Efficacy of revascularization in CTO patients based on hibernating myocardium therapy.

BACKGROUND: The effectiveness of percutaneous coronary intervention (PCI) for chronic total occlusion (CTO) is still uncertain, especially for patients with ischemic left ventricular dysfunction. This study aimed to assess hibernating myocardium (HM), as determined by single-photon emission computed tomography (SPECT) and 18F-FDG positron emission tomography (PET), and to compare the benefits of PCI and optimal medical therapy (OMT). METHODS: A retrospective study collected data from 332 patients with CTO and ischemic left ventricular dysfunction. The study compared patients who underwent PCI or OMT via propensity score matching (PSM) analysis which was performed with a 1:2 matching protocol using the nearest neighbour matching algorithm. The primary endpoint of the study was the occurrence of major adverse cardiac events (MACE), defined as a composite of cardiac death, readmission for worsening heart failure (WHF), revascularization and myocardial infarction (MI). RESULTS: After PSM, there were a total of 246 individuals in the PCI and OMT groups. Following Cox regression, hibernating myocardium/total perfusion defect (HM/TPD) was identified as an independent risk factor (hazard ratio (HR): 1.03, 95% confidence interval (CI): 1.008-1.052, p = .007). The cut-off value of HM/TPD was 38%. The results of the subgroup analysis suggest that for patients with HM/TPD >38%, the OMT group had a greater risk of MACE (p = .035). A sensitivity analysis restricting patients with single-vessel CTO lesions, HM/TPD remained an independent predictor (HR 1.025, 95% CI 1.008-1.043, p = .005). CONCLUSION: HM/TPD is an independent predictor of MACE, and for patients with HM/TPD > 38%, CTO-PCI had a lower risk of MACE compared with OMT. However, further validation is still needed through large-scale studies.

Clinical impact of multimodality assessment of myocardial viability.

Coronary artery disease (CAD) is a prevalent cause of left ventricular dysfunction. Nevertheless, effective elective revascularization, particularly surgical revascularization, can enhance long-term outcomes and, in selected cases, global left ventricular contractility. The assessment of myocardial viability and scars is still relevant in guiding treatment decisions and selecting patients who are likely to benefit most from blood flow restoration. Although the most recent randomized studies challenge the notion of "hibernating myocardium" and the clinical usefulness of assessing myocardial viability, the advancement of imaging techniques still renders this assessment valuable in specific situations. According to the guidelines of the European Society of Cardiology, non-invasive stress imaging may be employed to define myocardial ischemia and viability in patients with CAD and heart failure before revascularization. Currently, several non-invasive imaging techniques are available to evaluate the presence and extent of viable myocardium. The selection of the most suitable technique should be based on the patient, clinical context, and resource availability. This narrative review evaluates the characteristics of available imaging modalities for assessing myocardial viability to determine the most appropriate therapeutic strategy.

An Adjuvant Stem Cell Patch with Coronary Artery Bypass Graft Surgery Improves Diastolic Recovery in Porcine Hibernating Myocardium.

Diastolic dysfunction persists despite coronary artery bypass graft surgery (CABG) in patients with hibernating myocardium (HIB). We studied whether the adjunctive use of a mesenchymal stem cells (MSCs) patch during CABG improves diastolic function by reducing inflammation and fibrosis. HIB was induced in juvenile swine by placing a constrictor on the left anterior descending (LAD) artery, causing myocardial ischemia without infarction. At 12 weeks, CABG was performed using the left-internal-mammary-artery (LIMA)-to-LAD graft with or without placement of an epicardial vicryl patch embedded with MSCs, followed by four weeks of recovery. The animals underwent cardiac magnetic resonance imaging (MRI) prior to sacrifice, and tissue from septal and LAD regions were collected to assess for fibrosis and analyze mitochondrial and nuclear isolates. During low-dose dobutamine infusion, diastolic function was significantly reduced in HIB compared to the control, with significant improvement after CABG + MSC treatment. In HIB, we observed increased inflammation and fibrosis without transmural scarring, along with decreased peroxisome proliferator-activated receptor-gamma coactivator (PGC1α), which could be a possible mechanism underlying diastolic dysfunction. Improvement in PGC1α and diastolic function was noted with revascularization and MSCs, along with decreased inflammatory signaling and fibrosis. These findings suggest that adjuvant cell-based therapy during CABG may recover diastolic function by reducing oxidant stress-inflammatory signaling and myofibroblast presence in the myocardial tissue.

