Similar patterns of myocardial metabolism and perfusion in patients with type 2 diabetes and heart disease of ischaemic and non-ischaemic origin.

AIMS/HYPOTHESIS: Type 2 diabetes and insulin resistance are often associated with the co-occurrence of coronary atherosclerosis and cardiac dysfunction. The aim of this study was to define the independent relationships between left ventricular dysfunction or ischaemia and patterns of myocardial perfusion and metabolism in type 2 diabetes. METHODS: Twenty-four type 2 diabetic patients--12 with coronary artery disease (CAD) and preserved left ventricular function and 12 with non-ischaemic heart failure (HF)--were enrolled in a cross-sectional study. Positron emission tomography (PET) was used to assess myocardial blood flow (MBF) at rest, after pharmacological stress and under euglycaemic hyperinsulinaemia. Insulin-mediated myocardial glucose disposal was determined with 2-deoxy-2-[(18)F]fluoroglucose PET. RESULTS: There was no difference in myocardial glucose uptake (MGU) between the healthy myocardium of CAD patients and the dysfunctional myocardium of HF patients. MGU was strongly influenced by levels of systemic insulin resistance in both groups (CAD, r = 0.85, p = 0.005; HF, r = 0.77, p = 0.01). In HF patients, there was an inverse association between MGU and the coronary flow reserve (r = -0.434, p = 0.0115). A similar relationship was observed in non-ischaemic segments of CAD patients. Hyperinsulinaemia increased MBF to a similar extent in the non-ischaemic myocardial of CAD and HF patients. CONCLUSIONS/INTERPRETATION: In type 2 diabetes, similar metabolic and perfusion patterns can be detected in the non-ischaemic regions of CAD patients with normal cardiac function and in the dysfunctional non-ischaemic myocardium of HF patients. This suggests that insulin resistance, rather than diagnosis of ischaemia or left ventricular dysfunction, affects the metabolism and perfusion features of patients with type 2 diabetes.

Apolipoprotein A-I mimetic peptide L-4F prevents myocardial and coronary dysfunction in diabetic mice.

Diabetes is a major health problem associated with adverse cardiovascular outcomes. The apolipoprotein A-I mimetic peptide L-4F is a putative anti-diabetic drug, has antioxidant and anti-inflammatory proprieties and improves endothelial function. In obese mice L-4F increases adiponectin levels, improving insulin sensitivity, and reducing visceral adiposity. We hypothesized that the pleiotropic actions of L-4F can prevent heart and coronary dysfunction in a mouse model of genetically induced Type II diabetes. We treated db/db mice with either L-4F or vehicle for 8 weeks. Trans-thoracic echocardiography was performed; thereafter, isolated hearts were subjected to ischemia/reperfusion (IR). Glucose, insulin, adiponectin, and pro-inflammatory cytokines (IL-1ß, TNF-α, MCP-1) were measured in plasma and HO-1, pAMPK, peNOS, iNOS, adiponectin, and superoxide in cardiac tissue. In db/db mice L-4F decreased accumulation of subcutaneous and total fat, and increased insulin sensitivity and adiponectin levels while lowering inflammatory cytokines (P < 0.05). L-4F normalized in vivo left ventricular (LV) function of db/db mice, increasing (P < 0.05) fractional shortening and decreasing (P < 0.05) LV dimensions. In I/R experiments, L-4F prevented coronary microvascular resistance from increasing and LV function from deteriorating in the db/db mice. These changes were associated with increased cardiac expression of HO-1, pAMPK, peNOS, and adiponectin and decreased levels of superoxide and iNOS (P < 0.01). In the present study we showed that L-4F prevented myocardial and coronary functional abnormalities in db/db mice. These effects were associated with stimulation of HO-1 resulting in increased levels of anti-inflammatory, anti-oxidative, and vasodilatatory action through a mechanism involving increased levels of adiponectin, pAMPK, and peNOS.

Computer simulation of coronary flow waveforms during caval occlusion.

