Heterogeneity Of Myocardial Perfusion Research Articles

Radiomics analysis of myocardial perfusion SPECT images in patients with cardiomyopathy and heart failure

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): JSPS KAKENHI Grants Background Although myocardial perfusion heterogeneity due to focally damaged cardiomyocytes is observed in single−photon emission computed tomography (SPECT) imaging, a current perfusion defect scoring system does not allow us to provide sufficient diagnostic information for heterogeneity. Purpose The aim of this study was to perform radiomics analysis of myocardial perfusion SPECT (MPS) images to investigate the potential to detect myocardial perfusion heterogeneity. Methods Patients with hypertrophic cardiomyopathy (n = 3), heart failure (n = 9), and with a low likelihood of coronary artery disease (n =15) (Figure 1), who underwent a rest 99mTc-MIBI myocardial perfusion SPECT, were assessed using a LIFEx software. Four shape−based features, 6 histogram−based features, and 32 textural features were computed. The relevant features for the classification of the patients were selected using the Boruta algorithm, and hierarchical clustering of the selected features using the Spearman correlation coefficient was also performed for the feature reduction. The receiver operating characteristics (ROC) analysis was performed by the support vector machine to calculate the area under the ROC curve (AUC) for the selected features. Results Of 40 features, 17 were selected by the classification analysis, and these features were classified into 7 classes by the correlation analysis (Figure 2). The ROC AUCs for 7 features extracted from each class were 0.99, 0.97, 0.96, 0.92, 0.90, 0.86, and 0.83 for the contrast of NDGLDM, the entropy of histogram, ZLNU of GLZLM, the energy of GLCM, the energy of histogram, SZLGE of GLZLM, and the correlation of GLCM, respectively, as compared to 0.39 for a summed rest score. Conclusions Radiomics analysis successfully determined the myocardial perfusion heterogeneity in patients with cardiomyopathy and heart failure. It might be promising for the evaluation of myocardial damages that cannot be analyzed by the conventional scoring method.

Effects of Cardioprotective Tactics on the Myocardial Perfusion and Contractile Function of the Left Ventricular Myocardium in Cancer Patients with Evidence of Doxorubicin-Induced Cardiotoxicity.

Aim To study the effect of cardioprotective tactics on parameters of left ventricular myocardial perfusion and contractility as per data from single-photon emission computed tomography in oncological patients with signs of anthracycline-induced cardiotoxicity.Material and methods The study included patients with oncological diseases (n=61) referred to polychemotherapy (PCT). For patients with signs of anthracycline-induced cardiotoxicity, a cardioprotective tactics was used, which included changing the PCT schedule and administering beta-blockers and angiotensin-converting enzyme inhibitors. For all patients at baseline, after the first four PCH courses, after initiation of the cardioprotective tactics and the next four PTC courses, the level of N-terminal pro-brain natriuretic peptide was measured and echocardiography and perfusion single-photon emission computed tomography were performed with assessment of left ventricular (LV) perfusion heterogeneity, systolic and diastolic function.Results Following four PTC courses, signs of cardiotoxicity were detected in 13 (21.3 %) patients. On the background of the cardioprotective tactics, a further decrease in LV ejection fraction (EF) by -9±2 % (p<0.01) was observed in 4 (30.8 %) patients. In 9 (69.2 %) patients, LV EF increased by 4±2 % (p<0.01). Standard indexes of LV myocardial perfusion did not significantly change. In 7 patients, the cardioprotective tactics was associated with reduced severity of myocardial perfusion disorder, LV∆σТ = -1.37±1.29 (p<0.05), and in 4 patients, with reduced heterogeneity of myocardial perfusion, LV∆σН = -1.20±0.70 (p<0.05).Conclusion The cardioprotective tactics prevents both further disorder of perfusion and decreases in parameters of left ventricular myocardial contractility in patients with anthracycline-induced cardiotoxicity.

