Myocardial flow reserve recovery in patients with Takotsubo syndrome: Insights from positron emission tomography.

BACKGROUND: Coronary microvascular dysfunction (CMD) has been implicated in the pathogenesis of Takotsubo syndrome (TTS). Positron emission tomography (PET) plays a key role in the assessment of CMD through myocardial flow reserve (MFR). However, there is limited information on the temporal progression of MFR and its relationship to coronary artery disease (CAD) in TTS patients. METHODS: This study evaluated patients with TTS who underwent cardiac catheterization and PET within one year of hospitalization. Patients were categorized into acute (≤10 days), subacute (11-30 days), and chronic (≥31 days) stages based on post-onset time of PET assessment. MFR values and prevalence of abnormal MFR (<2.0) were compared between stages. Temporal MFR changes in patients with obstructive CAD (≥70% stenosis by coronary angiography), non-obstructive CAD, and normal coronaries were compared. RESULTS: Of the 88 patients studied (mean age 70; 96% female), 52 (59%) were in the acute, 17 (19%) in the subacute, and 19 (22%) in the chronic stage. Median MFR in the acute stage was 2.0 (1.5-2.3), with 58% of patients showing abnormal MFR. A significant time-dependent improvement in MFR was observed (P = 0.002), accompanied by a decreased prevalence of abnormal MFR (P = 0.016). While patients with normal coronaries showed significant MFR improvement over time (P = 0.045), patients with obstructive or non-obstructive CAD demonstrated no improvement across three stages (P = 0.346 and 0.174, respectively). CONCLUSION: PET-derived MFR was impaired in TTS patients during the acute phase, with improvement suggesting potential recovery from CMD over time. The concurrent presence of obstructive CAD might impede this recovery process.

Machine and deep learning models for accurate detection of ischemia and scar with myocardial blood flow positron emission tomography imaging.

BACKGROUND: Quantification of myocardial blood flow (MBF) is used for the noninvasive diagnosis of patients with coronary artery disease (CAD). This study compared traditional statistics, machine learning, and deep learning techniques in their ability to diagnose disease using only the rest and stress MBF values. METHODS: This study included 3245 rest and stress rubidium-82 positron emission tomography (PET) studies and matching diagnostic labels from perfusion reports. Standard logistic regression, lasso logistic regression, support vector machine, random forest, multilayer perceptron, and dense U-Net were compared for per-patient detection and per-vessel localization of scars and ischemia. RESULTS: Receiver-operator characteristic area under the curve (AUC) of machine learning models was significantly higher than those of traditional statistics models for per-patient detection of disease (0.92-0.95 vs. 0.87) but not for per-vessel localization of ischemia or scar. Random forest showed the highest AUC = 0.95 among the different models compared. On the final hold-out set for generalizability, random forest showed an AUC of 0.92 for detection and 0.89 for localization of perfusion abnormalities. CONCLUSIONS: For per-vessel localization, simple models trained on segmental data performed similarly to a convolutional neural network trained on polar-map data, highlighting the need to justify the use of complex predictive algorithms through comparison with simpler methods.

Rationale and design of the RAPID-WATER-FLOW trial: Radiolabeled perfusion to identify coronary artery disease using water to evaluate responses of myocardial FLOW.

