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.

Mortality trends in pulmonary arterial hypertension in Canada: a temporal analysis of survival per ESC/ERS guideline era.

BACKGROUND: The evolution in pulmonary arterial hypertension (PAH) management has been summarised in three iterations of the European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines. No study has assessed whether changes in management, as reflected in the changing guidelines, has translated to improved long-term survival in PAH. METHODS: We performed a mixed retrospective/prospective analysis of treatment-naïve, incident PAH patients (n=392) diagnosed at three major centres in Canada from 2009 to 2021. Patients were divided into two groups based on their diagnosis date and in accordance with the 2009 and 2015 ESC/ERS guideline iterations. Overall survival was assessed based on date of diagnosis and initial treatment strategy (i.e. monotherapy versus combination therapy). RESULTS: There was a shift towards more aggressive upfront management with combination therapy in Canada after the publication of the 2015 ESC/ERS guidelines (10.4% and 30.8% in patients from 2009 to 2015 and 36.0% and 57.4% in patients diagnosed after 2015 for baseline and 2-year follow-up, respectively). A key factor associated with combination therapy after 2015 was higher pulmonary vascular resistance (p=0.009). The 1-, 3- and 5-year survival rates in Canada were 89.2%, 75.6% and 56.0%, respectively. Despite changes in management, there was no improvement in long-term survival before and after publication of the 2015 ESC/ERS guidelines (p=0.53). CONCLUSIONS: There was an increase in the use of initial and sequential combination therapy in Canada after publication of the 2015 ESC/ERS guidelines, which was not associated with improved long-term survival. These data highlight the continued difficulties of managing this aggressive pulmonary disease in an era without a cure.

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.

Medical Therapy for Heart Failure Associated With Pulmonary Hypertension.

The past 2 decades have witnessed a >40% improvement in mortality for patients with heart failure and left ventricular systolic dysfunction. 1 This success has coincided with the stepwise availability of drugs that target neurohormonal activation: ß-adrenergic receptor blockers (ß-blockers), ACE (angiotensin-converting enzyme) inhibitors and ANG (angiotensin) II blockers, neprilysin inhibitors, and aldosterone antagonists. Our understanding of right heart failure (RHF) has lagged behind and many proven targeted therapies for left heart failure do not appear to provide similar benefits for RHF. Until recently, the right ventricle (RV) has often been viewed as less important than the left ventricle and in contemporary literature received the moniker "The Forgotten Ventricle". Recent advances in echocardiography and magnetic resonance imaging have enabled detailed assessments of RV anatomy and physiology in both health and disease allowing us to more accurately describe the clinical sequelae and end-organ manifestations of RHF. RV function is now recognized as one of the most important predictors of prognosis in many cardiovascular disease states. 2 Despite the significance of RV function to survival, there are no clinically approved therapies that directly nor selectively improve RV function. As well, relative to our understanding of left heart failure, the basis for RHF remains poorly understood. This article aims to condense the current knowledge on RV adaptation and failure, review current management strategies for RHF, and explore evolving therapeutic approaches.

[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.

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.

Reproducible Quantification of Regional Sympathetic Denervation with [11C]meta-Hydroxyephedrine PET Imaging.

BACKGROUND: Regional cardiac sympathetic denervation is predictive of sudden cardiac arrest in patients with ischemic cardiomyopathy. The reproducibility of denervation scores between automated software programs has not been evaluated. This study seeks to (1) compare the inter-rater reliability of regional denervation measurements using two analysis programs: FlowQuant® and Corridor4DM®; (2) evaluate test-retest repeatability of regional denervation scores. METHODS: N = 190 dynamic [11C]meta-hydroxyephedrine (HED) PET scans were reviewed from the PAREPET trial in ischemic cardiomyopathy patients with reduced left ventricular ejection fraction(LVEF ≤ 35%). N = 12 scans were excluded due to non-diagnostic quality. N = 178 scans were analyzed using FlowQuant and Corridor4DM software, each by two observers. Test-retest scans from N = 20 patients with stable heart failure were utilized for test-retest analysis. Denervation scores were defined as extent × severity of relative uptake defects in LV regions with < 75% of maximal uptake. Results were evaluated using intraclass correlation coefficient (ICC) and Bland-Altman coefficient of repeatability (RPC). RESULTS: Inter-observer, inter-software, and test-retest ICC values were excellent (ICC = 94% to 99%) and measurement variability was small (RPC < 11%). Mean differences between observers ranged .2% to 1.1% for Corridor4DM (P = .28), FlowQuant (P < .001), and between software programs (P < .001). Kaplan-Meier analysis demonstrated HED scores from both programs were predictive of SCA. CONCLUSION: Inter-rater reliability for both analysis programs was excellent and test-retest repeatability was consistent. The minimal difference in scores between FlowQuant and Corridor4DM supports their use in future trials.