Prognostic value of myocardial perfusion entropy in patients with normal thallium-201 myocardial perfusion with a CZT camera : PROMHETE study

Objectives We assessed the prognostic value of myocardial perfusion heterogeneity (entropy) in patients with normal myocardial perfusion as estimated from a dual isotope high-speed protocol (Thallium-201 stress and technetium- 99m-sestamibi rest) performed on a semiconductor camera. Background The prognostic value of normal myocardial perfusion scintigraphic imaging has been widely established for over twenty years but the clinical value of perfusion heterogeneity quantification beyond perfusion imaging as routinely performed is unknown. Methods From May 2011 to September 2012, 1159 patients with a normal scan or a non-significant perfusion abnormality (SSS 45%) were retrospectively identified. This study reports an interim analysis of 443 patients. A dual isotope high-speed protocol was performed on a semiconductor camera following exercise testing (37%) or pharmacological stress (63%). Myocardial perfusion images were then used to quantify myocardial perfusion heterogeneity as estimated by stress and rest image entropy. The primary endpoint was the occurrence of a cardiovascular event (cardiovascular death, non-fatal myocardial infarction, coronary angiography with or without revascularization, and stroke). Results The primary endpoint occurred in 73 patients during follow-up (3.3 ± 0.4 years). In a multivariate analysis, age (HR 1.04 [1.01; 1.06] P 4.06) underwent more events than those with a lower entropy ( Conclusions Myocardial perfusion heterogeneity (entropy) determined from thallium-201 stress perfusion images acquired on a semiconductor camera represent an independent prognostic factor of cardiovascular events with additive value over the classical interpretation of images from patients with normal myocardial perfusion scintigraphy. Myocardial perfusion heterogeneity (entropy) might represent a surrogate of coronary microvascular dysfunction.

IDENTIFICATION OF PATIENTS WITH FAMILIAL HYPERCHOLESTEROLEMIA IN THE RUSSIAN POPULATION USING THE EXAMPLE OF MOSCOW CITY AND MOSCOW REGION

Aim . To estimate the prevalence of familial hypercholesterolemia (FH) in a sample of Moscow city and Moscow region patients with hypercholesterolemia (HCh) based on lipid spectrum and instrumental methods. Material and methods . The study included two samples of patients (age >18 years), with total cholesterol (TCh) level ≥7.5 mmol/l and/or low-density lipoprotein (LDL) cholesterol level ≥4.9 mmol/l. First sample (n=60) was included to determine secondary hyperlipidemia frequency in newly diagnosed HCh, with measurement of thyroid hormone, glucose and glycated hemoglobin (HbA1c) levels. Patients of the second sample (n=432) from Russian registry of FH (RuFH) were studied by drug therapy assessment, lipid profile measurements, calculation of FH probability according to Dutch and British criteria, carotids duplex scanning (CDS), cardiac perfusion single-photon emission computed tomography (SPECT/CT) using rest/stress protocol. Results . The incidence of secondary dyslipidemia due to diabetes or hypothyroidism in patients with severe HCh was 18.3%. Monotherapy with atorvastatin (34.2%) or rosuvastatin (31.8%), combined therapy with statins and other lipid-lowering drugs (24.4%) prevails in the structure of lipidlowering therapy in patients with severe HCh. The frequency of FH according to Dutch criteria in HCh patients was 15.3%, – 18.1%. Patients with definite FH diagnosis showed higher level of TCh (p<0.001), LDL cholesterol (p<0.001), proprotein convertase subtilisin/kexin type 9 (p<0.001), lower high-density lipoprotein (HDL; p=0.02), and triglycerides (p<0.001). At that HDL cholesterol levels differed only in patients treated with lipid-lowering drugs. Patients with lipid-lowering therapy had significantly higher values of total stenosis percent, the number of plaques, intima-media complex thickness (p<0.001). Patients with lipid-lowering therapy with a definite and probable FH diagnosis had significantly worse values of CDS parameters. CDS parameters correlated with age in both therapeutic groups, and with maximal TCh levels in history in lipid-lowering therapy group (p<0.01). Patients with HCh and established ischemic heart disease showed higher frequency of positive exercise test result, higher values of left ventricle myocardial perfusion heterogeneity and defect severity parameters according to SPECT. Conclusion . Patients with severe HCh and suspected FH in Moscow city and region demonstrate satisfactory awareness, but low adherence to therapy, which is also extremely rarely sufficient to achieve target LDL levels and reduce coronary risks. This leads to early manifestations of atherosclerosis, including characteristic progressive impairments of myocardial perfusion. Despite the ongoing work on primary prevention, it is advisable to recommend sending such patients to specialized clinics for more qualified consultations and selection of optimal lipid-lowering therapy with mandatory further monitoring of its effectiveness.

