Epicardial adipose tissue and pericardial constraint in heart failure with preserved ejection fraction.

AIMS: Obesity and epicardial adiposity play a role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF), and both are associated with increased filling pressures and reduced exercise capacity. The haemodynamic basis for these observations remains inaccurately defined. We hypothesize that an abundance of epicardial adipose tissue (EAT) within the pericardial sac is associated with haemodynamic signs of pericardial constraint. METHODS AND RESULTS: HFpEF patients who underwent invasive heart catheterization with simultaneous echocardiography were included. Right atrial pressure (RAP), right ventricular end-diastolic pressure, and pulmonary capillary wedge pressure (PCWP) were invasively measured. The presence of a square root sign on the right ventricular pressure waveform and the RAP/PCWP ratio (surrogate parameters for pericardial constraint) were investigated. EAT thickness alongside the right ventricle was measured on echocardiography. Sixty-four patients were studied, with a mean age of 73 ± 10 years, 64% women, and a mean body mass index (BMI) of 28.6 ± 5.4 kg/m2. In total, 47 patients (73%) had a square root sign. The presence of a square root sign was associated with higher BMI (29.3 vs. 26.7 kg/m2, P = 0.02), higher EAT (4.0 vs. 3.4 mm, P = 0.03), and higher RAP (9 vs. 6 mmHg, P = 0.04). Women had more EAT than men (4.1 vs. 3.5 mm, P = 0.04), despite a comparable BMI. Women with a square root sign had significantly higher EAT (4.3 vs. 3.3 mm, P = 0.02), a higher mean RAP (9 vs. 5 mmHg, P = 0.02), and a higher RAP/PCWP ratio (0.52 vs. 0.26, P = 0.002). In men, such associations were not seen, although there was no significant interaction between men and women (P > 0.05 for all analyses). CONCLUSIONS: Obesity and epicardial adiposity are associated with haemodynamic signs of pericardial constraint in patients with HFpEF. The pathophysiological and therapeutic implications of this finding need further study.

Variant Location Is a Novel Risk Factor for Individuals With Arrhythmogenic Cardiomyopathy Due to a Desmoplakin (DSP) Truncating Variant.

BACKGROUND: Truncating variants in desmoplakin (DSPtv) are an important cause of arrhythmogenic cardiomyopathy; however the genetic architecture and genotype-specific risk factors are incompletely understood. We evaluated phenotype, risk factors for ventricular arrhythmias, and underlying genetics of DSPtv cardiomyopathy. METHODS: Individuals with DSPtv and any cardiac phenotype, and their gene-positive family members were included from multiple international centers. Clinical data and family history information were collected. Event-free survival from ventricular arrhythmia was assessed. Variant location was compared between cases and controls, and literature review of reported DSPtv performed. RESULTS: There were 98 probands and 72 family members (mean age at diagnosis 43±8 years, 59% women) with a DSPtv, of which 146 were considered clinically affected. Ventricular arrhythmia (sudden cardiac arrest, sustained ventricular tachycardia, appropriate implantable cardioverter defibrillator therapy) occurred in 56 (33%) individuals. DSPtv location and proband status were independent risk factors for ventricular arrhythmia. Further, gene region was important with variants in cases (cohort n=98; Clinvar n=167) more likely to occur in the regions resulting in nonsense mediated decay of both major DSP isoforms, compared with n=124 genome aggregation database control variants (148 [83.6%] versus 29 [16.4%]; P<0.0001). CONCLUSIONS: In the largest series of individuals with DSPtv, we demonstrate that variant location is a novel risk factor for ventricular arrhythmia, can inform variant interpretation, and provide critical insights to allow for precision-based clinical management.

Connecting epicardial adipose tissue and heart failure with preserved ejection fraction: mechanisms, management and modern perspectives.