Reliable quantification of myocardial sympathetic innervation and regional denervation using [11C]meta-hydroxyephedrine PET.

PURPOSE: Cardiac sympathetic nervous system (SNS) dysfunction is associated with poor prognosis in chronic heart failure patients. This study characterized the reproducibility and repeatability of [11C]meta-hydroxyephedrine (HED) positron emission tomography (PET) quantification of cardiac SNS innervation, regional denervation, and myocardial blood flow (MBF). METHODS: Dynamic HED PET-CT scans were performed 47 ± 22 days apart in 20 patients with stable heart failure and reduced ejection fraction. Three observers, blinded to clinical data, used FlowQuant® to evaluate the test-retest repeatability and inter- and intra-observer reproducibility of HED tracer uptake and clearance rates to measure global (LV-mean) retention index (RI), volume of distribution (VT), and MBF. Values were also compared with and without regional partial-volume correction. Regional denervation was quantified as %LV defect size of values < 75% of the LV-maximum. Test-retest repeatability and observer reproducibility were evaluated using intra-class-correlation (ICC) and Bland-Altman coefficient of repeatability (NPC). RESULTS: Intra- and inter-observer correlations of both VT and RI were excellent (ICC = 0.93-0.99). Observer reproducibility (NPC = 3-13%) was lower than test-retest repeatability (NPC = 12-61%). Both regional (%LV defect size) and global (LV-mean) measures of sympathetic innervation were more repeatable using the simple RI model compared to VT (NPC = 12% vs. 19% and 30% vs. 54%). Using either model, quantification of regional denervation (defect size) was consistently more reliable than the global LV-mean values of RI or VT. Regional partial-volume correction degraded repeatability of both the global and regional VT measures by 2-12%. Test-retest repeatability of MBF estimation was relatively poor (NPC = 30-61%) compared with the RI. CONCLUSIONS: Quantitative measures of global and regional SNS innervation were most repeatable using the simple RI method of analysis compared with the more complex VT. Observer variability was significantly lower than the test-retest repeatability using a highly automated analysis program. These results support the use of the simple RI method for reliable analysis of HED PET images in clinical research studies for future evaluation of new therapies and for risk stratification in patients with heart failure.

Correction to: PET imaging of sympathetic innervation with [18F]Flubrobenguane vs [11C]mHED in a patient with ischemic cardiomyopathy.

At time of initial publication, the USAN Council had assigned the generic name for LMI1195 as Flurobenguan. However, the Council has since changed and finalized this compound name as Flubrobenguane which is recommended as the generic name to be used in the future.

Magnesium Modifies the Impact of Calcitriol Treatment on Vascular Calcification in Experimental Chronic Kidney Disease.

Chronic kidney disease (CKD) patients are commonly treated with vitamin D analogs, such as calcitriol. Recent epidemiologic evidence revealed a significant interaction between vitamin D and magnesium, since an inverse relationship between vitamin D levels and mortality mainly occurs in patients with a high magnesium intake. The aim of the study was to assess the mechanisms involved by determining whether magnesium alone or combined with calcitriol treatments differentially impacts vascular calcification (VC) in male Sprague-Dawley rats with adenine-induced CKD. Treatment with moderate doses of calcitriol (80 µg/kg) suppressed parathyroid hormone to near or slightly below control levels. Given alone, this dose of calcitriol increased the prevalence of VC; however, when magnesium was given in combination, the severity of calcification was attenuated in the abdominal aorta (51% reduction), iliac (44%), and carotid arteries (46%) compared with CKD controls. The decreases in vascular calcium content were associated with a 20-50% increase in vascular magnesium. Calcitriol treatment alone significantly decreased TRPM7 protein (↓ to ∼11%), whereas the combination treatment increased both mRNA (1.7×) and protein (6.8×) expression compared with calcitriol alone. In summary, calcitriol increased VC in certain conditions, but magnesium prevented the reduction in TRPM7 and reduced the severity of VC, thereby increasing the bioavailable magnesium in the vascular microenvironment. These findings suggest that modifying the adverse effect profile of calcitriol with magnesium may be a plausible approach to benefiting the increasing number of CKD patients being prescribed calcitriol.

Reducing the volume of sprint interval training does not diminish maximal and submaximal performance gains in healthy men.

