Quantification of perivascular inflammation does not provide incremental prognostic value over myocardial perfusion imaging and calcium scoring.

AIMS: Perivascular fat attenuation index (FAI) has emerged as a novel coronary computed tomography angiography (CCTA)-based biomarker predicting cardiovascular outcomes by capturing early coronary inflammation. It is currently unknown whether FAI adds prognostic value beyond that provided by single-photon emission computed tomography myocardial perfusion imaging (SPECT-MPI) and CCTA findings including coronary artery calcium scoring (CACS). METHODS AND RESULTS: A total of 492 patients (mean age 62.5 ± 10.8 years) underwent clinically indicated multimodality CCTA and electrocardiography (ECG)-gated 99mTc-tetrofosmin SPECT-MPI between May 2005 and December 2008 at our institution, and follow-up data on major adverse cardiovascular events (MACE) was obtained for 314 patients. FAI was obtained from CCTA images and was measured around the right coronary artery (FAI[RCA]), the left anterior descending artery (FAI[LAD]), and the left main coronary artery (FAI[LMCA]). During a median follow-up of 2.7 years, FAI[RCA] > - 70.1 was associated with an increased rate of MACE (log rank p = 0.049), while no such association was seen for FAI[LAD] or FAI[LMCA] (p = NS). A multivariate Cox regression model accounting for cardiovascular risk factors, CCTA and SPECT-MPI findings identified FAI[RCA] as an independent predictor of MACE (HR 2.733, 95% CI: 1.220-6.123, p = 0.015). However, FAI[RCA] was no longer a significant predictor of MACE after adding CACS (p = 0.279). A first-order interaction term consisting of sex and FAI[RCA] was significant in both models (HR 2.119, 95% CI: 1.218-3.686, p = 0.008; and HR 2.071, 95% CI: 1.111-3.861, p = 0.022). CONCLUSION: FAI does not add incremental prognostic value beyond multimodality MPI/CCTA findings including CACS. The diagnostic value of FAI[RCA] is significantly biased by sex.

Age- and sex-dependent changes of resting amygdalar activity in individuals free of clinical cardiovascular disease.

PURPOSE: Amygdalar metabolic activity was shown to independently predict cardiovascular outcomes. However, little is known about age- and sex-dependent variability in neuronal stress responses among individuals free of cardiac disease. This study sought to assess age- and sex-specific differences of resting amygdalar metabolic activity in the absence of clinical cardiovascular disease. METHODS: Amygdalar metabolic activity was assessed in 563 patients who underwent multimodality imaging by 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography and echocardiography for the evaluation of cardiac function. RESULTS: After exclusion of 294 patients with structural or functional cardiovascular pathologies, 269 patients (128 women) remained in the final population. 18F-FDG amygdalar activity significantly decreased with age in men (r = - 0.278, P = 0.001), but not in women (r = 0.002, P = 0.983). Similarly, dichotomous analysis confirmed a lower amygdalar activity in men ≥ 50 years as compared to those < 50 years of age (0.79 ± 0.1 vs. 0.84 ± 0.1, P = 0.007), which was not observed in women (0.81 ± 0.1 vs. 0.82 ± 0.1, P = 0.549). Accordingly, a fully adjusted linear regression analysis identified age as an independent predictor of amygdalar activity only in men (B-coefficient - 0.278, P = 0.001). CONCLUSION: Amygdalar activity decreases with age in men, but not in women. The use of amygdalar activity for cardiovascular risk stratification merits consideration of inherent age- and sex-dependent variability.

Microvascular dysfunction and sympathetic hyperactivity in women with supra-normal left ventricular ejection fraction (snLVEF).

BACKGROUND: Recently, a new disease phenotype characterized by supra-normal left ventricular ejection fraction (snLVEF) has been suggested, based on large datasets demonstrating an increased all-cause mortality in individuals with an LVEF > 65%. The underlying mechanisms of this association are currently unknown. METHODS: A total of 1367 patients (352 women, mean age 63.1 ± 11.6 years) underwent clinically indicated rest/adenosine stress ECG-gated 13N-ammonia positron emission tomography (PET) between 1995 and 2017 at our institution. All patients were categorized according to LVEF. A subcohort of 698 patients (150 women) were followed for major adverse cardiac events (MACEs), a composite of cardiac death, non-fatal myocardial infarction, cardiac-related hospitalization, and revascularization. RESULTS: The prevalence of a snLVEF (≥ 65%) was higher in women as compared to that in men (31.3% vs 18.8%, p < 0.001). In women, a significant reduction in coronary flow reserve (CFR, p < 0.001 vs normal LVEF) and a blunted heart rate reserve (% HRR, p = 0.004 vs normal LVEF) during pharmacological stress testing-a surrogate marker for autonomic dysregulation-were associated with snLVEF. Accordingly, reduced CFR and HRR were identified as strong and independent predictors for snLVEF in women in a fully adjusted multinomial regression analysis. After a median follow-up time of 5.6 years, women with snLVEF experienced more often a MACE than women with normal (55-65%) LVEF (log rank p < 0.001), while such correlation was absent in men (log rank p = 0.76). CONCLUSION: snLVEF is associated with an increased risk of MACE in women, but not in men. Microvascular dysfunction and an increased sympathetic tone in women may account for this association.