Normal range and regional heterogeneity of myocardial perfusion in healthy human myocardium: assessment on dynamic perfusion CT using 128-slice dual-source CT

Information about myocardial perfusion in healthy hearts is essential for evaluating patients with ischemic heart disease. The purpose of this study was to determine the range and regional variability of myocardial perfusion in normal volunteers on dynamic perfusion computed tomography (CT). Myocardial perfusion was assessed in 19 healthy volunteers (age 33-60 years; 11 men) at rest and during adenosine-induced hyperemia using a 128-slice dual-source CT scanner. Data were quantified as cc/cc/min for the transmural myocardium based on a 17-segment American Heart Association model. Mean myocardial blood flows (MBF) were 1.73 ± 0.33 cc/cc/min during adenosine-induced hyperemia, 0.83 ± 0.21 cc/cc/min at rest, and perfusion reserve was 2.20 ± 0.53. Regional variability was 17 ± 5% for hyperemic perfusion, 18 ± 7% for resting, and 21 ± 6 % for perfusion reserve. Although statistically insignificant, perfusion in the septum was lower at rest and during hyperemia than in other regions. Women tended to have lower perfusion during hyperemia (1.65 ± 0.40 vs. 1.79 ± 0.28 cc/cc/min, P = 0.40), and higher perfusion at rest than men (0.91 ± 0.27 vs. 0.77 ± 0.15 cc/cc/min, P = 0.23), resulting in lower perfusion reserve (1.86 ± 0.31 vs. 2.45 ± 0.53, P = 0.11). This small cohort of healthy volunteers study reveals normal myocardial perfusion parameter on dynamic perfusion CT as follows: mean MBF is 1.73 ± 0.33 cc/cc/min during hyperemia, 0.83 ± 0.21 cc/cc/min at rest, and perfusion reserve is 2.20 ± 0.53. And the study also demonstrates considerable regional heterogeneity of the myocardial perfusion.

Physiology of endothelin in producing myocardial perfusion heterogeneity: A mechanistic study using darusentan and positron emission tomography

BackgroundHeterogeneity of resting perfusion may be due in part to up-regulation of coronary vasoconstriction via endothelin (ET) type A receptors, as homogeneity increases during subsequent vasodilatory hyperemia. Therefore, we conducted a mechanistic study using an ET receptor antagonist to determine if it could alter the homogeneity of myocardial perfusion. MethodsIncluded subjects demonstrated a low myocardial perfusion homogeneity index (HI) compared to normal volunteers. Four serial cardiac positron emission tomography Rb-82 scans were performed 2 weeks apart. Before the middle two scans, subjects were randomized to receive either darusentan first then placebo or visa versa. Absolute flow and coronary flow reserve were quantified for each study. Rest flow was adjusted for the pressure-rate product (PRP). ResultsWe screened 37 subjects and randomized 20 who satisfied entry criteria. Rest HI increased significantly while taking darusentan (0.39 ± 0.10 vs 0.33 ± 0.04 on placebo, P = .030, compared to a normal range of 0.52 ± 0.10) without an increase in the PRP (6,859 ± 1,503 vs 6,976 ± 1,092, P = .79), leading to a higher adjusted flow at rest (0.69 ± 0.18 cc/minute/g at 7,000 PRP vs 0.59 ± 0.07 with placebo). ConclusionsAntagonism of the type A ET receptor increases homogeneity of resting myocardial perfusion. The mechanism appears to be increased absolute rest flow without an increase in either the PRP or myocardial perfusion during hyperemia. Our translational results are consistent with one mechanism for the observed heterogeneity of myocardial perfusion in humans.

Attenuation of Adenosine-Induced Myocardial Perfusion Heterogeneity by Atenolol and Other Cardioselective β-Adrenoceptor Blockers: A Crossover Myocardial Perfusion Imaging Study

