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Mitochondrial dysfunction in obesity and diabetes can be caused by excessive production of free radicals, which can damage mitochondrial DNA. Because mitochondrial DNA plays a key role in the production of ATP necessary for cardiac work, we hypothesized that mitochondrial dysfunction, induced by mitochondrial DNA damage, uncouples coronary blood flow from cardiac work. Myocardial blood flow (contrast echocardiography) was measured in Zucker lean (ZLN) and obese fatty (ZOF) rats during increased cardiac metabolism (product of heart rate and arterial pressure, i.v. norepinephrine). In ZLN increased metabolism augmented coronary blood flow, but in ZOF metabolic hyperemia was attenuated. Mitochondrial respiration was impaired and ROS production was greater in ZOF than ZLN. These were associated with mitochondrial DNA (mtDNA) damage in ZOF. To determine if coronary metabolic dilation, the hyperemic response induced by heightened cardiac metabolism, is linked to mitochondrial function we introduced recombinant proteins (intravenously or intraperitoneally) in ZLN and ZOF to fragment or repair mtDNA, respectively. Repair of mtDNA damage restored mitochondrial function and metabolic dilation, and reduced ROS production in ZOF; whereas induction of mtDNA damage in ZLN reduced mitochondrial function, increased ROS production, and attenuated metabolic dilation. Adequate metabolic dilation was also associated with the extracellular release of ADP, ATP, and H2O2 by cardiac myocytes; whereas myocytes from rats with impaired dilation released only H2O2. In conclusion, our results suggest that mitochondrial function plays a seminal role in connecting myocardial blood flow to metabolism, and integrity of mtDNA is central to this process.

Background: We investigated the relationship between myocardial blood flow (MBF), fibrosis, risk factors for sudden death, and clinical manifestations in hypertrophic cardiomyopathy (HCM)., Methods and Results: Sixty-two patients with HCM (45 men, overall mean age 47 ± 16 years), 15 acromegalic patients with left ventricular hypertrophy (9 man, overall mean age 47 ± 12 years), and 20 healthy subjects underwent cardiac magnetic resonance. Resting MBF was measured as the ratio between coronary sinus flow measured by phase-contrast technique and left ventricular mass. Myocardial fibrosis was evaluated by late gadolinium enhancement (LGE) technique. In HCM patients, MBF was significantly lower than in control subjects and acromegalic patients. Patients with LGE had lower MBF than those without it (0.46 ± 0.2 vs 0.66 ± 0.29 mL·min(-1)·g(-1); P < .005). Patients with ventricular tachycardia at Holter monitoring had lower MBF (0.4 ± 0.14 vs 0.6 ± 0.29 mL·min(-1)·g(-1); P < .04). Among patients with preserved systolic function, those in New York Heart Association (NYHA) functional class ≥II had lower MBF than those in NYHA functional class I (0.46 ± 0.2 vs 0.69 ± 0.3 mL·min(-1)·g(-1); P < .003). MBF was the only independent predictor of worse clinical status (NYHA ≥II; P = .01)., Conclusions: In HCM patients low resting MBF is associated with the presence of fibrosis. MBF is a predictor of worse clinical status., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The aim of the current study was to assess the ability of amlodipine to dilate the coronary vessels in subjects with angiographically normal coronary arteries and normal left ventricular function. Ten patients, six women and four men (mean age 48 +/- 14 years, range 25-67 years) were enrolled. Coronary flow velocity and coronary perfusion pressure were invasively measured at baseline, during intracoronary adenosine (1-mg bolus) and at 5, 15, and 30 min following IV amlodipine (10 or 20 mg). Quantitative coronary angiography was performed at baseline and at 5, 15, and 30 min after amlodipine. Coronary cross-sectional area and mean coronary flow velocity progressively increased after amlodipine administration, resulting in an average increase in coronary flow at 30 min of 76%. On an individual basis, all patients but one showed a consistent trend toward a progressive coronary vasodilator effect of amlodipine over time. The peak effect of amlodipine on baseline mean coronary flow velocity was 43 +/- 12% that of adenosine. This is the first clinical study demonstrating that the IV administration of amlodipine produces a powerful coronary vasodilatation in subjects with angiographically normal coronary arteries and normal ventricular function, besides its known systemic vasodilating effects. The coronary vasodilating properties of amlodipine are particularly expressed at the microcirculatory level.

