Association of Left Atrial Stiffness With Risk of Cryptogenic Ischemic Stroke in Young Adults.

Background: Incidence of cryptogenic ischemic stroke (CIS) in young adults is increasing. Early left atrial (LA) myopathy might be 1 of the underlying mechanisms, but this has only been scarcely explored. Objectives: The purpose of this study was to assess the association between increased LA stiffness and CIS in young adults. Methods: In the multicenter SECRETO (Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Etiology, Triggers, and Outcome) study, LA function was analyzed by speckle tracking echocardiography in 150 CIS patients (aged 18-49 years) and 150 age- and sex-matched controls. Minimum and maximum LA volumes, LA reservoir and contractile strain were measured. LA stiffness was calculated by the ratio: mitral peak E-wave velocity divided by mitral annular e' velocity (E/e')/LA reservoir strain and considered increased if ≥0.22. Increased LA volumes, LA stiffness, and/or reduced LA strain indicated LA myopathy. Logistic regression was used to determine the relation between LA stiffness and CIS and the clinical variables associated with LA stiffness. Results: Increased LA stiffness was found in 36% of patients and in 18% of controls (P < 0.001). Increased LA stiffness was associated with a 2.4-fold (95% CI: 1.1-5.3) higher risk of CIS after adjustment for age, sex, comorbidities, and echocardiographic confounders (P = 0.03). In patients, obesity, pre-CIS antihypertensive treatment, older age, and lower LA contractile strain were all related to increased LA stiffness (all P < 0.05). Conclusions: LA myopathy with increased LA stiffness and impaired LA mechanics more than doubles the risk of CIS in patients under the age of 50 years. This provides new insights into the link between LA dysfunction and CIS at young ages. (Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Etiology, Triggers, and Outcome [SECRETO]; NCT01934725).

Bone marrow metabolism is affected by body weight and response to exercise training varies according to anatomical location.

AIM: High body weight is a protective factor against osteoporosis, but obesity also suppresses bone metabolism and whole-body insulin sensitivity. However, the impact of body weight and regular training on bone marrow (BM) glucose metabolism is unclear. We studied the effects of regular exercise training on bone and BM metabolism in monozygotic twin pairs discordant for body weight. METHODS: We recruited 12 monozygotic twin pairs (mean ± SD age 40.4 ± 4.5 years; body mass index 32.9 ± 7.6, mean difference between co-twins 7.6 kg/m2 ; eight female pairs). Ten pairs completed the 6-month long training intervention. We measured lumbar vertebral and femoral BM insulin-stimulated glucose uptake (GU) using 18 F-FDG positron emission tomography, lumbar spine bone mineral density and bone turnover markers. RESULTS: At baseline, heavier co-twins had higher lumbar vertebral BM GU (p < .001) and lower bone turnover markers (all p < .01) compared with leaner co-twins but there was no significant difference in femoral BM GU, or bone mineral density. Training improved whole-body insulin sensitivity, aerobic capacity (both p < .05) and femoral BM GU (p = .008). The training response in lumbar vertebral BM GU was different between the groups (time × group, p = .02), as GU tended to decrease in heavier co-twins (p = .06) while there was no change in leaner co-twins. CONCLUSIONS: In this study, regular exercise training increases femoral BM GU regardless of weight and genetics. Interestingly, lumbar vertebral BM GU is higher in participants with higher body weight, and training counteracts this effect in heavier co-twins even without reduction in weight. These data suggest that BM metabolism is altered by physical activity.

24-hour ambulatory blood pressure and cryptogenic ischemic stroke in young adults.

BACKGROUND: In young patients, up to 40% of ischemic strokes remain cryptogenic despite modern-day diagnostic work-up. There are limited data on blood pressure (BP) behavior in these patients. Thus, we aimed to compare ambulatory blood pressure (ABP) profiles between young patients with a recent cryptogenic ischemic stroke (CIS) and stroke-free controls. PATIENTS AND METHODS: In this substudy of the international multicenter case-control study SECRETO (NCT01934725), 24-hour ambulatory blood pressure monitoring (ABPM) was performed in consecutive 18-49-year-old CIS patients and stroke-free controls. The inclusion criteria were met by 132 patients (median age, 41.9 years; 56.1% males) and 106 controls (41.9 years; 56.6% males). We assessed not only 24-hour, daytime, and nighttime ABP but also hypertension phenotypes and nocturnal dipping status. RESULTS: 24-hour and daytime ABP were higher among controls. After adjusting for relevant confounders, a non-dipping pattern of diastolic blood pressure (DBP) was associated with CIS in the entire sample (odds ratio, 3.85; 95% confidence interval, 1.20-12.42), in participants without antihypertensives (4.86; 1.07-22.02), and in participants without a patent foramen ovale (PFO) (7.37; 1.47-36.81). After excluding patients in the first tertile of the delay between the stroke and ABPM, a non-dipping pattern of DBP was not associated with CIS, but a non-dipping pattern of both systolic BP and DBP was (4.85; 1.37-17.10). In participants with a PFO and in those without hypertension by any definition, no associations between non-dipping patterns of BP and CIS emerged. CONCLUSIONS: Non-dipping patterns of BP were associated with CIS in the absence of a PFO but not in the absence of hypertension. This may reflect differing pathophysiology underlying CIS in patients with versus without a PFO. Due to limitations of the study, results regarding absolute ABP levels should be interpreted with caution.Key MessagesNocturnal non-dipping patterns of blood pressure were associated with cryptogenic ischemic stroke except in participants with a patent foramen ovale and in those without hypertension by any definition, which may indicate differing pathophysiology underlying cryptogenic ischemic stroke in patients with and without a patent foramen ovale.It might be reasonable to include ambulatory blood pressure monitoring in the diagnostic work-up for young patients with ischemic stroke to detect not only the absolute ambulatory blood pressure levels but also their blood pressure behavior.

