Borlaug, Barry A.

Background Nonpulsatile pulmonary blood flow in Fontan circulation results in pulmonary vascular disease, but the potential relationships between pulmonary vascular resistance index (PVRI) and Fontan failure have not been studied. The objective was to determine whether the absence of subpulmonary ventricle in the Fontan circulation would make patients more vulnerable to even low-level elevations in PVRI, and when coupled with low cardiac index, this would identify patients at increased risk of Fontan failure. Methods and Results Two hundred sixty-one adult Fontan patients underwent cardiac catheterization; age 26±3 years, men 146 (56%), atriopulmonary Fontan 144 (55%). Patients were divided into 2 groups: those with high PVRI (>2 WU·m 2 ) and low cardiac index <2.5 L min −1 m −2 (group 1, n=70, 30%), and those with normal PVRI and normal cardiac index (group 2, n=182, 70%). Fontan failure was defined by the composite of all-cause mortality, listing for heart transplantation, or initiation of palliative care. There were 68 (26%) cases of Fontan failure during a mean follow-up of 8.6±2.4 years. When compared with group 2, freedom from Fontan failure was significantly lower in group 1: 66% versus 89% at 5 years. The combination of high PVRI and low cardiac index was an independent risk factor for Fontan failure (hazard ratio, 1.84; 95% confidence interval, 1.09–2.85). Conclusions When coupled with low cardiac index, even mild elevations in PVRI identify patients at high risk of Fontan failure. This suggests that pulmonary vascular disease is a key mechanism underlying Fontan failure and supports further studies to understand the pathophysiology and target treatments to pulmonary vascular tone in this population.

Background: We hypothesized that pulmonary venous hypertension in heart failure (HF) leads to predominate remodeling of pulmonary veins and that the severity of venous remodeling is associated with the severity of pulmonary hypertension (PH) in HF. Methods: Patients with HF (n=108; 53 preserved and 55 reduced ejection fraction) with PH (HF-PH; pulmonary artery systolic pressure [PASP] ≥40 mm Hg) were compared to normal controls (n=12) and patients with primary pulmonary veno-occlusive disease (PVOD; n=17). In lung specimens from autopsy (control, HF-PH, and 7 PVOD) or surgery (10 PVOD), quantitative histomorphometry was performed in all analyzable arteries (n=4949), veins (n=7630), and small indeterminate vessels (IV; n=2168) to define percent medial thickness (arteries) and percent intimal thickness (%IT) (arteries, veins, and IV) relative to external diameter. Results: The average arterial percent medial thickness (control, 6.9; HF-PH, 11.0; PVOD, 15.0), arterial %IT (control, 4.9; HF-PH, 14.9; PVOD, 31.1), venous %IT (control, 14.0; HF-PH, 24.9; PVOD, 43.9), and IV %IT (control, 10.6; HF-PH, 25.8; PVOD, 50.0) in HF-PH were higher than controls ( P <0.0001 for all) but lower than PVOD ( P ≤0.005 for all). PASP (mm Hg) was lower in HF-PH (median, 59 [interquartile range, 50–70]) than in PVOD (median, 91 [interquartile range, 82–103]). PASP correlated with arterial percent medial thickness ( r =0.41) and arterial %IT ( r =0.35) but more strongly with venous %IT ( r =0.49) and IV %IT ( r =0.55) ( P <0.0001 for all). Associations between PASP and venous or IV %IT remained significant after adjusting for arterial percent medial thickness and %IT and did not vary by HF type. In patients with right heart catheterization (30 HF-PH, 14 PVOD), similar associations between the transpulmonary gradient and pulmonary vascular remodeling existed, with numerically stronger associations for venous and IV %IT. Although the PASP was slightly higher in patients with HF-PH with right ventricular dysfunction, pulmonary vascular remodeling was not more severe. Pulmonary vascular remodeling severity was associated with reductions in the diffusing capacity of the lungs. Conclusions: In HF, PH is associated with global pulmonary vascular remodeling, but the severity of PH correlates most strongly with venous and small IV intimal thickening, similar to the pattern observed in PVOD. These findings expand our understanding of the pathobiology of PH in HF.

Abstract There is an unmet need for effective treatment strategies to reduce morbidity and mortality in patients with heart failure with preserved ejection fraction (HFpEF). Until recently, attention in patients with HFpEF was almost exclusively focused on the left side. However, it is now increasingly recognized that right heart dysfunction is common and contributes importantly to poor prognosis in HFpEF. More insights into the development of right heart dysfunction in HFpEF may aid to our knowledge about this complex disease and may eventually lead to better treatments to improve outcomes in these patients. In this position paper from the Heart Failure Association of the European Society of Cardiology, the Committee on Heart Failure with Preserved Ejection Fraction reviews the prevalence, diagnosis, and pathophysiology of right heart dysfunction and failure in patients with HFpEF. Finally, potential treatment strategies, important knowledge gaps and future directions regarding the right side in HFpEF are discussed.