Assessment of cerebral glucose metabolism in patients with heart failure by 18F-FDG PET/CT imaging.

BACKGROUND: To evaluate the cerebral metabolism in patients with heart failure (HF). METHODS: One hundred and two HF patients were prospectively enrolled, who underwent gated 99mTc-sestamibi single photon emission computed tomography (SPECT)/CT, cardiac and cerebral 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT. Fifteen healthy volunteers served as controls. Patients were stratified by extent of hibernating myocardium (HM) and left ventricular ejection fraction (LVEF) into 4 groups where Group1: HM < 10% (n = 33); Group2: HM ≥ 10%, LVEF < 25% (n = 34); Group3: HM ≥ 10%, 25% ≤ LVEF ≤ 40% (n = 16) and Group 4: LVEF > 40% (n = 19). The standardized uptake value (SUV) in the whole brain (SUVwhole-brain) and the SUV ratios (SUVR) in 24 cognition-related brain regions were determined. SUVwhole-brain and SUVRs were compared between the 4 patient groups and the healthy controls. RESULTS: SUVwhole-brain (r = 0.245, P = 0.013) and SUVRs in frontal areas, hippocampus, and para-hippocampus (r: 0.213 to 0.308, all P < 0.05) were correlated with HM. SUVwhole-brain differed between four patient groups and the healthy volunteers (P = 0.016) and SUVwhole-brain in Group 1 was lower than that in healthy volunteers (P < 0.05). SUVRs of Group 3 in frontal areas were the highest among four patient subgroups (P < 0.05). CONCLUSIONS: Cerebral metabolism in the whole brain was reduced but maintained in cognition-related frontal areas in HF patients with HM and moderately impaired global left ventricular function.

Incremental value of myocardial wall motion and thickening to perfusion alone by gated SPECT myocardial perfusion imaging for viability assessment in patients with ischemic heart failure.

PURPOSE: The objective of this study was to assess the incremental value of myocardial wall motion and thickening compared with perfusion alone obtained from gated single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) in diagnosing myocardial viability in patients with ischemic heart failure. METHODS: Eighty-three consecutive patients with ischemic heart failure who underwent both 99mTc-MIBI gated SPECT MPI and 18F-FDG positron emission tomography (PET) myocardial metabolic imaging were retrospectively enrolled. SPECT/PET myocardial viability was defined as the reference standard. Segmental myocardial perfusion, wall motion, and thickening were measured by an automated algorithm from gated SPECT MPI. Univariate and stepwise multivariate analysis were conducted to establish an optimal multivariate model for predicting hibernating myocardium and scar. RESULTS: Among the 1411 segments evaluated, 774 segments had normal perfusion and 637 segments had decreased perfusion. The latter were classified by 18F-FDG PET into 338 hibernating segments and 299 scarred segments. The multivariate regression analysis showed that the model that combined myocardial perfusion uptake with wall motion and thickening scores had the optimal predictive efficiency to distinguish hibernating myocardium from scar in the segments with decreased perfusion. The model had the largest C-statistic (0.753 vs 0.666, P < 0.0001), and the global chi-square was increased from 53.281 to 111.234 when compared with perfusion alone (P < 0.001). CONCLUSIONS: Assessment of myocardial wall motion and thickening in addition to conventional perfusion uptake in the segments with decreased perfusion enables better differentiation of hibernating myocardium from scar in patients with ischemic heart failure. Considering wide availability and high cost-effectiveness, regional myocardial function integrated with perfusion on gated SPECT MPI has great promise to become a clinical tool in the assessment of myocardial viability.

Multimodality Imaging of Myocardial Viability.

PURPOSE OF REVIEW: Myocardial viability is an important pathophysiologic concept which may have significant clinical impact in patients with left ventricular dysfunction due to ischemic heart disease. Understanding the imaging modalities used to assess viability, and the clinical implication of their findings, is critical for clinical decision-making in this population. RECENT FINDINGS: The ability of dobutamine echocardiography, single-photon emission computed tomography, positron emission tomography, and cardiac magnetic resonance imaging to predict functional recovery following revascularization is well-established. Despite different advantages and disadvantages for each imaging modality, each modality has demonstrated reasonable performance characteristics in identifying viable myocardium. Recent data, however, has called into question whether this functional recovery leads to improved clinical outcomes. Although the assessment of viability can be used to aid in clinical decision-making prior to revascularization, its broad application to all patients is limited by a lack of data confirming improvement in clinical outcomes. Thus, viability assessments may be best applied to select patients (such as those with increased surgical risk) and integrated with clinical, laboratory, and imaging data to guide clinical care. Future research efforts should be aimed at establishing the impact of viability on clinical outcomes.

