BMS-747158-02: a novel PET myocardial perfusion imaging agent.

BACKGROUND: BMS-747158-02 is a fluorine 18-labeled pyridaben derivative designed as a new myocardial perfusion imaging agent for use with positron emission tomography (PET). This study evaluated BMS-747158-02 in animal models of cardiac perfusion and compared it with established single photon emission computed tomography agents. METHODS AND RESULTS: In a rat biodistribution study, BMS-747158-02 (15 microCi) had substantially higher myocardial uptake than technetium 99m sestamibi (100 microCi) at 15 minutes (3.5% +/- 0.3% %ID/g vs 1.9% +/- 0.1% %ID/g) and 120 minutes (3.2% +/- 0.4% of injected dose per gram vs 1.8% +/- 0.0% of injected dose per gram) after intravenous administration. Uptake ratios of heart to lung and liver at 60 minutes were also higher for BMS-747158-02 (12.7 +/- 1.4 and 3.7 +/- 0.2, respectively) than Tc-99m sestamibi (5.9 +/- 0.5 and 2.4 +/- 0.4, respectively). In an isolated rabbit heart model at flow rates of 1.66 to 5.06 mL x min(-1).g(-1) wet left ventricular weight, the net BMS-747158-02 heart uptake increased proportionally (0.93 +/- 0.15 to 2.44 +/- 0.40 mL.min(-1) x g(-1)) and to a greater extent than that of thallium 201 (0.76 +/- 0.02 to 1.11 +/- 0.02 mL x min(-1) x g(-1)) or Tc-99m sestamibi (0.49 +/- 0.03 to 0.77 +/- 0.08 mL x min(-1) x g(-1)). PET imaging with BMS-747158-02 showed a clear and sustained cardiac uptake in rats, rabbits, and nonhuman primates with minimal lung interference and rapid liver clearance. Myocardial perfusion deficit zones created by either permanent left coronary ligation or reperfusion after ligation in rats were both clearly identified on PET cardiac images of BMS-747158-02 and had good agreement with in vitro histology. CONCLUSIONS: BMS-747158-02 exhibited high and sustained cardiac uptake that was proportional to blood flow, and it represents a new class of PET myocardial perfusion imaging agent.     

Insulin-induced increment of coronary flow reserve is not abolished by dexamethasone in healthy young men

Hyperinsulinemia is a risk factor for coronary artery disease. Previous studies have reported that hyperinsulinemia increases cardiac and skeletal muscle sympathetic nerve activity and skeletal muscle blood flow in normal subjects. However, little is known about insulin's effects on myocardial blood flow in humans. The purpose of this study was to investigate whether physiological hyperinsulinemia affects myocardial blood flow and flow reserve in healthy subjects. Additionally, the role of the sympathetic nervous system in regulating insulin's effects on coronary perfusion was tested. We used positron emission tomography and oxygen-15-labeled water to measure myocardial blood flow and coronary flow reserve in 16 healthy nonobese men (age, 34 +/- 4 yr; maximal aerobic capacity, 32 +/- 3 mL x g(-1) x min(-1); blood pressure, 118 +/- 10/65 +/- 8 mm Hg) at fasting and during euglycemic hyperinsulinemic clamp (1 mU x kg(-1) x min(-1) for 80 min). To study the role of the sympathetic nervous system, each subject was studied twice: once after administration of dexamethasone (dexa+) for 2 days (2 mg per day) and once without previous medication (dexa-). All studied subjects had normal left ventricular mass, function, and findings in stress echocardiography. Resting myocardial blood flow was 0.76 +/- 0.19 mL x g(-1) x min(-1), and a significant increase in flow was detected after adenosine infusion (140 microg/kg x min for 5 min i.v.), both in the basal fasting state (P < 0.001) and during hyperinsulinemia (P < 0.001). However, the flow response to adenosine was significantly higher during hyperinsulinemia, thus leading to a higher hyperemic flow (3.38 +/- 0.97 vs. 4.28 +/- 1.57 mL x g(-1) x min(-1), basal vs. hyperinsulinemic, P < 0.01) and higher coronary flow reserve (4.6 +/- 1.2 vs. 5.8 +/- 1.9, respectively, P < 0.05). Pretreatment with dexamethasone did not significantly change the resting blood flow [0.72 +/- 0.22 vs. 0.76 +/- 0.19 mL x g(-1) x min(-1), dexa+ vs. dexa-, not significant (NS)], the adenosine stimulated flow (3.56 +/- 1.49 vs. 3.38 +/- 0.97 mL x g(-1) x min(-1), respectively, NS), or the hyperinsulinemic adenosine-stimulated blood flow (4.68 +/- 1.74 vs. 4.28 +/- 1.57 mL x g(-1) x min(-1), respectively, NS). Coronary flow reserves in the basal state (5.3 +/- 2.7 vs. 4.6 +/- 1.2 mL x g(-1) x min(-1), dexa+ vs. dexa-, NS) and during hyperinsulinemia (6.8 +/- 2.9 vs. 5.8 +/- 1.9 mL x g(-1) x min(-1), respectively, NS) tended to be (but were not) significantly higher after dexamethasone treatment. These results demonstrate that insulin acts as a vasodilatory hormone also in the coronary vasculature. Because the insulin-induced increment of myocardial flow reserve remained unchanged by dexamethasone pretreatment, centrally mediated sympathetic activation seems not to play a major role in regulating insulin action on myocardial perfusion in healthy subjects.     