OBJECTIVES: The objective of this study was to determine the diagnostic performance of 15O-water positron emission tomography (PET) myocardial perfusion imaging to detect coronary artery disease (CAD) using the truth-standard of invasive coronary angiography (ICA) with fractional flow reserve (FFR) or instantaneous wave-Free Ratio (iFR) or coronary computed tomography angiogram (CCTA). BACKGROUND: 15O-water has a very high first-pass extraction that allows accurate quantification of myocardial blood flow and detection of flow-limiting CAD. However, the need for an on-site cyclotron and lack of automated production at the point of care and relatively complex image analysis protocol has limited its clinical use to date. METHODS: The RAPID WATER FLOW study is an open-label, multicenter, prospective investigation of the accuracy of 15O-water PET to detect obstructive angiographic and physiologically significant stenosis in patients with suspected CAD. The study will include the use of an automated system for producing, dosing, and injecting 15O-water and enrolling approximately 215 individuals with suspected CAD at approximately 10 study sites in North America and Europe. The primary endpoint of the study is the diagnostic sensitivity and specificity of the 15O-water PET study using the truth-standard of ICA with FFR or iFR to determine flow-limiting stenosis, or CCTA to rule out CAD and incorporating a quantitative analytic platform developed for the 15O-water PET acquisitions. Sensitivity and specificity are to be considered positive if the lower bound of the 95% confidence interval is superior to the threshold of 60% for both, consistent with prior registration studies. Subgroup analyses include assessments of diagnostic sensitivity, specificity, and accuracy in female, obese, and diabetic individuals, as well as in those with multivessel disease. All enrolled individuals will be followed for adverse and serious adverse events for up to 32 hours after the index PET scan. The study will have >90% power (one-sided test, α = 0.025) to test the hypothesis that sensitivity and specificity of 15O-water PET are both >60%. CONCLUSIONS: The RAPID WATER FLOW study is a prospective, multicenter study to determine the diagnostic sensitivity and specificity of 15O-water PET as compared to ICA with FFR/iFR or CCTA. This study will introduce several novel aspects to imaging registration studies, including a more relevant truth standard incorporating invasive physiologic indexes, coronary CTA to qualify normal individuals for eligibility, and a more quantitative approach to image analysis than has been done in prior pivotal studies. CLINICAL TRIAL REGISTRATION INFORMATION: Clinical-Trials.gov (#NCT05134012).

Automated dynamic motion correction improves repeatability and reproducibility of myocardial blood flow quantification with rubidium-82 PET imaging.

BACKGROUND: Patient motion reduces the accuracy of PET myocardial blood flow (MBF) measurements. This study evaluated the effect of automatic motion correction on test-retest repeatability and inter-observer variability in a clinically relevant population. METHODS: Patients with known or suspected CAD underwent repeat rest 82Rb PET scans within minutes as part of their scheduled rest-stress perfusion study. Two trained observers evaluated the presence of heart motion in each scan. Global LV and per-vessel MBF were computed from the dynamic rest images before and after automatic motion correction. Test-retest and inter-observer variability were assessed using intra-class correlation and Bland-Altman analysis. RESULTS: 140 pairs of test-retest scans were included, with visual motion noted in 18%. Motion correction decreased the global MBF values by 3.5% (0.80 ± 0.24 vs 0.82 ± 0.25 mL⋅min-1⋅g-1; P < 0.001) suggesting that the blood input function was underestimated in cases with patient motion. Test-retest repeatability of global MBF improved by 9.7% (0.25 vs 0.28 mL⋅min-1⋅g-1; P < 0.001) and inter-observer repeatability was improved by 7.1% (0.073 vs 0.079 mL⋅min-1⋅g-1; P = 0.012). There was a marked impact on both test-retest repeatability as well as inter-observer repeatability in the LCX territory, with improvements of 16.5% (0.30 vs 0.36 mL⋅min-1⋅g-1; P < 0.0000) and 18.4% (0.13 vs 0.16 mL⋅min-1⋅g-1; P < 0.001), respectively. CONCLUSION: Automatic motion correction improved test-retest repeatability and reduced differences between observers.

Exponential dosing to standardize myocardial perfusion image quality with rubidium-82 PET.

BACKGROUND: 82Rb PET is commonly performed using the same injected activity in all patients, resulting in lower image quality in larger patients. This study compared 82Rb dosing with exponential vs proportional functions of body weight on the standardization of myocardial perfusion image (MPI) quality. METHODS: Two sequential cohorts of N = 60 patients were matched by patient weight. Rest and dipyridamole stress 82Rb PET was performed using 0.1 MBq·kg-2 exponential and 9 MBq·kg-1 proportional dosing. MPI scans were compared qualitatively with visual image quality scoring (IQS) and quantitatively using the myocardium-to-blood contrast-to-noise ratio (CNR) and blood background signal-to-noise ratio (SNR) as a function of body weight. RESULTS: Average (min-max) patient body weight was 81 ± 18 kg (46-137 kg). Proportional dosing resulted in decreasing CNR, SNR, and visual IQS with increasing body weight (P < 0.05). Exponential dosing eliminated the weight-dependent decreases in these image quality metrics that were observed in the proportional dosing group. CONCLUSION: 82Rb PET dosing as an exponential (squared) function of body weight produced consistent stress perfusion image quality over a wide range of patient weights. Dramatically lower doses can be used in lighter patients, with the equivalent population dose shifted toward the heavier patients to standardize diagnostic image quality.

