Balloon pulmonary angioplasty under awake veno-arterial extracorporeal membrane oxygenation in a patient with class III obesity with chronic thromboembolic pulmonary hypertension complicated with multiple serious comorbidities.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a chronic disease that can rapidly deteriorate into circulatory collapse when complicated by comorbidities. We herein describe a case involving a 43-year-old woman with class III obesity (body mass index of 63 kg/m2) and severe CTEPH associated with total occlusion of the left main pulmonary artery who subsequently developed circulatory collapse along with multiple comorbidities, including acute kidney injury, pulmonary tuberculosis, and catastrophic antiphospholipid syndrome. The patient was successfully treated with two sessions of rescue balloon pulmonary angioplasty with veno-arterial extracorporeal membrane oxygenation (V-A ECMO) support under local anesthesia without sedation, at cannulation and during the V-A ECMO run, to avoid invasive mechanical ventilation. This case suggests the potential usefulness of rescue balloon pulmonary angioplasty under awake V-A ECMO support for rapidly deteriorating, inoperable CTEPH in a patient with class III obesity complicated with multiple comorbidities.

Balloon Pulmonary Angioplasty for Takayasu Arteritis and Peripheral Pulmonary Artery Stenosis Mimicking Chronic Thromboembolic Pulmonary Hypertension.

Balloon pulmonary angioplasty (BPA) has been reported to be effective and safe to an acceptable level in patients with distal-type, inoperable chronic thromboembolic pulmonary hypertension (CTEPH), resulting in improved long-term survival. However, evidenced treatment options and strategy including medical therapy of antithrombotic therapy, glucocorticoids, immunosuppressants, and pulmonary hypertension (PH)-specific therapies are scarce in patients with significant PH and right heart failure associated with Takayasu arteritis and peripheral pulmonary artery stenosis, both of which mimic CTEPH. Moreover, there has been still concern on safety and lack of established methodology in performing BPA for these conditions. In this report, we would like to review recent publications including several case reports and discuss the efficacy, safety, and suitable methods of BPA in this population.

Predictors of recurrence of atrial tachyarrhythmias after pulmonary vein isolation by functional and structural mapping of nonparoxysmal atrial fibrillation.

BACKGROUND: This study aimed to evaluate the predictors of recurrence of atrial tachyarrhythmias by structural and functional mapping: voltage, dominant frequency (DF), and rotor mapping after a pulmonary vein isolation (PVI) in nonparoxysmal atrial fibrillation (AF) patients. METHODS: A total of 66 nonparoxysmal AF patients were prospectively investigated. After the PVI, an online real-time phase mapping system was used to detect the location of rotors with critical nonpassively activated ratios (%NPs) of ≧50% in each left atrial (LA) segment, and high-DFs of ≧7 Hz were simultaneously mapped. After restoring sinus rhythm, low-voltage areas (LVAs < 0.5 mV) were mapped using the Advisor HD grid catheter (HDG). RESULTS: Sixty-four of 66 (97%) AF patients had minimum to mild LVAs regardless of an enlarged LAD and LA volume (45 ± 6.0 mm and 141 ± 29 ml). There were no significant differences in the max and mean DF values and %NPs between the patients with and without recurrent atrial tachyarrhythmias. However, there was a significant difference in the LVA/LA surface area between the patients with and without recurrent atrial tachyarrhythmias (p = .004). Atrial tachyarrhythmia freedom was significantly greater in those with LVAs of ≤3.3% than in those >3.3% after one procedure over 11.6 ± 0.8 months of follow-up (77.1% vs. 33.3%, p < .001). In a multivariate analysis, the LVA/LA surface area after the PVI (HR 1.079; CI, 1.025-1.135, p = .003) was an independent predictor of AF recurrence. CONCLUSIONS: The predictor of atrial tachyarrhythmia recurrence after the PVI was LVAs rather than DFs and rotors in nonparoxysmal AF patients.

Asymptomatic takotsubo syndrome occurring during Holter monitoring.

