Testani, Jeffrey M.

BACKGROUND: Acoramidis achieves near-complete (≥90%) transthyretin stabilization and is approved to reduce cardiovascular-related mortality and hospitalization in transthyretin amyloid cardiomyopathy. Its effects on kidney function are not well characterized. METHODS: Data from randomized phase 2 (N=49) and phase 3 (N=632) studies in transthyretin amyloid cardiomyopathy were included. The estimated glomerular filtration rate (eGFR) slope was generated using a linear spline mixed-effects model. The urinary albumin-to-creatinine ratio was measured longitudinally. Relationships between changes in kidney function and clinical outcomes were explored using Cox proportional hazards models. RESULTS: Acoramidis initiation resulted in a modest acute dip in eGFR that was dose-dependent, reversible, and not associated with adverse kidney-related events. At Day 28, the mean (±SE) dip in eGFR from baseline with acoramidis was 8.5±0.48 mL/min per 1.73 m 2 ; the placebo-corrected reduction in the urinary albumin-to-creatinine ratio was 15.5% (95% CI, 0.4%–28.4%; P =0.044). The rate of decline in kidney function (chronic eGFR slope) was significantly improved with acoramidis versus placebo (−1.01 versus −3.48 mL/min per 1.73 m 2 per year; P <0.001), and the reduction in the urinary albumin-to-creatinine ratio was sustained (13.7% [95% CI, 1.7%–24.2%]; P =0.026) over time. Concomitant tafamidis use did not influence the chronic eGFR slope in either arm. Comparing acoramidis versus placebo subgroups with acute eGFR dips ≥ the median (4.89 mL/min per 1.73 m 2 ) favored acoramidis for all-cause mortality or cardiovascular-related hospitalization (hazard ratio, 0.42 [95% CI, 0.22–0.78]; P =0.006; P interaction=0.043) and cardiovascular-related hospitalization (hazard ratio, 0.34 [95% CI, 0.17–0.66]; P =0.002, P interaction=0.025). Within the placebo arm, eGFR dips portended worse outcomes. CONCLUSIONS: Acoramidis initiation resulted in an acute dip in eGFR and reductions in both the chronic eGFR slope and urinary albumin-to-creatinine ratio versus placebo without adverse kidney-related events. Acoramidis effects on kidney function may be mediated through direct kidney-protective hemodynamic effects. Importantly, the acute dip in eGFR was associated with a reduced risk of adverse clinical outcomes within the first year. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifiers: NCT03458130, NCT03536767, NCT03860935, NCT04988386.

Abstract Aims Chronic kidney disease (CKD) is common in patients with heart failure (HF) with preserved ejection fraction (HFpEF), and its presence is associated with more severe echocardiographic abnormalities and poorer outcomes through unclear mechanisms. CKD-associated endothelial dysfunction, inflammation, and activation of profibrotic pathways could worsen pulmonary vascular disease (PVD) in HFpEF, but such relationships have not been explored. Methods Consecutively evaluated patients with HFpEF undergoing invasive haemodynamic cardiopulmonary exercise testing were stratified by baseline kidney function to characterize potential differences in pulmonary vascular loading, haemodynamics, cardiopulmonary reserve, and outcomes based upon the presence and severity of kidney dysfunction. Results Of 925 patients with HFpEF, 319 (34.5%) had estimated glomerular filtration rate (eGFR) &lt; 60 ml/min/1.73 m2. Patients with more severe kidney dysfunction were older and more likely to have diabetes, atrial fibrillation, and hypertension. At rest, reduced kidney function was associated with lower haemoglobin, higher biventricular filling pressures, and lower cardiac output, but the severity of kidney dysfunction was most conspicuously associated with worsening PVD, evidenced by increasing pulmonary arterial (PA) pressures due to marked increases in pulmonary vascular resistance (PVR) as kidney dysfunction progressed (median [IQR] 1.3 [0.86, 1.88] to 2.8 [2.0, 3.8] WU from eGFR ≥ 90 to eGFR &lt; 30, P &lt; .001), along with progressively lower PA compliance (PAC, 4.7 [3.6, 5.8] to 2.2 [1.8, 3.4] ml/mmHg from eGFR ≥ 90 to eGFR &lt; 30, P &lt; .001). With exercise, differences in the severity of PVD became even more striking, with more severe elevation in PA pressures and PVR, and lower PA compliance, leading to lower transmural left-sided distending pressures, with no difference in exertional PA wedge pressure. Patients with worse kidney dysfunction displayed the most dramatic cardiac output limitations with exercise, which along with more severe anaemia and markedly reduced O2 delivery, caused marked impairment in aerobic capacity. Worsening kidney function was associated with a striking gradient of increased risk of a composite of all-cause death and HF hospitalization [ranging from HR 2.38 (95% CI 1.01–5.59) for eGFR 60–90 to HR 16.77 (95% CI 6.65–42.28) for eGFR &lt; 30 (vs. reference eGFR ≥ 90)]. Conclusions Kidney dysfunction in patients with HFpEF is characterized by more severe PVD at rest and with exercise, leading to reduced cardiac output reserve, impaired exercise capacity, and increased risk for adverse events. Further study is warranted to better understand causal relationships between CKD and PVD, and determine whether novel therapies to improve kidney function might target these impairments to improve clinical status.