Objective: To verify the behavior of coronary microvascular tone during spontaneous ischemia in patients with unstable angina (UA)., Background: In UA, the pathogenetic role of vasoconstriction is classically confined at the stenotic coronary segment. However, microcirculatory vasoconstriction has been also suggested by previous experimental and clinical studies., Methods: The study included 10 patients with UA (recent worsening of anginal threshold and appearance of angina at rest) and single-vessel CAD. Blood flow velocity was monitored by a Doppler catheter in the diseased artery. Transstenotic pressure gradient was monitored by aortic and distal coronary pressure monitoring. Stenosis resistance was calculated as the ratio between pressure gradient and blood flow, microvascular resistance as the ratio between distal pressure and blood flow. Measurements were obtained at baseline, following intracoronary adenosine (2 mg) and during transient ischemia. Aortic and distal coronary pressures were also measured during balloon coronary occlusion., Results: Adenosine did not affect stenosis resistance, while it decreased (p < 0.05) microvascular resistance to 52 +/- 22% of baseline. Angina and ischemic ST segment shift were associated with transient angiographic coronary occlusion in 7 of 10 patients; however, in no case was ischemia associated with interruption of flow. Despite markedly different flow values, distal coronary pressure was similar during adenosine and during spontaneous ischemia (48 +/- 15 vs. 46 +/- 20 mm Hg, respectively, NS). During ischemia, a marked increase in the resistance of both coronary stenosis and coronary microcirculation was observed (to 1,233% +/- 1,298% and 671% +/- 652% of baseline, respectively, p < 0.05). Distal coronary pressure was markedly reduced during balloon coronary occlusion (14 +/- 7 mm Hg, p < 0.05 vs. both adenosine and ischemia), suggesting the absence of significant collateral circulation., Conclusions: In patients with UA, transient myocardial ischemia is associated with vasoconstriction of both stenotic arterial segment and downstream microcirculation.

Background: Even late restoration of anterograde coronary flow may have beneficial effects on left ventricular function, electrophysiology, and survival in postinfarction patients., Hypothesis: The patency or occlusion of an infarct-related coronary artery in the chronic phase may also be associated with myocardial ischemia provoked by pharmacologic and physiologic stress tests., Methods: High-dose dipyridamole echocardiography test (DET) (up to 0.84 mg/kg over 10 min), exercise electrocardiography (EET), and coronary angiographic data in a group of 127 in-hospital patients who had survived an acute myocardial infarction were analyzed. Patients who had only angiographic evidence of infarct-related single artery disease (> or = 50% luminal diameter reduction) and no previous revascularization were enrolled in the study. DET and EET were performed (DET in all, EET in 118 patients) within 5 days before coronary angiography. Fifty-seven patients had total occluded infarct arteries (Group 1) with various degrees of collateral circulation (2.6 +/- 1.1 collateral score, by a 3 grading system), whereas the other 70 patients had patent infarct arteries (Group 2) with significant residual stenoses (82 +/- 13% diameter reduction)., Results: The prevalence of rest angina or effort angina and topography of the infarct-related coronary artery did not differ between the two groups (all p = NS). There were more patients with Q wave in Group 1 than in Group 2 (72 vs. 57%, p = 0.08) compared with non-Q wave infarction (Group 1 = 28 vs. Group 2 = 43%, p = 0.08). Ischemia in the infarct-related artery territory detected by DET (defined as new wall motion dyssynergy or marked worsening of resting hypokinesia) was 61% in Group 1 and 41% in Group 2 (p = 0.025). EET was positive in 26 of 54 (48%) Group 1 and in 21 of 64 (33%) Group 2 patients (p = 0.09)., Conclusions: Patients with occluded infarct-related arteries have a higher prevalence of ischemia during DET and EET regardless of the presence of collateral flow. These results suggest that the presence of partial anterograde flow in the prolonged period could have a favorable influence on prevalence of residual ischemia in these patients.