Little is known about the effect of chronic beta-blockade on adenosine actions. We sought to investigate the effect of oral beta-blockers on the presence, extent, and severity of myocardial perfusion abnormality induced by adenosine in patients with coronary artery disease. In this crossover study, 45 male patients with coronary artery disease on beta-blocker therapy with atenolol, bisoprolol, or metoprolol underwent adenosine myocardial perfusion imaging both on and off beta-blockade in a random order on separate days. Myocardial perfusion was assessed both qualitatively and quantitatively. Hemodynamic response, image analysis, and sensitivity for the detection of coronary stenosis (>or=50% luminal diameter reduction on x-ray coronary angiography) were compared between the on and off beta-blocker studies. Rate pressure product both at baseline and at peak adenosine infusion decreased by 23% +/- 15% and 21% +/- 18%, respectively, after beta-blockade (P < 0.001 for all). The median (interquartile range) summed difference score, a measure of defect reversibility, and quantitative defect size were both significantly lower after beta-blockade (median, 7.0 [interquartile range, 2.0-9.5] vs. median, 5.0 [interquartile range, 0-8.0], P = 0.002; and quantitative defect size, 18% [interquartile range, 9%-34%] vs. quantitative defect size, 6% [interquartile range, 0%-19%], P < 0.001, respectively). The overall sensitivity for the detection of coronary stenosis decreased from 0.76 (95% confidence interval, 0.65-0.88) to 0.58 (95% confidence interval, 0.45-0.71) after beta-blockade (P = 0.03). beta-blockade causes a small but significant reduction in the extent and severity of perfusion abnormality by adenosine. This may reduce the diagnostic sensitivity of adenosine myocardial perfusion imaging for the detection of flow-limiting coronary stenosis.

Imaging Left Ventricular Muscarinic Receptor Heterogeneity

As pointed out by Mazzadi et al1 in this issue of Circulation: Cardiovascular Imaging , parasympathetic tone plays a critical role as modulator of the cardiac sympathetic nervous system in both health and disease. Decreased tone, as reflected by decreased heart rate variability (HRV), has an important role in prognosis after myocardial infarction (MI).2 HRV is also associated with worse outcome in some patients with heart failure.3,4 Sudden increases in parasympathetic tone, identified by increase in HRV, may precipitate ventricular fibrillation in selected individuals.5 Other investigators have not found any of a multitude of HRV components to be predictive of outcome.6 The predictive value of HRV is insufficient to be used alone and must be part of a multivariate assessment. Article see p 365 Given the wealth of data demonstrating that HRV and its derivatives provide useful but not highly predictive clinical information and at a relatively low cost, what added value is gained by the use of a complicated and expensive imaging method? There are limitations to measurement of HRV that generally require the patient to be in sinus rhythm without sinoatrial dysfunction, to have ≤20% ectopic beats, have good quality tracings and, ideally, at least 24 hours of recording.2 The requirement for sinus rhythm limits it application in the largest population in which it is most likely beneficial, those with heart failure. Also, imaging of presynaptic sympathetic function has been shown to better predict adverse events.6 The results of the Mazzadi et al1 study suggest that imaging of parasympathetic function also may be predictive. Probably the most important rationale for the use of imaging to measure muscarinic cholinergic function relates directly to the regional heterogeneity of myocardial perfusion and sympathetic and parasympathetic function. As noted by Mazzadi et al,1 …

Positron emission tomo graphy imaging in the differentiatial diagnosis of cardio megaly of ischemic and noncoronarogenic origin

Objective. The study addresses differentiation of ischemic and non-ischemic cardiomegaly by positron emission tomography (PET). Design and methods. Based on echocardiography data 50 patients with cardiomegaly and reduced systolic function were included in the study: 32 patients with coronary heart disease (CHD) and 18 patients with normal coronary arteries according to angiography results (6 of them had alcohol abuse). All patients underwent PET with [13N]-ammonia and [18F]-FDG for myocardial perfusion and metabolism evaluation. A semiquantitative analysis of the images was performed. Results. All patients with CHD showed large hypoperfusion areas (more than 3 segments) matching the coronary artery flow. Perfusion/metabolism match was revealed in all (100 %) patients with CHD and perfusion/metabolism mismatch was observed in 25 (79 %) patients of the same group. The patients with noncoronarogenic cardiomegaly (NCM) had diffuse heterogeneity of myocardial perfusion, 5 of them showed small and mild perfusion defects with non-segmental distribution. The areas of abnormal perfusion were significantly larger in cases of CHD. Perfusion/metabolism match was noted in 2 (11 %) patients with NCM and none of the patients with NCM showed perfusion/metabolism mismatch. Conclusion. Diffuse heterogeneity of myocardial perfusion, non-segmental distribution of perfusion defects and lack of perfusion/metabolism mismatch are the most important features of noncoronarogenic cardiomegaly as compared to ischemic cardiomegaly.