Asymptomatic takotsubo syndrome was observed during periodic Holter monitoring in a man in his 60s undergoing maintenance dialysis. No emotional or physical stress was noticed. The electrocardiographic changes at onset were determined, and repeated ST elevation and progressive formation of giant negative T waves were recorded.

Impaired glucose tolerance and albuminuria in patients with chronic heart failure: a subanalysis of the SUPPORT trial.

AIMS: The study aims to evaluate the prognostic significance of impaired glucose tolerance (IGT) with reference to albuminuria in patients with chronic heart failure (CHF). METHODS AND RESULTS: We examined 535 CHF patients (mean 66 years, women 25%) in the control arm of our SUPPORT trial, in which we examined additive impact of olmesartan in hypertensive patients with symptomatic CHF treated with ß-blockers and/or angiotensin-converting enzyme inhibitors. We examined the association between glycaemic abnormality (assessed by 75 g of oral glucose tolerance test) and albuminuria for a composite outcome of all-cause death, myocardial infarction, stroke, and HF hospitalization. IGT patients (N = 113, mean 67.2 years) were older and more frequently treated with ß-blockers compared with those with normal glucose regulation (N = 142, mean 64.0 years) and those with diabetes mellitus (N = 280, mean 65.7 years). Multivariable Cox proportional hazard models revealed that, as compared with normal glucose regulation (NGR), IGT was associated with increased risk of the outcome when complicated by albuminuria [hazard ratio (HR) 2.25; 95% confidence interval (CI) 1.14-4.42; P = 0.019] but not when uncomplicated by albuminuria (HR 0.76; 95% CI 0.35-1.60, P = 0.47) (P for interaction = 0.041). This was also the case for diabetes mellitus and albuminuria (HR 2.06; 95% CI 1.17-3.61; P = 0.012). Among IGT patients without albuminuria, 21 (29%) developed albuminuria at 1-year visit, which was again associated with poor prognosis (HR 7.36; 95% CI 1.39-38.98, P = 0.019). CONCLUSIONS: These results indicate that IGT is associated with poor prognosis when complicated by albuminuria in CHF patients, demonstrating the importance of combined early stages of glucose intolerance and renal dysfunction in the management of CHF.

Effect of ablation at high-dominant frequency sites overlapping with low-voltage areas after pulmonary vein isolation of nonparoxysmal atrial fibrillation.

BACKGROUND: The relationship between high-dominant frequency (DF) sites and low-voltage areas (LVAs) in nonparoxysmal atrial fibrillation (AF) patients still remains unknown. OBJECTIVE: This study aimed to evaluate the effect of ablation at high-DF sites overlapping with LVAs after pulmonary vein ablation (PVI) of nonparoxysmal AF. METHODS: A total of 128 consecutive nonparoxysmal patients with atrial fibrillation (53 persistent AF) were retrospectively investigated. The patients with AF were divided into two groups: patients with circumferential PVI alone (PVI group, n = 57) and those with PVI followed by a DF-based ablation (DF group, n = 71). RESULTS: The patient characteristics did not significantly differ between the two groups. However, the LVA ( < 0.5 mV)/left atrial (LA) surface was significantly greater in the DF than the PVI group (22% vs 16%, P = .02). The total max-DF sites overlapping with LVAs in the LA were significantly greater in the DF than the PVI group (91% vs 10%, P = .001). The atrial arrhythmia freedom on antiarrhythmic drugs in the DF group was significantly greater than that in the PVI group during 10.0 ± 3.2 months of follow-up (83.1% vs 64.9%, log-rank test P = .021). The event-free survival in the PVI group decreased according to the LVA extent while it was > 80% in the DF group. The event-free survival in patients with AF especially with extensive LVAs ( ≥ 30%) in the DF group was significantly greater than that in the PVI group (81.0% vs 45.5%, log-rank test P = .035). CONCLUSIONS: High-DF sites overlapping with LVAs after the PVI may be potential selective targets for modification of atrial substrates in nonparoxysmal AF patients.