Background: In patients with coronary artery disease, a maximal vasodilation of the coronary microcirculation is generally assumed to occur during myocardial ischemia induced by rises in metabolic demand. However, vasoconstriction has been documented during severe prolonged ischemia in animals. The aim of this study was to investigate coronary vasomotor tone during pacing-induced ischemia in humans., Methods and Results: The study included 11 patients with exercise-induced ischemia and single-vessel disease of the left anterior descending artery and 7 control subjects with normal coronary arteries. Blood flow velocity was monitored with a Doppler catheter in the left anterior descending artery. Coronary resistance index was calculated as the ratio between mean arterial pressure and flow velocity. Measurements were obtained at baseline, after intracoronary adenosine (2 mg), and during maximal atrial pacing in the absence and presence of adenosine. After adenosine administration at rest, coronary resistance decreased more in control subjects than in patients (25 +/- 7% of baseline versus 61 +/- 19%; P < .01). Coronary resistance decreased in all control subjects (P < .01) both at maximal pacing (60 +/- 17% of baseline) and after administration of adenosine during tachycardia (31 +/- 13% of baseline). By contrast, all 10 ischemic patients displayed increased coronary resistance at maximal heart rate (221 +/- 131% of baseline; P < .01 versus baseline, P < .01 versus control subjects). At this stage, adenosine decreased coronary resistance to 44 +/- 20% of values observed before injection. Additionally, it reduced ST-segment depression in 5 of 8 patients., Conclusions: In patients with coronary artery disease, transient myocardial ischemia induced by increased metabolic demand is not associated with maximal vasodilation. Rather, an inappropriate severe microvascular vasoconstriction is present that can be abolished by intracoronary adenosine.

Background: Intravascular ultrasound imaging provides information on vascular lumen and arterial wall structure and it has potential application in arterial wall dynamic study. The aim of this study was to develop a computer assisted system for analysing digitised cross sectional ultrasound images of coronaries to easily display and quantify coronary dynamic and its relationship with arterial wall morphology., Methods and Results: To extract the anatomical regions of interest from the digitised sonograms, automatic image segmentation and interactive procedures for manual correction were implemented. This step included the recognition of the lumen edge and an analysis of gray level intensity of the wall. Subsequently, a virtual 3D reconstruction of lumen and vessel wall was done in a Cartesian system where the XY plane was parallel to each cross-sectional sonogram, while the Z axis corresponded to the acquisition time. The baricentre of vascular lumen was used as a reference for alignment. We obtained a cylinder-like solid representing the behavior of the arterial cross-sectional sonogram in time, with the possibility to look either at the wall or at the lumen. In this virtual solid it was possible to measure the variation of lumen area and of 16 hemidiameters; in addition, the derivatives of these values, allowing an estimate of the velocity of events, can be obtained., Conclusions: The described computerised system for the analysis of intravascular ultrasound images could become a very useful tool for 3D representation and quantitative monitoring of coronary compliance and their relationship with segmental arterial wall morphology.

According to the Stewart-Hamilton equation flow is inversely related to the area under the time-concentration curve produced by the transit of a detectable indicator. To verify the applicability of this principle for contrast echocardiography, we bolus injected a saccharide echo contrast agent (0.8 ml) into an in vitro circulatory model at variable flow rates. Two-dimensional echo images were digitized, and curves demonstrating the ratio of videointensity over time were derived. As expected, flow was inversely related to the area under the curves (r = 0.93). To apply this principle to human coronary circulation, we bolus injected sonicated iopamidol (4 ml) into the normal left coronary artery of six patients at baseline and after intravenous administration of dipyridamole (0.84 mg/kg in 10 minutes). Echo images were digitized, and myocardial time-intensity curves were derived. The area under the curve after dipyridamole administration (210 +/- 128 gray level.sec) did not appear significantly different from that at baseline (177 +/- 80 gray level.sec). Thus a mismatch exists between contrast echo data obtained in vitro and in human coronary circulation.