Spatial heterogeneity of myocardial perfusion predicts local potassium channel expression and action potential duration

In the heart, there is not only a transmural gradient of left ventricular perfusion and action potential duration (APD), but also spatial heterogeneity within each myocardial layer, where local blood flow and energy turnover vary more than three-fold between individual regions. We analysed at high spatial resolution whether a corresponding heterogeneity also extends to ion channel gene expression and APD. In the open-chest beagle dog, left ventricular 300 microL samples of very low or high flow were identified by radioactive microspheres and expression levels determined by quantitative PCR. The distribution of epicardial APD was assessed by mapping local activation repolarization intervals (ARIs) and QT interval (QT). ERG, the potassium channel mediating IKr, and KChIP2, the interacting protein modulating Ito, were increased in Low flow (3.3- and 2.5-fold, P < 0.001 and <0.05, respectively; n = 6 hearts, 30-31 samples each) as compared with High flow areas. This suggested enhanced repolarizing currents in Low flow areas, and in consequence, mathematical model analysis predicted a shorter local APD upon enhanced ERG and IKr. Epicardial mapping revealed a patchy, temporally stable APD pattern (n = 11), a small apico-basal gradient and an APD prolongation induced by the ERG blocker dofetilide predominantly in areas of short basal ARI or QT, respectively (n = 9). In addition, in Short QT areas, ERG expression was three-fold increased (P < 0.05, n = 4). The spatial pattern of perfusion is matched by the novel patterns of K+ channel expression and APD. Whenever this newly recognized intramural dispersion of APD increases, it may contribute to arrhythmogenesis.

Heterogeneity of Myocardial Perfusion in Distal Coronary Embolism with Different Particle Sizes

We hypothesized that altered myocardial perfusion distribution patterns could be seen with coronary distal emboli of different particle sizes using myocardial contrast echocardiography. In 16 open-chest anesthetized dogs, microsphere suspensions of 9 or 500 microm in diameter were injected into the left anterior descending coronary artery until the mean left anterior descending coronary artery flow rate was reduced to less than 30% of baseline flow. During baseline conditions and after maximal embolization, real-time myocardial contrast echocardiography was performed by intravenous infusion of an echocontrast agent. In animals infused with 9-microm microspheres, a transmural perfusion defect was seen at the time of maximal embolization. In contrast, in animals infused with 500-microm microspheres, a subendocardial perfusion defect was observed. The particle size of coronary distal emboli affects myocardial perfusion distribution.

Regional Heterogeneity of Myocardial Perfusion in Healthy Human Myocardium: Assessment with Magnetic Resonance Perfusion Imaging #

The knowledge of myocardial perfusion in healthy volunteers is fundamental for evaluation of patients with ischemic heart disease. The study was conducted to determine range, regional variability, and transmural gradient of myocardial perfusion in normal volunteers with Magnetic Resonance Perfusion Imaging (MRPI). Perfusion was assessed in 17 healthy volunteers (age: 20-47 yr, 11 males) at rest and adenosine-induced hyperemia using a 1.5 T MR scanner. Perfusion was quantified (mL/g/min) for the transmural myocardium and separately for the endo- and epimyocardium in the anterior, lateral, posterior, and septal left ventricular wall using the Fermi model for constrained deconvolution. Regional variabilities for resting, hyperemic perfusion, and perfusion reserve were 22 +/- 8%, 21 +/- 10%, and 35 +/- 18%. Mean resting, hyperemic perfusion, and perfusion reserve were 1.1 +/- 0.4 mL/g/min, 4.2 +/- 1.1 mL/g/min, and 4.1 +/- 1.4. Perfusion in the septum was higher at rest (1.3 +/- 0.3 mL/g/min vs. 1.0 +/- 0.3 mL/g/min, p < 0.05) and lower during hyperemia (3.6 +/- 0.8 mL/g/min vs. 4.5 +/- 1.1 mL/g/min, p < 0.03), resulting in a reduced perfusion reserve (PR) (3.2 +/- 0.9 vs. 4.5 +/- 1.4, p < 0.01) in the septum vs. the combined anterior, lateral, and posterior segments. Resting (0.9 +/- 0.3 mL/g/min vs. 1.4 +/- 0.5 mL/g/min, p < 0.01), but not hyperemic perfusion, was lower in the epi- vs. endomyocardium, resulting in a higher epimyocardial PR (4.8 +/- 1.8 vs. 3.5 +/- 1.4, p < 0.01) in all regions but the septum, where endo- and epimyocardial perfusion and perfusion reserve were not different. A considerable regional variability of myocardial perfusion was confirmed with MRPI. The exceptional anatomical position of the septum is reflected by the lack of a perfusion gradient, which was demonstrated in all other regions but the septum.