Obesity is very common in patients with heart failure with preserved ejection fraction (HFpEF) and it has been suggested that obesity plays an important role in the pathophysiology of this disease. While body mass index defines the presence of obesity, this measure provides limited information on visceral adiposity, which is probably more relevant in the pathophysiology of HFpEF. Epicardial adipose tissue is the visceral fat situated directly adjacent to the heart and recent data demonstrate that accumulation of epicardial adipose tissue is associated with the onset, symptomatology and outcome of HFpEF. However, the mechanisms by which epicardial adipose tissue may be involved in HFpEF remain unclear. It is also questioned whether epicardial adipose tissue may be a specific target for therapy for this disease. In the present review, we describe the physiology of epicardial adipose tissue and the pathophysiological transformation of epicardial adipose tissue in response to chronic inflammatory diseases, and we postulate conceptual mechanisms on how epicardial adipose tissue may be involved in HFpEF pathophysiology. Lastly, we outline potential treatment strategies, knowledge gaps and directions for further research.

Association of epicardial adipose tissue with different stages of coronary artery disease: A cross-sectional UK Biobank cardiovascular magnetic resonance imaging substudy.

Objective: Increased epicardial adipose tissue (EAT) has been identified as a risk factor for the development of coronary artery disease (CAD). However, the exact role of EAT in the development of CAD is unclear. This study aims to compare EAT volumes between healthy controls and individuals with stable CAD and a history of myocardial infarction (MI). Furthermore, associations between clinical and biochemical parameters with EAT volumes are examined. Methods: This retrospective cross-sectional study included 171 participants from the United Kingdom Biobank (56 healthy controls; 60 stable CAD; 55 post MI), whom were balanced for age, sex and body mass index (BMI). EAT volumes were quantified on end-diastolic cardiac magnetic resonance (CMR) imaging short-axis slices along the left and right ventricle and indexed for body surface area (iEAT) and iEAT volumes were compared between groups. Results: iEAT volumes were comparable between control, CAD and MI cases (median [IQR]: 66.1[54.4-77.0] vs. 70.9[55.8-85.5] vs. 67.6[58.6-82.3] mL/m2, respectively (p > 0.005 for all). Increased HDL-cholesterol was associated with decreased iEAT volume (ß = -14.8, CI = -24.6 to -4.97, p = 0.003) and suggestive associations (P-value < 0.05 and ≥ 0.005) were observed between iEAT and triglycerides (ß = 3.26, CI = 0.42 to 6.09, p = 0.02), Apo-lipoprotein A (ß = -16.3, CI = -30.3 to -2.24, p = 0.02) and LDL-cholesterol (ß = 3.99, CI = -7.15 to -0.84, p = 0.01). Conclusions: No significant differences in iEAT volumes were observed between patients with CAD, MI and healthy controls. Our results indicate the importance of correcting for confounding by CVD risk factors, including circulating lipid levels, when studying the relationship between EAT volume and CAD. Further mechanistic studies on causal pathways and the role of EAT composition are warranted.

Bariatric surgery and cardiovascular disease: a systematic review and meta-analysis.

AIMS: Obesity is a global health problem, associated with significant morbidity and mortality, often due to cardiovascular (CV) diseases. While bariatric surgery is increasingly performed in patients with obesity and reduces CV risk factors, its effect on CV disease is not established. We conducted a systematic review and meta-analysis to evaluate the effect of bariatric surgery on CV outcomes, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline. METHODS AND RESULTS: PubMed and Embase were searched for literature until August 2021 which compared bariatric surgery patients to non-surgical controls. Outcomes of interest were all-cause and CV mortality, atrial fibrillation (AF), heart failure (HF), myocardial infarction, and stroke. We included 39 studies, all prospective or retrospective cohort studies, but randomized outcome trials were not available. Bariatric surgery was associated with a beneficial effect on all-cause mortality [pooled hazard ratio (HR) of 0.55; 95% confidence interval (CI) 0.49-0.62, P < 0.001 vs. controls], and CV mortality (HR 0.59, 95% CI 0.47-0.73, P < 0.001). In addition, bariatric surgery was also associated with a reduced incidence of HF (HR 0.50, 95% CI 0.38-0.66, P < 0.001), myocardial infarction (HR 0.58, 95% CI 0.43-0.76, P < 0.001), and stroke (HR 0.64, 95% CI 0.53-0.77, P < 0.001), while its association with AF was not statistically significant (HR 0.82, 95% CI 0.64-1.06, P = 0.12). CONCLUSION: The present systematic review and meta-analysis suggests that bariatric surgery is associated with reduced all-cause and CV mortality, and lowered incidence of several CV diseases in patients with obesity. Bariatric surgery should therefore be considered in these patients.