Assessment of myocardial perfusion by dynamic O-15-labeled water PET imaging: validation of a new fast factor analysis.

BACKGROUND: Factor analysis (FA) is an established method for separating myocardium from blood pool by use of oxygen 15-labeled water and positron emission tomography for analyzing myocardial blood flow (MBF). Conventional FA methods generating images from sinograms (sinoFA) are time-consuming, whereas FA can be performed on the reconstructed images (reconFA) in a fraction of time. We validated the MBF values obtained by reconFA versus sinoFA. METHODS AND RESULTS: In 23 volunteers (mean age, 26.6 +/- 3.4 years) MBF was calculated from sinoFA and reconFA and blindly reanalyzed 1 month later by the same observer. Intraobserver agreement and reconFA-versus-sinoFA agreement were assessed according to Bland and Altman (BA). Reproducibility proved excellent for global sinoFA (r = 0.968; P < .001; BA limits, -0.617 to 0.676 mL x min(-1) x g(-1)) and slightly superior for reconFA (r = 0.979; P < .001; BA limits, -0.538 to 0.558 mL x min(-1) x g(-1)), with wider limits of agreement for segmental MBF from sinoFA (r = 0.777; P < .001; BA limits, -1.676 to 1.656 mL x min(-1) x g(-1)) and reconFA (r = 0.844; P < .001; BA limits, -1.999 to 1.992 mL x min(-1) x g(-1)). In addition, sinoFA and reconFA showed excellent correlation (r = 0.975, P < .001) and agreement (BA limits, -0.528 to 0.648 mL x min(-1) x g(-1)) for global and segmental values (r = 0.955; P < .001; BA limits, -1.371 to 1.491 mL x min(-1) x g(-1)). CONCLUSIONS: Use of reconFA allows rapid and reliable quantitative MBF assessment with O-15-labeled water.     

Sex differences in myocardial oxygen and glucose metabolism.

BACKGROUND: Both physiologic and pathophysiologic conditions affect the myocardium's substrate use and, consequently, its structure, function, and adaptability. The effect of sex on myocardial oxygen, glucose, and fatty acid metabolism in humans is unknown. METHODS AND RESULTS: We studied 25 young subjects (13 women and 12 men) using positron emission tomography, quantifying myocardial blood flow, myocardial oxygen consumption (MVO2), and glucose and fatty acid extraction and metabolism. MVO2 was higher in women than in men (5.74 +/- 1.08 micromol x g(-1) x min(-1) vs 4.26 +/- 0.69 micromol x g(-1) x min(-1), P < .005). Myocardial glucose extraction fraction and utilization were lower in women than in men (0.025 +/- 0.019 vs 0.062 +/- 0.028 [P < .001] and 133 +/- 96 nmol x g(-1) x min(-1) vs 287 +/- 164 nmol x g(-1) x min(-1) [P < .01], respectively). There were no sex differences in myocardial blood flow, fatty acid metabolism, or plasma glucose, fatty acid, or insulin levels. Female sex was an independent predictor of increased MVO2 (P = .01) and decreased myocardial glucose extraction fraction and utilization (P < .005 and P < .05, respectively). Insulin sensitivity was an independent predictor of increased myocardial glucose extraction fraction and utilization (P < .01 and P = .01, respectively). CONCLUSIONS: Further studies are necessary to elucidate the mechanisms responsible for sex-associated differences in myocardial metabolism. However, the presence of such differences may provide a partial explanation for the observed sex-related differences in the prevalence and manifestation of a variety of cardiac disorders.     