Systemic cross-talk between brain, gut, and peripheral tissues in glucose homeostasis: effects of exercise training (CROSSYS). Exercise training intervention in monozygotic twins discordant for body weight.

BACKGROUND: Obesity and physical inactivity are major global public health concerns, both of which increase the risk of insulin resistance and type 2 diabetes. Regulation of glucose homeostasis involves cross-talk between the central nervous system, peripheral tissues, and gut microbiota, and is affected by genetics. Systemic cross-talk between brain, gut, and peripheral tissues in glucose homeostasis: effects of exercise training (CROSSYS) aims to gain new systems-level understanding of the central metabolism in human body, and how exercise training affects this cross-talk. METHODS: CROSSYS is an exercise training intervention, in which participants are monozygotic twins from pairs discordant for body mass index (BMI) and within a pair at least the other is overweight. Twins are recruited from three population-based longitudinal Finnish twin studies, including twins born in 1983-1987, 1975-1979, and 1945-1958. The participants undergo 6-month-long exercise intervention period, exercising four times a week (including endurance, strength, and high-intensity training). Before and after the exercise intervention, comprehensive measurements are performed in Turku PET Centre, Turku, Finland. The measurements include: two positron emission tomography studies (insulin-stimulated whole-body and tissue-specific glucose uptake and neuroinflammation), magnetic resonance imaging (brain morphology and function, quantification of body fat masses and organ volumes), magnetic resonance spectroscopy (quantification of fat within heart, pancreas, liver and tibialis anterior muscle), echocardiography, skeletal muscle and adipose tissue biopsies, a neuropsychological test battery as well as biosamples from blood, urine and stool. The participants also perform a maximal exercise capacity test and tests of muscular strength. DISCUSSION: This study addresses the major public health problems related to modern lifestyle, obesity, and physical inactivity. An eminent strength of this project is the possibility to study monozygotic twin pairs that share the genome at the sequence level but are discordant for BMI that is a risk factor for metabolic impairments such as insulin resistance. Thus, this exercise training intervention elucidates the effects of obesity on metabolism and whether regular exercise training is able to reverse obesity-related impairments in metabolism in the absence of the confounding effects of genetic factors. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03730610 . Prospectively registered 5 November 2018.

Predicting Skeletal Muscle and Whole-Body Insulin Sensitivity Using NMR-Metabolomic Profiling.

PURPOSE: Abnormal lipoprotein and amino acid profiles are associated with insulin resistance and may help to identify this condition. The aim of this study was to create models estimating skeletal muscle and whole-body insulin sensitivity using fasting metabolite profiles and common clinical and laboratory measures. MATERIAL AND METHODS: The cross-sectional study population included 259 subjects with normal or impaired fasting glucose or type 2 diabetes in whom skeletal muscle and whole-body insulin sensitivity (M-value) were measured during euglycemic hyperinsulinemic clamp. Muscle glucose uptake (GU) was measured directly using [18F]FDG-PET. Serum metabolites were measured using nuclear magnetic resonance (NMR) spectroscopy. We used linear regression to build the models for the muscle GU (Muscle-insulin sensitivity index [ISI]) and M-value (whole-body [WB]-ISI). The models were created and tested using randomly selected training (n = 173) and test groups (n = 86). The models were compared to common fasting indices of insulin sensitivity, homeostatic model assessment-insulin resistance (HOMA-IR) and the revised quantitative insulin sensitivity check index (QUICKI). RESULTS: WB-ISI had higher correlation with actual M-value than HOMA-IR or revised QUICKI (ρ = 0.83 vs -0.67 and 0.66; P < 0.05 for both comparisons), whereas the correlation of Muscle-ISI with the actual skeletal muscle GU was not significantly stronger than HOMA-IR's or revised QUICKI's (ρ = 0.67 vs -0.58 and 0.59; both nonsignificant) in the test dataset. CONCLUSION: Muscle-ISI and WB-ISI based on NMR-metabolomics and common laboratory measurements from fasting serum samples and basic anthropometrics are promising rapid and inexpensive tools for determining insulin sensitivity in at-risk individuals.