The value of echocardiographic measurement of epicardial adipose tissue in heart failure patients.

AIMS: Epicardial adipose tissue (EAT) is increasingly recognized as an important factor in the pathophysiology of heart failure (HF). Cardiac magnetic resonance (CMR) imaging is the gold-standard imaging modality to evaluate EAT size, but in contrast to echocardiography, CMR is costly and not widely available. We investigated EAT thickness on echocardiography in relation to EAT volume on CMR, and we assessed the agreement between observers for measuring echocardiographic EAT. METHODS AND RESULTS: Patients with HF and left ventricular ejection fraction >40% were enrolled. All patients underwent CMR imaging and transthoracic-echocardiography. EAT volume was quantified on CMR short-axis cine-stacks. Echocardiographic EAT thickness was measured on parasternal long-axis and short-axis views. Linear regression analyses were used to assess the association between EAT volume on CMR and EAT thickness on echocardiography. Intraclass correlation coefficient (ICC) was used to assess the interobserver agreement as well as the intraobserver agreement. EAT on CMR and echocardiography was evaluated in 117 patients (mean age 71 ± 10 years, 49% women and mean left ventricular ejection fraction 54 ± 7%). Mean EAT volume on CMR was 202 ± 64 mL and ranged from 80 to 373 mL. Mean EAT thickness on echocardiography was 3.8 ± 1.5 mm and ranged from 1.7 to 10.2 mm. EAT volume on CMR and EAT thickness on echocardiography were significantly correlated (junior-observer: r = 0.62, P < 0.001, senior-observer: r = 0.33, P < 0.001), and up to one-third of the variance in EAT volume was explained by EAT thickness (R2  = 0.38, P < 0.001). The interobserver agreement between junior and senior observers for measuring echocardiographic EAT was modest [ICC, 0.65 (95% confidence interval (CI) 0.47-0.77], whereas the intraobserver agreement was good (ICC 0.98, 95% CI 0.84-0.99). CONCLUSIONS: There was a modest correlation between EAT volume on CMR and EAT thickness on echocardiography. Limited agreement between junior and senior observers for measuring echocardiographic EAT was observed. EAT thickness on echocardiography is limited in estimating EAT volume.

The clinical and prognostic value of late Gadolinium enhancement imaging in heart failure with mid-range and preserved ejection fraction.

Heart failure (HF) with mid-range or preserved ejection fraction (HFmrEF; HFpEF) is a heterogeneous disorder that could benefit from strategies to identify subpopulations at increased risk. We tested the hypothesis that HFmrEF and HFpEF patients with myocardial scars detected with late gadolinium enhancement (LGE) are at increased risk for all-cause mortality. Symptomatic HF patients with left ventricular ejection fraction (LVEF) > 40%, who underwent cardiac magnetic resonance (CMR) imaging were included. The presence of myocardial LGE lesions was visually assessed. T1 mapping was performed to calculate extracellular volume (ECV). Multivariable logistic regression analyses were used to determine associations between clinical characteristics and LGE. Cox regression analyses were used to assess the association between LGE and all-cause mortality. A total of 110 consecutive patients were included (mean age 71 ± 10 years, 49% women, median N-terminal brain natriuretic peptide (NT-proBNP) 1259 pg/ml). LGE lesions were detected in 37 (34%) patients. Previous myocardial infarction and increased LV mass index were strong and independent predictors for the presence of LGE (odds ratio 6.32, 95% confidence interval (CI) 2.07-19.31, p = 0.001 and 1.68 (1.03-2.73), p = 0.04, respectively). ECV was increased in patients with LGE lesions compared to those without (28.6 vs. 26.6%, p = 0.04). The presence of LGE lesions was associated with a fivefold increase in the incidence of all-cause mortality (hazards ratio 5.3, CI 1.5-18.1, p = 0.009), independent of age, sex, New York Heart Association (NYHA) functional class, NT-proBNP, LGE mass and LVEF. Myocardial scarring on CMR is associated with increased mortality in HF patients with LVEF > 40% and may aid in selecting a subpopulation at increased risk.