Collateral-flow measurements in humans by myocardial contrast echocardiography: validation of coronary pressure-derived collateral-flow assessment.

AIMS: Myocardial blood flow (MBF) is the gold standard to assess myocardial blood supply and, as recently shown, can be obtained by myocardial contrast echocardiography (MCE). The aims of this human study are (i) to test whether measurements of collateral-derived MBF by MCE are feasible during elective angioplasty and (ii) to validate the concept of pressure-derived collateral-flow assessment. METHODS AND RESULTS: Thirty patients with stable coronary artery disease underwent MCE of the collateral-receiving territory during and after angioplasty of 37 stenoses. MCE perfusion analysis was successful in 32 cases. MBF during and after angioplasty varied between 0.060-0.876 mL min(-1) g(-1) (0.304+/-0.196 mL min(-1) g(-1)) and 0.676-1.773 mL min(-1) g(-1) (1.207+/-0.327 mL min(-1) g(-1)), respectively. Collateral-perfusion index (CPI) is defined as the rate of MBF during and after angioplasty varied between 0.05 and 0.67 (0.26+/-0.15). During angioplasty, simultaneous measurements of mean aortic pressure, coronary wedge pressure, and central venous pressure determined the pressure-derived collateral-flow index (CFI(p)), which varied between 0.04 and 0.61 (0.23+/-0.14). Linear-regression analysis demonstrated an excellent agreement between CFI(p) and CPI (y=0.88 x +0.01; r(2)=0.92; P<0.0001). CONCLUSION: Collateral-derived MBF measurements by MCE during angioplasty are feasible and proved that the pressure-derived CFI exactly reflects collateral relative to normal myocardial perfusion in humans.     

Influence of the interleukin-converting enzyme inhibitor HMR-3480 on myocardial stunning in pigs in vivo

BACKGROUND: The proinflammatory cytokine interleukin-1 beta is converted into its active form by interleukin-1 beta-converting enzyme (ICE). Circulating cytokines may promote myocardial dysfunction (stunning) after ischemia. OBJECTIVE: To investigate whether ICE inhibition by HMR-3840 improves myocardial stunning in vivo. METHODS: Anesthetized (isoflurane and fentanyl) pigs were used for measurement of left ventricular (LV) pressure, cardiac output and blood flow in the left anterior descending coronary artery (LAD) and left circumflex coronary artery. Regional myocardial function was assessed by sonomicrometry as systolic wall thickening and mean systolic thickening velocity in the anteroapical and posterobasal walls. The animals were subjected to 10 min of LAD occlusion followed by 4 h of reperfusion. The ICE inhibitor (flow-adjusted to achieve coronary plasma concentrations of 10 mug/mL) (ISCH, n=7) or the vehicle (CON, n=7) was infused via a side branch into the LAD during ischemia, or during ischemia and the first 60 min of reperfusion (REP, n=6). RESULTS: Occlusion of the LAD resulted in systolic outward movement (bulging) of the anteroapical wall during ischemia in all groups. Infusion of the ICE inhibitor had no effect on functional recovery when given during ischemia or when given during reperfusion (at the end of reperfusion in the anteroapical wall, values for systolic wall thickening were: CON 17.3+/-7.3%, ISCH 23.2+/-9.8% and REP 19.3+/-6.1%; and values for mean systolic thickening velocity were: CON 4.3+/-1.1 mm/s, ISCH 6.1+/-3.9 mm/s and REP 5.2+/-1.7 mm/s; all P values not significant for CON versus ISCH or REP). LAD blood flow was not affected by HMR-3840 (23.4+/-5.2 mL/min versus 24.3+/-8.1 mL/min; P not significant). Global myocardial function (LV pressure, maximum rate of LV pressure increase and cardiac output) was not different between controls and treatment groups during reperfusion. CONCLUSION: ICE inhibition by HMR-3480 had no effect on myocardial stunning in pigs in vivo.     