Transmural variation in microvascular remodeling following percutaneous revascularization of a chronic coronary stenosis in swine.

Remodeling of the coronary microcirculation is known to occur distal to a chronic coronary stenosis, but the reversibility of these changes and their functional significance on maximum myocardial perfusion before and after revascularization is unknown. Accordingly, swine instrumented with a chronic silastic stenosis on the left anterior descending coronary artery to produce hibernating myocardium underwent percutaneous coronary intervention (PCI; n = 8) and were compared with animals with a persistent stenosis (n = 8), as well as sham controls (n = 6). Stenotic animals demonstrated an increased subendocardial arteriolar wall thickness-to-lumen ratio (37.8 ± 3.3 vs. 28.3 ± 1.3% in sham, P = 0.04), reduced lumen area per arteriole (597 ± 88 vs. 927 ± 113 µm2, P = 0.04), and a compensatory increase in arteriolar density (9.4 ± 1.0 vs. 5.3 ± 0.4 arterioles/mm2, P < 0.01). As a result, vasodilated flow immediately after PCI was similar to normally perfused remote regions (5.1 ± 1.0 vs. 4.8 ± 0.9 ml·min-1·g-1, P = 0.87). When assessed 1-mo after PCI, increases in wall thickness-to-lumen diameter (42.2 ± 3.3%) and reductions in lumen area per arteriole (638 ± 59 µm2) remained unchanged, but arteriolar density returned to normal (5.2 ± 0.5 arterioles/mm2). As a result, maximum subendocardial flow during adenosine declined and was lower than remote regions (2.6 ± 0.3 vs. 5.9 ± 1.1 ml·min-1·g-1, P = 0.01). There was no microvascular remodeling in subepicardial arterioles, and maximum perfusion remained unchanged. These data demonstrate that subendocardial microvascular remodeling occurs distal to a chronic epicardial stenosis. The regression of arteriolar density without increases in luminal area may precipitate stress-induced subendocardial ischemia in the absence of a physiologically significant stenosis.NEW & NOTEWORTHY Swine with a chronic coronary stenosis exhibit subendocardial microvascular remodeling distal to a critical stenosis characterized by an increase in arteriolar wall thickness and reduction in lumen area with a compensatory increase in arteriolar density. The present study is the first to demonstrate that subendocardial arteriolar density normalizes 1-mo after revascularization, but the lumen area of individual arterioles remains reduced. This leads to a reduction in maximal subendocardial perfusion at this time point despite initial normalization of vasodilator reserve after revascularization. This pattern of chronic microvascular structural remodeling could contribute to recurrent subendocardial ischemia in the absence of coronary restenosis during tachycardia and increases in myocardial oxygen demand.

Translational large animal model of hibernating myocardium: characterization by serial multimodal imaging.

Nonrevascularizable coronary artery disease is a frequent cause of hibernating myocardium leading to heart failure (HF). Currently, there is a paucity of therapeutic options for patients with this condition. There is a lack of animal models resembling clinical features of hibernating myocardium. Here we present a large animal model of hibernating myocardium characterized by serial multimodality imaging. Yucatan minipigs underwent a surgical casein ameroid implant around the proximal left anterior descending coronary artery (LAD), resulting in a progressive obstruction of the vessel. Pigs underwent serial multimodality imaging including invasive coronary angiography, cardiac magnetic resonance (CMR), and hybrid 18F-Fluorodeoxyglucose positron emission tomography-computed tomography (FDG-PET/CT). A total of 43 pigs were operated on and were followed for 120 ± 37 days with monthly multimodality imaging. 24 pigs (56%) died during the follow-up. Severe LAD luminal stenosis was documented in all survivors. In the group of 19 long-term survivors, 17 (90%) developed left ventricular systolic dysfunction [median LVEF of 35% (IQR 32.5-40.5%)]. In 17/17, at-risk territory was viable on CMR and 14 showed an increased glucose uptake in the at-risk myocardium on 18FDG-PET/CT. The present pig model resembles most of the human hibernated myocardium characteristics and associated heart failure (systolic dysfunction, viable myocardium, and metabolic switch to glucose). This human-like model might be used to test novel interventions for nonrevascularizable coronary artery disease and ischemia heart failure as a previous stage to clinical trials.