Abstract Aims Patients with heart failure (HF) with reduced (HFrEF) or preserved (HFpEF) ejection fraction demonstrate an increased ventilatory equivalent for carbon dioxide (V̇E/V̇CO2) slope. The physiological correlates of the V̇E/V̇CO2 slope remain unclear in the two HF phenotypes. We hypothesized that changes in the physiological dead space to tidal volume ratio (VD/VT) and arterial CO2 tension (PaCO2) differentially contribute to the V̇E/V̇CO2 slope in HFrEF vs. HFpEF. Methods and results Adults with HFrEF (n = 32) and HFpEF (n = 27) [mean ± standard deviation (SD) left ventricular ejection fraction: 22 ± 7% and 61 ± 9%, respectively; mean ± SD body mass index: 28 ± 4 kg/m2 and 33 ± 6 kg/m2, respectively; P &lt; 0.01] performed cardiopulmonary exercise testing with breath-by-breath ventilation and gas exchange measurements. PaCO2 was measured via radial arterial catheterization. We calculated the V̇E/V̇CO2 slope via linear regression, and VD/VT = 1 − [(863 × V̇CO2)/(V̇E × PaCO2)]. Resting VD/VT (0.48 ± 0.08 vs. 0.41 ± 0.11; P = 0.04), but not PaCO2 (38 ± 5 mmHg vs. 40 ± 3 mmHg; P = 0.21) differed between HFrEF and HFpEF. Peak exercise VD/VT (0.39 ± 0.08 vs. 0.32 ± 0.12; P = 0.02) and PaCO2 (33 ± 6 mmHg vs. 38 ± 4 mmHg; P &lt; 0.01) differed between HFrEF and HFpEF. The V̇E/V̇CO2 slope was higher in HFrEF compared with HFpEF (44 ± 11 vs. 35 ± 8; P &lt; 0.01). Variance associated with the V̇E/V̇CO2 slope in HFrEF and HFpEF was explained by peak exercise VD/VT (R2 = 0.30 and R2 = 0.50, respectively) and PaCO2 (R2 = 0.64 and R2 = 0.28, respectively), but the relative contributions of each differed (all P &lt; 0.01). Conclusions Relationships between the V̇E/V̇CO2 slope and both VD/VT and PaCO2 are robust, but differ between HFpEF and HFrEF. Increasing V̇E/V̇CO2 slope appears to be strongly explained by mechanisms influential in regulating PaCO2 in HFrEF, which contrasts with the strong role of increased VD/VT in HFpEF.

Abstract Aims Patients with heart failure and preserved ejection fraction (HFpEF) are characterized by functional impairment and an abnormal haemodynamic response to exercise. The six-minute walk test (6MWT) serves as a standardized test for functional capacity quantification in heart failure patients, and is associated with cardiovascular outcomes. However, as the association between 6MWT and haemodynamic parameters during rest and exercise in HFpEF patients is unknown, we sought to elucidate this relationship. Methods and results Overall, 64 patients enrolled in the REDUCE LAP-HF trial completed a 6MWT at baseline. Univariate and multivariable linear regression models were used to assess the associations between 6MWT and measured or derived haemodynamic variables at baseline, during light/moderate exercise (20 W), and at peak supine exercise. The average 6MWT distance was 318 ± 106 m. At rest, in a multivariable model, only pulmonary capillary wedge pressure (PCWP) was significantly associated with 6MWT [coefficient: –5.4, 95% confidence interval (CI) –10.4, –0.5, P = 0.033]. During light/moderate exercise, mean pulmonary artery pressure was associated with 6MWT in a multivariable model (coefficient: –3.5, 95% CI –6.8, –0.3, P = 0.033). During peak exercise, central venous pressure, cardiac index (CI), and PCWP/CI correlated with 6MWT; however, workload corrected PCWP was the only variable independently associated with 6MWT (coefficient: –0.8, 95% CI –1.3, –0.4, P &lt; 0.001). The variance in 6MWT was modestly explained by measured or derived haemodynamic variables at rest or at any stage of exercise (r2 = 7–17%). Conclusion Workload corrected PCWP correlated best with 6MWT performance in HFpEF patients. Baseline haemodynamic variables were modestly correlated with 6MWT, suggesting that 6MWT performance in HFpEF patients may be significantly influenced by extra-cardiac factors.

Background The mechanisms and relevance of impaired glucose homeostasis in advanced heart failure ( HF ) are poorly understood. The study goals were to examine glucose regulation, pancreatic endocrine function, and metabolic factors related to prognosis in patients with nondiabetic advanced HF. Methods and Results In total, 140 advanced HF patients without known diabetes mellitus and 21 sex‐, age‐, and body mass index–matched controls underwent body composition assessment, oral glucose tolerance testing, and measurement of glucose‐regulating hormones to model pancreatic β‐cell secretory response. Compared with controls, HF patients had similar fasting glucose and insulin levels but higher levels after oral glucose tolerance testing. Insulin secretion was not impaired, but with increasing HF severity, there was a reduction in glucose, insulin, and insulin/glucagon ratio—a signature of starvation. The insulin/C‐peptide ratio was decreased in HF , indicating enhanced insulin clearance, and this was correlated with lower cardiac output, hepatic insufficiency, right ventricular dysfunction, and body wasting. After a median of 449 days, 41% of patients experienced an adverse event (death, urgent transplant, or assist device). Increased glucagon and, paradoxically, low fasting plasma glucose displayed the strongest relations to outcome ( P =0.01). Patients in the lowest quartile of fasting plasma glucose (3.8–5.1 mmol·L −1 , 68–101 mg·dL −1 ) had 3‐times higher event risk than in the top quartile (6.0–7.9 mmol·L −1 , 108–142 mg·dL −1 ; relative risk: 3.05 [95% confidence interval, 1.46–6.77]; P =0.002). Conclusions Low fasting plasma glucose and increased glucagon are robust metabolic predictors of adverse events in advanced HF . Pancreatic insulin secretion is preserved in advanced HF , but levels decrease with increasing HF severity due to enhanced insulin clearance that is coupled with right heart failure and cardiac cachexia.