Epicardial Adipose Tissue and Outcome in Heart Failure With Mid-Range and Preserved Ejection Fraction.

BACKGROUND: Epicardial adipose tissue (EAT) accumulation is thought to play a role in the pathophysiology of heart failure (HF) with mid-range and preserved ejection fraction, but its effect on outcome is unknown. We evaluated the prognostic value of EAT volume measured with cardiac magnetic resonance in patients with HF with mid-range ejection fraction and HF with preserved ejection fraction. METHODS: Patients enrolled in a prospective multicenter study that investigated the value of implantable loop-recorders in HF with mid-range ejection fraction and HF with preserved ejection fraction were analyzed. EAT volume was quantified with cardiac magnetic resonance. Main outcome was the composite of all-cause mortality and first HF hospitalizations. Hazard ratios (HR) and 95% CI are described per SD increase in EAT. RESULTS: We studied 105 patients (mean age 72±8 years, 50% women, and mean left ventricular ejection fraction 53±8%). During median follow-up of 24 (17-25) months, 31 patients (30%) died or were hospitalized for HF. In univariable analysis, EAT was significantly associated with a higher risk of the composite outcome (HR, 1.76 [95% CI, 1.24-2.50], P=0.001), and EAT remained associated with outcome after adjustment for age, sex, and body mass index (HR, 1.61 [95% CI, 1.13-2.31], P=0.009), and after adjustment for New York Heart Association functional class and N-terminal of pro-brain natriuretic peptide (HR, 1.53 [95% CI, 1.04-2.24], P=0.03). Furthermore, EAT was associated with all-cause mortality alone (HR, 2.06 [95% CI, 1.26-3.37], P=0.004) and HF hospitalizations alone (HR, 1.54 [95% CI, 1.04-2.30], P=0.03). CONCLUSIONS: EAT accumulation is associated with adverse prognosis in patients with HF with mid-range ejection fraction and HF with preserved ejection fraction. This finding supports the importance of EAT in these patients with HF. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01989299.

Importance of epicardial adipose tissue localization using cardiac magnetic resonance imaging in patients with heart failure with mid-range and preserved ejection fraction.

BACKGROUND: Epicardial adipose tissue (EAT) has been implicated in the pathophysiology of heart failure (HF) with left ventricular ejection fraction (LVEF) >40%, but whether this is due to a regional or global effect of EAT remains unclear. HYPOTHESIS: Regional EAT is associated with alterations in local cardiac structure and function. METHODS: Patients with HF and LVEF >40% were studied. Cardiac Magnetic Resonance imaging was used to localize EAT surrounding the right ventricle (RV) and LV separately, using anterior- and posterior interventricular grooves as boundaries. Atrial- and ventricular EAT were differentiated using the mitral-valve position. All EAT depots were related to the adjacent myocardial structure. RESULTS: 102 consecutive HF patients were enrolled. The majority of EAT was present around the RV (42% of total EAT, p < .001). RV-EAT showed a strong association with increased RV mass (ß = 0.60, p < .001) and remained associated with RV mass after adjusting for total EAT, sex, N-terminal prohormone of brain natriuretic peptide (NT-proBNP), renal function and blood glucose. LV-EAT showed a similar association with LV mass in univariable analysis, albeit less pronounced (ß = 0.24, p = .02). Atrial EAT was increased in patients with atrial fibrillation compared to those without atrial fibrillation (30 vs. 26 ml/m2 , p = .04), whereas ventricular EAT was similar (74 vs. 75 ml/m2 , p = .9). CONCLUSIONS: Regional EAT is strongly associated with local cardiac structure and function in HF patients with LVEF >40%. These data support the hypothesis that regional EAT is involved in the pathophysiology of HF with LVEF >40%.