Altered regulation of the myocardial microcirculation in young smokers

Smoking is known to affect microcirculatory function in a middle-aged population. However, the effects of smoking on myocardial perfusion in young smokers have not been studied. Myocardial perfusion was measured in 15 smokers (24 +/- 2 years) and 15 nonsmokers (24 +/- 3 years) using positron emission tomography. Myocardial perfusion was measured at rest, during cold stress and during dipyridamole. Resting myocardial blood flow was similar in the two groups. The well-described correlation between rate-pressure product and myocardial blood flow was present only in the nonsmokers (r(2) = 0.61, p < 0.001). Myocardial blood flow corrected for the rate-pressure product declined during cold by 20% in the smokers [1.11 +/- 0.28 vs. 0.92 +/- 0.20 ml x g(-1) x min(-1) (p = 0.012)], but remained unchanged in nonsmokers [1.11 +/- 0.25 vs. 1.09 +/- 0.30 ml x g(-1) x min(-1) (p = NS)]. Dipyridamole-induced hyperemia was similar in the two groups [2.23 +/- 0.78 vs. 2.42 +/- 0.65 ml x g(-1) x min(-1) (p = NS)]. In conclusion, smoking induces abnormalities in myocardial microcirculatory regulation in young otherwise healthy smokers. The coronary flow reserve, however, is not significantly altered.     

Regional blood flow during hypothermic arrest

Little is known about the efficacy of CPR in the setting of hypothermia-induced cardiac arrest. We measured organ blood flow produced by conventional closed-chest CPR in eight swine following normothermic KCl-induced cardiac arrest and in seven swine surface-cooled until cardiac arrest occurred. Radiomicrospheres were injected in the unanesthetized basal state, after five minutes of CPR, and after 20 minutes of CPR. After five minutes of CPR, the cardiac output and cerebral and myocardial blood flows (mean +/- SD) of hypothermic animals were 15.3 +/- 7.5 mL/min/kg, 0.16 +/- 0.11 mL/min/g, and 0.20 +/- 0.15 mL/min/g, respectively. Mean percentage flows were 7%, 15%, and 8%, respectively, of those measured in the unanesthetized prearrest state, and 50%, 55%, and 31%, respectively, of the flow produced during CPR in normothermic animals. Blood flow during hypothermic CPR did not change significantly over time; however, during normothermic CPR, cardiac output and cerebral and myocardial flows decreased so that at 20 minutes there were no significant differences from those values measured in hypothermic animals. The reduction in organ flow produced by external chest compression in hypothermic animals may be a result of the changes in the viscoelastic properties of the thorax that occur during profound hypothermia.     

The effects of atrial fibrillation on regional blood flow in the awake dog

To determine the acute effects of atrial fibrillation on regional blood flow, measurements were made in awake dogs with this arrhythmia induced and sustained by rapid atrial stimulation. Atrial fibrillation reduced cardiac output (from 3.7 +/- 0.3 to 3.0 +/- 0.2 L/min, P less than 0.05), but mean aortic and left atrial pressures were not changed. Although average ventricular myocardial blood flow remained the same, dogs with an average basal myocardial blood flow less than 106 mL/min/100g showed an immediate increase (from 85 +/- 5 to 120 +/- 9 mL/min/100g, P less than 0.05), whereas those with a higher basal value showed a decrease (from 144 +/- 14 to 110 +/- 18 mL/min/100g, P less than 0.05). Moreover, change in myocardial blood flow with atrial pacing, at a rate equal to the average ventricular rate of atrial fibrillation, was directionally similar to that found during atrial fibrillation. However, left atrial myocardial blood flow increased significantly both during atrial fibrillation and pacing. Sustained atrial fibrillation resulted in a fall in splanchnic and renal cortical flow. Brain blood flow also decreased during atrial fibrillation. While the fall in cerebral blood flow was immediately evident, in the cerebellum and brain stem, this decrease was not statistically significant until the 15 min measurement. Also, presence of a ligated common carotid artery did not influence cerebral regional blood flow either under basal conditions or with atrial fibrillation. Thus, in awake dogs the fall in cardiac output that occurs with atrial fibrillation may be accompanied by diverse effects on regional circulations.     

Regional heterogeneity of resting perfusion in hypertrophic cardiomyopathy is related to delayed contrast enhancement but not to systolic function: a PET and MRI study.

BACKGROUND: Regional differences in resting myocardial blood flow (MBF) have been observed in patients with hypertrophic cardiomyopathy (HCM), but their determinants are currently unknown. This study verifies whether MBF at rest in HCM is related to delayed contrast enhancement (DCE) or regional systolic function (or both) as determined by magnetic resonance imaging. METHODS AND RESULTS: Fourteen patients with HCM were studied. MBF was measured with positron emission tomography by use of oxygen 15-labeled water. DCE and tissue tagging, to calculate end-systolic circumferential shortening (Ecc), were obtained with magnetic resonance imaging. The mean resting MBF was 0.78 +/- 0.19 mL x min(-1) x mL(-1), and there was a trend toward reduced MBF in the septum (0.72 +/- 0.11 mL x min(-1) x mL(-1)) compared with that in the lateral wall (0.84 +/- 0.29 mL x min(-1) x mL(-1)) (P = .092). The distribution patterns of DCE and Ecc were both heterogeneous, displaying significantly increased enhancement and impaired regional systolic function in the hypertrophic septum compared with the lateral wall (both P < .001). Resting MBF was inversely related to the extent of DCE (r = -0.30, P < .001), whereas MBF was not significantly related to Ecc (r = -0.15, P = .072). CONCLUSIONS: Regional heterogeneity of resting perfusion in HCM is related to the extent of DCE but not to regional systolic function.     