No differences in rest myocardial blood flow in stunned and hibernating myocardium: insights into the pathophysiology of ischemic cardiomyopathy.

PURPOSE: The human pathophysiology of stunned, hibernating and scarred myocardium in ischemic cardiomyopathy is a subject of controversy. While the "smart heart" theory postulates that reduced myocardial blood flow (MBF) at rest is responsible for myocytes switching to a state of hibernation, other theories suggest that a reduced myocardial flow reserve (MFR) may be the cause. METHODS: We included 110 patients with ischemic cardiomyopathy. Based on quantitative myocardial perfusion assessment and viability imaging with 13N-NH3 and 18F-FDG positron emission tomography, respectively, as well as wall motion assessment from echocardiography, myocardial tissue was characterized as remote (i.e., normal myocardium), stunned (i.e., dysfunctional but viable myocardium with normal rest perfusion), hibernating (i.e., dysfunctional but viable myocardium with impaired rest perfusion), or scarred myocardium (i.e., non-viable myocardium). RESULTS: Compared to remote myocardium, dysfunctional but viable myocardium (including stunned and hibernating) had reduced rest MBF (0.89 mL/min/g vs. 0.79 and 0.76 mL/min/g, respectively; p < 0.001) and MFR (1.53 vs. 1.27 and 1.17; p < 0.001). Between stunned and hibernating myocardium, however, rest MBF and MFR did not differ (p = 0.40). In scarred myocardium, rest MBF was lowest (0.66 mL/min/g; p < 0.001) but, in contrast to the other myocardial states, k2 (i.e., tracer washout) was increased (0.199/min vs. 0.178/min to 0.181/min; all p < 0.05 in pairwise comparison). CONCLUSIONS: In patients with ischemic cardiomyopathy, impaired MFR is associated with stunning and hibernation. These states of dysfunctional but viable myocardium have lower rest MBF compared to remote myocardium. At the end of the continuum, rest MBF is lowest in scar tissue and linked to increased rate of tracer washout.

The utility of 82Rb PET for myocardial viability assessment: Comparison with perfusion-metabolism 82Rb-18F-FDG PET.

BACKGROUND: 82Rb kinetics may distinguish scar from viable but dysfunctional (hibernating) myocardium. We sought to define the relationship between 82Rb kinetics and myocardial viability compared with conventional 82Rb and 18F-fluorodeoxyglucose (FDG) perfusion-metabolism PET imaging. METHODS: Consecutive patients (N = 120) referred for evaluation of myocardial viability prior to revascularization and normal volunteers (N = 37) were reviewed. Dynamic 82Rb 3D PET data were acquired at rest. 18F-FDG 3D PET data were acquired after metabolic preparation using a standardized hyperinsulinemic-euglycemic clamp. 82Rb kinetic parameters K1, k2, and partition coefficient (KP) were estimated by compartmental modeling RESULTS: Segmental 82Rb k2 and KP differed significantly between scarred and hibernating segments identified by Rb-FDG perfusion-metabolism (k2, 0.42 ± 0.25 vs. 0.22 ± 0.09 min-1; P < .0001; KP, 1.33 ± 0.62 vs. 2.25 ± 0.98 ml/g; P < .0001). As compared to Rb-FDG analysis, segmental Rb KP had a c-index, sensitivity and specificity of 0.809, 76% and 84%, respectively, for distinguishing hibernating and scarred segments. Segmental k2 performed similarly, but with lower specificity (75%, P < .001) CONCLUSIONS: In this pilot study, 82Rb kinetic parameters k2 and KP, which are readily estimated using a compartmental model commonly used for myocardial blood flow, reliably differentiated hibernating myocardium and scar. Further study is necessary to evaluate their clinical utility for predicting benefit after revascularization.

The role of nuclear cardiac imaging in risk stratification of sudden cardiac death.

Sudden cardiac death (SCD) represents a significant portion of all cardiac deaths. Current guidelines focus mainly on left ventricular ejection fraction (LVEF) as the main criterion for SCD risk stratification and management. However, LVEF alone lacks both sensitivity and specificity in stratifying patients. Recent research has provided interesting data which supports a greater role for advanced cardiac imaging in risk stratification and patient management. In this article, we will focus on nuclear cardiac imaging, including left ventricular function assessment, myocardial perfusion imaging, myocardial blood flow quantification, metabolic imaging, and neurohormonal imaging. We will discuss how these can be used to better understand SCD and better stratify patient with both ischemic and non-ischemic cardiomyopathy.