Obesity-induced activation of JunD promotes myocardial lipid accumulation and metabolic cardiomyopathy.

AIMS: Metabolic cardiomyopathy (MC)-characterized by intra-myocardial triglyceride (TG) accumulation and lipotoxic damage-is an emerging cause of heart failure in obese patients. Yet, its mechanisms remain poorly understood. The Activator Protein 1 (AP-1) member JunD was recently identified as a key modulator of hepatic lipid metabolism in obese mice. The present study investigates the role of JunD in obesity-induced MC. METHODS AND RESULTS: JunD transcriptional activity was increased in hearts from diet-induced obese (DIO) mice and was associated with myocardial TG accumulation and left ventricular (LV) dysfunction. Obese mice lacking JunD were protected against MC. In DIO hearts, JunD directly binds PPARγ promoter thus enabling transcription of genes involved in TG synthesis, uptake, hydrolysis, and storage (i.e. Fas, Cd36, Lpl, Plin5). Cardiac-specific overexpression of JunD in lean mice led to PPARγ activation, cardiac steatosis, and dysfunction, thereby mimicking the MC phenotype. In DIO hearts as well as in neonatal rat ventricular myocytes exposed to palmitic acid, Ago2 immunoprecipitation, and luciferase assays revealed JunD as a direct target of miR-494-3p. Indeed, miR-494-3p was down-regulated in hearts from obese mice, while its overexpression prevented lipotoxic damage by suppressing JunD/PPARγ signalling. JunD and miR-494-3p were also dysregulated in myocardial specimens from obese patients as compared with non-obese controls, and correlated with myocardial TG content, expression of PPARγ-dependent genes, and echocardiographic indices of LV dysfunction. CONCLUSION: miR-494-3p/JunD is a novel molecular axis involved in obesity-related MC. These results pave the way for approaches to prevent or treat LV dysfunction in obese patients.

Heart non-specific effector CD4+ T cells protect from postinflammatory fibrosis and cardiac dysfunction in experimental autoimmune myocarditis.

Heart-specific CD4+ T cells have been implicated in development and progression of myocarditis in mice and in humans. Here, using mouse models of experimental autoimmune myocarditis (EAM) we investigated the role of heart non-specific CD4+ T cells in the progression of the disease. Heart non-specific CD4+ T cells were obtained from DO11.10 mice expressing transgenic T cell receptor recognizing chicken ovalbumin. We found that heart infiltrating CD4+ T cells expressed exclusively effector (Teff) phenotype in the EAM model and in hearts of patients with lymphocytic myocarditis. Adoptive transfer experiments showed that while heart-specific Teff infiltrated the heart shortly after injection, heart non-specific Teff effectively accumulated during myocarditis and became the major heart-infiltrating CD4+ T cell subset at later stage. Restimulation of co-cultured heart-specific and heart non-specific CD4+ T cells with alpha-myosin heavy chain antigen showed mainly Th1/Th17 response for heart-specific Teff and up-regulation of a distinct set of extracellular signalling molecules in heart non-specific Teff. Adoptive transfer of heart non-specific Teff in mice with myocarditis did not affect inflammation severity at the peak of disease, but protected the heart from adverse post-inflammatory fibrotic remodelling and cardiac dysfunction at later stages of disease. Furthermore, mouse and human Teff stimulated in vitro with common gamma cytokines suppressed expression of profibrotic genes, reduced amount of α-smooth muscle actin filaments and decreased contraction of cardiac fibroblasts. In this study, we provided a proof-of-concept that heart non-specific Teff cells could effectively contribute to myocarditis and protect the heart from the dilated cardiomyopathy outcome.

Potential Impact of Statins on Neuronal Stress Responses in Patients at Risk for Cardiovascular Disease.

BACKGROUND: Recent studies indicate that enhanced neuronal stress responses are associated with adverse cardiovascular outcomes. A chronic inflammatory state seems to mediate this detrimental neuro-cardiac communication. Statins are among the most widely prescribed medications in primary and secondary cardiovascular disease (CVD) prevention and not only lower lipid levels but also exhibit strong anti-inflammatory and neuroprotective effects. We therefore sought to investigate the influence of statins on neuronal stress responses in a patient cohort at risk for CVD. METHODS: 563 patients (61.5 ± 14.0 years) who underwent echocardiography and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) were retrospectively identified. Metabolic activity of the amygdala, a part of the brain's salience network, was quantified by 18F-FDG uptake, while normal cardiac morphology and function were assured by echocardiography. Vertebral bone marrow metabolism, a marker of inflammatory activity, was measured by 18F-FDG PET. RESULTS: Increased neuronal stress responses were associated with an increased inflammatory activity in the bone marrow (r = 0.152, p = 0.015) as well as with a subclinical reduction in left ventricular ejection fraction (LVEF, r = -0.138, p = 0.025). In a fully-adjusted linear regression model, statin treatment was identified as an independent, negative predictor of amygdalar metabolic activity (B-coefficient -0.171, p = 0.043). CONCLUSIONS: Our hypothesis-generating investigation suggests a potential link between the anti-inflammatory actions of statins and reduced neuronal stress responses which could lead to improved cardiovascular outcomes. The latter warrants further studies in a larger and prospective population.