Effect of hyperinsulinemia on myocardial amino acid uptake in patients with coronary artery disease

Branched-chain amino acids (BCAAs) are oxidative energy substrates for the heart and may exert anabolic effects on myocardial protein. The factors regulating their myocardial uptake in patients with ischemic heart disease are therefore of interest. To examine whether myocardial BCAA utilization is influenced by the circulating insulin concentration, in 10 patients with chronic ischemic heart disease, we measured transmyocardial amino acid balance during fasting and again during a 90-minute euglycemic insulin infusion (plasma insulin, 218+/-25 microU x mL(-1)) with plasma BCAA concentrations held constant by coinfusion. In the fasting state, the myocardial fractional extraction of leucine (8%), isoleucine (9%), and valine (5%) from arterial plasma was slightly greater than that of glucose (3%), while net myocardial BCAA uptake (leucine, 409+/-207 nmol x min(-1); isoleucine, 220+/-144 nmol x min(-1); valine, 407+/-326 nmol x min(-1); and total BCAA uptake, 1.0+/-0.3 micromol x min(-1)) was about 13% that of glucose (8+/-2 micromol x min(-1)). During euglycemic hyperinsulinemia, myocardial glucose uptake increased 3-fold, but there was no change in the arterial-coronary sinus balance or net myocardial uptake of any BCAA under conditions where their plasma concentrations were held constant. Instead, the myocardial uptake of each BCAA correlated positively with its concentration in arterial plasma. These results demonstrate that in patients with cardiovascular disease, myocardial utilization of BCAAs is insensitive to the circulating insulin level and is regulated instead by their availability in arterial plasma. Hyperinsulinemia reduced the magnitude of both net glutamate uptake and alanine release, suggesting a possible salutary effect on myocardial oxidative efficiency.     

Minimal coronary stenoses and left ventricular blood flow during CPR.

STUDY OBJECTIVE: To assess the effect of a 33% coronary stenosis on myocardial blood flow during normal sinus rhythm and CPR. DESIGN: Prospective, before and after cardiac arrest and CPR; before and after creation of a 33% stenosis. SETTING: The University of Arizona Resuscitation Research Laboratory. SUBJECTS: Ten domestic closed-chest swine with patent coronary stenoses. INTERVENTIONS: A Teflon cylinder was placed in the mid-left anterior descending coronary artery to create a 33% stenosis. Myocardial blood flow was measured with colored microspheres both proximal and distal to the stenosis during normal sinus rhythm and during CPR. MEASUREMENTS AND MAIN RESULTS: During normal sinus rhythm, the stenosis did not alter the amount of myocardial blood flow distribution or quantity. Proximal to the stenosis the endocardial/epicardial flow ratio was 1.49 +/- 0.33, and distal to the stenosis it was 1.50 +/- 0.50. Likewise, during normal sinus rhythm, blood flow proximal and distal to the stenosis did not differ for either the epicardium (79 +/- 9 versus 66 +/- 13 mL/min/100 g) or the endocardium (111 +/- 27 versus 83 +/- 19 mL/min/100 g). However, the distribution of myocardial blood flow was markedly altered during CPR. The resultant endocardial/epicardial flow ratios were significantly less than during normal sinus rhythm, 0.49 +/- 0.11 (three minutes of CPR) and 0.74 +/- 0.07 (eight minutes of CPR) proximal to the stenosis and 0.39 +/- 0.15 (three minutes of CPR) and 0.49 +/- 0.14 (eight minutes of CPR) distal to the stenosis (P less than .05 versus normal sinus rhythm). In the presence of a 33% mid-left anterior descending coronary artery stenosis, endocardial blood flow at eight minutes of CPR was significantly lower distal to the stenosis compared with proximal to the stenosis (23 +/- 7 mL/min/100 g versus 74 +/- 18 mL/min/100 g; P less than .02). CONCLUSION: Minimal coronary lesions that do not diminish myocardial perfusion during normal physiologic conditions appear to significantly decrease subendocardial blood flow during cardiac arrest and CPR.     