Anti-inflammatory effect of biologic therapy in patients with psoriatic disease: A prospective cohort FDG PET study.

AIM: The aim of the study was to evaluate the changes in central vascular inflammation measured by FDG PET and myocardial blood flow reserve (MFR) determined by 82Rb PET following therapy with biologic agents for 6 months in patients with psoriatic arthritis (PsA) and/or cutaneous psoriasis (PsO) (group 1) and compare with PsO subjects receiving non-biologic therapy (group 2) and controls (group 3). METHODS AND RESULTS: Target-to-background ratio (TBR) by FDG PET in the most diseased segment of the ascending aorta (TBRmax) was measured to assess vascular inflammation. 82Rb PET studies were used to assess changes in left ventricular MFR. A total of 34 participants were enrolled in the study (11 in group 1, 13 in group 2, and 10 controls). A significant drop in the thoracic aorta uptake was observed in the biologic-treated group (ΔTBRmax: - .46 ± .55) compared to the PsO group treated with non-biologic therapy (ΔTBRmax: .23 ± .67). Those showing response to biologic agents maintained MFR compared to who showed no response. CONCLUSION: In a cohort of psoriasis patients treated with biologics, FDG uptake in the thoracic aorta decreased over the study period. Patients who demonstrated a significant anti-inflammatory response on FDG PET imaging maintained their MFR compared to non-responders.

Pharmacological and metabolic parameters of [18F]flubrobenguane in clinical imaging populations.

BACKGROUND: Cardiac sympathetic nervous system molecular imaging has demonstrated prognostic value. Compared with meta-[11C]hydroxyephedrine, [18F]flubrobenguane (FBBG) facilitates reliable estimation of SNS innervation using similar analytical methods and possesses a more convenient physical half-life. The aim of this study was to evaluate pharmacokinetic and metabolic properties of FBBG in target clinical cohorts. METHODS: Blood sampling was performed on 20 participants concurrent to FBBG PET imaging (healthy = NORM, non-ischemic cardiomyopathy = NICM, ischemic cardiomyopathy = ICM, post-traumatic stress disorder = PTSD). Image-derived blood time-activity curves were transformed to plasma input functions using cohort-specific corrections for plasma protein binding, plasma-to-whole blood distribution, and metabolism. RESULTS: The plasma-to-whole blood ratio was 0.78 ± 0.06 for NORM, 0.64 ± 0.06 for PTSD and 0.60 ± 0.14 for (N)ICM after 20 minutes. 22 ± 4% of FBBG was bound to plasma proteins. Metabolism of FBBG in (N)ICM was delayed, with a parent fraction of 0.71 ± 0.05 at 10 minutes post-injection compared to 0.53 ± 0.03 for PTSD/NORM. While there were variations in metabolic rate, metabolite-corrected plasma input functions were similar across all cohorts. CONCLUSIONS: Rapid plasma clearance of FBBG limits the impact of disease-specific corrections of the blood input function for tracer kinetic modeling.

Age, Not Sex, Modifies the Effect of Frailty on Long-term Outcomes After Cardiac Surgery.

OBJECTIVE: To examine the prevalence of frailty in surgical patients and determine whether age and sex modify the relationship between frailty and long-term mortality. BACKGROUND: Frailty is a complex and prevalent clinical syndrome. The cardiac surgery literature consists mostly of small, single-center studies, and the epidemiology of frailty remains to be fully elucidated in a real-world surgical population. METHODS: This retrospective cohort study included patients who underwent coronary artery bypass grafting, and/or aortic, mitral or tricuspid valve surgery in Ontario, Canada, between 2008 and 2016. The primary outcome was all-cause mortality. Survival probabilities were calculated using the Kaplan-Meier method, and the association of covariates with the hazard of death was assessed using multivariable Cox proportional hazard models. Frailty was assessed using the Johns Hopkins Adjusted Clinical Groups frailty-defining diagnoses indicator. RESULTS: Of 72,824 patients, 11,685 (16%) were frail. At median 5 ±â€Š2 years of follow-up, 2921 (25.0%) frail patients and 8637 (14.1%) non-frail patients had died [adjusted hazard ratio 1.60; 95% confidence interval (CI), 1.53-1.68]. The adjusted hazard ratio was highest in patients who underwent isolated mitral (2.18; 95% CI, 1.71-2.77) and mitral + aortic valve surgery (1.85; 95% CI, 1.33-2.58) and lowest after coronary artery bypass grafting + mitral valve surgery (1.38; 95% CI, 1.11-1.70). Age, but not sex, modified the effect of frailty on mortality; such that the rate of death decreased linearly with increasing patient age. CONCLUSIONS: We observed a high prevalence of frailty in patients undergoing cardiac surgery, and a statistically significant association between frailty and long-term mortality after cardiac procedures. Importantly, the rate of death was inversely proportional to age, such that frailty had a stronger adverse impact on younger patients. Our findings highlight the need to incorporate frailty into the preoperative risk stratification and investigate strategies to support younger patients who are frail.