A Simple Numerical Body Surface Mapping Parameter Signifies Successful Percutaneous Coronary Artery Intervention.

BACKGROUND: In coronary artery disease (CAD), body surface potential mapping (BSPM) may reveal minor electrical potential changes appearing in the depolarization phase even if pathological changes are absent on the conventional 12-lead ECG. We hypothesized that a simple BSPM parameter, Max/Min signifies successful percutaneous coronary intervention (PCI). METHODS: Ninety-two adult Caucasian patients with stable CAD and positive exercise test underwent coronary angiography. Seventy patients (age, 59 ± 8; 46 males) were revascularized by PCI (left anterior descending [LAD] in 38, right [RCA] in 17 and left circumflex [LCX] coronary artery in 15). Control groups contained 22 patients (age, 60 ± 8; 14 males) without intervention and 35 healthy subjects (age, 58 ± 2; 15 males). Left ventricular ejection fraction (LVEF, transthoracic echocardiography) and Max/Min BSPM parameter (63-lead Montreal system) were evaluated before and 4-40 days following coronary angiography. Max/Min was defined by the ratio of the highest maximum to the deepest minimum potential of all leads recorded by BSPM. RESULTS: Before PCI, Max/Min value of patients with LAD lesion (0.83 [0.74; 0.93]) was significantly lower while that with RCA lesion (1.63 [1.35; 1.99]) was significantly higher than that of healthy group (1.01 [0.970; 1.13]) (P < 0.05) and LVEF was significantly lower in LAD lesion (46.50% [43.00; 51.00]) than in the healthy group (55.00% [50.00; 58.75]) (P < 0.01). Max/Min value significantly increased from 0.83 [0.74; 0.93] to 0.92 [0.82; 0.99] (P < 0.01) following LAD PCI while significantly decreased from 1.63 [1.35; 1.98] to 1.35 [1.21; 1.43] (P < 0.01) post-RCA PCI. It did not vary significantly, however, either following LCX PCI or without intervention. LVEF significantly increased (from 46.50% [43.00; 51.00] to 49.00% [46.00; 51.00]) only after LAD PCI. CONCLUSION: Max/Min parameter is suitable to follow patients after LAD and RCA PCI.

Expression of uncoupling protein-2 remains increased within hibernating myocardium despite successful coronary artery bypass grafting at 4 wk post-revascularization.

BACKGROUND: We have previously shown that mitochondrial uncoupling protein-2 (UCP-2) is increased in a swine model of hibernating myocardium (HM). Although UCP-2 reduces oxidant stress, it can promote inefficiency of the electron transport chain. In this study, we tested whether UCP-2 remains increased in revascularized HM (RHM) after coronary artery bypass grafting (CABG). METHODS: Seven swine underwent thoracotomy with placement of a constrictor on the left anterior descending artery (LAD). Twelve weeks later, a left internal mammary artery graft was placed on the distal LAD. Four weeks post-CABG, computed tomography angiography documented patent grafts and function. At the terminal study, blood flow to the LAD and remote territories were assessed during high dose dobutamine and mitochondria isolated from both regions for analysis. Comparisons were made to a group of swine with HM who underwent constrictor placement without bypass grafting (n = 4). RESULTS: During dobutamine infusion, RHM demonstrated lower blood flows (2.44 ± 0.23 versus 3.43 ± 0.30 mL/min/g; P < 0.05) and reduced wall thickening (33 ± 9% versus 52 ± 13%; P < 0.05) compared with remote regions. RHM had lower respiratory control indices (3.7 ± 0.3 versus 4.3 ± 0.4; P < 0.05) with persistently increased UCP-2 content. CONCLUSIONS: Despite patent grafts, RHM demonstrates a submaximal response to dobutamine infusion and increased mitochondrial UCP-2 expression. These data support the notion that recovery of the mitochondria in RHM is delayed early post-CABG and may contribute to impaired oxygen consumption and contractile reserve during catecholamine challenges.

Mitochondrial fusion proteins in revascularized hibernating hearts.