PURPOSE: The present study examined the effect of reducing sprint interval training (SIT) work-interval duration on increases in maximal and submaximal performance. METHODS: Subjects (n = 36) were assigned to one of three training groups: endurance training (ET; 60 min per session for weeks 1-2, increasing to 75 min per session for weeks 3-4), or sprint interval training consisting of either repeated 30 (SIT 30) or 15 (SIT 15) second all-out intervals (starting with 4 bouts per session for weeks 1-2, increasing to 6 intervals per session for weeks 3-4). Training consisted of cycling 3 times per week for 4 weeks. RESULTS: While there was a significant main effect of training on VO2peak such that VO2peak was elevated post-training, no significant difference was observed in the improvements observed between groups (ET ~13%, SIT 30-4%, SIT 15-8%). A significant main effect of training was observed such that lactate threshold and critical power were higher during post-testing across all groups (p < 0.05). There was a main effect of training (p < 0.05) on Wingate peak power with no differences observed between groups at post-training. CONCLUSIONS: Together, these results indicate that reducing SIT work-interval duration from 30 to 15 s had no impact on training-induced increases in aerobic or anaerobic power, or on increases in lactate threshold (absolute) and critical power.

Role of Nuclear Imaging in Cardiac Stereotactic Body Radiotherapy for Ablation of Ventricular Tachycardia.

Ventricular tachycardia (VT) is a life-threatening arrhythmia common in patients with structural heart disease or nonischemic cardiomyopathy. Many VTs originate from regions of fibrotic scar tissue, where delayed electrical signals exit scar and re-enter viable myocardium. Cardiac stereotactic body radiotherapy (SBRT) has emerged as a completely noninvasive alternative to catheter ablation for the treatment of recurrent or refractory ventricular tachycardia. While there is no common consensus on the ideal imaging workflow, therapy planning for cardiac SBRT often combines information from a plurality of imaging modalities including MRI, CT, electroanatomic mapping and nuclear imaging. MRI and CT provide detailed anatomic information, and late enhancement contrast imaging can indicate regions of fibrosis. Electroanatomic maps indicate regions of heterogenous conduction voltage or early activation which are indicative of arrhythmogenic tissue. Some early clinical adopters performing cardiac SBRT report the use of myocardial perfusion and viability nuclear imaging to identify regions of scar. Nuclear imaging of hibernating myocardium, inflammation and sympathetic innervation have been studied for ventricular arrhythmia prognosis and in research relating to catheter ablation of VT but have yet to be studied in their potential applications for cardiac SBRT. The integration of information from these many imaging modalities to identify a target for ablation can be challenging. Multimodality image registration and dedicated therapy planning tools may enable higher target accuracy, accelerate therapy planning workflows and improve patient outcomes. Understanding the pathophysiology of ventricular arrhythmias, and localizing the arrhythmogenic tissues, is vital for successful ablation with cardiac SBRT. Nuclear imaging provides an arsenal of imaging strategies to identify regional scar, hibernation, inflammation, and sympathetic denervation with some advantages over alternative imaging strategies.

Vascular calcification maladaptively participates in acute phosphate homeostasis.

AIMS: Non-renal extravasation of phosphate from the circulation and transient accumulation into tissues and extracellular fluid is a regulated process of acute phosphate homeostasis that is not well understood. This process is especially relevant in the setting of chronic kidney disease (CKD), where exposure to increased phosphate is prolonged due to inefficient kidney excretion. Furthermore, CKD-associated mineral dysregulation induces pathological accumulation of phosphate causing vascular calcification (VC). Our objective was to determine whether the systemic response to acute phosphate challenges is altered by VC. METHODS AND RESULTS: After bolus phosphate administration, circulating and tissue deposition of this challenge was assessed in two rat models of VC using a radiolabelled phosphate tracer. In an adenine-induced model of CKD (N = 70), animals with VC had a blunted elevation of circulating 33PO4 following oral phosphate administration (P < 0.01), and the discordant deposition could be traced to the calcified arteries (11.4 [7.5-13.1] vs.43.0 [35.5-53.7] pmol/ng tissue, P < 0.001). In a non-CKD model of VC, calcification was induced with 0.5 ug/kg calcitriol and then withdrawn (N = 24). New phosphate uptake by the calcified vasculature correlated to the pre-existing burden of calcification (r = 38, P < 0.001) and was substantially attenuated in the absence of calcification stimulus (P < 0.01). Phosphate accrual was stimulated by the phosphate challenge and not present to the same degree during passive disposition of circulating phosphate. Further, the form of phosphate that deposited to the vasculature was predominately amorphous inorganic phosphate and not that which was bound in matured calciprotein particles. CONCLUSIONS: In the process of calcification, arteries acutely deposit substantial amorphous phosphate while blunting the elevation in the circulation, thereby altering the systemic disposition of phosphate and identifying VC as a participatory mineral homeostatic organ. This study demonstrates the negative vascular consequence of acute fluctuations in circulating phosphate, and supports the importance of phosphate bioavailability and diet management in CKD patients as a mediator of cardiovascular risk.