Low forced expiratory volume in one second is associated with the history of acute coronary syndrome in patients with organic coronary stenosis.

BACKGROUND: Chronic obstructive pulmonary disease often coexists with cardiovascular diseases and airflow limitation has been known as a risk of cardiovascular death. However, the association between airflow limitation and the history of acute coronary syndrome (ACS) in patients with coronary stenosis remains to be determined. METHODS: Study subjects were 271 consecutive patients (age: 70.6±9.5 years, sex: 200 males) who underwent coronary angiography and in whom organic coronary stenosis was detected. We collected spirometric data from those patients and investigated the association of the pulmonary function and the history of ACS. We also compared the prevalence of airflow limitation of the present subjects with Japanese epidemiological data that had been previously published. RESULTS: Multivariate analysis with multiple logistic regression analysis showed that the reduced forced expiratory volume in one second (FEV1.0) less than 80% of predicted value was significantly associated with a history of ACS (odds ratio: 2.81, 95% CI: 1.27-6.20, p<0.02) independently of age, sex, body mass index, and classic coronary risk factors including smoking habit, diabetes mellitus, hypertension, and dyslipidemia. Furthermore, the airflow limitation was more prevalent in the present subjects than in the Japanese general population (25.8% vs. 10.9%, p<0.05). CONCLUSIONS: Reduced FEV1.0 is associated with a history of ACS in patients with coronary arterial stenosis irrespective of any coronary risk factors. Airflow limitation is more prevalent in patients with coronary stenosis than in the general population.

Influence of Left Ventricular Ejection Fraction on the Effects of Supplemental Use of Angiotensin Receptor Blocker Olmesartan in Hypertensive Patients With Heart Failure.

BACKGROUND: There is no robust evidence of pharmacological interventions to improve mortality in heart failure (HF) patients with preserved left ventricular ejection fraction (LVEF) (HFpEF). In this subanalysis study of the SUPPORT Trial, we addressed the influence of LVEF on the effects of olmesartan in HF. METHODS AND RESULTS: Among 1,147 patients enrolled in the SUPPORT Trial, we examined 429 patients with reduced LVEF (HFrEF, LVEF <50%) and 709 with HFpEF (LVEF ≥50%). During a median follow-up of 4.4 years, 21.9% and 12.5% patients died in the HFrEF and HFpEF groups, respectively. In HFrEF patients, the addition of olmesartan to the combination of angiotensin-converting enzyme inhibitor (ACEI) and ß-blocker (BB) was associated with increased incidence of death (hazard ratio (HR) 2.26, P=0.002) and worsening renal function (HR 2.01, P=0.01), whereas its addition to ACEI or BB alone was not. In contrast, in HFpEF patients, the addition of olmesartan to BB alone was significantly associated with reduced mortality (HR 0.32, P=0.03), whereas with ACEIs alone or in combination with BB and ACEI was not. The linear mixed-effect model showed that in HFpEF, the urinary albumin/creatinine ratio was unaltered when BB were combined with olmesartan, but significantly increased when not combined with olmesartan (P=0.01). CONCLUSIONS: LVEF substantially influences the effects of additive use of olmesartan, with beneficial effects noted when combined with BB in hypertensive HFpEF patients. (Circ J 2016; 80: 2155-2164).

Clinical impacts of additive use of olmesartan in hypertensive patients with chronic heart failure: the supplemental benefit of an angiotensin receptor blocker in hypertensive patients with stable heart failure using olmesartan (SUPPORT) trial.

