis) were 83% and 80%, respectively. CONCLUSIONS: Results suggest that ATP SPECT may be useful for assessment of the severity of coronary artery stenosis in patients with single-vessel disease.

[Magnesium (Mg) status in patients with cardiovascular diseases].

Mg is the fourth most abundant total cation in the human body and the second most abundant intracellular cation. Moreover, Mg is an important cofactor for many enzymes especially those involved in phosphate transfer reactions. Mg is therefore essential in the regulation of the metabolism of other ions and cellular functions. Mg deficiency has been shown to be associated with fatal cardiovascular diseases such as cardiac arrhythmias and coronary heart disease, as well as with risk factors for these diseases, such as hypertension, and diabetes mellitus. Clinical evaluation of Mg status has been limited by the lack of suitable technology for measuring this cation. Although the measurement of serum total Mg is routinely available, ionized Mg is physiologically active. Furthermore, most of the body's Mg is present in the intracellular space. Our findings showed that serum total Mg was similar in all groups, but patients with arrhythmias and diabetes mellitus revealed lower levels of serum ionized Mg. On the other hand, patients with essential hypertension exhibited higher intraerythrocyte Mg concentrations than healthy controls. The measurement of serum total Mg may obscure the diagnosis of an abnormality in Mg metabolism in patients with arrhythmias and diabetes mellitus. Furthermore, the intracellular accumulation of Mg does not support the hypothesis of Mg deficiency in patients with essential hypertension.

Relation between QT dispersion and adenosine triphosphate stress thallium-201 single-photon emission computed tomographic imaging for detecting myocardial ischemia and scar.

It is not known if QT dispersion is useful for detecting coronary artery disease. We investigated whether QT dispersion at baseline and during adenosine triphosphate (ATP) infusion correlate with the imaging patterns obtained from ATP stress thallium-201 single-photon emission computed tomography (ATP-SPECT). QT dispersion was determined in 169 patients who underwent ATP-SPECT from 12-lead electrocardiograms obtained at baseline and 3 minutes after the beginning of ATP infusion. Based on the results of ATP-SPECT, patients were divided into 4 groups: normal (n = 55), ischemia (n = 38), ischemia and scar (n = 42), and scar (n = 34). Baseline QT dispersions (mean +/- SD) in the normal, ischemia, ischemia and scar, and scar groups were 48 +/- 15, 50 +/- 17, 69 +/- 25, and 70 +/- 24 ms, respectively. Baseline QT dispersion was significantly greater in the groups with myocardial scar. QT dispersions during ATP infusion were 43 +/- 16, 63 +/- 20, 76 +/- 20, and 62 +/- 25 ms in the normal, ischemia, ischemia and scar, and scar groups, respectively. QT dispersion increased with ATP infusion in patients with myocardial ischemia. QT dispersion at baseline and during ATP infusion correlated with the ATP-SPECT imaging pattern. These findings suggest that baseline QT dispersion and ATP-induced changes in QT dispersion may help detect the presence of myocardial ischemia and scar.

Vasomotility and nitric oxide bioactivity of the bridging segments of the left anterior descending coronary artery.

We compared bridging and nonbridging coronary artery segments with respect to the vasoconstrictor effect of acetylcholine. Bridging segments were hypersensitive to the constrictor effect of acetylcholine, and results suggest that the effect of nitric oxide on the acetylcholine-stimulated condition is decreased, or that the smooth muscle sensitivity to acetylcholine is increased.

Portal-hepatic venous shunt through a portal aneurysm complicated by hepatic encephalopathy and pulmonary hypertension.

We report a rare case of portal-hepatic venous shunt through an enormous portal aneurysm complicated by pulmonary hypertension. A 66-year-old woman was admitted to our hospital for hepatic encephalopathy. Chest roentgenography revealed pulmonary hypertension. Computed tomography and ultrasound examination demonstrated a shunt between the portal and hepatic veins through an enormous portal aneurysm. The diagnoses of portal-hepatic venous shunt and pulmonary hypertension were confirmed by hepatic venous catheterization and cardiac catheterization. Pulmonary hypertension might result from the effects of vasoconstrictive agents, which should be metabolized by the liver in normal subjects, passing through the intrahepatic shunt into the lung.