Preoperative cardiac screening using NT-proBNP in obese patients 50 years and older undergoing bariatric surgery: a study of 310 consecutive patients.

BACKGROUND: Obesity is associated with cardiovascular (CV) risk factors and diseases. Because bariatric surgery is increasingly performed in relatively elderly patients, a risk for pre- and postoperative CV complications exists. OBJECTIVES: We aimed to assess the value of plasma N-terminal-probrain natriuretic peptide (NT-proBNP) as a CV screening tool. SETTING: High-volume bariatric center. METHODS: Between June 2019 and January 2020, all consecutive bariatric patients 50 years and older underwent preoperative NT-proBNP assessment in this cohort study to screen for CV disease. Patients with elevated NT-proBNP (≥125 pg/mL) were referred for further cardiac evaluation, including electrocardiography and echocardiography. RESULTS: We included 310 consecutive patients (median age, 56 years; 79% female; body mass index = 43±6.5 kg/m2). A history of CV disease was present in 21% of patients, mainly atrial fibrillation (7%) and coronary artery disease (10%). A total of 72 patients (23%) had elevated NT-proBNP levels, and 67 of them underwent further cardiac workup. Of these 67 patients, electrocardiography (ECG) showed atrial fibrillation in 7 patients (10%). On echocardiography, 3 patients had left ventricular ejection fraction (LVEF) <40%, 9 patients had LVEF 40%-49%, and 13 patients had LVEF ≥50% with structural and/or functional remodeling. In 2 patients, elevated NT-proBNP prompted workup leading to a diagnosis of coronary artery disease and consequent percutaneous coronary intervention in 1 patient. CONCLUSIONS: Elevated NT-proBNP levels are present in 23% of patients 50 years and older undergoing bariatric surgery. In 37% of them, there was echocardiographic evidence for structural and/or functional remodeling. Further studies are needed to assess if these preliminary results warrant routine application of NT-proBNP to identify patients at risk for CV complications after bariatric surgery.

Epicardial Adipose Tissue and Invasive Hemodynamics in Heart Failure With Preserved Ejection Fraction.

OBJECTIVES: This study examined associations between epicardial adipose tissue (EAT), invasive hemodynamics, and exercise capacity in patients with heart failure with preserved ejection fraction (HFpEF). BACKGROUND: EAT is increased in patients with HFpEF and may play a role in the pathophysiology of this disorder. METHODS: Patients with heart failure and a left ventricular ejection fraction >45% who underwent right and left heart catheterization with simultaneous echocardiography were included. Pulmonary capillary wedge pressure (PCWP), left ventricular end-diastolic pressure (LVEDP), right ventricular end-diastolic pressure (RVEDP), and pulmonary vascular resistance (PVR) were invasively measured. Obesity was defined as body mass index (BMI) ≥30 kg/m2. EAT thickness alongside the right ventricle was measured on echocardiographic long- and short-axis views. Cardiopulmonary exercise testing was performed to obtain maximal oxygen uptake (VO2-max). RESULTS: This study examined 75 patients, mean age 74 ± 9 years; 68% were women, mean BMI was 29 ± 6 kg/m2, and 36% were obese. Higher BMI was strongly associated with increased EAT (r = 0.74; p < 0.001). Increased EAT was associated with higher RVEDP, independent of PVR (odds ratio [OR]: 1.16; 95% confidence interval [CI]: 1.02 to 1.34; p = 0.03), but not independent of obesity (p = 0.10). Increased EAT and higher RVEDP were both associated with lower VO2-max (r = -0.43; p < 0.001 and r = -0.43; p = 0.001, respectively). Increased EAT remained associated with lower VO2-max after adjustment for PVR (OR: 0.64; 95% CI: 0.49 to 0.84; p = 0.002) and obesity (OR: 0.69; 95% CI: 0.53 to 0.92; p = 0.01). EAT thickness was not associated with left-sided filling pressures (i.e., PCWP and LVEDP). CONCLUSIONS: In HFpEF, obesity and increased EAT were associated with higher right-sided filling pressures and with reduced exercise capacity.