Reversibility of myocardial metabolism and remodelling in morbidly obese patients 6 months after bariatric surgery.

AIMS: To study myocardial substrate uptake, structure and function, before and after bariatric surgery, to clarify the interaction between myocardial metabolism and cardiac remodelling in morbid obesity. METHODS: We studied 46 obese patients (age 44 ± 10 years, body mass index [BMI] 42 ± 4 kg/m2 ), including 18 with type 2 diabetes (T2D) before and 6 months after bariatric surgery and 25 healthy age-matched control group subjects. Myocardial fasting free fatty acid uptake (MFAU) and insulin-stimulated myocardial glucose uptake (MGU) were measured using positron-emission tomography. Myocardial structure and function, and myocardial triglyceride content (MTGC) and intrathoracic fat were measured using magnetic resonance imaging and magnetic resonance spectroscopy. RESULTS: The morbidly obese study participants, with or without T2D, had cardiac hypertrophy, impaired myocardial function and substrate metabolism compared with the control group. Surgery led to marked weight reduction and remission of T2D in most of the participants. Postoperatively, myocardial function and structure improved and myocardial substrate metabolism normalized. Intrathoracic fat, but not MTGC, was reduced. Before surgery, BMI and MFAU correlated with left ventricular hypertrophy, and BMI, age and intrathoracic fat mass were the main variables associated with cardiac function. The improvement in whole-body insulin sensitivity correlated positively with the increase in MGU and the decrease in MFAU. CONCLUSIONS: In the present study, obesity and age, rather than myocardial substrate uptake, were the causes of cardiac remodelling in morbidly obese patients with or without T2D. Cardiac remodelling and impaired myocardial substrate metabolism are reversible after surgically induced weight loss and amelioration of T2D.

Task-based evaluation of a 4D MAP-RBI-EM image reconstruction method for gated myocardial perfusion SPECT using a human observer study.

We evaluated the performance of a new 4D image reconstruction method for improved 4D gated myocardial perfusion (MP) SPECT using a task-based human observer study. We used a realistic 4D NURBS-based Cardiac-Torso (NCAT) phantom that models cardiac beating motion. Half of the population was normal; the other half had a regional hypokinetic wall motion abnormality. Noise-free and noisy projection data with 16 gates/cardiac cycle were generated using an analytical projector that included the effects of attenuation, collimator-detector response, and scatter (ADS), and were reconstructed using the 3D FBP without and 3D OS-EM with ADS corrections followed by different cut-off frequencies of a 4D linear post-filter. A 4D iterative maximum a posteriori rescaled-block (MAP-RBI)-EM image reconstruction method with ADS corrections was also used to reconstruct the projection data using various values of the weighting factor for its prior. The trade-offs between bias and noise were represented by the normalized mean squared error (NMSE) and averaged normalized standard deviation (NSDav), respectively. They were used to select reasonable ranges of the reconstructed images for use in a human observer study. The observers were trained with the simulated cine images and were instructed to rate their confidence on the absence or presence of a motion defect on a continuous scale. We then applied receiver operating characteristic (ROC) analysis and used the area under the ROC curve (AUC) index. The results showed that significant differences in detection performance among the different NMSE-NSDav combinations were found and the optimal trade-off from optimized reconstruction parameters corresponded to a maximum AUC value. The 4D MAP-RBI-EM with ADS correction, which had the best trade-off among the tested reconstruction methods, also had the highest AUC value, resulting in significantly better human observer detection performance when detecting regional myocardial wall motion abnormality. We concluded that the NMSE-NSDav trade-off was shown to agree with observer performance for the detection task of the regional motion abnormality, and the optimized 4D MAP-RBI-EM method with ADS corrections provides significant improvement compared to 3D FBP and 3D OS-EM with ADS corrections in detecting regional myocardial wall motion abnormali in 4D gated MP SPECT.

Mechanistic Insights into Sympathetic Neuronal Regeneration: Multitracer Molecular Imaging of Catecholamine Handling After Cardiac Transplantation.

BACKGROUND: Post-transplant reinnervation is a unique model to study sympathetic neuronal regeneration in vivo. The differential role of subcellular mechanisms of catecholamine handling in nerve terminals has not been investigated. METHODS AND RESULTS: Three different carbon-11-labeled catecholamines were used for positron emission tomography of transport (C-11 m-hydroxyephedrine, HED), vesicular storage (C-11 epinephrine, EPI), and metabolic degradation (C-11 phenylephrine). A 2-day protocol was used, including quantification of myocardial blood flow by N-13 ammonia. Resting myocardial blood flow and EPI, HED and phenylephrine retention were homogeneous in healthy volunteers (n=7). Washout was only observed for phenylephrine (T(1/2) 49±6 min). In nonrejecting, otherwise healthy heart transplant recipients (>1 year after surgery, n=10), resting myocardial blood flow was also homogenous. Regional catecholamine uptake of varying degrees was observed in the anterior left ventricular wall and septum. Overall, 24±19% of left ventricle showed HED uptake levels comparable with healthy volunteers, whereas it was only 8±7% for EPI (P=0.004 versus HED). Phenylephrine washout was not different from healthy volunteers in the area with restored EPI and HED retention (T(1/2) 41±7 min; P>0.05), but was significantly enhanced in the EPI/HED mismatch area (T(1/2) 36±8 min; P=0.008), consistent with inefficient vesicular storage and enhanced metabolic degradation. CONCLUSIONS: Regeneration of subcellular components of sympathetic nerve terminal function does not occur simultaneously. In the reinnervating transplanted heart, a region with normal catecholamine transport and vesicular storage is surrounded by a borderzone, where transport is already restored but vesicular storage remains inefficient, suggesting that vesicular storage is a more delicate mechanism. This observation may have implications for other pathologies involving cardiac autonomic innervation.