Adverse effects of interferon on the cardiovascular system in patients with chronic hepatitis C.

The therapeutic effects of interferon in chronic hepatitis C and many of its adverse effects have been well documented. However, there are only a few reports regarding its adverse effects on the cardiovascular system. The aim of this study was to clarify the clinical features of the adverse effects of interferon on the cardiovascular system in patients with chronic hepatitis C. We monitored 295 patients with chronic active hepatitis C during 312 courses of interferon therapy and for 1 year after the end of treatment for the presence of cardiovascular adverse effects. We found 6 patients with cardiovascular adverse effects during interferon therapy and 4 more patients within 1 year after the end of therapy (10/312, 3.2%). The adverse effects of interferon on the cardiovascular system included arrhythmia (n = 4), ischemic heart disease (n = 4) and myocardial disease (n = 2). None of the clinical factors, including history of cardiovascular disease, were related to these cardiovascular adverse effects. In all instances the patient's condition improved after discontinuation of interferon and adequate therapy. The cardiovascular adverse effects of interferon occurred frequently in patients with chronic hepatitis C, even after the end of therapy and they were unpredictable. Thus, all patients undergoing interferon therapy should be monitored not only during but also after the end of treatment.

Sarcoidosis after interferon therapy for chronic active hepatitis C.

Sarcoidosis is characterized by multisystemic granulomatous lesions of unknown etiology. A 62-year-old woman developed sarcoidosis after treatment with alpha-2a interferon (IFN) for 24 weeks (total dose: 522 million units) for chronic hepatitis C. She developed complete atrioventricular block and multiple noncaseating granulomatous lesions in the lung. IFN therapy, which may disturb cellular immune activation in some patients, may have contributed to the onset and progression of sarcoidosis.

Cardiogenic shock following recombinant alpha-2b interferon therapy for chronic hepatitis C. A case report.

A 57-year-old woman with chronic hepatitis C was treated with alpha-2b interferon (IFN). Forty-five days after the initiation of IFN therapy, she developed cardiogenic shock. Acute perimyocarditis as a cause of cardiogenic shock was clinically suspected by the findings of complete atrioventricular block, regional wall motion abnormality and pericardial effusion. Since IFN therapy may induce cardiogenic shock in some patients, it is important to carefully monitor patients under treatment with IFN for abnormal cardiac signs.

Short- and mid-term follow-up results after percutaneous transvenous mitral commissurotomy.

This study reports the clinical follow-up for 6 months of 52 patients who underwent percutaneous transvenous mitral commissurotomy (PTMC). PTMC resulted in an increase in mitral valve area from 1.1 +/- 0.3 to 1.7 +/- 0.4 cm2 (p < 0.0001), a decrease in mean left atrial pressure from 16 +/- 7 to 13 +/- 5 mmHg (p < 0.0001), and an increase in exercise time from 4.6 +/- 2.1 to 6.3 +/- 2.3 min (p < 0.0001). At 6 months follow-up, mitral valve area was unchanged (1.7 +/- 0.4 cm2). Of 52 patients, 33 showed clinical improvement and 19 had no clinical improvement after PTMC. Univariate analysis showed (1) younger age, (2) echocardiographic score of 8 or less, (3) existence of mitral regurgitation of less than grade 2 after PTMC, and (4) amelioration in left atrial dimension, mean pulmonary artery pressure and exercise time after PTMC as correlative factors for clinical improvement. In conclusion, PTMC was an effective procedure for mitral stenosis, especially in younger patients with an echocardiographic score of 8 or less. Change in left atrial dimension was a good indicator of the effectiveness of PTMC.