The adaptor protein c-Cbl-associated protein (CAP) limits pro-inflammatory cytokine expression by inhibiting the NF-κB pathway.

C-Cbl-associated protein (CAP), also known as Sorbin and SH3 domain-containing protein 1 (Sorbs1) or ponsin, an adaptor protein of the insulin-signalling pathway, mediates anti-viral and anti-cytotoxic protection in acute viral heart disease. In the present study we describe a novel protective immuno-modulatory function of CAP in inflammation. Among the three members of the Sorbs family of adapter molecules, which include CAP (Sorbs1), ArgBP2 (Sorbs2), and Vinexin (Sorbs3), CAP consistently down-regulated the expression of pro-inflammatory cytokines in mouse fibroblasts, cardiomyocytes, and myeloid-derived leukocytes, after Toll-like receptor (TLR) stimulation. Upon the same TLR stimulation, ArgBP2 partially down-regulated pro-inflammatory cytokine production in mouse fibroblasts and cardiomyocytes, while Vinexin rather promoted their production. Mechanistically, CAP limited pro-inflammatory cytokine expression by suppressing the phosphorylation of Inhibitor of kappa B (IκB) kinase (Iκκ)-α and Iκκ-ß and their downstream NF-κB-dependent signalling pathway. Molecular affinity between CAP and Iκκ-α/ Iκκ-ß was necessary to block the NF-κB pathway. The CAP-dependent inhibitory mechanism - in vivo exclusively IL-6 inhibition - was confirmed after collecting blood from mice with systemic inflammation induced by lipopolysaccharide (LPS) and in the heart tissue collected from mice infected with the cardiotropic Coxsackievirus B3 (CVB3). Taken together, CAP down-regulates pro-inflammatory cytokines by interfering with the normal function of the NF-κB pathway. The promotion of CAP production could support the development of new strategies aiming to limit excessive and detrimental activation of the immune system.

Myocardial 18F-FDG Uptake Pattern for Cardiovascular Risk Stratification in Patients Undergoing Oncologic PET/CT.

OBJECTIVE: Positron emission tomography/computed tomography with 18F-fluorodeoxy-glucose (18F-FDG-PET/CT) has become the standard staging modality in various tumor entities. Cancer patients frequently receive cardio-toxic therapies. However, routine cardiovascular assessment in oncologic patients is not performed in current clinical practice. Accordingly, this study sought to assess whether myocardial 18F-FDG uptake patterns of patients undergoing oncologic PET/CT can be used for cardiovascular risk stratification. METHODS: Myocardial 18F-FDG uptake pattern was assessed in 302 patients undergoing both oncologic whole-body 18F-FDG-PET/CT and myocardial perfusion imaging by single-photon emission computed tomography (SPECT-MPI) within a six-month period. Primary outcomes were myocardial 18F-FDG uptake pattern, impaired myocardial perfusion, ongoing ischemia, myocardial scar, and left ventricular ejection fraction. RESULTS: Among all patients, 109 (36.1%) displayed no myocardial 18F-FDG uptake, 77 (25.5%) showed diffuse myocardial 18F-FDG uptake, 24 (7.9%) showed focal 18F-FDG uptake, and 92 (30.5%) had a focal on diffuse myocardial 18F-FDG uptake pattern. In contrast to the other uptake patterns, focal myocardial 18F-FDG uptake was predominantly observed in patients with myocardial abnormalities (i.e., abnormal perfusion, impaired LVEF, myocardial ischemia, or scar). Accordingly, a multivariate logistic regression identified focal myocardial 18F-FDG uptake as a strong predictor of abnormal myocardial function/perfusion (odds ratio (OR) 5.32, 95% confidence interval (CI) 1.73-16.34, p = 0.003). Similarly, focal myocardial 18F-FDG uptake was an independent predictor of ongoing ischemia and myocardial scar (OR 4.17, 95% CI 1.53-11.4, p = 0.005 and OR 3.78, 95% CI 1.47-9.69, p = 0.006, respectively). CONCLUSIONS: Focal myocardial 18F-FDG uptake seen on oncologic PET/CT indicates a significantly increased risk for multiple myocardial abnormalities. Obtaining and taking this information into account will help to stratify patients according to risk and will reduce unnecessary cardiovascular complications in cancer patients.