Prognostic utility of longitudinal quantification of PET myocardial blood flow early post heart transplantation.

BACKGROUND: Myocardial blood flow (MBF) quantification by Rubidium-82 positron emission tomography (PET) has shown promise for cardiac allograft vasculopathy (CAV) surveillance and risk stratification post heart transplantation. The objective was to determine the prognostic value of serial PET performed early post transplantation. METHODS AND RESULT: Heart transplant (HT) recipients at the University of Ottawa Heart Institute with 2 PET examinations (PET1 = baseline, PET2 = follow-up) within 6 years of transplant were included in the study. Evaluation of PET flow quantification included stress MBF, coronary vascular resistance (CVR), and myocardial flow reserve (MFR). The primary composite outcome was all-cause death, re-transplant, myocardial infarction, revascularization, allograft dysfunction, cardiac allograft vasculopathy (CAV), or heart failure hospitalization. A total of 121 patients were evaluated (79% male, mean age 56 ± 11 years) with consecutive scans performed at mean 1.4 ± 0.7 and 2.6 ± 1.0 years post HT for PET1 and PET2, respectively. Over a mean follow-up of 3.0 (IQR 1.8, 4.6) years, 26 (22%) patients developed the primary outcome: 1 death, 11 new or progressive angiographic CAV, 2 percutaneous coronary interventions, 12 allograft dysfunction. Unadjusted Cox analysis showed a significant reduction in event-free survival in patients with PET1 stress MBF < 2.1 (HR: 2.43, 95% CI 1.11-5.29 P = 0.047) and persistent abnormal PET1 to PET2 CVR > 76 (HR: 2.19, 95% CI 0.87-5.51 P = 0.045). There was no association between MFR and outcomes. CONCLUSION: Low-stress MBF and persistent increased CVR on serial PET imaging early post HT are associated with adverse cardiovascular outcomes. Early post-transplant and longitudinal assessment by PET may identify at-risk patients for increased surveillance post HT.

Does quantification of [11C]meta-hydroxyephedrine and [13N]ammonia kinetics improve risk stratification in ischemic cardiomyopathy.

BACKGROUND: In ischemic cardiomyopathy patients, cardiac sympathetic nervous system dysfunction is a predictor of sudden cardiac arrest (SCA). This study compared abnormal innervation and perfusion measured by [11C]meta-hydroxyephedrine (HED) vs [13N]ammonia (NH3), conventional uptake vs parametric tracer analysis, and their SCA risk discrimination. METHODS: This is a sub-study analysis of the prospective PAREPET trial, which followed ischemic cardiomyopathy patients with reduced left ventricular ejection fraction (LVEF ≤ 35%) for events of SCA. Using n = 174 paired dynamic HED and NH3 positron emission tomography (PET) scans, regional defect scores (%LV extent × severity) were calculated using HED and NH3 uptake, as well as HED distribution volume and NH3 myocardial blood flow by kinetic modeling. RESULTS: During 4.1 years follow-up, there were 27 SCA events. HED defects were larger than NH3, especially in the lowest tertile of perfusion abnormality (P < .001). Parametric defects were larger than their respective tracer uptake defects (P < .001). SCA risk discrimination was not significantly improved with parametric or uptake mismatch (AUC = 0.73 or 0.70) compared to HED uptake defect scores (AUC = 0.67). CONCLUSION: Quantification of HED distribution volume and NH3 myocardial blood flow produced larger defects than their respective measures of tracer uptake, but did not lead to improved SCA risk stratification vs HED uptake alone.