OBJECTIVES: Mathematical modeling of the cardiovascular system is a powerful tool to extract physiologically relevant information from multi-parametric experiments. The purpose of the present work was to reproduce by means of a computer simulator, systemic and coronary measurements obtained by in vivo experiments in the pig. METHODS: We monitored in anesthetized open-chest pig the phasic blood flow of the left descending coronary artery, aortic pressure, left ventricular pressure and volume. Data were acquired before, during, and after caval occlusion. Inside the software simulator (CARDIOSIM) of the cardiovascular system, coronary circulation was modeled in three parallel branching sections. Both systemic and pulmonary circulations were simulated using a lumped parameter mathematical model. Variable elastance model reproduced Starling's law of the heart. RESULTS: Different left ventricular pressure-volume loops during experimental caval occlusion and simulated cardiac loops are presented. The sequence of coronary flow-aortic pressure loops obtained in vivo during caval occlusion together with the simulated loops reproduced by the software simulator are reported. Finally experimental and simulated instantaneous coronary blood flow waveforms are shown. CONCLUSIONS: The lumped parameter model of the coronary circulation, together with the cardiovascular system model, is capable of reproducing the changes during caval occlusion, with the profound shape deformation of the flow signal observed during the in vivo experiment. In perspectives, the results of the present model could offer new tool for studying the role of the different determinants of myocardial perfusion, by using the coronary loop shape as a "sensor" of ventricular mechanics in various physiological and pathophysiological conditions.

Radionuclide PET and PET/CT in coronary artery disease.

In the present review, the basis of non invasive assessment of CAD, the most recent technical developments and results obtained by PET in cardiovascular research and clinical cardiology are described. PET has provided a wealth of new information in the field of cardiac pathophysiology and remains the gold standard for non-invasive measurements of MBF and CFR against which new techniques should be tested. The possibility to combine this relevant functional information with the anatomic details on luminal and arterial wall abnormalities, provided by multislice CT with or without the use of "hybrid" scanners, offers new opportunities for comprehensive non-invasive assessment of CAD and efficacy of new treatments.

CSF phosporylated TAU protein levels correlate with cerebral glucose metabolism assessed with PET in Alzheimer's disease.

One major goal of drug development would be the establishment of biomarkers as objective indicators of normal biological and pathogenetic processes, or pharmacological response to a therapeutic intervention. A potential approach is to investigate proteins in CSF linked to key neuropathological features of Alzheimer's disease (AD). Recently CSF phosphorylated-Tau (p-Tau) levels have been reported to reflect neurofibrillary changes within the brain of patients with AD, however the use of serial CSF investigations in order to monitor the disease progression is not applicable. PET with FDG reveals characteristic patterns in AD patients, however so far no correlation between in vivo metabolic information and pathological features has been reported. In the present study, we tested whether CSF Tau levels correlate with metabolic rate for glucose consumption in a cohort of 28 AD patients. We found a statistically significative correlation between both CSF total and p-TAU protein and relative metabolic indexes obtained from 18FDG-PET scans in parietal, temporal and occipital lobes bilaterally. These results indicate the existence of a correlation between impairment of cerebral metabolism, estimated throughout FDG-PET, and CSF Tau protein levels.

Churg-Strauss syndrome: clinical and serological features of 19 patients from a single Italian centre.

OBJECTIVE: Churg-Strauss syndrome is a rare multisystem vasculitis of unknown aetiology. Due to the rarity of the disease, few single-centre case series have been described. The aim of this study was to evaluate a small series from a single Italian centre in order to describe the clinical features of the disease, the treatment and long-term follow-up. METHODS: Nineteen Churg-Strauss syndrome patients were selected from the medical records of all vasculitis patients attending the Immunology Unit at the Department of Internal Medicine of the University of Pisa in the decade between 1989 and 2000. Data were obtained retrospectively. RESULTS: All the patients had asthma and hypereosinophilia. As in other case series, the lungs, skin and peripheral nervous system were the most commonly involved organs. The majority of our patient received i.v. pulses of methylprednisolone followed by i.v. pulses of cyclophosphamide. The outcome and long-term follow-up were good. There were no fatalities observed in this series during the follow-up period. CONCLUSIONS: Churg-Strauss syndrome is a systemic vasculitis occurring in patients with a history of asthma and allergic rhinitis. The positive results of the treatment protocol used in this preliminary study deserve to be tested in controlled multicentre studies.