BACKGROUND: Systemic arterial compliance and venous capacitance are typically impaired in patients with heart failure with preserved ejection fraction (HFpEF), contributing to hemodynamic congestion with stress. Sodium-glucose cotransporter-2 inhibitors reduce hemodynamic congestion and improve clinical outcomes in patients with HFpEF, but the mechanisms remain unclear. This study tested the hypothesis that Dapagliflozin would improve systemic arterial compliance and venous capacitance during exercise in patients with HFpEF. METHODS: In this secondary analysis from the CAMEO-DAPA trial (Cardiac and Metabolic Effects of Dapagliflozin in Heart Failure With Preserved Ejection Fraction Trial), 37 patients with HFpEF (mean age 68 ± 9 years, women 65%) underwent invasive hemodynamic exercise testing with simultaneous echocardiography at baseline and following treatment for 24 weeks with Dapagliflozin or placebo. Radial artery pressure (BP) was measured continuously using a fluid-filled catheter with transformation to aortic pressure, central hemodynamics were measured using high-fidelity micromanometers, and stressed blood volume was estimated from hemodynamic indices fit to a comprehensive cardiovascular model. RESULTS: There was no statistically significant effect of Dapagliflozin on resting BP, but Dapagliflozin reduced systolic BP during peak exercise (estimated treatment difference [ETD], −18.8 mm Hg [95% CI, −33.9 to −3.7] P =0.016). Reduction in BP was related to improved exertional total arterial compliance (ETD, 0.06 mL/mm Hg/m 2 [95% CI, 0.003–0.11] P =0.039) and aortic root characteristic impedance (ETD, −2.6 mm Hg/mL*sec [95% CI: −5.1 to −0.03] P =0.048), with no significant effect on systemic vascular resistance. Dapagliflozin reduced estimated stressed blood volume at rest and during peak exercise (ETD, −292 mm Hg [95% CI, −530 to −53] P =0.018), and improved venous capacitance evidenced by a decline in ratio of estimated stressed blood volume to total blood volume (ETD, −7.3% [95% CI, −13.3 to −1.3] P =0.020). Each of these effects of Dapagliflozin at peak exercise were also observed during matched 20W exercise intensity. Improvements in total arterial compliance and estimated stressed blood volume were correlated with decreases in body weight, and reduction in systolic BP with treatment was correlated with the change in estimated stressed blood volume during exercise (r=0.40, P =0.019). Decreases in BP were correlated with reduction in pulmonary capillary wedge pressure during exercise (r=0.56, P <0.001). CONCLUSIONS: In patients with HFpEF, treatment with Dapagliflozin improved systemic arterial compliance and venous capacitance during exercise, while reducing aortic characteristic impedance, suggesting a reduction in arterial wall stiffness. These vascular effects may partially explain the clinical benefits with sodium-glucose cotransporter-2 inhibitors in HFpEF. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04730947.

ABSTRACT Aims The management of congestion is one of the key treatment targets in heart failure. Assessing congestion is, however, difficult. The purpose of this study was to investigate the safety and dynamic response of a novel, passive, inferior vena cava (IVC) sensor in a chronic ovine model. Methods and results A total of 20 sheep divided into three groups were studied in acute and chronic in vivo settings. Group I and Group II included 14 sheep in total with 12 sheep receiving the sensor and two sheep receiving a control device (IVC filter). Group III included an additional six animals for studying responses to volume challenges via infusion of blood and saline solutions. Deployment was 100% successful with all devices implanted; performing as expected with no device-related complications and signals were received at all observations. At similar volume states no significant differences in IVC area normalized to absolute area range were measured (55 ± 17% on day 0 and 62 ± 12% on day 120, p = 0.51). Chronically, the sensors were completely integrated with a thin, reendothelialized neointima with no loss of sensitivity to infused volume. Normalized IVC area changed significantly from 25 ± 17% to 43 ± 11% (p = 0.007) with 300 ml infused. In contrast, right atrial pressure required 1200 ml of infused volume prior to a statistically significant change from 3.1 ± 2.6 mmHg to 7.5 ± 2.0 mmHg (p = 0.02). Conclusion In conclusion, IVC area can be measured remotely in real-time using a safe, accurate, wireless, and chronic implantable sensor promising to detect congestion with higher sensitivity than filling pressures.