We examined whether an additive treatment with an angiotensin receptor blocker, olmesartan, reduces the mortality and morbidity in hypertensive patients with chronic heart failure (CHF) treated with angiotensin-converting enzyme (ACE) inhibitors, ß-blockers, or both. In this prospective, randomized, open-label, blinded endpoint study, a total of 1147 hypertensive patients with symptomatic CHF (mean age 66 years, 75% male) were randomized to the addition of olmesartan (n = 578) to baseline therapy vs. control (n = 569). The primary endpoint was a composite of all-cause death, non-fatal acute myocardial infarction, non-fatal stroke, and hospitalization for worsening heart failure. During a median follow-up of 4.4 years, the primary endpoint occurred in 192 patients (33.2%) in the olmesartan group and in 166 patients (29.2%) in the control group [hazard ratio (HR) 1.18; 95% confidence interval (CI), 0.96-1.46, P = 0.112], while renal dysfunction developed more frequently in the olmesartan group (16.8 vs. 10.7%, HR 1.64; 95% CI 1.19-2.26, P = 0.003). Subgroup analysis revealed that addition of olmesartan to combination of ACE inhibitors and ß-blockers was associated with increased incidence of the primary endpoint (38.1 vs. 28.2%, HR 1.47; 95% CI 1.11-1.95, P = 0.006), all-cause death (19.4 vs. 13.5%, HR 1.50; 95% CI 1.01-2.23, P = 0.046), and renal dysfunction (21.1 vs. 12.5%, HR 1.85; 95% CI 1.24-2.76, P = 0.003). Additive use of olmesartan did not improve clinical outcomes but worsened renal function in hypertensive CHF patients treated with evidence-based medications. Particularly, the triple combination therapy with olmesartan, ACE inhibitors and ß-blockers was associated with increased adverse cardiac events. This study is registered at clinicaltrials.gov-NCT00417222.

Effect of the Great East Japan Earthquake on cardiovascular diseases--report from the 10 hospitals in the disaster area.

BACKGROUND: We reported an increased occurrence of cardiovascular diseases (CVDs) after the Great East Japan Earthquake by examining ambulance records, but it had to be confirmed by cardiologists. METHODS AND RESULTS: We enrolled patients admitted to the cardiology department of the 10 hospitals in the disaster area from 4 weeks prior to 15 weeks after March 11 in the years 2008-2011 (n=14,078). The weekly occurrence of several CVDs, including heart failure (HF), pulmonary thromboembolism (PTE) and infectious endocarditis (IE), was sharply and significantly increased after the Earthquake. CONCLUSIONS: The Disaster caused significantly increases in the occurrence of HF, PTE and IE.

Detection of asymptomatic cardiac metastasis and successful salvage chemotherapy comprising a prednisone, Etoposide, procarbazine, and cyclophosphamide regimen in an elderly Japanese patient suffering from a delayed recurrence of diffuse large B-cell lymphoma.

We report a case of facial diffuse large B-cell lymphoma (DLBCL) associated with recurrent metastasis in the heart and other sites in a 76-year-old Japanese woman. Initially, she developed DLBCL in her left upper eyelid that spread into the left orbit (Ann Arbor classification stage I). The lesion went into clinical regression after 4 cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy followed by radiotherapy. More than 3 years later, the lymphoma recurred in her facial skin, together with metastases in the mediastinal lymph nodes and the heart; the tumor in the heart was successfully detected by PET/CT and cardiac MRI. To treat the recurrent lesions, we performed a salvage chemotherapy regimen comprising prednisone, etoposide, procarbazine, and cyclophosphamide, which successfully induced tumor regression.

Hydrogen peroxide derived from beating heart mediates coronary microvascular dilation during tachycardia.

OBJECTIVE: Coronary flow is closely correlated to the myocardial metabolic demand. We tested the hypothesis that hydrogen peroxide (H2O2) derived from beating hearts mediates metabolic coronary microvascular dilation. METHODS AND RESULTS: We used a bioassay method in which an isolated microvessel is placed on a beating heart to detect myocardium-derived vasoactive mediators. A rabbit coronary arterial microvessel (detector vessel [DV], n=25) was pressurized and placed on a canine beating heart. After intrinsic tone of DV had developed, we observed DV at rest (heart rate, 120 bpm) and during tachypacing (heart rate, 240 bpm) using an intravital microscope equipped with a floating objective. The tachypacing produced DV dilation by 8.2% (P<0.01 versus baseline), and the dilation was abolished by cell-impermeable catalase (a H2O2 scavenger, 500 U/mL). We performed myocardial biopsy at rest and tachypacing. The biopsy specimens were loaded with 2',7'-dichlorodihydrofluorescein diacetate (10 micromol/L) to visualize H2O2, and observed with confocal microscopy. Dichlorofluorescein fluorescence was diffusely identified in the myocardium and the tachypacing increased the fluorescence intensity (P<0.01). Exogenous H2O2 caused vasodilation of arterial microvessels in vitro in a concentration-dependent manner that was abolished by catalase. CONCLUSIONS: H2O2 derived from the beating heart mediates tachypacing-induced metabolic coronary vasodilation in vivo.