BACKGROUND: Hibernating myocardium is characterized by viable yet dysfunctional myocardium secondary to chronic ischemia, with studies demonstrating incomplete early recovery after coronary artery bypass graft (CABG). We tested whether mitochondrial fusion proteins, an indicator of mitochondrial biogenesis, are increased in hibernating myocardium post-CABG. METHODS: A constrictor was placed on the left anterior descending (LAD) artery of nine pigs. Four of these pigs additionally underwent CABG 12 wk later with a left internal mammary artery graft to the LAD distal to the constrictor. Five pigs had a constrictor placed but did not undergo CABG (Hib). Five pigs did not have a constrictor placed (control). Computerized tomography angiography was used to confirm stenosis at the site of constrictor placement and patency of left internal mammary artery grafts. Regional blood flows were determined at baseline and during 40 µg/kg/min dobutamine infusion. Mitochondrial proteins were quantified by Western blot. RESULTS: Blood flow in the LAD region after CABG was lower than remote regions during dobutamine infusion (2.54 ± 0.24 versus 3.46 ± 0.33 mL/min/g; P < 0.05). Electron transport chain proteins were ∼70% lower in Hib compared with those in control and failed to normalize after CABG. Post-CABG, PGC1α nuclear-bound content was increased compared with Hib (9.02 ± 0.48 versus 5.54 ± 0.98 arbitrary units, respectively; P < 0.05), and expression of mitofusins-1 and 2 and optic atrophy-1 more than doubled. CONCLUSIONS: PGC1α and mitochondrial fusion proteins are increased 4 wk post-CABG in hibernating hearts, indicating mitochondrial fusion has begun to occur and signaling early mitochondrial recovery. Future studies should address changes in maximal myocardial oxygen consumption relative to mitochondrial protein expression.

Regional mapping of myocardial hibernation phenotype in idiopathic end-stage dilated cardiomyopathy.

Myocardial hibernation (MH) is a well-known feature of human ischaemic cardiomyopathy (ICM), whereas its presence in human idiopathic dilated cardiomyopathy (DCM) is still controversial. We investigated the histological and molecular features of MH in left ventricle (LV) regions of failing DCM or ICM hearts. We examined failing hearts from DCM (n = 11; 41.9 ± 5.45 years; left ventricle-ejection fraction (LV-EF), 18 ± 3.16%) and ICM patients (n = 12; 58.08 ± 1.7 years; LVEF, 21.5 ± 6.08%) undergoing cardiac transplantation, and normal donor hearts (N, n = 8). LV inter-ventricular septum (IVS) and antero-lateral free wall (FW) were transmurally (i.e. sub-epicardial, mesocardial and sub-endocardial layers) analysed. LV glycogen content was shown to be increased in both DCM and ICM as compared with N hearts (P < 0.001), with a U-shaped transmural distribution (lower values in mesocardium). Capillary density was homogenously reduced in both DCM and ICM as compared with N (P < 0.05 versus N), with a lower decrease independent of the extent of fibrosis in sub-endocardial and sub-epicardial layers of DCM as compared with ICM. HIF1-α and nestin, recognized ischaemic molecular hallmarks, were similarly expressed in DCM-LV and ICM-LV myocardium. The proteomic profile was overlapping by ~50% in DCM and ICM groups. Morphological and molecular features of MH were detected in end-stage ICM as well as in end-stage DCM LV, despite epicardial coronary artery patency and lower fibrosis in DCM hearts. Unravelling the presence of MH in the absence of coronary stenosis may be helpful to design a novel approach in the clinical management of DCM.

Association between hibernating myocardium and collateral circulation in patients with coronary chronic total occlusion.

Objective: To explore the association between the quantity of hibernating myocardium (HM) and collateral circulation in patients with coronary chronic total occlusion (CTO). Materials and methods: 88 CTO patients were retrospectively analyzed who underwent evaluation for HM using both 99mTc-sestamibi Single photon emission computed tomography (99mTc-MIBI SPECT) myocardial perfusion imaging (MPI) combined with 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) myocardial metabolism imaging (MMI). They were divided into two groups according Rentrop grading: the poorly/well-developed collateral circulation group (PD/WD group, Rentrop grades 0-1/2-3). After adjusting for the potential confounding factors and conducting a stratified analysis, we explored the association between the HM index within CTO region and the grading of collateral circulation. Results: In the WD group, the HM index was notably higher than PD group (46.2 ± 15.7% vs. 20.9 ± 16.7%, P < 0.001). When dividing the HM index into tertiles and after adjusting for potential confounders, we observed that the proportion of patients with WD rose as the HM index increased (OR: 1.322, 95% CI: 0.893-1.750, P < 0.001), the proportion of patients with WD was 17.4%, 63.3%, and 88.6% for Tertile 1 to Tertile 3.This increasing trend was statistically significant (OR: 1.369, 95% CI: 0.873-1.864, P < 0.001), especially between Tertile 3 vs. Tertile 1 (OR: 4.330, 95% CI: 1.459-12.850, P = 0.008). Curve fitting displaying an almost linear positive correlation between the two. Conclusion: The HM index within CTO region is an independent correlation factor for the grading of coronary collateral circulation. A greater HM index corresponded to an increased likelihood of WD.