Hibernating myocardium retains metabolic and contractile reserve despite regional reductions in flow,function, and oxygen consumption at rest

Hibernating myocardium, characterized by reductions in flow and function at rest, has limited contractile reserve in response to increases in external workload. We hypothesized that this attenuation of function reflects an adaptive downregulation that prevents the development of metabolic evidence of ischemia during stress. To test this hypothesis, pigs were chronically instrumented with a proximal left anterior descending artery stenosis for 3 months, resulting in severe anteroapical hypokinesis with reduced resting perfusion (0.78+/-0.05 versus 0.94+/-0.07 mL x min(-1)x g(-1) in remote, P<0.01; and 0.99+/-0.08 in controls, P<0.05). Open-chest studies confirmed resting dysfunction compared with normal controls (segment shortening 9.2+/-2.2% versus 23.5+/-1.1%, P<0.05). Resting myocardial oxygen consumption was reduced (63+/-3 versus 77+/-6 microL x g(-1) x min(-1) in controls, P<0.05), yet lactate consumption was normal. Although subendocardial perfusion failed to increase during graded, intravenous epinephrine infusion (n=8), peak segment shortening (to 17.3+/-3.1%, P<0.05) and oxygen consumption (to 90+/-6 microL x g(-1) x min(-1), P<0.01) increased from the depressed resting levels. There was no lactate production in hibernating myocardium, and lactate uptake increased during stress (0.7+/-0.1 to 1.2+/-0.1 micromol x g(-1) x min(-1), P<0.05). The absence of metabolic evidence of ischemia was also confirmed during atrial pacing to a rate of 120 bpm (n=8). Thus, despite reductions in function and oxygen consumption at rest, hibernating myocardium retains the ability to increase metabolism without the development of acute ischemia. This supports the hypothesis that the downregulation of oxygen consumption and function in hibernating myocardium is an adaptive response that prevents a supply-demand imbalance during submaximal increases in cardiac workload when coronary flow reserve is limited.     

Ventricular and myocardial function in mitral regurgitation (author's transl)]

Left ventricular and myocardial performance were analyzed in 9 patients with chronic volume overload by mitral regurgitation from biplane cineventriculograms, simultaneous pressure recordings and cardiac output (thermodilution method) determinations. In spite of a considerable regurgitant fraction (49 +/- 17% of total stroke volume) cardiac index on the average is normal (CI = 3.3 +/- 0.7 l . min-1). The main compensatory mechanism to maintain cardiac ouput in hypertorphy (WED = 1.1 +/- 0.2 cm; LVMI = 216 +/- 62 g . m-2; LVMI/EDVI = 1.3 +/- 0.3 g . ml-1) and dilatation (EDVI = 163 +/- 37 ml . m-2). An increase of preload is of minor importance (PLVED = 15 +/- 7 mmHg; sigma ED = (40 +/- 19) x 10(3) dyn . cm-2). Left ventricular enlargement and wall mass are related to the degree of clinical heart failure (NYHA). Enddiastolic volume on the average is more increased than total stroke volume (89 +/- 31 ml . m-2). Ejection fraction (EF = 54 +/- 7%) was depressed despite a normal afterload (sigma tej = (171 +/- 37 x 10(3) dyn. cm-2; sigma max = (247 +/- 48 x 10(3) dyn . cm-2). The reduced ejection fraction and diminished myocardial power are related to an impairment of myocardial function (VMW . sigma tej = (83 +/- 39) x 10(3) dyn . cm-2 . s-1; VMW . sigma tej/ln sigma ED = 7.9 +/- 3.6 x 10(3) dyn . cm-2 . s-1). In comparable degrees of heart failure myocardial function is more compromised in patients with mitral than with aortic regurgitation.     

Coronary vasodilator reserve and Framingham risk scores in subjects at risk for coronary artery disease.