Background: Improvement in renal function (IRF) in acute decompensated heart failure is associated with adverse outcomes. The mechanisms driving this paradox remain undefined. Methods: Using the ROSE-AHF study (Renal Optimization Strategies Evaluation–Acute Heart Failure), 277 patients were grouped according to renal function, with IRF defined by a ≥20% increase (N=75), worsening renal function by a ≥20% decline (N=53), and stable renal function (SRF) by a <20% change (N=149) in estimated glomerular filtration rate between baseline and 72 hours. Three well-validated renal tubular injury markers, NGAL (neutrophil gelatinase-associated lipocalin), NAG (N-acetyl-β-d-glucosaminidase), and KIM-1 (kidney injury molecule 1), were evaluated at baseline and 72 hours. Patients were also classified by the pattern of change in these markers. Results: Patients with IRF had the lowest admission estimated glomerular filtration rate (IRF, 37 [28 to 51] mL/min per 1.73 m 2 ; worsening renal function, 43 [35 to 55] mL/min per 1.73 m 2 ; and SRF, 43 [32 to 55] mL/min per 1.73 m 2 ; P trend =0.032) but greater cumulative urine output (IRF, 8780 [7025 to 11 208] mL; worsening renal function, 7860 [5555 to 9765] mL; and SRF, 8150 [6325 to 10 456] mL; P trend =0.024) and weight loss (IRF, –9.0 [–12.4 to –5.3] lb; worsening renal function, –5.1 [–8.1 to –1.3] lb; and SRF, –7.1 [–11.9 to –3.2] lb; P trend <0.001) despite similar diuretic doses ( P trend =0.16). There were no differences in the relative change in NGAL, NAG, or KIM-1 between renal function groups ( P trend >0.19 for all). Patients with IRF had worse survival than patients with SRF (27% versus 54%; hazard ratio, 1.98 [1.10–3.58]; P =0.024). Conclusions: IRF during decongestive therapy for acute decompensated heart failure was not associated with improved markers of renal tubular injury and was associated with worsened survival, likely driven by the presence of greater underlying cardiorenal dysfunction and more severe congestion.

Aims Remote monitoring of pulmonary artery pressure has reduced heart failure (HF) hospitalizations in chronic HF as elevation of pulmonary artery pressure provides information that can guide treatment. The venous system is characterized by high capacitance, thus substantial increases in intravascular volume can occur before filling pressures increase. The inferior vena cava (IVC) is a highly compliant venous conduit and thus a candidate for early detection of change in intravascular volume. We aimed to compare IVC cross‐sectional area using a novel sensor with cardiac filling pressures during experimental manipulation of volume status, vascular tone, and cardiac function. Methods and results Experiments were conducted in sheep to manipulate volume status (colloid infusion), vascular tone (nitroglycerin infusion) and cardiac function (rapid cardiac pacing). A wireless implantable IVC sensor was validated ex‐vivo and in‐vivo , and then used to measure the cross‐sectional area of the IVC. Right‐ and left‐sided cardiac filling pressures were obtained via right heart catheterization. The IVC sensor provided highly accurate and precise measurements of cross‐sectional area in ex‐vivo and in‐vivo validation. IVC area changes were more sensitive than the corresponding changes in cardiac filling pressures during colloid infusion ( p < 0.001), vasodilatation ( p < 0.001) and cardiac dysfunction induced by rapid pacing ( p ≤ 0.02). Conclusions Inferior vena cava area can be remotely and accurately measured in real time with a wireless implantable sensor. Changes in IVC area are more sensitive than corresponding changes in filling pressures following experimental volume loading and fluid redistribution. Additional research is warranted to understand if remote monitoring of the IVC may have advantages over pressure‐based monitors in HF.

Heart failure is characterized by pathologic hemodynamic derangements, including elevated cardiac filling pressures (“backward” failure), which may or may not coexist with reduced cardiac output (“forward” failure). Even when normal during unstressed conditions such as rest, hemodynamics classically become abnormal during stressors such as exercise in patients with heart failure. This has important upstream and downstream effects on multiple organ systems, particularly with respect to the lungs and kidneys. Hemodynamic abnormalities in heart failure are affected by processes that extend well beyond the cardiac myocyte, including important roles for pericardial constraint, ventricular interaction, and altered venous capacity. Hemodynamic perturbations have widespread effects across multiple heart failure phenotypes, ranging from reduced to preserved ejection fraction, acute to chronic disease, and cardiogenic shock to preserved perfusion states. In the lung, hemodynamic derangements lead to the development of abnormalities in ventilatory control and efficiency, pulmonary congestion, capillary stress failure, and eventually pulmonary vascular disease. In the kidney, hemodynamic perturbations lead to sodium and water retention and worsening renal function. Improved understanding of the mechanisms by which altered hemodynamics in heart failure affect the lungs and kidneys is needed in order to design novel strategies to improve clinical outcomes.