Outcomes Of Intermittent Hemodialysis During Support With Ventricular Assist Devices: A Potential Bridge To Heart/kidney Transplantation?
HFSA ePoster Library. daSilva-deAbreu A. 09/10/21; 343618; 61
Adrian daSilva-deAbreu
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Abstract
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Background: In acute decompensated heart failure (ADHF), atrial and b-type natriuretic peptides (ANP and BNP) are elevated as a compensatory mechanism to maintain cardiorenal homeostasis. As ANP and BNP are secreted, they bind to the guanylyl cyclase A receptor (GC-A) to generate the effector molecule, cGMP. We recently reported that in ADHF, a subpopulation of patients are deficient in ANP which is consistent with reports of a BNP deficiency in hospitalized HF patients. Extending beyond this concept, we tested the hypothesis that the ANP and BNP produced in ADHF patients possess reduced potency in GC-A activation, thereby over-estimating the biological potency of elevated endogenous cardiac NP levels. Thus, we developed a novel NP/GC-A/cGMP potency assay to assess the biological potency of patients’ circulating ANP and BNP ex vivo to investigate whether ANP and BNP levels in ADHF are of reduced biological potency.
Methods: HEK293 cells overexpressing human GC-A receptor were treated with plasma from normal human subjects(N=4) and ADHF patients with either low ANP and BNP(N=4) or elevated ANP and BNP(N=4) and subsequent cGMP generation was measured. cGMP levels were compared to that of the cGMP generated from the treatment of combined synthetic ANP and BNP resembling the concentration of ANP and BNP found in the plasma of the healthy and ADHF subjects. MANP, a novel GC-A activator was additionally tested in the plasma at 10-10M and 10-8M to evaluate cGMP producing capability in ADHF subjects as a viable therapeutic agent rescuing this pathophysiology.
Results: Plasma from normal human subjects with normal circulating levels of ANP (25.5±4.8 pg/mL) and BNP (27±5.7 pg/mL) produced a cGMP level of 10.3 pmol/mL which was similar to cGMP levels generated from combined synthetic ANP and BNP treatment (10.5 pmol/mL). In ADHF patients with low plasma ANP (16.8±4.4 pg/mL) and BNP (47.4 ±7.5 pg/mL), human plasma generated a cGMP concentration significantly lower than the combined synthetic ANP and BNP (9.5 pmol/mL vs. 15.7 pmol/mL, p=0.03). Similarly, plasma from ADHF patients with markedly elevated ANP (350±57.2 pg/mL) and BNP (1225.7±290.1 pg/mL) generated a cGMP concentration markedly lower than that of combined synthetic ANP and BNP (23.5 pmol/mL vs. 117.5 pmol/mL, p=0.03). The novel designer GC-A peptide, MANP, significantly activated cGMP (>8x) in our potency assay when added to both normal and ADHF plasma.
Conclusion: The cardiac NP/GC-A/cGMP system is impaired in HF through a reduction in peptide potency and subsequent impaired GC-A/cGMP activation, despite marked ANP and BNP peptide elevation. This cardiac endocrinopathy in ADHF warrants NP replacement therapy through novel GC-A activators such as MANP, which is now in human clinical trials to rescue this impaired NP state.
Methods: HEK293 cells overexpressing human GC-A receptor were treated with plasma from normal human subjects(N=4) and ADHF patients with either low ANP and BNP(N=4) or elevated ANP and BNP(N=4) and subsequent cGMP generation was measured. cGMP levels were compared to that of the cGMP generated from the treatment of combined synthetic ANP and BNP resembling the concentration of ANP and BNP found in the plasma of the healthy and ADHF subjects. MANP, a novel GC-A activator was additionally tested in the plasma at 10-10M and 10-8M to evaluate cGMP producing capability in ADHF subjects as a viable therapeutic agent rescuing this pathophysiology.
Results: Plasma from normal human subjects with normal circulating levels of ANP (25.5±4.8 pg/mL) and BNP (27±5.7 pg/mL) produced a cGMP level of 10.3 pmol/mL which was similar to cGMP levels generated from combined synthetic ANP and BNP treatment (10.5 pmol/mL). In ADHF patients with low plasma ANP (16.8±4.4 pg/mL) and BNP (47.4 ±7.5 pg/mL), human plasma generated a cGMP concentration significantly lower than the combined synthetic ANP and BNP (9.5 pmol/mL vs. 15.7 pmol/mL, p=0.03). Similarly, plasma from ADHF patients with markedly elevated ANP (350±57.2 pg/mL) and BNP (1225.7±290.1 pg/mL) generated a cGMP concentration markedly lower than that of combined synthetic ANP and BNP (23.5 pmol/mL vs. 117.5 pmol/mL, p=0.03). The novel designer GC-A peptide, MANP, significantly activated cGMP (>8x) in our potency assay when added to both normal and ADHF plasma.