Anti-inflammatory effect of rosuvastatin in patients with HIV infection: An FDG-PET pilot study.

AIMS: This study aimed to evaluate markers of systemic as well as imaging markers of inflammation in the ascending aorta, bone marrow, and spleen measured by 18F-FDG PET/CT, in HIV+ patients at baseline and following therapy with rosuvastatin. METHODS AND RESULTS: Of the 35 HIV+ patients enrolled, 17 were randomized to treatment with 10 mg/day rosuvastatin and 18 to usual care for 6 months. An HIV- control cohort was selected for baseline comparison of serum inflammatory markers and monocyte markers of inflammation. 18F-FDG-PET/CT imaging of bone marrow, spleen, and thoracic aorta was performed in the HIV+ cohort at baseline and 6 months. While CD14++CD16- and CCR2 expressions were reduced, serum levels of IL-7, IL-8, and MCP-1 were elevated in the HIV+ population compared to the controls. There was a significant drop in FDG uptake in the bone marrow (TBRmax), spleen (SUVmax) and thoracic aortic (TBRmax) in the statin-treated group compared to the control group (bone marrow: - 10.3 ± 16.9% versus 5.0 ± 18.9%, p = .0262; spleen: - 9.8 ± 20.3% versus 11.3 ± 28.8%, p = .0497; thoracic aorta: - 19.1 ± 24.2% versus 4.3 ± 15.4%, p = .003). CONCLUSIONS: HIV+ patients had significantly markers of systemic inflammation including monocyte activation. Treatment with low-dose rosuvastatin in the HIV+ cohort significantly reduced bone marrow, spleen and thoracic aortic FDG uptake.

Metabolic activity of the left and right atria are differentially altered in patients with atrial fibrillation and LV dysfunction.

BACKGROUND: Alterations in atrial metabolism may play a role in the perpetuation of atrial fibrillation (AF). This study sought to compare 18F-fluorodeoxyglucose (FDG) uptake on PET, in patients with LV dysfunction versus those without AF. METHODS: Seventy-two patients who underwent myocardial viability assessment were evaluated. AF patients (36) had persistent or permanent AF based on history and ECG. Patients without AF (36) were matched to AF patients based on sex, diabetes, age, and LVEF. Maximum and mean FDG Standard Uptake Values (SUV) in the left atrial (LA) wall and right atrial (RA) wall were measured. Tissue-to-blood ratios (TBR) were calculated as atrial wall to blood-pool activity. Atrial volumes were measured by echocardiography. RESULTS: Maximum and mean FDG SUV and TBRs were significantly increased in the RA (but not the LA) of patients with AF compared to those without (P < 0.01). When accounting for changes in atrial volume, the presence of AF remained a significant predictor of higher RAMAX, but not RAMEAN FDG uptake. CONCLUSION: In patients with LV dysfunction from ischemic cardiomyopathy, LA and RA glucose metabolism are differentially altered in those with persistent atrial fibrillation. Further investigations should elucidate the temporal relationship between AF and glucose metabolic changes, as a potential target for therapy.

OUTSMART HF: A Randomized Controlled Trial of Routine Versus Selective Cardiac Magnetic Resonance for Patients With Nonischemic Heart Failure (IMAGE-HF 1B).

BACKGROUND: Cardiac magnetic resonance (CMR) is a recommended imaging test for patients with heart failure (HF); however, there is a lack of evidence showing incremental benefit over transthoracic echocardiography. Our primary hypothesis was that routine use of CMR will yield more specific diagnoses in nonischemic HF. Our secondary hypothesis was that routine use of CMR will improve patient outcomes. METHODS: Patients with nonischemic HF were randomized to routine versus selective CMR. Patients in the routine strategy underwent echocardiography and CMR, whereas those assigned to selective use underwent echocardiography with or without CMR according to the clinical presentation. HF causes was classified from the imaging data as well as by the treating physician at 3 months (primary outcome). Clinical events were collected for 12 months. RESULTS: A total of 500 patients (344 male) with mean age 59±13 years were randomized. The routine and selective CMR strategies had similar rates of specific HF causes at 3 months clinical follow-up (44% versus 50%, respectively; P=0.22). At image interpretation, rates of specific HF causes were also not different between routine and selective CMR (34% versus 30%, respectively; P=0.34). However, 24% of patients in the selective group underwent a nonprotocol CMR. Patients with specific HF causes had more clinical events than those with nonspecific caused on the basis of imaging classification (19% versus 12%, respectively; P=0.02), but not on clinical assessment (15% versus 14%, respectively; P=0.49). CONCLUSIONS: In patients with nonischemic HF, routine CMR does not yield more specific HF causes on clinical assessment. Patients with specific HF causes from imaging had worse outcomes, whereas HF causes defined clinically did not. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01281384.