Real-world evidence to advance knowledge in pulmonary hypertension: Status, challenges, and opportunities. A consensus statement from the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative's Real-world Evidence Working Group.

This manuscript on real-world evidence (RWE) in pulmonary hypertension (PH) incorporates the broad experience of members of the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative Real-World Evidence Working Group. We aim to strengthen the research community's understanding of RWE in PH to facilitate clinical research advances and ultimately improve patient care. Herein, we review real-world data (RWD) sources, discuss challenges and opportunities when using RWD sources to study PH populations, and identify resources needed to support the generation of meaningful RWE for the global PH community.

Right Ventricular Maladaptation to Pressure Overload in Fischer Rats Is Associated With Profound Deficiency in Adenylate Kinase 1 and Impaired Ventricular Energetics.

BACKGROUND: We explored the mechanism of maladaptive right ventricular (RV) remodeling in Fischer compared with Sprague-Dawley (SD) rats exposed to pressure overload. METHODS: Pulmonary hypertension was induced by injection of the VEGFR antagonist, SU5416, followed by a 3-week exposure to hypoxia (Sugen chronic hypoxia). In vivo oxidative metabolism was assessed by RV/left ventricle ratio of [11C]acetate positron emission tomography clearance (kmono). Unbiased, global transcriptional and proteomic profiling was performed in Fischer and SD rats at baseline and after Sugen chronic hypoxia. RESULTS: All Fischer rats succumbed to RV failure by 5 weeks, whereas SD rats showed preserved RV function and 88% survival beyond 9 weeks (P<0.0001). Fischer rats exhibited increased oxidative metabolism at 4 weeks (P<0.05) and impaired RV efficiency compared with SD (work metabolic index: 52±10 versus 91±27 mmHg·mL/cm2, respectively; P<0.05), but no differences in mitochondrial complex activity. AK1 (adenylate kinase 1) was among the top 10 differentially expressed genes between Fischer and SD rats, with markedly lower RV expression in Fischer rats (FC: 3.36, P<0.05), confirmed by proteomic analysis and validated by Western blotting (>10-fold reduction, P<0.001). While whole-genome sequencing failed to reveal any coding region mutations in Fischer rats, there was a unique variant in a highly conserved upstream flanking region likely involved in the regulation of AK1 expression. CONCLUSIONS: Therefore, Fischer rats exhibit profound AK1 deficiency and inefficient cardiac energetics likely related to reduced adenosine triphosphate shuttling from the mitochondria to the contractile fibers. This represents a novel mechanism for RV failure in response to chronic increases in afterload.

Regional Distribution of Fluorine-18-Flubrobenguane and Carbon-11-Hydroxyephedrine for Cardiac PET Imaging of Sympathetic Innervation.

OBJECTIVES: The aim of this study was to investigate the regional distribution of novel 18F-labeled positron emission tomographic (PET) tracer flubrobenguane (FBBG) (whose longer half-life could enable more widespread use) to assess myocardial presynaptic sympathetic nerve function in humans in comparison to [11C]meta-hydroxyephedrine (HED). BACKGROUND: The sympathetic nervous system (SNS) is vitally linked to cardiovascular regulation and disease. SNS imaging has shown prognostic value. HED is the most commonly used PET tracer for evaluation of sympathetic function in humans, but widespread clinical use is limited because of the short half-life of 11C. METHODS: A total of 25 participants (n = 6 healthy; n = 14 ischemic cardiomyopathy, left ventricular [LV] ejection fraction [EF] = 34 ± 5%; and n = 5 nonischemic cardiomyopathy, EF = 33 ± 3%) underwent 2 separate PET imaging visits 8.7 ± 7.6 days apart. On 1 visit, participants underwent dynamic HED PET imaging. On a different visit, participants underwent dynamic FBBG PET imaging. The order of testing was random. HED and FBBG global innervation (retention index [RI] and distribution volume [DV]) and regional denervation (% nonuniformity) were quantified to assess regional presynaptic sympathetic innervations. RESULTS: FBBG RI (r2 = 0.72; ICC = 0.79; p < 0.0001), DV (r2 = 0.62; ICC = 0.78; p < 0.0001), and regional denervation (r2 = 0.97; ICC = 0.98; p < 0.0001) correlated highly with HED. Average LV RI values were highly similar between HED (7.3 ± 2.4%/min) and FBBG (7.0 ± 1.7%/min; p = 0.33). Post-hoc analysis did not reveal any between-tracer differences on a regional level (17-segment), suggesting equivalent regional distributions in both patients with and without ischemic cardiomyopathy. CONCLUSIONS: FBBG and HED yield equivalent global and regional distributions in both patients with and without ischemic cardiomyopathy. 18F-labeled PET tracers, such as FBBG, are critical for widespread distribution necessary for multicenter clinical trials and to maximize patient impact.