BACKGROUND: The relationship between coronary vasodilator reserve and risk of coronary heart disease (CHD) in subjects without coronary artery disease (CAD) is not well known. METHODS AND RESULTS: We studied 289 subjects (mean age, 58 +/- 10 years) without overt CAD and at low (< 10%) to intermediate risk (10%-20%) for CHD based on Framingham risk scores (RAMPART [Relative and Absolute Myocardial Perfusion changes as measured by Positron Emission Tomography to Assess the Effects of ACAT Inhibition: A Double-Blind, Randomized, Controlled, Multicenter Trial]). Coronary flow reserve (CFR) and coronary vascular resistance (CVR) were calculated from rest and adenosine nitrogen 13 ammonia positron emission tomography studies. Framingham-estimated CHD risk was used to as a surrogate for outcomes. Compared with subjects with low-risk scores (n = 150), those with intermediate-risk scores (n = 139) had a higher minimal CVR (49.3 +/- 17.41 mm Hg x mL(-1) x min(-1) x g(-1) vs 52.4 +/- 16.4 mm Hg x mL(-1) x min(-1) x g(-1), P = .05) and lower CFR (2.8 +/- 1.0 vs 2.5 +/- 0.8, P = .02). CFR was inversely related to CHD risk (R = -0.2, P = .006), and CVR was directly related to CHD risk (R = 0.2, P < .001). The mean CFR was significantly lower in patients in the first quartile of CHD risk compared with those in the fourth quartile (2.3 +/- 0.7 vs 2.8 +/- 1.0, P = .02), and the minimal CVR was significantly higher (44 +/- 15 mm Hg x mL(-1) x min(-1) x g(-1) vs 53 +/- 14 mm Hg x mL(-1) x min(-1) x g(-1), P < or = .05). CONCLUSIONS: In subjects without clinical CAD and at low to intermediate risk, CFR assessed by positron emission tomography is inversely related to estimated 10-year CHD risk.     

Quantification of regional myocardial blood flow using first-pass multidetector-row computed tomography and adenosine triphosphate in coronary artery disease

BACKGROUND: The feasibility of using cardiac multidetector-row computed tomography (MDCT) technology in the quantitative assessment of myocardial blood flow (MBF) using the adenosine triphosphate (ATP) load technique was investigated in the present study. METHODS AND RESULTS: The study group comprised 14 patients (11 men, 3 women, age range 52-79 years, mean age 69.2 years) who underwent cardiac cine MDCT using the ATP-load technique. MBF was estimated from the slope of the linear regression equation with Patlak plots analysis. The overall average MBF was 1.83+/-0.62 ml . g(-1) . min(-1). Mean MBF in territories with stenosis on coronary angiography was 1.19+/-0.36 ml . g(-1) . min(-1) and 2.06+/-0.54 ml . g(-1) . min(-1) (p<0.01) in territories without stenosis. The average MBF in territories with moderate to severe ischemia on myocardial perfusion scintigraphy was 1.32+/-0.14 ml .g(-1 ). min(-1 )and 1.95+/-0.64 ml . g(-1) . min(-1) (p<0.01) in territories without ischemia. CONCLUSION: MDCT can be used to quantify MBF using first-pass dynamic data.     

Adenosine-induced coronary flow reserve in Watanabe heritable hyperlipidemic rabbits

The Watanabe heritable hyperlipidemic (WHHL) rabbit develops coronary atherosclerosis and hypercholesterolemia because of a genetic deficiency of low-density lipoprotein receptors and is therefore a good animal model for studying the relationships of coronary atherosclerosis, hypercholesterolemia and coronary flow reserve. The aim of the present study was to assess myocardial perfusion at baseline and during adenosine infusion (0.2 mg x kg(-1) x min(-1)) in 8 WHHL rabbits (13.8+/-0.5 months) with 13N-ammonia, small-animal positron emission tomography (PET) and colored microspheres. Results were compared with those from 6 age-matched Japanese white rabbits. Plaque distribution was also examined in the extramural coronary arteries. All 8 WHHL rabbits had coronary plaques, with 6 showing multiple plaques. Mean global myocardial blood flow (ml x min(-1) x g(-1)) did not differ significantly between control and WHHL groups both at baseline (3.67+/-0.72 vs 4.26+/-1.12 ml x min(-1) x g(-1), p=NS) and with adenosine (7.92+/-2.00 vs 9.27+/-2.91 ml x min(-1) x g(-1), p=NS), nor did coronary flow reserve (2.16+/-0.37 vs 2.18+/-0.41, p=NS). None showed evidence of regional perfusion abnormalities by visual and semiquantitative analyses of PET images. It was concluded that WHHL rabbits preserve adenosine-induced coronary flow reserve despite coronary atherosclerosis and hypercholesterolemia, suggesting that a compensatory mechanism develops in this animal model.     