A computer model of fractal myocardial perfusion heterogeneity to elucidate mechanisms of changes in critical coronary stenosis and hypotension

Critical coronary stenosis (critical CS) alone does not lead to an alteration of fractal dimension ( D) under resting conditions in a pig model, indicating undisturbed local myocardial perfusion. If critical CS is combined with hypovolemic anemia the resulting hypotension leads to a significant decline of D. The mechanisms involved in this phenomenon have not yet been elucidated. A computer program was developed enabling calculation of D for normal vascular trees, for single vessel coronary stenosis (CS), and for CS in combination with reduced coronary perfusion pressure (CPP). The values of D obtained by the computer program were compared to those available from an existing animal study to confirm that changes of D can largely be explained by changes of arterial branching pattern simulated by the computer program. Using our computer model, D was 1.15±0.06 in normal vascular trees. Third branch critical CS did not alter D (1.14±0.06; n.s.) , wheras critical CS combined with a reduction of CPP to 40 mmHg reduced D (1.07±0.03; P<0.05) . These data are comparable to those obtained in the animal study, and therefore show that alterations of vessel diameter and regional blood flow can largely explain changes of fractal dimension during critical CS and hypotension while changes of functional myocardial parameters might play a minor role.

Use of wavelet transforms in analysis of time-activity data from cardiac PET.

Because of its intrinsic quantitative properties, PET permits measurement of myocardial perfusion and metabolism in absolute terms (i.e., mL/g/min). However, quantification has been limited by errors produced in image acquisition, selection of regions of interest, and data analysis. The goal of this study was to evaluate a newly developed, novel, wavelet-based noise-reduction approach that can objectively extract biologic signals hidden within dynamic PET data. Quantification of myocardial perfusion using dynamic PET imaging with 82Rb, H2(15)O, and 13NH3 was selected to evaluate the effects of the wavelet-based noise-reduction protocol. Dynamic PET data were fitted to appropriate mathematic models before and after wavelet-based noise reduction to get flow estimates. Time-activity curves, precision, accuracy, and differentiating capacity derived from the wavelet protocol were compared with those obtained from unmodified data processing. A total of 84 human studies was analyzed, including 43 at rest (18 82Rb scans, 18 H2(15)O scans, and 7 13NH3 scans) and 41 after coronary hyperemia with dipyridamole (17 82Rb scans, 17 H2(15)O scans, and 7 13NH3 scans). For every tracer tested under all conditions, the wavelet method improved the shape of blood and tissue time-activity curves, increased estimate-to-error ratios, and maintained fidelity of flow in regions as small as 0.85 cm3. It also improved the accuracy of flow estimates derived from 82Rb to the level of that achieved with H2(15)O, which was not affected markedly by the wavelet process. In studies of patients with coronary disease, regional heterogeneity of myocardial perfusion was preserved and flow estimates in infarcted regions were differentiated more easily from normal regions. The wavelet-based noise-reduction method effectively and objectively extracted tracer time-activity curves from data with low signal-to-noise ratios and improved the accuracy and precision of measurements with all tracer techniques studied. The approach should be generalizable to other image modalities such as functional MRI and CT and, therefore, improve the ability to quantify dynamic physiologic processes.

Prognostic utility of myocardial blood flow assessed by N-13 ammonia positron emission tomography in patients with idiopathic dilated cardiomyopathy

Previous studies in patients with idiopathic dilated cardiomyopathy (IDC) have suggested that myocardial perfusion is impaired and spatially heterogeneous in such cases. Our objective was to identify any association between an abnormality in myocardial perfusion and the prognosis of patients with IDC. We collected data on N-13 ammonia positron emission tomography (PET) studies performed in 26 patients with IDC (9 nonsurvivors, 17 survivors) and in 8 normal control subjects. Regional myocardial blood flow (rMBF) was quantified using N-13 ammonia positron emission tomography and the Simple flow model. The spatial heterogeneity of myocardial perfusion was assessed by calculating the coefficient of variance of rMBF. Mean rMBF of the survivors was significantly lower (0.54 ± 0.13 ml/min/g) than that of control subjects (0.66 ± 0.06 ml/min/g) (p = 0.03 vs control), but did not differ significantly between nonsurvivors (0.58 ± 0.15 ml/min/g) and control subjects. The coefficient of variance of rMBF was significantly higher in nonsurvivors than in either survivors or control subjects (0.24 ± 0.08 vs 0.15 ± 0.08, p = 0.007, and 0.16 ± 0.05, p = 0.03, respectively). The probability of 3-year survival (Kaplan-Meier method) was 33.0% in subjects whose coefficient of variance of rMBF was above the median compared with 90.0% in subjects whose coefficient of variance of rMBF was below the median (p = 0.01). The probability of 3-year survival did not differ among subjects whose mean rMBF was above versus below the median (61.5% vs 62.9%, respectively). The results suggest that the prognosis of patients with IDC is associated with the spatial heterogeneity of myocardial perfusion, not with initial absolute rMBF.