Positron Emission Tomography Imaging of Regional Versus Global Myocardial Sympathetic Activity to Improve Risk Stratification in Patients With Ischemic Cardiomyopathy.

BACKGROUND: Current risk assessment approaches fail to identify the majority of patients at risk of sudden cardiac arrest (SCA). Noninvasive imaging of the cardiac sympathetic nervous system using single-photon emission computed tomography and positron emission tomography offers the potential for refining SCA risk assessment. While various [11C]meta-hydroxyephedrine quantification parameters have been proposed, it is currently unknown whether regional denervation or global innervation yields greater SCA risk discrimination. The aim of the study was to determine whether the global innervation parameters yield any independent and additive prognostic value over the regional denervation alone. METHODS: In a post hoc competing-risks analysis of the PAREPET trial (Prediction of Arrhythmic Events With Positron Emission Tomography), we compared global innervation and regional denervation parameters using the norepinephrine analog [11C]meta-hydroxyephedrine for SCA risk discrimination. Patients with ischemic cardiomyopathy (n=174) eligible for an implantable cardioverter-defibrillator for the primary prevention of SCA were recruited into the trial. [11C]meta-hydroxyephedrine uptake and clearance rates were measured to assess global (left ventricle mean) retention index and volume of distribution. Regional defects were quantified as the percentage of the left ventricle having values <75% of the maximum. RESULTS: During a median follow-up of 4.2 years, there were 56 cardiac-related deaths, of which 26 were SCAs. For any given regional denervation volume, there was substantial heterogeneity in global innervation scores. Global retention index and distribution volume did not decrease until regional defects exceeded 40% left ventricle. Global scale parameters, retention index, and distribution volume (area under the curve=0.61, P=0.034, P=0.046, respectively), yielded inferior SCA risk discrimination compared to regional heterogeneity (area under the curve=0.74). CONCLUSIONS: Regional denervation volume has superior cause-specific mortality prediction for SCA versus global parameters of sympathetic innervation. These results have widespread implications for future cardiac sympathetic imaging, which will greatly simplify innervation analysis. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01400334.

Incorporation of renal function in mortality risk assessment for pulmonary arterial hypertension.

BACKGROUND: Risk assessment is important for prognostication and individualized treatment decisions for patients with pulmonary arterial hypertension (PAH). The purpose was (1) to compare contemporary risk assessment tools and (2) to determine the prognostic significance of risk parameters of kidney function and whether they can further improve risk prediction for patients with PAH. METHODS: We identified a cohort of treatment-naive patients (n = 211) who received an incident diagnosis of PAH at the University of Ottawa Heart Institute. Using demographics, disease characteristics, and hemodynamic data at diagnosis, we categorized patients as low, intermediate, or high risk according to current European guidelines (European Society of Cardiology [ESC]) and registry to evaluate early and long-term pulmonary arterial hypertension disease management (REVEAL) risk scores. The primary end-point was transplant-free survival (TFS). RESULTS: Patients were predominantly women (64.6%) with World Health Organization function Class III symptoms (66.5%). The median TFS was 7.09 years. There was little agreement between ESC- and REVEAL-based risk estimates (weighted kappa = 0.21-0.34). Although both the ESC (log-rank, p = 0.0002) and REVEAL algorithms stratified TFS risk (p < 0.0001), the REVEAL score provided superior discrimination (C-statistic = 0.70 vs 0.59, p = 0.004). Renal function at diagnosis (p < 0.0001) and Δ renal function at 6 months (p < 0.0001) were identified as novel risk parameters and served to reclassify some patients in the intermediate-risk category to a lower or higher risk stratum (p < 0.0001). CONCLUSION: REVEAL-based strategies provide superior TFS risk discrimination to ESC/European Respiratory Society-based approaches. However, the classification of intermediate-risk patients varied significantly across tools. We demonstrate the importance of renal function, which further improved the stratification of risk in patients with PAH, particularly in patients who are considered intermediate risk.