Significance of both negative T waves and stress-induced normalization of the repolarization phase in infarcted patients: a positron-emission-tomography assessment of regulation of myocardial blood flow and viability of myocardium.

BACKGROUND: The clinical correlation of stress-induced normalization of previously negative T waves (NNTW) to regulation of regional myocardial blood flow (MBF) and tissue viability is still being debated. OBJECTIVE: To clarify its meaning. METHODS: We studied 25 patients, who had previously suffered anterior myocardial infarction and for whom negative T waves were recorded on baseline electrocardiographic precordial leads, by means of positron emission tomography. We obtained MBF in the infarcted myocardial regions under resting conditions for all patients, during infusion of dipyridamole (17 patients) and dobutamine (20 patients), using [13N]-ammonia as a flow tracer. RESULTS: During stress tests, 13 patients exhibited NNTW (group 1) whereas the remaining 12 presented persistent negative T waves (group 2). NNTW was observed in 18 stress studies (for 10 and eight patients during administration of dobutamine and dipyridamole, respectively) whereas persistent negative T waves occurred 19 times (for 10 patients during infusion of dobutamine and nine patients during administration of dipyridamole). A complete concordance of the modifications of the repolarization phase was observed for patients who were subjected both to dipyridamole and to dobutamine studies. Furthermore, we assessed viability of myocardium in 20 of 25 patients using [18F]-fluorodeoxyglucose. For the remaining five patients not subjected to metabolic imaging, a coronary reserve of 1.65 was considered a cut-off of viability. Resting MBF for patients in groups 1 and 2 were similar (0.53 +/- 0.20 versus 0.47 +/- 0.17 ml/min per g, respectively, NS) whereas during pharmacological stress, MBF of patients in group 1 was significantly higher than that for patients in group 2 (0.99 +/- 0.41 versus 0.56 +/- 0.26 ml/min per g, respectively, P < 0.0001). Coronary vasodilating capability, expressed as stress/resting MBF ratio, turned out to be 1.88 +/- 0.49 and 1.16 +/- 0.37 for patients in groups 1 and 2, respectively (P < 0.0001). We observed no difference in mean exercise work load (9.6 +/- 2.80 versus 8.46 +/- 2.18 min, NS) and rate- pressure product (24230 +/- 6425 versus 24207 +/- 8146 mmHg beats/ min, NS) at peak for the two categories of patients. All 13 patients in group 1 (100%) had viable myocardium in the anterior infarcted areas whereas only one of 12 patients in group 2 did (9%, P< 0.0001 versus group 1). Finally, a subanalysis for the specific pharmacological agent used was performed and it gave similar results. CONCLUSION: Regardless of the specific stress test able to elicit the electrocardiographic sign, infarcted dysfunctional areas with stress-induced NNTW were demonstrated to have a higher coronary vasodilating capability and a greater probability of viability of myocardium than had persistent negative T wave regions. Therefore, detection of NNTW appears to be a cheap first-line method for the identification both of a better preserved coronary microcirculatory function and of the persistence of viability of myocardium in the infarcted areas.

Increased circulating levels of ouabain-like factor in patients with asymptomatic left ventricular dysfunction.

BACKGROUND: Much evidence has been accumulated that human plasma contains digitalis-like factor(s) with Na/K ATPase inhibitor properties. Increased concentrations of ouabain-like factor (OLF) have been reported in patients with moderate to severe hypertension and in patients with overt congestive heart failure due to dilated cardiomyopathy. AIM: The presence of circulating OLF has not been investigated in borderline to mild hypertension or in the early stage of dilated cardiomyopathy. METHODS AND RESULTS: The study population consisted of 18 normal volunteers, 24 patients with borderline to mild hypertension, 47 patients with asymptomatic left ventricular dysfunction (ALVD) due to dilated cardiomyopathy and 26 patients with cardiac arrhythmias but normal left ventricular function. OLF values (pM ouabain equivalent) were assayed in extracted plasma, using a radioimmunoassay for ouabain. OLF was, respectively, 29.4+/-20.6 pM in normal controls, 39.1+/-23.8 pM in hypertensives, 35+/-18 pM in patients with cardiac arrhythmias, 52.3+/-25.8 pM in ALVD patients not treated with digoxin and 64.6+/-29.6 pM in ALVD patients treated with digoxin. Patients with ALVD, both treated and not treated with digoxin, had OLF significantly higher (P<0.05) than all the other groups. In patients with ALVD no correlation between OLF and left ventricular ejection fraction was observed. In the hypertensive group no correlation between OLF and both diastolic and systolic pressure was found. CONCLUSION: Increased concentrations of OLF were observed in patients with left ventricular dysfunction due to dilated cardiomyopathy, before the occurrence of overt heart failure, suggesting that OLF may be an early marker of the disease.