Machine learning predictions of the adverse events of different treatments in patients with ischemic left ventricular systolic dysfunction.

This study aimed to develop several new machine learning models based on hibernating myocardium to predict the major adverse cardiac events(MACE) of ischemic left ventricular systolic dysfunction(LVSD) patients receiving either percutaneous coronary intervention(PCI) or optimal medical therapy(OMT). This study included 329 LVSD patients, who were randomly assigned to the training or validation cohort. Least absolute shrinkage and selection operator(LASSO) regression was used to identify variables associated with MACE. Subsequently, various machine learning models were established. Model performance was compared using receiver operating characteristic(ROC) curves, the Brier score(BS), and the concordance index(C-index). A total of 329 LVSD patients were retrospectively enrolled between January 2016 and December 2021. Utilizing LASSO regression analysis, five factors were selected. Based on these factors, RSF, GBM, XGBoost, Cox, and DeepSurv models were constructed. In the development and validation cohorts, the C-indices were 0.888 vs. 0.955 (RSF). The RSF model (0.991 vs. 0.982 vs. 0.980) had the highest area under the ROC curve (AUC) compared with the other models. The BS (0.077 vs. 0.095vs. 0.077) of RSF model were less than 0.25 at 12, 18, and 24 months. This study developed a novel predictive model based on RSF to predict MACE in LVSD patients who underwent either PCI or OMT.

Prediction of Major Arrhythmic Outcomes in Ischemic Cardiomyopathy: Value of Hibernating Myocardium in PET/CT.

AIMS: Known predictors of major arrhythmic events (MAE) in patients with ischemic cardiomyopathy (ICM) include previous MAE and left ventricular ejection fraction (LVEF) ≤35%. Myocardial scars detected by perfusion imaging in ICM have been linked to MAE, but the prognostic significance of hibernating myocardium (HM) is unclear. The objective was to predict major arrhythmic events (MAE) from combined 13N-ammonia (NH3) and 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in ischemic cardiomyopathy (ICM). METHODS AND RESULTS: Consecutive patients with ICM undergoing combined NH3- and FDG-PET/CT were included. HM was quantified in relation to total left ventricular myocardium (i.e. ≥7% is large). The primary outcome was MAE (sudden cardiac death, ICD therapy, sustained ventricular tachycardia/fibrillation).Among 254 patients, median baseline LVEF was 35% (IQR 28-45) and 10% had an ICD. PET/CT identified ischemia in 94 (37%), scar in 229 (90%) and HM in 195 (77%) patients. Over a median follow-up of 5.4 (IQR 2.2-9.5) years, MAE occurred in 34 patients (13%). Large HM was associated with a lower incidence of MAE (HR 0.31, 95% CI 0.1-0.8, p=0.001). After multivariate adjustment for history of MAE, LVEF ≤35% and scar ≥10%, large HM remained significantly associated with a lower incidence of MAE (p=0.016). LVEF improved over time among patients with large HM (p=0.006) but did not change in those without (p=0.610) or small HM (p=0.240). CONCLUSIONS: HM conveys a lower risk of MAE in patients with ICM. This may be explained by an increase in LVEF when a large extent of HM is present.

A Novel Approach to Identifying Hibernating Myocardium Using Radiomics-Based Machine Learning.