Multiparametric molecular imaging provides mechanistic insights into sympathetic innervation impairment in the viable infarct border zone.

UNLABELLED: Impaired catecholamine handling in the viable infarct border zone may play an important role in ventricular remodeling and lethal arrhythmia. We sought to get further biologic insights into cardiac sympathetic neuronal pathology after myocardial infarction, using multiple tomographic imaging techniques. METHODS: In a porcine model of myocardial infarction (n = 13), PET and MR imaging were performed after 4-6 wk and integrated with electrophysiologic testing and postmortem histology. RESULTS: PET with the physiologic neurotransmitter (11)C-epinephrine, which is sensitive to metabolic degradation unless it is stored and protected in neuronal vesicles, identified a defect exceeding the perfusion defect (defined by (13)N-ammonia; defect size in all animals, 42 ± 12 vs. 35% ± 12% of left ventricle, P < 0.001). In a subgroup of 7 animals, defect of the metabolically resistant catecholamine (11)C-hydroxyephedrine was smaller than epinephrine (41 ± 8 vs. 47% ± 6% of left ventricle, P = 0.004), whereas defect of a third catecholamine, (11)C-phenylephrine, which is sensitive to metabolic degradation, was similar to epinephrine (48 ± 6 vs. 47% ± 6%, P = 0.011 vs. perfusion defect). Histology confirmed the presence of nerve fibers in the infarct border zone. Tagged MR imaging identified impaired peak circumferential wall strain and wall thickening in myocardial segments with epinephrine/perfusion mismatch (n = 6). Confirmatory of prior work, inducible ventricular tachycardia was associated with a larger epinephrine/perfusion mismatch (n = 11). CONCLUSION: In the viable infarct border zone, neuronal vesicular catecholamine storage and protection from metabolic degradation are more severely altered than catecholamine uptake. This alteration may reflect an intermediate state between normal innervation and complete denervation in advanced disease.

Systemic metabolic markers and myocardial glucose uptake in type 2 diabetic and coronary artery disease patients treated for 16 weeks with rosiglitazone, a PPARγ agonist.

INTRODUCTION: Treatment with rosiglitazone, a peroxisome proliferator-activated receptor-γ agonist, in type 2 diabetic mellitus (T2DM) patients is under scrutiny because it affects adversely cardiovascular outcomes. In T2DM patients, with existing coronary heart disease, short-term treatment with rosiglitazone increases myocardial glucose uptake (MGU). Serum metabolic and lipoprotein subclass changes, which may be associated with this rosiglitazone-induced improvement, are unknown. METHODS: Patients with both T2DM and coronary heart disease were separated into placebo (n = 26) and treatment (rosiglitazone 4-8 mg; n = 25) groups. After 16 weeks of treatment, serum NMR metabolomics was used to measure circulating low-molecular-weight metabolites and lipoprotein subclasses and lipids that are associated with T2DM before and after the treatment. Significant metabolic measure changes after rosiglitazone treatment were correlated to MGU values assessed with [(18)F]fluorodeoxyglucose positron emission tomography. RESULTS: Compared to placebo, the treatment significantly increased circulating glutamine and decreased lactate concentrations. Circulating lactate concentrations showed a significant inverse association with MGU after rosiglitazone treatment. CONCLUSION: In T2DM patients with existing coronary heart disease, short-term rosiglitazone treatment caused minor improvements in metabolism: serum lactate and glutamine concentrations changed, reflecting improvements in insulin sensitivity, and circulating lactate concentrations inversely correlated to increases in myocardial glucose uptake.

Impaired global myocardial flow dynamics despite normal left ventricular function and regional perfusion in chronic kidney disease: a quantitative analysis of clinical 82Rb PET/CT studies.