Revisiting the Evidence for Dipyridamole in Reducing Restenosis: A Systematic Review and Meta-analysis.

ABSTRACT: Atherosclerosis remains a leading cause of morbidity and mortality, with revascularization remaining a cornerstone of management. Conventional revascularization modalities remain challenged by target vessel reocclusion-an event driven by mechanical, thrombotic, and proliferative processes. Despite considerable advancements, restenosis remains the focus of ongoing research. Adjunctive agents, including dipyridamole, offer a multitude of effects that may improve vascular homeostasis. We sought to quantify the potential therapeutic impact of dipyridamole on vascular occlusion. We performed a literature search (EMBASE and MEDLINE) examining studies that encompassed 3 areas: (1) one of the designated medical therapies applied in (2) the setting of a vascular intervention with (3) an outcome including vascular occlusion rates and/or quantification of neointimal proliferation/restenosis. The primary outcome was vascular occlusion rates. The secondary outcome was the degree of restenosis by neointimal quantification. Both human and animal studies were included in this translational analysis. There were 6,839 articles screened, from which 73 studies were included, encompassing 16,146 vessels followed up for a mean of 327.3 days (range 7-3650 days). Preclinical studies demonstrate that dipyridamole results in reduced vascular occlusion rates {24.9% vs. 48.8%, risk ratio 0.53 [95% confidence interval (CI) 0.40-0.70], I2 = 39%, P < 0.00001}, owing to diminished neointimal proliferation [standardized mean differences -1.13 (95% CI -1.74 to -0.53), I2 = 91%, P = 0.0002]. Clinical studies similarly demonstrated reduced occlusion rates with dipyridamole therapy [23.5% vs. 31.0%, risk ratio 0.77 (95% CI 0.67-0.88), I2 = 84%, P < 0.0001]. Dipyridamole may improve post-intervention vascular patency and mitigate restenosis. Dedicated studies are warranted to delineate its role as an adjunctive agent after revascularization.

Comparison of myocardial blood flow and flow reserve with dobutamine and dipyridamole stress using rubidium-82 positron emission tomography.

BACKGROUND: The objective of this study was to compare the hyperemic myocardial blood flow (MBF) and myocardial flow reserve (MFR) obtained with dobutamine to those of dipyridamole in patients referred for myocardial perfusion imaging (MPI) using 82Rb positron emission tomography. METHODS: One hundred and fifty-six patients who underwent a 82Rb PET MPI study with dobutamine stress were included. A matching cohort of patients who underwent a 82Rb PET MPI study with dipyridamole stress was created, accounting for sex, age, history of coronary artery disease (CAD), prior revascularization, CAD risk factors, body mass index, and MPI interpretation. RESULTS: Global rest MBF (median [interquartile range] 0.84 [0.64-1.00] vs 0.69 [0.59-0.85]), stress MBF (2.36 [1.73-3.08] vs 1.66 [1.25-2.06]), MFR (2.75 [2.19-3.64] vs 2.29 [1.78-2.84]), and corrected MFR (2.85 [2.14-3.64] vs 2.20 [1.65-2.75]) were all significantly higher (P < 0.0001) in the dobutamine cohort compared to the dipyridamole cohort. CONCLUSION: The results of this study suggest that dobutamine produces higher MBF compared to dipyridamole in a representative population referred to nuclear cardiology laboratories.

[11C]meta-hydroxyephedrine PET evaluation in experimental pulmonary arterial hypertension: Effects of carvedilol of right ventricular sympathetic function.