Effects of long-term treatment with verapamil on left ventricular function and myocardial blood flow in patients with dilated cardiomyopathy without overt heart failure.

Myocardial blood flow (MBF) abnormalities are present in early stage dilated cardiomyopathy (DCM) and have been attributed to coronary microvascular abnormalities. The favorable effects of verapamil on coronary microcirculation might indicate its use in early stage DCM. We assessed the safety of long-term combination therapy of verapamil and enalapril and its effects on both left ventricular function and myocardial perfusion compared with enalapril alone in 18 patients with DCM (15 men, 3 women; mean age, 50+/-9 years) without overt heart failure (NYHA class I-II). At baseline and after 6 months of randomized treatment with either enalapril (10-20 mg) (nine patients, group 1) or enalapril (10-20 mg) and verapamil (120-240 mg) (nine patients, group 2), left ventricular function was assessed at rest, during handgrip, and during bicycle exercise by equilibrium radionuclide angiography. Mean MBF was measured at rest and after dipyridamole by positron emission tomography (PET) and 13N-ammonia as a flow tracer. At baseline, the two groups had reduced left ventricular ejection fraction at rest, which was further impaired during isometric exercise, but increased at peak bicycle exercise. MBF was similarly reduced in the two groups at rest and during dipyridamole. During treatment, no adverse events occurred in either group. After 6 months there was no significant difference in the main study variables either between the two groups or within each group before and after treatment. Long-term combination therapy with verapamil and enalapril is safe in patients with DCM without overt heart failure. Despite no favorable effect on myocardial perfusion, combined treatment prevented deterioration of left ventricular function, similarly to enalapril alone.

Myocardial blood flow and perfusion reserve in infarcted patients with stress-induced normalization of previously negative T waves: a positron emission tomography study.

BACKGROUND: The clinical correlations between stress-induced normalization of previously negative T waves (NTW) and regional myocardial blood flow (MBF) regulation and tissue viability remain debatable. METHODS AND RESULTS: To confirm these correlations, 14 patients with previous anterior myocardial infarction (13 Q waves) and NTW on baseline electrocardiographic precordial leads and 10 healthy subjects were studied by means of positron emission tomography (PET). The MBF values were obtained in the anterior infarcted myocardial regions in either resting condition or during dipyridamole infusion, using N-13 ammonia as a flow tracer. Seven subjects had normalization of NTW (Group 1) and 7 had persistent NTW (Group 2) during dipyridamole infusion. The resting MBF values were similar for both Group 1 and Group 2 (0.43+/-0.13 versus 0.51+/-0.15 mL.min(-1).g(-1), respectively; P = not significant) and were significantly lower than in the anterior myocardial regions of healthy subjects (1.03+/-0.23 mL.min(-1).g(-1), P < .001). After administration of dipyridamole, the MBF was significantly higher in Group 1 than in Group 2 (0.88 +/- 0.37 versus 0.55 +/- 0.17 mL.min(-1).g(-1), respectively; P < .05) and markedly lower than in healthy subjects (3.78+/-0.64 mL.min(-1).g(-1), P < .001). Coronary reserves (dipyridamole/resting MBF) were 2.03+/-0.40 and 1.14+/-0.44 in Group 1 and Group 2, respectively (P < .002). CONCLUSION: Despite similar values of resting perfusion, infarcted dysfunctional areas with or without NTW during stress may present different regional MBF responses; normalization of NTW demonstrates higher coronary flow reserve than persistent NTW, suggesting a better preserved coronary microcirculatory function in the former, indicative of the presence of myocardial viability.