gamma-tocopherol, but not alpha-tocopherol, potently inhibits neointimal formation induced by vascular injury in insulin resistant rats.

Insulin resistance may enhance the neointima formation via increased oxidative stress. However, clinical trials investigating the benefit of antioxidant therapy with alpha-tocopherol showed negative results. Recent studies showed that chemical characteristics of gamma-tocopherol are distinct from those of alpha-tocopherol. We hypothesized that gamma-tocopherol is superior to alpha-tocopherol in preventing the neointima growth after arterial injury in insulin resistance. Male rats were fed with standard chow or a high fructose diet for induction of insulin resistance. Thereafter, the left carotid artery was injured with a balloon catheter. After 2 weeks, the carotid arteries were harvested and histomorphometrically analyzed. The neointima-media ratio of the injured artery was significantly greater in insulin resistance group (n=8, 1.33+/-0.12) than in normal group (n=10, 0.76+/-0.11, p<0.01). gamma-Tocopherol (100 mg/kg/day) reduced the ratio (n=5, 0.55+/-0.21, p<0.01 vs. insulin resistance group), while alpha-tocopherol was without effect (n=7, 1.08+/-0.14). The quantification of plasma phosphatidylcholine hydroperoxide, an indicator of systemic oxidative stress, and dihydroethidium fluorescence staining of the carotid artery, an indicator of the local superoxide production, showed that oxidative stress in the systemic circulation and local arterial tissue was increased in insulin resistance. Both tocopherols decreased plasma phosphatidylcholine hydroperoxide, but failed to suppress the superoxide production in the carotid arteries. Increased 3-nitrotyrosine in neointima by insulin resistance was greatly reduced only by gamma-tocopherol. In conclusion, gamma-tocopherol, but not alpha-tocopherol, reduces the neointima proliferation in insulin resistance, independently of its effects on superoxide production. The beneficial effect may be related with its inhibitory effects on nitrosative stress.

Beating myocardium counteracts myogenic tone of coronary microvessels: involvement of ATP-sensitive potassium channels.

Myogenic tone is intrinsic to vascular tissue and plays an important role in determining basal coronary resistance. However, the effect of the beating heart on myogenic tone is unknown. We investigated the effects of myocardium-derived vasoactive factors on the myogenic tone of coronary microvessels in the resting condition and during increased metabolism. Pressurized isolated coronary vessels (detector vessel, DV) of rabbits (n = 33, maximal inner diameter 201 +/- 8 microm) were gently placed on beating hearts of anesthetized dogs and observed with an intravital microscope equipped with a floating objective. To shut off the myocardium-derived vasoactive signals, we placed plastic film between DV and the heart. The intravascular pressure was changed from 120 to 60 cmH(2)O, and pressure-diameter curves were obtained with and without the contact of DV and the myocardium. The direct contact shifted the pressure-diameter curve upward (P < 0.05 vs. without contact), and myogenic tone was reduced by approximately 40%. When endothelium of DV was denuded, the shift persisted, but the degree of shift was reduced to 10% (P < 0.05 vs. with endothelium). The shift was abolished by glibenclamide, an ATP-sensitive potassium (K(ATP)) channel blocker. A similar upward shift was induced by rapid pacing, but the shift was not blocked by glibenclamide. We conclude that the beating myocardium counteracts myogenic tone by releasing transferable vasoactive signals that affect the endothelium and the vascular smooth muscle, and that the signals are solely mediated by the activation of K(ATP) channels, unlike the rapid pacing-induced vasoactive factors.