The effect of carbochromen on total and regional coronary blood flow was investigated in 6 anesthetized open-chest dogs. Total and regional myocardial blood flow was measured by radioactive microspheres, using the reference sample method. Left circumflex coronary flow was monitored by an electromagnetic flowmeter. In 4 dogs (Group 1) carbochromen was injected intravenously; in 2 dogs (Group 2) it was infused directly in the circumflex coronary artery. No significant changes in heart rate, left atrial left ventricular and aortic pressures were observed following carbochromen administration in both Groups. Left circumflex coronary blood flow progressively increased and a level slightly higher than peak reactive hyperemia was reached in both Groups. Regional myocardial blood flow measurements in Group 1 showed that the inner third of the left ventricular wall (ENDO) increased 2.7 times relative to control, the middle layer increased 3.4 times relative to control and the external third 4.5 times relative to control. A similar pattern was observed after intracoronary administration of carbochromen (Group 2). The ENDO/EPI flow ratio dropped from 0.98 +/- 0.16 to 0.58 +/- 0.18 in Group 1 and from 1.03 and 1.20 to 0.71 and 0.53 respectively in the two experiments of Group 2. Replacement of carbochromen with adenosine infusion in Group 2 produced a further increase in flow, mainly in the subendocardium resulting in ENDO/EPI flow ratio close to unity. These data demonstrate that the powerful coronary vasodilatory effect of carbochromen is not uniform being vasodilation more prominent in the vasculature of the external third of the left ventricular wall as compared to the inner third. Consequently a major redistribution of coronary blood flow, favouring the external layers of the left ventricle, results from carbochromen administration. This effect distinguishes carbochromen from other vasodilating stimuli than elicit a uniform response in the coronary vasculature and do not affect the ENDO/EPI ratio, including transient ischemia, adenosine, and dipyridamole.

The effects of acute subtotal embolisation of small coronary arteries on regional coronary flow and vasodilator reserve were investigated in seven open chest dogs. Unlabelled plastic microspheres (26(2) micron in diameter) were injected as boluses of 200,000-400,000 microspheres into the circumflex artery. Embolisation was repeated until reactive hyperaemia was totally abolished, which occurred after the injection of 62,000(4000) microspheres per gram. Intracoronary adenosine was then infused for 20 min at 1.2 mg.min-1. Regional myocardial blood flow was measured by radioactive microspheres under control conditions, after coronary embolisation, and during adenosine infusion. Coronary blood flow (0.98(0.07) ml.min-1.g-1) was reduced to 0.66(0.08) ml.min-1.g-1 after embolisation (p less than 0.005) when reactive hyperaemia was practically abolished. Embolisation reduced epicardial flow from 0.93(0.08) to 0.40(0.09) ml.min-1.g-1 (p less than 0.001), whereas endocardial flow was unchanged (1.03(0.11) vs 0.92(0.14) ml.min-1.g-1; NS); as a consequence, the endocardial to epicardial flow ratio increased from the control value of 1.11(0.06) to 2.31(0.35) (p less than 0.005). Adenosine infusion increased coronary blood flow from 0.66(0.08) to 1.66(0.41) ml.min-1.g-1 (p less than 0.05). Endocardial blood flow increased more than epicardial blood flow, leading to a further increase in the endocardial to epicardial flow ratio (3.79(0.13); p less than 0.05). Thus it is concluded that (a) embolisation of small arteries abolishes the reactive hyperaemic response to transient coronary occlusion; (b) microembolisation predominantly reduces subepicardial perfusion; and (c) adenosine administration may increase total and regional flow after subtotal occlusion of coronary small arteries.