Ventricular tachyarrhythmia detection by implantable loop recording in patients with heart failure and preserved ejection fraction: the VIP-HF study.

AIMS: The primary aim of the VIP-HF study was to examine the incidence of sustained ventricular tachyarrhythmias (VTs) in heart failure (HF) with mid-range (HFmrEF) or preserved ejection fraction (HFpEF). Secondary aims were to examine the incidence of non-sustained VTs, bradyarrhythmias, HF hospitalizations and mortality. METHODS AND RESULTS: This was an investigator-initiated, prospective, multicentre, observational study of patients with HF and left ventricular ejection fraction (LVEF) >40%. Patients underwent extensive phenotyping, after which an implantable loop recorder was implanted. We enrolled 113 of the planned 250 patients [mean age 73 ± 8 years, 51% women, New York Heart Association class II/III 54%/46%, median N-terminal pro B-type natriuretic peptide 1367 (710-2452) pg/mL and mean LVEF 54 ± 6%; 75% had LVEF >50%]. Eighteen percent had non-sustained VTs and 37% had atrial fibrillation on Holter monitoring. During a median follow-up of 657 (219-748) days, the primary endpoint of sustained VT was observed in one patient. The incidence of the primary endpoint was 0.6 (95% confidence interval 0.2-3.5) per 100 person-years. The incidence of the secondary endpoint of non-sustained VT was 11.5 (7.1-18.7) per 100 person-years. Five patients developed bradyarrhythmias [3.2 (1.4-7.5) per 100 person-years], three were implanted with a pacemaker. In total, 23 patients (20%) were hospitalized for HF [16.3 (10.9-24.4) per 100 person-years]. Fourteen patients (12%) died [8.7 (5.2-14.7) per 100 person-years]; 10 due to cardiovascular causes, and four sudden deaths, one with implantable loop recorder-confirmed bradyarrhythmias as terminal event, three others undetermined. CONCLUSION: Despite the lower than expected number of included patients, the incidence of sustained VTs in HFmrEF/HFpEF was low. Clinically relevant bradyarrhythmias were more often observed than expected.

Epicardial fat in heart failure patients with mid-range and preserved ejection fraction.

AIMS: Adipose tissue and inflammation may play a role in the pathophysiology of patients with heart failure (HF) with mildly reduced or preserved ejection fraction. We therefore investigated epicardial fat in patients with HF with preserved (HFpEF) and mid-range ejection fraction (HFmrEF), and related this to co-morbidities, plasma biomarkers and cardiac structure. METHODS AND RESULTS: A total of 64 HF patients with left ventricular ejection fraction >40% and 20 controls underwent routine cardiac magnetic resonance examination. Epicardial fat volume was quantified on short-axis cine stacks covering the entire epicardium and was related to clinical correlates, biomarkers associated with inflammation and myocardial injury, and cardiac function and contractility on cardiac magnetic resonance. HF patients and controls were of comparable age, sex and body mass index. Total epicardial fat volume was significantly higher in HF patients compared to controls (107 mL/m2 vs. 77 mL/m2 , P <0.0001). HF patients with atrial fibrillation and/or type 2 diabetes mellitus had more epicardial fat than HF patients without these co-morbidities (116 vs. 100 mL/m2 , P =0.03, and 120 vs. 97 mL/m2 , P =0.001, respectively). Creatine kinase-MB, troponin T and glycated haemoglobin in patients with HF were positively correlated with epicardial fat volume (R =0.37, P =0.006; R =0.35, P =0.01; and R =0.42, P =0.002, respectively). CONCLUSION: Heart failure patients had more epicardial fat compared to controls, despite similar body mass index. Epicardial fat volume was associated with the presence of atrial fibrillation and type 2 diabetes mellitus and with biomarkers related to myocardial injury. The clinical implications of these findings are unclear, but warrant further investigation.