UNLABELLED: Impaired global myocardial flow reserve (MFR) may be associated with increased risk for cardiac events and coronary artery disease progression. Chronic kidney disease (CKD) is also considered a risk factor for cardiovascular disease. We sought to investigate the effect of CKD on the myocardial microcirculation in patients referred for clinical (82)Rb PET/CT, who had normal left ventricular (LV) function and no flow-limiting coronary artery disease. METHODS: Estimated glomerular filtration rate (eGFR) was available for 230 patients who had undergone rest and pharmacologic stress (82)Rb PET/CT for suspected coronary artery disease. CKD was defined as an eGFR less than 60 mL/min/1.73 m(2). After patients with hemodialysis, a renal transplant, abnormal regional perfusion (summed stress score > 4), or reduced LV function (LV ejection fraction < 45%) were excluded, 40 CKD patients remained. Those were compared with a control group without CKD, which was matched for age, sex, coronary risk factors, and systemic hemodynamics (n = 42). List-mode acquisition of PET enabled quantification of myocardial blood flow (MBF) and MFR using a previously validated retention model with correction for (82)Rb extraction. Rest MBF was normalized to rate-pressure product. RESULTS: Mean eGFR in the CKD group was reduced (44 ± 14 vs. 99 ± 28 mL/min/1.73 m(2); P < 0.0001), and creatinine was significantly elevated, compared with controls (1.9 ± 1.1 vs. 0.8 ± 0.2 mg/dL; P < 0.0001). MFR was significantly reduced in CKD (2.2 ± 1.0 vs. 3.0 ± 1.2 for controls; P = 0.027). This reduction was mainly due to increased rest MBF (1.1 ± 0.4 in CKD vs. 0.8 ± 0.2 mL/min/g in controls; P = 0.007). Stress myocardial flow was comparable between both groups (2.3 ± 0.9 vs. 2.3 ± 0.8 mL/min/g; P = 0.08). Overall, MFR was significantly correlated with eGFR (r = 0.41; P = 0.0005). Stress MBF did not correlate with eGFR (r = 0.002; P = 0.45), but rest MBF showed an inverse correlation (r = -0.49; P < 0.0001). Rest MBF was also inversely correlated with hemoglobin (r = -0.28; P = 0.014), but only eGFR was an independent correlate at multivariate analysis. CONCLUSION: MFR is impaired in patients with renal insufficiency with normal regional perfusion and LV function, mostly because of elevated rest flow. Absolute quantification of flow may be useful to identify microvascular dysfunction as a precursor of clinically overt coronary disease in this specific risk group.

Cardiac Function, Perfusion, Metabolism, and Innervation following Autologous Stem Cell Therapy for Acute ST-Elevation Myocardial Infarction. A FINCELL-INSIGHT Sub-Study with PET and MRI.

PURPOSE: Beneficial mechanisms of bone marrow cell (BMC) therapy for acute ST-segment elevation myocardial infarct (STEMI) are largely unknown in humans. Therefore, we evaluated the feasibility of serial positron emission tomography (PET) and MRI studies to provide insight into the effects of BMCs on the healing process of ischemic myocardial damage. METHODS: Nineteen patients with successful primary reteplase thrombolysis (mean 2.4 h after symptoms) for STEMI were randomized for BMC therapy (2.9 × 10(6) CD34+ cells) or placebo after bone marrow aspiration in a double-blind, multi-center study. Three days post-MI, coronary angioplasty, and paclitaxel eluting stent implantation preceded either BMC or placebo therapy. Cardiac PET and MRI studies were performed 7-12 days after therapies and repeated after 6 months, and images were analyzed at a central core laboratory. RESULTS: In BMC-treated patients, there was a decrease in [(11)C]-HED defect size (-4.9 ± 4.0 vs. -1.6 ± 2.2%, p = 0.08) and an increase in [(18)F]-FDG uptake in the infarct area at risk (0.06 ± 0.09 vs. -0.05 ± 0.16, p = 0.07) compared to controls, as well as less left ventricular dilatation (-4.4 ± 13.3 vs. 8.0 ± 16.7 mL/m(2), p = 0.12) at 6 months follow-up. However, BMC treatment was inferior to placebo in terms of changes in rest perfusion in the area at risk (-0.09 ± 0.17 vs. 0.10 ± 0.17, p = 0.03) and infarct size (0.4 ± 4.2 vs. -5.1 ± 5.9 g, p = 0.047), and no effect was observed on ejection fraction (p = 0.37). CONCLUSION: After the acute phase of STEMI, BMC therapy showed only minor trends of long-term benefit in patients with rapid successful thrombolysis. There was a trend of more decrease in innervation defect size and enhanced glucose metabolism in the infarct-related myocardium and also a trend of less ventricular dilatation in the BMC-treated group compared to placebo. However, no consistently better outcome was observed in the BMC-treated group compared to placebo.

Perfusion defect size predicts engraftment but not early retention of intra-myocardially injected cardiosphere-derived cells after acute myocardial infarction.