Homogeneously reduced versus regionally impaired myocardial blood flow in hypertensive patients: two different patterns of myocardial perfusion associated with degree of hypertrophy.

OBJECTIVES: The aim of this study was to quantitatively measure regional and global myocardial blood flow and coronary reserve in hypertensive patients without coronary artery disease and to assess the correlation with left ventricular mass. BACKGROUND: The effect of left ventricular hypertrophy on regional vasodilating coronary capability in arterial hypertension is controversial, and no quantitative method has been applied to assess a possible correlation. METHODS: Positron emission tomography was performed in 50 untreated hypertensive patients and 13 normotensive subjects. Blood flow at baseline and after dipyridamole was globally and regionally measured by using nitrogen-13 ammonia; coronary reserve and resistance were calculated. Left ventricular mass was assessed by two-dimensional echocardiography. RESULTS: In hypertensive patients, flow at baseline was similar to that of normotensive subjects (p = 0.21), but values were reduced after pharmacologic vasodilation (p < 0.05). This impairment of maximal coronary flow was not correlated with left ventricular mass (p = 0.13). Among hypertensive patients, we identified a group with a homogeneous distribution of perfusion and a group with a heterogeneous flow pattern. Flow was globally reduced in the former group, but it was abnormal only at the site of perfusion defects in the latter. Patients with regional defects showed the highest likelihood of having an increased left ventricular mass. CONCLUSIONS: In arterial hypertension, left ventricular mass is not correlated with global myocardial blood flow. Nevertheless, patients with ventricular hypertrophy are likely to show a heterogeneous flow pattern with regional defects and almost normal blood flow in nonaffected regions. In hypertensive patients with a homogeneous perfusion pattern during stress, myocardial blood flow frequently shows a diffuse reduction.

Comparative effects of enalapril and verapamil on myocardial blood flow in systemic hypertension.

BACKGROUND: The comparative effects of calcium channel blockers and ACE inhibitors on myocardial blood flow (MBF) in hypertensive patients after long-term treatment are still unknown. METHODS AND RESULTS: Twenty hypertensive subjects with normal coronary arteries were randomly assigned to verapamil 240 to 480 mg/d or enalapril 10 to 40 mg/d. MBF was quantified at rest, during pacing tachycardia, and after dipyridamole by positron emission tomography and 13N-ammonia before and 6 months after treatment after 1 week of pharmacological washout. In both groups, blood pressure and heart rate during flow measurements were not different before and after therapy. Before treatment, mean MBF at rest, during pacing tachycardia, and after dipyridamole infusion was similar in the two groups; however, pacing and dipyridamole flows were significantly lower than those obtained in a control group of normotensive subjects. After treatment, in the enalapril-treated patients, MBF did not change in the three study conditions. In the verapamil-treated patients, MBF did not change at rest and significantly increased during pacing and after dipyridamole. The inhomogeneity of regional MBF distribution, evaluated from the coefficient of variation, decreased at rest after both treatments and, in the enalapril group, also during pacing. No relation was found between changes in MBF and changes in left ventricular mass. CONCLUSIONS: In arterial hypertension, MBF during pacing tachycardia and after dipyridamole is impaired. Successful therapy with verapamil increases MBF response to these stimuli, independent of changes in perfusion pressure and left ventricular mass. These results suggest that verapamil directly improves coronary microcirculatory function in hypertension. Enalapril does not significantly change MBF but reduces the inhomogeneity of regional flow distribution.

Myocardial and forearm blood flow reserve in mild-moderate essential hypertensive patients.