The time course of the vasodilation of different segments of the epicardial coronary vasculature after three different doses of intracoronary isosorbide dinitrate (ISDN) was investigated in angiographically normal coronary arteries in 10 patients with quantitative coronary angiography. In five patients, 0.1 mg and 0.3 mg ISDN were injected intracoronary 30 minutes apart, and the effect of each dose was assessed at 1, 5, 10, and 15 minutes after the administration by serial angiograms. In five additional patients, a single dose of 3 mg was injected and coronary vasodilation was assessed at 1, 5, 10, 15, and 20 minutes. After each dose, dilation of epicardial coronary arteries occurred within 1 minute, peaked at 5 minutes and progressively decreased thereafter. Relative to control, peak percent diameter increase was (mean +/- SEM) 10% +/- 0.9% (p less than 0.01), 18.5% +/- 1.5% (p less than 0.01), and 26% +/- 2.1% (p less than 0.01) after 0.1, 0.3, and 3.0 mg, respectively. When small (1 to 2 mm), medium (2 to 3 mm), and large (greater than 3 mm) vessels were separately analyzed, peak response was respectively 12% +/- 1.3% (p less than 0.01), 9% +/- 1.9% (p less than 0.01), and 7% +/- 1% (p less than 0.05) after 0.1 mg ISDN; 22% +/- 1.8% (p less than 0.01), 16% +/- 1.3% (p less than 0.01), and 12% +/- 0.8% (p less than 0.01) after 0.3 mg; and 38% +/- 2.4% (p less than 0.01), 22% +/- 2.1% (p less than 0.01), and 17% +/- 2% (p less than 0.01) after 3.0 mg. The duration of the response increased with the dose, but was inversely related to the size of the vessel.(ABSTRACT TRUNCATED AT 250 WORDS)

This study explores the relation between coronary arterial spasm and the development of coronary atherosclerosis. The clinical history and coronary angiographic and electrocardiographic data in 212 consecutive patients with ischemic heart disease were correlated. These patients were classified into four groups: Group 1, patients without angiographic evidence of atherosclerosis; Group 2, patients with single vessel disease; Group 3, patients with double vessel disease; and Group 4, patients with significant narrowing of major coronary arteries. Although spontaneous angina occurred in all four groups, it was more common (55 percent) in the patients in Group 1, who were predominantly female and young. Spontaneous angina was confirmed in Group 1 with several techniques, including thallium-201 scintigraphy, ergonovine administration and electrocardiography during attacks of pain. Prior myocardial infarction was present with similar frequency in all four groups. A patient is discussed whose spontaneously occurring coronary arterial spasm later progressed to fixed arteriosclerotic narrowing requiring coronary bypass surgery. These observations and a review of the literature lend support to the hypothesis that coronary arterial spasm can be a possible antecedent leading to the later development of fixed atherosclerotic coronary arterial obstruction.

Intramyocardial pressure and segment length were measured during control conditions, during 30 sec coronary artery occlusion, and during reperfusion in the subendocardial (ENDO) and in the subepicardial (EPI) layers of the left ventricular wall, in 9 open-chest dogs. Under control conditions systolic subendocardial pressure, 179 +/- 11 mmHg, exceeded subepicardial pressure, 97 +/- 9 mmHg (P less than .001); the maximal rate of change of pressure in the subendocardium, 2231 +/- 170 mmHg/sec, was greater than in the subepicardium, 960 +/- 125 mmHg/sec, (P less than .001). Subendocardial systolic shortening, 23 +/- 2% was greater than subepicardial systolic shortening 16 +/- 1% (P less than .001). The maximal rate of systolic shortening in the subendocardium, 32 +/- 5 mm/sec, was also higher than in the subepicardial, 14 +/- 1 mm/sec (P less than .001). When the left anterior descending coronary artery was closed, subendocardial and subepicardial systolic pressures decreased immediately; conversely, appreciable changes in segment length were delayed 10-12 heart beats. After 30 sec of coronary occlusion a 35% reduction was observed in subendocardial and subepicardial systolic pressures, and systolic lengthening occurred. During reperfusion systolic shortening showed a brief overshooting and was back to control after 10 +/- 2 sec in subepicardium and 13 +/- 2 sec in subendocardium. Systolic intramyocardial pressure recovered in 14 +/- 3 sec in EPI and 18 +/- 2 sec in ENDO and subsequently rose above control level. Peak rebound occurred after 50-75 sec of reperfusion and was 27% higher than control in subendocardium and 20% in subepicardium. In 5 dogs the effects of coronary occlusions lasting 5, 15, 30, 45 and 60 sec were investigated. A progressive increase in ischemic depression and reperfusion rebound in subendocardial and subepicardial pressures was observed. These data show that subendocardial and subepicardial are both functionally depressed by coronary occlusion and that subendocardial and subepicardial both contribute to reperfusion hyperkinesis. Systolic intramyocardial pressures persist when shortening is abolished. Ischemic depression and reperfusion rebound of systolic intramyocardial pressures are affected by duration of coronary occlusion.