Therapeutic cell retention and engraftment are critical for myocardial regeneration. Underlying mechanisms, including the role of tissue perfusion, are not well understood. In Wistar Kyoto rats, syngeneic cardiosphere-derived cells (CDCs) were injected intramyocardially, after experimental myocardial infarction. CDCs were labeled with [(18)F]-FDG (n = 7), for quantification of 1-h retention, or with sodium-iodide-symporter gene (NIS; n = 8), for detection of 24-h engraftment by reporter imaging. Perfusion was imaged simultaneously. Infarct size was 37 ± 9 and 38 ± 9% of LV in FDG and NIS groups. Cell signal was located in the infarct border zone in all animals. No significant relationship was observed between infarct size and 1-h CDC retention (r = -0.65; P = 0.11). However, infarct size correlated significantly with 24-h engraftment (r = 0.75; P = 0.03). Residual perfusion at the injection site was not related to cell retention/engraftment. Larger infarcts are associated with improved CDC engraftment. This observation encourages further investigation of microenvironmental conditions after ischemic damage and their role in therapeutic cell survival.

Prediction of short-term cardiovascular events using quantification of global myocardial flow reserve in patients referred for clinical 82Rb PET perfusion imaging.

UNLABELLED: Current noninvasive tests for coronary artery disease detect atherosclerosis or regional ischemia. Global myocardial flow reserve is not routinely identified, although it may be an additional marker of disease development and progression. METHODS: For the clinical work-up of suspected or known stable coronary artery disease, 275 individuals had undergone rest-dipyridamole (82)Rb myocardial perfusion imaging using PET. In addition to clinical measures of regional perfusion and function, an experimentally validated approach to quantify global myocardial flow reserve was used. Follow-up was obtained for 362 ± 277 d. RESULTS: Myocardial blood flow and flow reserve showed significant correlation to systemic and cardiac hemodynamics and a weak association with risk factors such as age and history of hyperlipidemia. Flow reserve was expectedly lower in subjects with regional ischemia (1.70 ± 0.65 vs. 2.31 ± 0.97 in those without; P < 0.0001), but a wide range was observed in those without regional perfusion abnormalities. We used a composite endpoint of hard and soft events to determine that flow reserve below the median was predictive of adverse outcome in the overall population (P = 0.001) and in subjects with normal regional perfusion (n = 178; P = 0.036), whereas stress flow was predictive only in the overall population (P = 0.001). Age-adjusted multivariate analysis confirmed regional perfusion defects (relative hazard, 2.51; 95% confidence interval, 1.24-5.10; P = 0.009) and low global flow reserve (relative hazard, 2.93; 95% confidence interval, 1.30-6.65; P = 0.011) as independent predictors of cardiac events. CONCLUSION: In clinical cardiac (82)Rb PET, globally impaired flow reserve is a relevant marker for predicting short-term cardiovascular events. It may be used for integration with currently established functional and morphologic test results and for guidance of preventive measures, especially in the absence of regional flow-limiting disease.

Myocardial substrate and route of administration determine acute cardiac retention and lung bio-distribution of cardiosphere-derived cells.

BACKGROUND: Quantification of acute myocardial retention and lung bio-distribution of cardiosphere-derived cells (CDCs) following transplantation is important to improve engraftment. METHODS AND RESULTS: We studied acute(1 hour) cardiac/lung retention in 4 groups (n = 25) of rats (normal--NL, acute ischemia-reperfusion--AI-RM, acute permanent ligation-PL, and chronic infarct by ischemia-reperfusion--CI-R) using intra-myocardial delivery, 1 group using intracoronary delivery (acute ischemia-reperfusion, AI-RC, n = 5) and 1 group using intravenous delivery (acute ischemia-reperfusion, AI-RV, n = 5) of CDCs by PET. Cardiac retention was similar in the NL, AI-RM, CI-R, and A-IRC groups (13.6% ± 2.3% vs. 12.0% ± 3.9% vs. 9.9 ± 2.8 vs. 15.4% ± 5.5%; P = NS), but higher in PL animals (22.9% ± 5.2%; P < .05). Low cardiac retention was associated with significantly higher lung activity in NL and AI-RM groups (43.3% ± 5.6% and 39.9% ± 9.3%), compared to PL (28.5% ± 5.9%), CI-R (20.2% ± 9.3%), and A-IRC (19.9% ± 5.6%) animals (P < .05 vs. AI-RM and NL). Lung activity was highest following intravenous CDC delivery (55.1% ± 9.3%, P < .001) and was associated with very low cardiac retention (0.8% ± 1.06%). Two-photon microscopy indicated that CDCs escaped to the lungs via the coronary veins following intra-myocardial injection. CONCLUSIONS: Acute cardiac retention and lung bio-distribution vary with the myocardial substrate and injection route. Intra-myocardially injected CDCs escape into the lungs via coronary veins, an effect that is more pronounced in perfused myocardium.

Radionuclide imaging of angiotensin II type 1 receptor upregulation after myocardial ischemia-reperfusion injury.