Altered calcium uptake by the sarcoplasmic reticulum following cardiac transplantation in humans

Abnormalities in the diastolic properties of the heart have been described following human cardiac transplantation and may reflect, at least in part, decreased Ca2+ uptake by the sarcoplasmic reticulum. This possibility was evaluated by obtaining serial myocardial biopsies in 13 patients who underwent cardiac transplantation for severe heart failure. Oxalate-supported Ca2+ uptake by the sarcoplasmic reticulum was measured in homogenates of 83 ventricular biopsies from transplanted hearts. Biopsies from seven subjects with normal cardiac function and morphology served as controls. In the transplanted hearts, there was a tendency for Ca2+ uptake rate to decline with time so that 4-5 months postoperatively, it was significantly lower (4.5 +/- 0.5 nmoles Ca2+/mg/min) compared to controls (5.6 +/- 0.5 nmoles Ca2+/mg/min, p less than 0.01). Plasma norepinephrine levels fell from the high preoperative values (689 +/- 50 pg/mL) towards normal (215 +/- 7 pg/mL) within 30 days after transplantation. Subsequently, however, there was a tendency for norepinephrine levels to increase (369 +/- 55 pg/mL at 4 months). In four patients for which serial observations were available, there was an inverse relationship between myocardial Ca2+ uptake and plasma norepinephrine levels. These results indicate the feasibility of obtaining reproducible serial measurements of Ca2+ uptake in human cardiac biopsies. The decline in sarcoplasmic reticulum function following cardiac transplantation may be, in part, the biochemical basis for the reported impairment in diastolic relaxation.     

Reconstruction of rapidly acquired Germanium-68 transmission scans for cardiac PET attenuation correction.

BACKGROUND: Transmission (TX) scan time by use of radionuclide sources for cardiac positron emission tomography prolong imaging and increase the likelihood of patient motion artifacts. A reconstruction algorithm combining ordered-subsets expectation maximization with a Bayesian prior was developed and applied to rapid Germanium-68 (Ge-68) TX scans. METHODS AND RESULTS: A cardiac phantom with Fluorine-18 (Fl-18) was used to determine a minimal count threshold for Ge-68 TX scanning. Images were acquired over a count range from 2.5 x 10(6) to 8 x 10(7) and for a high-count scan of 1.6 x 10(9) counts to study reconstruction parameters and to determine the minimum TX count threshold. The method was compared against clinical 4-minute TX scans in ten Rubidium-82 (Rb-82) rest/stress myocardial perfusion studies (body mass index, 30 +/- 4 kg/m(2)). The minimal count threshold was 20 x 10(6), and the mean scan time for the Rb-82 studies was 70.5 +/- 3.4 seconds. More than 90% of the segmental scores computed from images acquired via rapid TX scans differed by less than 5% from those obtained with 4-minute TX scans. The mean differences in perfusion scores between the rapid and 4-minute TX scans were 0.46% (95% confidence interval, -1.84% to 0.93%) at rest and 0.39% (95% confidence interval, -1.84% to 1.07%) at stress, demonstrating equivalency of the rapid and 4-minute scans. CONCLUSIONS: Ordered-subsets expectation maximization with a Bayesian prior accurately and efficiently reconstructs rapidly acquired Ge-68 TX scans for Rb-82 myocardial perfusion positron emission tomography studies.     

The influence of bradycardia and normofrequent ventricular pacing on myocardial blood flow and energy demand in rats

The purpose of the present study was to determine the effect of beta-blockade-induced bradycardia and normofrequent ventricular pacing (VP) on regional myocardial (MBF) and cerebral blood flow (CBF) as well as on myocardial oxygen consumption (MVO(2)) using colored microspheres. The MBF at sinus rhythm (SR) was 4.60 +/- 1.27 ml/g/min and decreased to 3.80 +/- 0.74 ml/g/min (p < 0.05) during beta-blockade. The MBF was 5.10 +/- 1.88 ml/g/min during VP with beta-blockade. The endo-/epicardial MBF ratio during VP was significantly reduced. MVO(2) at beta-blockade was significantly lower (0.21 +/- 0.06 ml/g x min(-1), p < 0.05) than at SR (0.47 +/- 0.15 ml/g x min(-1)) and during VP with beta-blockade (0.54 +/- 0.14 ml/g x min(-1)). RESULTS: (i) MBF and MVO(2) are reduced with decreasing mean arterial pressure (MAP) during beta-blockade-induced bradycardia, but MBF and MVO(2) are significantly increased during normofrequent VP with beta-blockade despite a further reduction in MAP. (ii) The MBF ratio is constant during beta-blockade but is significantly lower during normofrequent VP with beta-blockade. (iii) CBF remained constant during all experimental conditions. CONCLUSION: Despite beta-blockade, the subendocardium is jeopardized during normofrequent VP by ischemia.