The mechanism of electrocardiographic ST segment changes during acute coronary occlusion was evaluated in 28 consecutive patients with single vessel coronary artery disease undergoing coronary angioplasty. Patients were continuously monitored with a six lead electrocardiogram. Twenty-three patients showed ST changes in the primary zone of occlusion, and 13 of these had additional ST changes in a remote zone. Ten of these 13 had unusually extensive arteries supplying the remote zone. The balloon occluded two adjacent normal arteries in two patients, and no coronary anatomic explanation was evident in one patient. Ten patients with striking primary zone ST changes showed no remote change. Seven had nonextensive primary zone arteries, and three others had abundant collateral vessels. Five patients showed no electrocardiographic changes in primary or remote zones. Four had collateral vessels, and one had left ventricular hypertrophy on the baseline electrocardiogram. It was concluded that remote electrocardiographic changes are probably due to occlusion of unusually extensive coronary arteries and are not simply reciprocal.

Intramyocardial pressure is an indicator of coronary extravascular resistance. During systole, pressure in the subendocardium exceeds left ventricular intracavitary pressure; whereas pressure in the subepicardium is lower than left ventricular intracavitary pressure. Conversely, during diastole, subepicardial pressure exceeds both subendocardial pressure and left ventricular pressure. These observations suggest that coronary flow during systole is possible only in the subepicardial layers. During diastolic, however, a greater driving pressure is available for perfusion of the subendocardial layers relative to the subepicardial layers. On this basis, measurements of intramyocardial pressure contribute to an understanding of the mechanisms of regulation of the phasic and transmural distribution of coronary blow flow.

To investigate the pathogenesis of myocardial infarction we undertook a systematic study of patients with angina at rest, a syndrome known to evolve frequently into infarction. Among 187 consecutive patients, 37 had infarction, all in the area that showed electrocardiographic changes during angina. In all 76 patients who underwent hemodynamic monitoring, 201thallium myocardial scintigraphy or angiography during angina, a vasospastic origin of the attacks was documented. In six patients with infarction shortly after these studies and in two in whom the infarction developed during hemodynamic monitoring or during angiography the onset of infarction was indistinguishable from the onset of anginal attacks. One patient in whom spasm was observed at the onset of infarction died six hours later; at post-mortem examination, a fresh laminar thrombus was found at the site of the spasm. After infarction, complete thrombotic occlusion of the branch shown to undergo vasospasm was documented in two patients by angiography.

The possible role of prostaglandins in mediating coronary vasodilation by nitrates was investigated in 13 patients. In nine patients (Group 1), the effects of ISDN on coronary-artery diameter and (in four of the nine) coronary sinus flow before and after administration of ASA were compared. In four additional patients (Group 2) the first ISDN administration was omitted in order to investigate the effect of ASA on resting coronary artery tone. Dosages used were 3 mg intracoronary ISDN and 1.0 g intravenous and 100 mg intracoronary ASA. Coronary artery diameter was analyzed by means of quantitative magnification coronary angiography. Coronary sinus flow was investigated by means of coronary sinus thermodilution. ASA was not able to induce significant changes in coronary artery diameter when injected before administration of ISDN or to prevent ISDN-induced vasodilation. At the coronary resistance level, ASA was not able to prevent the relative vasodilation induced by ISDN. It is concluded that coronary vasodilation by nitrates is not mediated by the prostaglandin system.