Spatial heterogeneity of myocardial perfusion and metabolism.

Left ventricular myocardium is characterized by a substantial spatial heterogeneity of both perfusion and metabolism. Under resting conditions, the transmural gradient of myocardial oxygen consumption (MVO2) from the subepi- to the subendocardial layer exceeds that of coronary flow, resulting in a lower subendocardial PO2, altered kinetics of oxidative phosphorylation, and enhanced free cytosolic adenosine. Within each layer, there is a major spatial variability of perfusion: Local flow rates in individual myocardial samples (200 mg) range from 20-250% of the mean myocardial blood flow. Low flow areas (< 50% of mean flow) display a rather low uptake of fatty acids and glucose; the uptake of these substrates increases in proportion to local flow. There is also a close relationship between local perfusion and the local turnover of the tricarboxylic acid cycle and, thus, MVO2 as was recently demonstrated using 13C NMR techniques. Consequently, within the well perfused left ventricular myocardium local MVO2 and, thus, energy turnover varies more than 3-fold between low and high flow areas. Low flow areas are not ischemic, since local lactate, adenosine, and ATP are comparable to mean flow areas. When coronary perfusion pressure is reduced, the transmural perfusion gradient reverses resulting in impaired energy status and enhanced adenosine predominantly in the subendocardium. This rise in local adenosine or lactate requires a decrease of the individual local flow by more than 50% of its preischemic value. It, thus, appears that not the absolute level of local flow predicts the impact of ischemia but its relative change.

Temporospatial heterogeneity of myocardial perfusion and blood volume in the porcine heart wall.

Spatial heterogeneity of myocardial perfusion has been recognized for many years. Whether this is primarily the result of heterogeneity of parameters such as myocardial metabolism, of intramyocardial mechanical forces, or of vasomotor function within the myocardial microcirculation, is not clear. A practical problem is that it has been almost impossible to measure any two of these parameters simultaneously in the same piece of myocardium so that an unambiguous correlation, much less a cause-and-effect relationship, has been difficult to establish. In this study of six anesthetized pigs, we propose that whole-body computed tomography is a method for providing the simultaneous measurement of heterogeneity of myocardial perfusion (F) and myocardial blood volume (rho). The first finding was that the empirical relationship rho=AF+BF(0.5) between myocardial blood flow (F) and intramyocardial blood volume (rho) is maintained over a range of sizes of regions of interest (approximately 1 to 0.125 cm3) within the myocardium of each individual animal despite the spatial heterogeneity of the F and the rho values. The value of A ranges from 0.014 to 0.021 min and of B ranges from 0.061 to 0.076 ml(0.5) g(-0.5) min(0.5). A second finding was that the pattern of spatial heterogeneity of F and of rho remained reasonably stable over at least a 1 h period.

Normovolaemic haemodilution and hyperoxia have no effect on fractal dimension of regional myocardial perfusion in dogs.

Hypervolaemic haemodilution makes myocardial perfusion more homogenous as reflected by reduced fractal dimension of regional myocardial perfusion. The clinically more commonly performed acute normovolaemic haemodilution, however, has not yet been studied in this respect. Hyperoxic ventilation with 100% oxygen is used in conjunction with haemodilution to compensate for low oxygen content by increasing physically dissolved oxygen in plasma. Since hyperoxia is known to cause disturbance in microcirculatory regulation we studied the effects of acute normovolaemic haemodilution to haematocrit (hct) 20 +/- 1% and hyperoxia on regional myocardial perfusion heterogeneity in 22 anaesthetized dogs using fractal and correlation analysis. Regional myocardial perfusion was assessed with radioactive microspheres. The results of the study were that heart rate, blood volume and arterial pressure were unchanged during haemodilution. Cardiac index was 3.6 +/- 0.7 L min-1 m-2 before and 4.6 +/- 0.7 L min-1 m-2 after haemodilution (P < 0.05). Fractal dimension (D) of regional myocardial perfusion was 1.17 +/- 0.10 at baseline. Neither haemodilution (D = 1.19 +/- 0.10) nor hyperoxia (D = 1.17 +/- 0.10) altered fractal properties of regional myocardial perfusion. Spatial correlation of blood flow to adjacent tissue samples before haemodilution was 0.58 +/- 0.15. Haemodilution and hyperoxia did not significantly influence spatial correlation (0.57 +/- 0.12 vs. 0.60 +/- 0.09; ns). We conclude that neither acute normovolaemic haemodilution nor haemodilution in combination with hyperoxic ventilation alter physiological myocardial perfusion heterogeneity.