UNLABELLED: The renin-angiotensin system (RAS) mediates proapoptotic, profibrotic, and proinflammatory processes in maladaptive conditions. Activation after myocardial infarction may initialize and promote cardiac remodeling. Using a novel positron-emitting ligand, we sought to determine the presence and time course of regional myocardial upregulation of the angiotensin II type 1 receptor (AT1R) and the blocking efficacy of various anti-RAS agents. METHODS: In male Wistar rats (n = 31), ischemia-reperfusion damage was induced by 20- to 25-min ligation of the left coronary artery. The AT1R blocker (11)C-2-butyl-5-methoxymethyl-6-(1-oxopyridin-2-yl)-3-[[2-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-3H-imidazo[4,5-b]pyridine ((11)C-KR31173) was injected intravenously at different times until 6 mo after surgery and sacrifice. Autoradiography, histology, and immunohistochemistry were performed for ex vivo validation. Additional in vivo PET was conducted in 3 animals. A second series of experiments (n = 16) compared untreated animals with animals treated with oral valsartan (50 mg/kg/d), oral enalapril (10 mg/kg/d), and complete intravenous blockage (SK-1080, 2 mg/kg, 10 min before imaging). RESULTS: Transient regional AT1R upregulation was detected in the infarct area, with a peak at 1-3 wk after surgery (autoradiographic infarct-to-remote ratio, 1.07 ± 0.09, 1.68 ± 0.34, 2.54 ± 0.40, 2.98 ± 0.70, 3.16 ± 0.57, 1.86 ± 0.65, and 1.28 ± 0.27 at control, day 1, day 3, week 1, week 3, month 3, and month 6, respectively). The elevated uptake of (11)C-KR31173 in the infarct area was detectable by small-animal PET in vivo, and it was blocked completely by intravenous SK-1080. Although oral treatment with enalapril did not reduce focal tracer uptake, oral valsartan resulted in partial blockade (infarct-to-remote ratio, 2.94 ± 0.52, 2.88 ± 0.60, 2.07 ± 0.25, and 1.26 ± 0.10 for no treatment, enalapril, valsartan, and SK-1080, respectively). CONCLUSION: After ischemic myocardial damage in a rat model, transient regional AT1R upregulation is detectable in the infarct area using (11)C-KR31173. Inhibitory effects of the clinical AT1R blocker valsartan can be identified, whereas blockage of upstream angiotensin-converting enzyme with enalapril does not affect AT1R density. These results provide a rationale for subsequent testing of AT1R-targeted imaging to predict the risk for ventricular remodeling and to monitor the efficacy of anti-RAS drug therapy.

Definition of vascular territories on myocardial perfusion images by integration with true coronary anatomy: a hybrid PET/CT analysis.

UNLABELLED: For interpretation of myocardial perfusion studies, tissue segments are usually assigned to coronary vascular territories based on general assumptions about the most frequent vascular distribution pattern. These assumptions may be inaccurate because of interindividual variability of coronary anatomy. This limitation may be overcome by hybrid imaging through the individual integration of coronary anatomy with myocardial tissue regions. METHODS: We studied 71 consecutive patients who underwent (82)Rb perfusion PET/CT, including CT angiography, for work-up of coronary artery disease on a 64-slice PET/CT scanner. Coronary vessels as defined by CT were assigned to each of 17 myocardial segments for PET analysis using fusion images. Reassigned segmental maps were compared with standard assignment as proposed by the American Heart Association model, without knowledge of individual anatomy. The validity of segmental assignment was tested in 6 dogs by comparison of PET/CT with ex vivo dye staining of coronary territories. RESULTS: Dog studies showed excellent agreement between PET/CT-defined segments and ex vivo-stained territories (kappa, 0.80). In patients, 72% (51/71) demonstrated differences from the standard assignment in at least 1 myocardial segment; 112 of 1,207 segments were reassigned to nonstandard vascular territories. Most frequently, standard right coronary segments were reassigned to the left circumflex territory (39% of reassigned segments), standard circumflex segments were reassigned to the left anterior descending territory (30%), and standard left anterior descending segments were reassigned to either circumflex or right coronary (12% and 11%, respectively). In 27 studies with a myocardial perfusion defect, relative uptake in the vascular territory with the defect was significantly lower after CT-based reassignment and was higher in remote territories, resulting in better separation (ratio of defect to remote, 0.75 +/- 0.13 vs. 0.81 +/- 0.12 before reassignment; P = 0.0014). CONCLUSION: Standard assumptions about vascular territory distribution in myocardial perfusion analysis are frequently inaccurate because of morphologic variability of the coronary tree. If hybrid imaging has been used to study coronary anatomy and myocardial tissue perfusion, then localization of perfusion abnormalities should be based on CT-derived anatomy. This may bring about more accurate assignment to culprit vessels and thus improved guidance and monitoring of targeted therapy.

Contribution of glucose tolerance and gender to cardiac adiposity.