Nitric oxide inhibition unmasks ischemic myocardium-derived vasoconstrictor signals activating endothelin type A receptor of coronary microvessels.

NO plays an important role in the compensatory increase in coronary flow conductance against myocardial ischemia, and NO bioavailability is impaired in various diseases. We tested the hypothesis that, when NO production is inhibited, vasoconstrictor signals from the ischemic myocardium are unmasked. We investigated the involvement of endothelin type A (ETA) receptors in the transduction of the constrictor signal. To detect coronary vasoactive signals derived from ischemic myocardium, we used a bioassay system in which an isolated rabbit coronary microvessel (detector vessel, DV) was placed on beating myocardium perfused by the left anterior descending coronary artery (LAD) of an anesthetized open-chest dog (n = 38). The DV was pressurized to 60 cmH2O throughout the experiment and observed with an intravital microscope equipped with a floating objective. After the intrinsic tone of the DV was established, vehicle (n = 7), Nomega-nitro-L-arginine (L-NNA, 100 micromol/l; n = 13), L-NNA + BQ-123 (a selective ETA receptor blocker, 1 micromol/l; n = 7), or BQ-123 alone (1 micromol/l; n = 7) was superfused onto the DV. Thereafter, the LAD of the beating heart was occluded. Coronary occlusion produced significant dilation of the DV by 10 +/- 4%. When L-NNA was applied, the DV significantly constricted by 12 +/- 5% in response to LAD occlusion, and BQ-123 abolished the vasoconstriction. Pretreatment with BQ-123 alone produced an enhancement of the ischemia-induced dilation. We conclude that ischemic myocardium releases transferable vasomotor signals that produce coronary microvascular constriction during the blockade of NO production and the constrictor signal is mediated by ETA receptors.

Prognostic value of plasma brain natriuretic peptide combined with left ventricular dimensions in predicting sudden death of patients with chronic heart failure.

BACKGROUND: We evaluated a combined assessment of brain natriuretic peptide (BNP) with left ventricular dimensions as a prognostic marker for sudden death in patients with chronic heart failure (CHF). Ventricular dimensions and BNP are separately recognized as prognostic markers for sudden death in patients with CHF. METHODS AND RESULTS: CHF patients at Stage C and B were registered for a prospective study. From the database, we analyzed 417 patients with coronary arterial disease (CAD) or primary/secondary dilated cardiomyopathy (DCM). Main effects of BNP, left ventricular ejection fraction (EF), LV diastolic dimension (LVDD), and interaction of BNP with the EF and LVDD were tested with Cox's proportional hazard model. BNP in sudden death patients was significantly higher than that in event-free patients. Although multivariate analysis revealed that BNP by itself was not an independent risk factor for sudden death after adjustments, it was revealed that BNP entered the model via interaction with EF as a risk factor associating with sudden death. On the other hand, BNP was an independent risk factor associating with heart failure events (death and hospitalization), and BNP did not enter the model via an interaction with EF. CONCLUSION: BNP by itself was an independent risk factor for the heart failure events, but not for sudden death in CHF patients of the present study. However, BNP should be important in predicting sudden death when measured with EF.

Myocardial ischemia and coronary microvascular vasomotion: the impact of hypercholesterolemia.

Coronary microvascular dilation in response to myocardial ischemia is an important defense mechanism for minimizing heart injury. Since myocardial ischemia is an intense stimulus for a living body, many biologic signals that affect the vascular tone are activated. Recent evidence demonstrated that among them, ischemic myocardium-derived factors play dominant roles as mediators of ischemic vasodilation, and that ischemic myocardium releases vasoconstrictor signals simultaneously. Hypercholesterolemia, a major risk factor for coronary atherosclerosis, is known to produce microvascular dysfunction, although it does not produce atherosclerotic lesions at the microvascular level. A recent bioassay study demonstrated that the vasodilator signal transduction from the myocardium to coronary microvessels is severely impaired in hypercholesterolemia. It is likely that redox-sensitive mechanisms play a major role in the impairment of the defensive responses. The present understanding of the mechanism of ischemic vasodilation and the impact of hypercholesterolemia on coronary microvascular regulation shall be discussed in this review.