BACKGROUND: Little is known about the sequelae of chronic sympathetic nervous system (SNS) activation in patients with pulmonary arterial hypertension (PAH) and right heart failure (RHF). We aimed to, (1) validate the use of [11C]-meta-hydroxyephedrine (HED) for assessing right ventricular (RV) SNS integrity, and (2) determine the effects of ß-receptor blockade on ventricular function and myocardial SNS activity in a PAH rat model. METHODS: PAH was induced in male Sprague-Dawley rats (N = 36) using the Sugen+chronic hypoxia model. At week 5 post-injection, PAH rats were randomized to carvedilol (15 mg·kg-1·day-1 oral; N = 16) or vehicle (N = 16) for 4 weeks. Myocardial SNS function was assessed with HED positron emission tomography(PET). RESULTS: With increasing PAH disease severity, immunohistochemistry confirmed selective sympathetic denervation within the RV and sparing of parasympathetic nerves. These findings were confirmed on PET with a significant negative relationship between HED volume of distribution(DV) and right ventricular systolic pressure (RVSP) in the RV (r = -0.90, p = 0.0003). Carvedilol did not reduce hemodynamic severity compared to vehicle. RV ejection fraction (EF) was lower in both PAH groups compared to control (p < 0.05), and was not further reduced by carvedilol. Carvedilol improved SNS function in the LV with significant increases in the HED DV, and decreased tracer washout in the LV (p < 0.05) but not RV. CONCLUSIONS: PAH disease severity correlated with a reduction in HED DV in the RV. This was associated with selective sympathetic denervation. Late carvedilol treatment did not lead to recovery of RV function. These results support the role of HED imaging in assessing SNS innervation in a failing right ventricle.

Internal validation of myocardial flow reserve PET imaging using stress/rest myocardial activity ratios with Rb-82 and N-13-ammonia.

BACKGROUND: Myocardial flow reserve (MFR) measurement provides incremental diagnostic and prognostic information. The objective of the current study was to investigate the application of a simplified model for the estimation of MFR using only the stress/rest myocardial activity ratio (MAR) in patients undergoing rest-stress cardiac PET MPI. METHODS AND RESULTS: Rest and dipyridamole stress dynamic PET imaging was performed in consecutive patients using 82Rb or 13NH3 (n = 250 each). Reference standard MFR was quantified using a standard one-tissue compartment model. Stress/rest myocardial activity ratio (MAR) was calculated using the LV-mean activity from 2 to 6 minutes post-injection. Simplified estimates of MFR (MFREST) were then calculated using an inverse power function. For 13NH3, there was good correlation between MFR and MFREST values (R = 0.63), with similar results for 82Rb (R = 0.73). There was no bias in the MFREST values with either tracer. The overall diagnostic performance of MFREST for detection of MFR < 2 was good with ROC area under the curve (AUC) = 83.2 ± 1.2% for 13NH3 and AUC = 90.4 ± 0.7% for 82Rb. CONCLUSION: MFR was estimated with good accuracy using 82Rb and 13NH3 with a simplified method that relies only on stress/rest activity ratios. This novel approach does not require dynamic imaging or tracer kinetic modeling. It may be useful for routine quality assurance of PET MFR measurements, or in scanners where full dynamic imaging and tracer kinetic modeling is not feasible for technical or logistical reasons.

Validation of multiparametric rubidium-82 PET myocardial blood flow quantification for cardiac allograft vasculopathy surveillance.

BACKGROUND: We previously demonstrated high diagnostic accuracy of Rubidium-82 positron emission tomography (PET) myocardial blood flow (MBF) quantification for CAV. The purpose of this study was to validate multiparametric PET detection of CAV by combined rate-pressure-product-corrected myocardial flow reserve (cMFR), stress MBF, and coronary vascular resistance (CVR) assessment. METHODS AND RESULTS: Diagnostic CAV cut-offs of cMFR < 2.9, stress MBF < 2.3, CVR > 55 determined in a previous study (derivation) were assessed in heart transplant recipients referred for coronary angiography and intravascular ultrasound (IVUS) (validation). CAV was defined as International Society of Heart and Lung Transplantation CAV1-3 on angiography; and maximal intimal thickness ≥ 0.5 mm on IVUS. Eighty patients (derivation n = 40, validation n = 40) were included: 80% male, mean age 54±14 years, 4.5±5.6 years post transplant. The prevalence of CAV was 44% on angiography and 78% on IVUS. Combined PET cMFR < 2.9, stress MBF < 2.3, CVR > 55 CAV assessment yielded high 88% (specificity 75%) and 83% (specificity 40%) sensitivity for ≥ 1 abnormal parameter and high 88% (sensitivity 59%) and 90% (sensitivity 43%) specificity for 3 abnormal parameters, in the derivation and validation cohorts, respectively. CONCLUSION: We validate the diagnostic accuracy of multiparametric PET flow quantification by cMFR, stress MBF, and CVR for CAV.