CONTEXT AND OBJECTIVE: To examine whether pericardial and myocardial fat depots may contribute to the association between diabetes and cardiovascular risk, including sex-related differences, and the role of adiponectin, we evaluated data in patients with obesity and without diabetes [nondiabetic (ND)] or with impaired glucose tolerance or type 2 diabetes and in lean ND controls. METHODS: Magnetic resonance imaging and spectroscopy were used to measure left ventricular (LV) function and abdominal sc and visceral fat areas to estimate respective masses, pericardial fat depots, and myocardial triglyceride content in 53 subjects (10 lean ND, 25 obese ND, six impaired-glucose-tolerance, and 12 type 2 diabetic patients with macrovascular disease); gender effects and adiponectin levels were evaluated in the available subset of subjects. RESULTS: Myocardial and pericardial fat increased progressively across study groups. They were lower in obese women than men (P = 0.002), but cardiac steatosis caught up in hyperglycemic women (+81% vs. ND, P = 0.01). Adiponectin was inversely related with both fat depots (P < 0.01) and LV mass (P = 0.003) and positively with LV function (P = 0.03). In multiple regression analysis, myocardial and pericardial fat were independently related with plasma glucose levels, only pericardial fat mass was associated with visceral adiposity and myocardial fat with cardiac output and work. CONCLUSIONS: We conclude that glycemia, gender, adiponectin, and cardiac workload are associated with, and hyperglycemia and male gender are independent positive predictors of, heart adiposity. Once glucose tolerance becomes impaired, the evolution of cardiac steatosis is more pronounced in women.

Integration of infarct size, tissue perfusion, and metabolism by hybrid cardiac positron emission tomography/computed tomography: evaluation in a porcine model of myocardial infarction.

BACKGROUND: Hybrid positron emission tomography/computed tomography (PET-CT) allows for combination of PET perfusion/metabolism imaging with infarct detection by CT delayed contrast enhancement. We used this technique to obtain biomorphological insights into the interrelation between tissue damage, inflammation, and microvascular obstruction early after myocardial infarction. METHODS AND RESULTS: A porcine model of left anterior descending coronary artery occlusion/reperfusion was studied. Seven animals underwent PET-CT within 3 days of infarction, and a control group of 3 animals was scanned at >4 weeks. Perfusion and glucose uptake were assessed by [(13)N]-ammonia/[(18)F]-deoxyglucose (FDG), and 64-slice CT delayed contrast enhancement was measured. In the acute infarct model, CT revealed a no-reflow phenomenon suggesting microvascular obstruction in 80% of all infarct segments. PET showed increased FDG uptake in 68% of the CT-defined infarct segments. Ex vivo staining and histology showed active inflammation in the acute infarct area as an explanation for increased glucose uptake. In chronic infarction, CT showed no microvascular obstruction and agreed well with matched perfusion/metabolism defects on PET. CONCLUSIONS: Perfusion/metabolism PET and delayed enhancement CT can be combined within a single hybrid PET-CT session. Increased regional FDG uptake in the acute infarct area is frequently observed. In contrast to the chronic infarct setting, this indicates tissue inflammation that is commonly associated with microvascular obstruction as identified by no reflow on CT. The consequences of these pathophysiological findings for subsequent ventricular remodeling should be explored in further studies.

Noninvasive quantification and optimization of acute cell retention by in vivo positron emission tomography after intramyocardial cardiac-derived stem cell delivery.

OBJECTIVES: The aim of this study was to quantify acute myocardial retention of cardiac-derived stem cells (CDCs) and evaluate different delivery methods with positron emission tomography (PET). BACKGROUND: Success of stem cell transplantation for cardiac regeneration is partially limited by low retention/engraftment of the delivered cells. A clinically applicable method for accurate quantification of cell retention would enable optimization of cell delivery. METHODS: The CDCs were derived from syngeneic, male Wistar Kyoto (WK) rats labeled with [(18)F]-fluoro-deoxy-glucose ((18)FDG) and injected intramyocardially into the ischemic region of female WK rats after permanent left coronary artery ligation. The effects of fibrin glue (FG), bradycardia (adenosine), and cardiac arrest were examined. Imaging with (18)FDG PET was performed for quantification of cell retention. Quantitative polymerase chain reaction (PCR) for the male-specific SRY gene was performed to validate the PET results. RESULTS: Myocardial retention of cells suspended in phosphate-buffered saline 1 h after delivery was 17.6 +/- 11.5% by PCR and 17.8 +/- 7.3% by PET. When CDCs were injected immediately after induction of cardiac arrest, retention was increased to 75.6 +/- 18.6%. Adenosine slowed the ventricular rate and doubled CDC retention (35.4 +/- 5.3%). A similar increase in CDC retention was observed after epicardial application of FG at the injection site (37.5 +/- 8.2%). The PCR revealed a significant increase in 3-week cell engraftment in the FG animals (22.1 +/- 18.6% and 5.3 +/- 3.1%, for FG and phosphate-buffered saline, respectively). CONCLUSIONS: In vivo PET permits accurate measurement of CDC retention early after intramyocardial delivery. Sealing injection sites with FG or lowering ventricular rate by adenosine might be clinically translatable methods for improving stem cell engraftment in a beating heart.