BACKGROUND: Structural readaptation of systemic resistance-sized arterioles in response to an elevated blood pressure reduces the forearm vasodilator reserve in patients with essential hypertension. The development of a similar process at the coronary microvascular level has frequently been hypothesized, but little information about coronary remodeling during the uncomplicated stage of hypertension has been obtained, and the relationship with concomitant changes in forearm blood flow reserve is not known. OBJECTIVE: To assess the minimal myocardial resistance and its relationship with the minimal forearm resistance in a group of male patients with mild-to-moderate uncomplicated hypertension and carefully matched controls. MATERIAL AND METHODS: The minimal myocardial resistance (Rmin(myocardia), the mean arterial pressure: hyperemic myocardial flow ratio after administration of 0.84 mg/kg dipyridamole, measured by using positron emission tomography and [3N]-ammonia), minimal forearm vascular resistance (Rmin(forearm), a hemodynamic index of arteriolar structure derived from the mean blood pressure and maximal postischemic forearm blood flow by venous plethysmography), echocardiographic cardiac mass and wall thickness were measured in 25 male patients with mild-to-moderate uncomplicated essential hypertension, most of whom had previously been treated, and in seven sex- and age-matched normotensive controls. RESULTS: Rmin(myocardial) (and hyperemia: baseline myocardial flow ratios) did not differ significantly between the two groups, whereas Rmin(forearm) was significantly higher in hypertensives. There was no significant intra-individual correlation between the two parameters. The left ventricular mass index was greater in patients and was related previously to Rmin(forearm) but not to Rmin(myocardial) for the overall sample. In a subgroup analysis, Rmin(forearm) values were 2SD above control values in nine patients and within the normal range in the remaining 16. The myocardial reserve was very similar in the two subgroups. CONCLUSIONS: The myocardial vasodilator reserve appeared to be preserved in these mild-to-moderate uncomplicated hypertensive patients, whereas the forearm vasodilator capacity was reduced, suggesting that the hypertensive readaptation process was not distributed homogeneously over the two vascular beds.

Microvascular dysfunction in collateral-dependent myocardium.

OBJECTIVES: The aim of this study was to evaluate myocardial blood flow regulation in collateral-dependent myocardium of patients with coronary artery disease. BACKGROUND: Despite great clinical relevance, perfusion correlates of collateral circulation in humans have rarely been estimated by quantitative methods at rest and during stress. METHODS: Nineteen patients with angina and isolated occlusion of the left anterior descending (n = 14) or left circumflex (n = 5) coronary artery were evaluated. Using positron emission tomography and nitrogen-13 ammonia, we obtained flow measurements at baseline, during atrial pacing-induced tachycardia and after intravenous administration of dipyridamole (0.56 mg/kg body weight over 4 min). Flow values in collateral-dependent and remote areas were compared with values in 13 normal subjects. RESULTS: Flow at rest was similar in collateralized and remote myocardium (0.61 +/- 0.11 vs. 0.63 +/- 0.17 ml/min per g, mean +/- 1 SD), and both values were lower than normal (1.00 +/- 0.20 ml/min per g, p < 0.01). During pacing, blood flow increased to 0.83 +/- 0.25 and 1.11 +/- 0.39 ml/min per g in collateral-dependent and remote areas, respectively (p < 0.05 vs. baseline); both values were lower than normal (1.86 +/- 0.61 ml/min per g, p < 0.01). Dipyridamole induced a further increase in perfusion in remote areas (1.36 +/- 0.57 ml/min per g, p < 0.01 vs. pacing) but not in collateral-dependent regions (0.93 +/- 0.37 ml/min per g, p = NS vs. pacing); again, both values were lower (p < 0.01) than normal (3.46 +/- 0.78 ml/min per g). Dipyridamole flow in collateral-dependent myocardium was slightly lower in patients with poorly developed than in those with well developed collateral channels (0.75 +/- 0.29 vs. 1.06 +/- 0.38 ml/min per g, respectively, p = 0.06); however, the former showed higher flow inhomogeneity (collateral/control flow ratio 0.58 +/- 0.10 vs. 0.81 +/- 0.22, respectively, p < 0.02). A linear direct correlation was observed between flow reserve of collateral-dependent and remote regions (r = 0.83, p < 0.01). CONCLUSIONS: Despite rest hypoperfusion, collateral-dependent myocardium maintains a vasodilator reserve that is almost fully utilized during increases in oxygen consumption. A global microvascular disorder might hamper adaptation to chronic coronary occlusion.