Hypercholesterolemia impairs transduction of vasodilator signals derived from ischemic myocardium: myocardium-microvessel cross-talk.

OBJECTIVE: Coronary microvessels are functionally coupled to the myocardial metabolic state. In hypercholesterolemia, the coronary vascular dysfunction extends to microvascular levels. We hypothesized that the vasodilator signal transduction from ischemic heart is impaired in the coronary microvascular wall of hypercholesterolemia. METHODS AND RESULTS: Rabbits were fed with normal chow (control group) or 2% high-cholesterol diet (hypercholesterolemia group) for 8 weeks. Coronary microvessels isolated from rabbit hearts were pressurized and gently placed on a beating canine heart. Myocardial ischemia was produced in the beating heart and the diameter of the isolated microvessel was observed using an intravital microscope with a floating objective. In control group, the isolated microvessels significantly dilated 2 minutes after the onset of ischemia, and a plateau was observed at 10 minutes. In contrast, the microvessels from hypercholesterolemia group did not dilate during ischemia. Dihydroethidium fluorescence microscopy revealed an elevated superoxide level in the microvessels of hypercholesterolemia group. The application of tiron (free radical scavenger) significantly dilated the isolated microvessels only from hypercholesterolemic animals. CONCLUSIONS: We conclude that the transduction of vasodilator signals derived from ischemic myocardium is impaired in the coronary microvascular wall of hypercholesterolemia. Enhanced oxidative stress in hypercholesterolemia may alter the microvascular function.

Cytochrome P-450 metabolites but not NO, PGI2, and H2O2 contribute to ACh-induced hyperpolarization of pressurized canine coronary microvessels.

The endothelium-dependent hyperpolarization of cells has a crucial role in regulating vascular tone, especially in microvessels. Nitric oxide (NO) and prostacyclin (PGI2), in addition to endothelium-derived hyperpolarizing factor (EDHF), have been reported to hyperpolarize vascular smooth muscle in several organs. Studies have reported the hyperpolarizing effects of these factors are increased by a stretch in large coronary arteries. EDHF has not yet been identified and cytochrome P-450 metabolites and H2O2 are candidates for EDHF. With the use of the membrane potential-sensitive fluorescent dye bis-(1,3-dibutylbarbituric acid)trimethione oxonol [DiBAC4(3)], we examined whether NO, PGI2, cytochrome P-450 metabolites, and H2O2 contribute to ACh-induced hyperpolarization in pressurized coronary microvessels. Canine coronary arterial microvessels (60-356 mum internal diameter) were cannulated and pressurized at 60 cmH2O in a vessel chamber perfused with physiological salt solution containing DiBAC4(3). Fluorescence intensity and diameter were measured on a computer. There was a linear correlation between changes in the fluorescence intensity and membrane potential. ACh significantly decreased the fluorescence intensity (hyperpolarization) of the microvessels without any inhibitors. Endothelial damage caused by air perfusion abolished the ACh-induced decrease in fluorescence intensity. The inhibitors of NO synthase and cyclooxygenase did not affect the ACh-induced decreases in the fluorescence intensity. The addition of 17-octadecynoic acid, a cytochrome P-450 monooxygenase inhibitor, to those inhibitors significantly attenuated the ACh-induced decreases in fluorescence intensity, whereas catalase, an enzyme that dismutates H2O2 to form water and oxygen, did not. Furthermore, catalase did not affect the vasodilation produced by ACh. These results indicate that NO and PGI2 do not contribute to the ACh-induced hyperpolarization and that the cytochrome P-450 metabolites but not H2O2 are involved in EDHF-mediated hyperpolarization in canine coronary arterial microvessels.