Increased myocardial oxygen consumption rates are associated with maladaptive right ventricular remodeling and decreased event-free survival in heart failure patients.

BACKGROUND: Reduced left ventricular (LV) function is associated with increased myocardial oxygen consumption rate (MVO2) and altered sympathetic activity, the role of which is not well described in right ventricular (RV) dysfunction. METHODS AND RESULTS: 33 patients with left heart failure were assessed for RV function/size using echocardiography. Positron emission tomography (PET) was used to measure 11C-acetate clearance rate (kmono), 11C-hydroxyephedrine (11C-HED) standardized uptake value (SUV), and retention rate. RV MVO2 was estimated from kmono. 11C-HED SUV and retention indicated sympathetic neuronal function. A composite clinical endpoint was defined as unplanned cardiac hospitalization within 5 years. Patients with (n = 10) or without (n = 23) RV dysfunction were comparable in terms of sex (male: 70.0 vs 69.5%), LV ejection fraction (39.6 ± 9.0 vs 38.6 ± 9.4%), and systemic hypertension (70.0 vs 78.3%). RV dysfunction patients were older (70.9 ± 13.5 vs 59.4 ± 11.5 years; P = .03) and had a higher prevalence of pulmonary hypertension (60.0% vs 13.0%; P = .01). RV dysfunction was associated with increased RV MVO2 (.106 ± .042 vs .068 ± .031 mL/min/g; P = .02) and decreased 11C-HED SUV and retention (6.05 ± .53 vs 7.40 ± 1.39 g/mL (P < .001) and .08 ± .02 vs .11 ± .03 mL/min/g (P < .001), respectively). Patients with an RV MVO2 above the median had a shorter event-free survival (hazard ratio = 5.47; P = .01). Patients who died within the 5-year follow-up period showed a trend (not statistically significant) for higher RV MVO2 (.120 ± .026 vs .074 ± .038 mL/min/g; P = .05). CONCLUSIONS: RV dysfunction is associated with increased oxygen consumption (also characterized by a higher risk for cardiac events) and impaired RV sympathetic function.

Assessing myocardial perfusion in suspected coronary artery disease: rationale and design of the second phase 3, open-label multi-center study of flurpiridaz (F-18) injection for positron emission tomography (PET) imaging.

BACKGROUND: Positron emission tomography (PET) myocardial perfusion imaging (MPI) with the novel radiopharmaceutical Fluorine-18 Flurpiridaz has been shown in Phase 1, 2, and first Phase 3 clinical studies to be safe and effective in diagnosing coronary artery disease (CAD). We describe the methodology of the second FDA-mandated phase 3 prospective, open-label, international, multi-center trial of F-18 Flurpiridaz PET MPI. METHODS: The primary study end point is to assess the diagnostic efficacy of F-18 Flurpiridaz PET MPI in the detection of significant CAD [≥ 50% by quantitative invasive coronary angiography (ICA)] in patients with suspected CAD. The secondary endpoints are to evaluate the diagnostic efficacy of F-18 Flurpiridaz PET MPI compared to Tc-99 m-labeled SPECT MPI in the detection of CAD in all patients and in the following subgroups: (1) females; (2) patients with body mass index ≥ 30 kg/m2; and (3) diabetic patients. This trial's design differs from the first phase 3 trial in that (1) comparison to SPECT is now a secondary end point; (2) patients with known CAD are excluded; and (3) both SPECT and PET MPI are performed before ICA. CONCLUSIONS: This second phase 3 study will provide additional evidence on the diagnostic efficacy of F-18 Flurpiridaz PET MPI in the detection of significant CAD. TRIAL REGISTRATION NUMBER: NCT03354273.