Long-term cigarette smoking is associated with increased myocardial perfusion heterogeneity assessed by positron emission tomography.

The pathophysiology of smoking-related coronary events in patients with normal coronary arteries is incompletely understood. This study was conducted to explore, in subjects without symptoms of cardiovascular disease, the long-term effects of smoking on regional coronary artery vasoactivity, especially during sympathetic stimulation. In ten smoking and ten non-smoking sex- and age-matched healthy volunteers, segmental myocardial perfusion was studied using dynamic parametric nitrogen-13 ammonia positron emission tomography at rest and during sympathetic stimulation evoked by the cold pressor stimulation. Smokers demonstrated a higher myocardial perfusion at rest (116+/-17 ml/min/100 g vs 96+/-20 ml/min/100 g, P <0.01) and an impaired myocardial perfusion increase during cold pressor stimulation (1.02+/-0.15 vs 1.18+/-0.17, P <0.05). The heterogeneity of perfusion, expressed as coefficient of variation, was significantly different between the smoking and the non-smoking group. The coefficient of variation of segmental myocardial perfusion was higher in smokers at rest (17.5%+/-4.2% vs 13.5%+/-1. 9%, P <0.05) and during cold pressor stimulation (17.0%+/-3.2% vs 13. 9%+/-1.8%, P <0.05). We conclude that the long-term effects of smoking in healthy volunteers are associated with (1) increased myocardial perfusion at rest, (2) impaired myocardial perfusion response to cold pressor stimulation, and (3) increased myocardial perfusion heterogeneity both at rest and during cold pressor stimulation. These results may suggest that in healthy subjects the long-term effect of smoking is related to abnormal coronary artery vasoactivity, presumably induced by an interplay of regional endothelial dysfunction and autonomic dysregulation.

Spatial heterogeneity of blood flow in the dog heart. I. Glucose uptake, free adenosine and oxidative/glycolytic enzyme activity.

The spatial heterogeneity of myocardial perfusion and metabolism was studied in 11 anaesthetized dogs under resting conditions. In each heart local myocardial blood flow was assessed using the tracer microsphere technique in 256 samples (mean mass: 83.1 mg) taken from the left anterior ventricular wall. In the same samples, the following biochemical parameters were determined: accumulation of [3H]-deoxyglucose (a measure of glucose uptake), free cytosolic adenosine (S-adenosylhomocysteine accumulation technique, a measure of tissue oxygenation and a possible mediator of blood flow regulation), and the specific activities of oxidative (citrate synthase, cytochrome-c-oxidase) and glycolytic (hexokinase, phosphoglycerate kinase) enzymes. Capillary density and mitochondrial and myofibril volume densities were determined by morphometry. Myocardial perfusion in each sample (average 0.77 ml min-1 g-1) varied between 0.1 and 2.5 times the mean (coefficient of variation 0.30+/-0.02). [3H]-deoxyglucose was deposited locally in proportion to perfusion. Samples showing low flow (<0.2 ml min-1 g-1) did not exhibit increased levels of cytosolic adenosine. The specific activities of the oxidative and glycolytic enzymes, however, were uniformly distributed between low and high flow areas. Furthermore, capillary density and mitochondrial and myofibril densities were similar in high and low flow regions. The results show firstly that local glucose metabolism in the heart occurs in proportion to local blood flow, suggesting that high flow regions have a higher than average metabolic rate. Secondly, regions of low flow are not compromized by critical oxygenation and most likely have a lower than average oxygen demand and finally, the homogeneous distribution of oxidative and glycolytic enzymes, as well as the homogeneous myocardial ultrastructure, suggest that areas with high and low blood flow under resting conditions may increase their metabolic rate to similar levels when required.