Borlaug, Barry A

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 < 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 < 0.01) differed between HFrEF and HFpEF. The V̇E/V̇CO2 slope was higher in HFrEF compared with HFpEF (44 ± 11 vs. 35 ± 8; P < 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 < 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 < 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.

Reversal of pulmonary hypertension has been observed in patients during a bridge to transplant with a left ventricular assist device. Total artificial heart (TAH) implant prevents subsequent right heart catheterization. Consequently, controversy exists over whether the prosthetic right ventricle improves or exacerbates pulmonary hypertension. A pulmonary artery (PA) pressure monitor was placed in two patients undergoing TAH implant, as a bridge to transplant. One patient had pulmonary hypertension at implant; the other had normal pulmonary pressures. Daily measurements were taken of systolic, diastolic, and mean PA pressures throughout support. Patient 1 received successful transplant after TAH support of 91 days. Systolic/diastolic (mean) PA pressures steadily decreased from 55/39 (28) mm Hg at implant to 29/18 (7) mm Hg currently. Patient 2 received support for 101 days before death due to abdominal ischemic complications. Pulmonary arterial pressures stayed consistent throughout this period, from 26/17 (20) mm Hg at implant to 23/13 (17) mm Hg at the time of death. These findings suggest that an implantable PA pressure monitor may be useful in optimizing hemodynamics and planning appropriate timing of transplant with TAH support.

Approximately half of patients with heart failure have preserved ejection fraction. There is no proven treatment that improves outcome. The pathophysiology of heart failure with preserved ejection fraction is complex and includes left ventricular systolic and diastolic dysfunction, pulmonary vascular disease, endothelial dysfunction, and peripheral abnormalities. Multiple lines of evidence point to impaired nitric oxide (NO)-cGMP bioavailability as playing a central role in each of these abnormalities. In contrast to traditional organic nitrate therapies, an alternative strategy to restore NO-cGMP signaling is via inorganic nitrite. Inorganic nitrite, previously considered to be an inert byproduct of NO metabolism, functions as an important in vivo reservoir for NO generation, particularly under hypoxic and acidosis conditions. As such, inorganic nitrite becomes most active at times of greater need for NO signaling, as during exercise when left ventricular filling pressures and pulmonary artery pressures increase. Herein, we present the rationale and design for the INDIE-HFpEF trial (Inorganic Nitrite Delivery to Improve Exercise Capacity in Heart Failure with Preserved Ejection Fraction), which is a multicenter, randomized, double-blind, placebo-controlled cross-over study assessing the effect of inhaled inorganic nitrite on peak exercise capacity, conducted in the National Heart, Lung, and Blood Institute–sponsored Heart Failure Clinical Research Network. Clinical Trial Registration URL: http://www.clinicaltrials.gov . Unique identifier: NCT02742129.

Background— People with heart failure and preserved ejection fraction develop increases in left ventricular (LV) end-diastolic pressures during exercise that contribute to dyspnea. In normal open-chest animal preparations, the pericardium restrains LV filling when central blood volume increases. We hypothesized that resection of the pericardium using a minimally invasive epicardial approach would mitigate the increase in LV end-diastolic pressure that develops during volume loading in normal and diseased hearts with the chest intact. Methods and Results— Invasive hemodynamic assessment was performed at baseline and after saline load before and after pericardial resection in normal canines with open (n=3) and closed chest (n=5) and in a pig model with features of human heart failure and preserved ejection fraction with sternum intact (n=4). In closed-chest animals, pericardiotomy was performed using a novel subxiphoid procedure. In both experimental preparations of normal dogs, pericardiotomy blunted the increase in LV end-diastolic pressure with saline infusion, while enhancing the saline-mediated increase in LV end-diastolic volume. With chest intact in the pig model, percutaneous pericardial resection again blunted the increase in LV end-diastolic pressure secondary to volume expansion (+4±3 versus +13±5 mm Hg; P =0.014), while enhancing the saline-mediated increase in LV end-diastolic volume (+17±1 versus +10±2 mL; P =0.016). Conclusions— This proof of concept study demonstrates that pericardial resection through a minimally invasive percutaneous approach mitigates the elevation in LV filling pressures with volume loading in both normal animals and a pig model with diastolic dysfunction. Further study is warranted to determine whether this method is safe and produces similar acute and chronic hemodynamic benefits in people with heart failure and preserved ejection fraction.