Background To assess the feasibility of a machine learning (ML) approach using radiomics features of perfusion defects on rest myocardial perfusion imaging (MPI) to detect the presence of hibernating myocardium. Methodology Data of patients who underwent 99mTc-sestamibi MPI and 18F-FDG PET/CT for myocardial viability assessment were retrieved. Rest MPI data were processed on ECToolbox, and polar maps were saved using the NFile PMap tool. The reference standard for defining hibernating myocardium was the presence of mismatched perfusion-metabolism defect with impaired myocardial contractility at rest. Perfusion defects on the polar maps were delineated with regions of interest (ROIs) after spatial resampling and intensity discretization. Replicable random sampling allocated 80% (257) of the perfusion defects of the patients from January 2017 to September 2022 to the training set and the remaining 20% (64) to the validation set. An independent dataset of perfusion defects from 29 consecutive patients from October 2022 to January 2023 was used as the testing set for model evaluation. One hundred ten first and second-order texture features were extracted for each ROI. After feature normalization and imputation, 14 best-ranked features were selected using a multistep feature selection process including the Logistic Regression and Fast Correlation-Based Filter. Thirteen supervised ML algorithms were trained with stratified five-fold cross-validation on the training set and validated on the validation set. The ML algorithms with a Log Loss of <0.688 and <0.672 in the cross-validation and validation steps were evaluated on the testing set. Performance matrices of the algorithms assessed included area under the curve (AUC), classification accuracy (CA), F1 score, precision, recall, and specificity. To provide transparency and interpretability, SHapley Additive exPlanations (SHAP) values were assessed and depicted as beeswarm plots. Results Two hundred thirty-nine patients (214 males; mean age 56 ± 11 years) were enrolled in the study. There were 371 perfusion defects (321 in the training and validation sets; 50 in the testing set). Based on the reference standard, 168 perfusion defects had hibernating myocardium (139 in the training and validation sets; 29 in the testing set). On cross-validation, six ML algorithms with Log Loss <0.688 had AUC >0.800. On validation, 10 ML algorithms had a Log Loss value <0.672, among which six had AUC >0.800. On model evaluation of the selected models on the unseen testing set, nine ML models had AUC >0.800 with Gradient Boosting Random Forest (xgboost) [GB RF (xgboost)] achieving the highest AUC of 0.860 and could detect the presence of hibernating myocardium in 21/29 (72.4%) perfusion defects with a precision of 87.5% (21/24), specificity 85.7% (18/21), CA 78.0% (39/50) and F1 Score 0.792. Four models depicted a clear pattern of model interpretability based on the beeswarm SHAP plots. These were GB RF (xgboost), GB (scikit-learn), GB (xgboost), and Random Forest. Conclusion Our study demonstrates the potential of ML in detecting hibernating myocardium using radiomics features extracted from perfusion defects on rest MPI images. This proof-of-concept underscores the notion that radiomics features capture nuanced information beyond what is perceptible to the human eye, offering promising avenues for improved myocardial viability assessment.

Dissociation of hemodynamic and electrocardiographic indexes of myocardial ischemia in pigs with hibernating myocardium and sudden cardiac death.

Many survivors of sudden cardiac death (SCD) have normal global ventricular function and severe coronary artery disease but no evidence of symptomatic ischemia or infarction before the development of lethal ventricular arrhythmias, and the trigger for ventricular tachycardia (VT)/ventricular fibrillation (VF) remains unclear. We sought to identify the role of spontaneous ischemia and temporal hemodynamic factors preceding SCD using continuous telemetry of left ventricular (LV) pressure and the ECG for periods up to 5 mo in swine (n = 37) with hibernating myocardium who experience spontaneous VT/VF in the absence of heart failure or infarction. Hemodynamics and ST deviation at the time of VT/VF were compared with survivors with hibernating myocardium as well as sham controls. All episodes of VT/VF occurred during sympathetic activation and were initiated by single premature ventricular contractions, and the VT degenerated into VF in ∼ 30 s. ECG evidence of ischemia was infrequent and no different from those that survived. Baseline hemodynamics were no different among groups, but LV end-diastolic pressure during sympathetic activation was higher at the time of SCD (37 ± 4 vs. 26 ± 4 mmHg, P < 0.05) and the ECG demonstrated QT shortening (155 ± 4 vs. 173 ± 5 ms, P < 0.05). The week before SCD, both parameters were no different from survivors. These data indicate that there are no differences in the degree of sympathetic activation or hemodynamic stress when VT/VF develops in swine with hibernating myocardium. The transiently elevated LV end-diastolic pressure and QT shortening preceding VT/VF raises the possibility that electrocardiographically silent subendocardial ischemia and/or mechanoelectrical feedback serve as a trigger for the development of SCD in chronic ischemic heart disease.