Conclusion: The cardiac NP/GC-A/cGMP system is impaired in HF through a reduction in peptide potency and subsequent impaired GC-A/cGMP activation, despite marked ANP and BNP peptide elevation. This cardiac endocrinopathy in ADHF warrants NP replacement therapy through novel GC-A activators such as MANP, which is now in human clinical trials to rescue this impaired NP state.
Background: In acute decompensated heart failure (ADHF), atrial and b-type natriuretic peptides (ANP and BNP) are elevated as a compensatory mechanism to maintain cardiorenal homeostasis. As ANP and BNP are secreted, they bind to the guanylyl cyclase A receptor (GC-A) to generate the effector molecule, cGMP. We recently reported that in ADHF, a subpopulation of patients are deficient in ANP which is consistent with reports of a BNP deficiency in hospitalized HF patients. Extending beyond this concept, we tested the hypothesis that the ANP and BNP produced in ADHF patients possess reduced potency in GC-A activation, thereby over-estimating the biological potency of elevated endogenous cardiac NP levels. Thus, we developed a novel NP/GC-A/cGMP potency assay to assess the biological potency of patients’ circulating ANP and BNP ex vivo to investigate whether ANP and BNP levels in ADHF are of reduced biological potency.
Methods: HEK293 cells overexpressing human GC-A receptor were treated with plasma from normal human subjects(N=4) and ADHF patients with either low ANP and BNP(N=4) or elevated ANP and BNP(N=4) and subsequent cGMP generation was measured. cGMP levels were compared to that of the cGMP generated from the treatment of combined synthetic ANP and BNP resembling the concentration of ANP and BNP found in the plasma of the healthy and ADHF subjects. MANP, a novel GC-A activator was additionally tested in the plasma at 10-10M and 10-8M to evaluate cGMP producing capability in ADHF subjects as a viable therapeutic agent rescuing this pathophysiology.
Results: Plasma from normal human subjects with normal circulating levels of ANP (25.5±4.8 pg/mL) and BNP (27±5.7 pg/mL) produced a cGMP level of 10.3 pmol/mL which was similar to cGMP levels generated from combined synthetic ANP and BNP treatment (10.5 pmol/mL). In ADHF patients with low plasma ANP (16.8±4.4 pg/mL) and BNP (47.4 ±7.5 pg/mL), human plasma generated a cGMP concentration significantly lower than the combined synthetic ANP and BNP (9.5 pmol/mL vs. 15.7 pmol/mL, p=0.03). Similarly, plasma from ADHF patients with markedly elevated ANP (350±57.2 pg/mL) and BNP (1225.7±290.1 pg/mL) generated a cGMP concentration markedly lower than that of combined synthetic ANP and BNP (23.5 pmol/mL vs. 117.5 pmol/mL, p=0.03). The novel designer GC-A peptide, MANP, significantly activated cGMP (>8x) in our potency assay when added to both normal and ADHF plasma.
Conclusion: The cardiac NP/GC-A/cGMP system is impaired in HF through a reduction in peptide potency and subsequent impaired GC-A/cGMP activation, despite marked ANP and BNP peptide elevation. This cardiac endocrinopathy in ADHF warrants NP replacement therapy through novel GC-A activators such as MANP, which is now in human clinical trials to rescue this impaired NP state.
Methods: HEK293 cells overexpressing human GC-A receptor were treated with plasma from normal human subjects(N=4) and ADHF patients with either low ANP and BNP(N=4) or elevated ANP and BNP(N=4) and subsequent cGMP generation was measured. cGMP levels were compared to that of the cGMP generated from the treatment of combined synthetic ANP and BNP resembling the concentration of ANP and BNP found in the plasma of the healthy and ADHF subjects. MANP, a novel GC-A activator was additionally tested in the plasma at 10-10M and 10-8M to evaluate cGMP producing capability in ADHF subjects as a viable therapeutic agent rescuing this pathophysiology.
Results: Plasma from normal human subjects with normal circulating levels of ANP (25.5±4.8 pg/mL) and BNP (27±5.7 pg/mL) produced a cGMP level of 10.3 pmol/mL which was similar to cGMP levels generated from combined synthetic ANP and BNP treatment (10.5 pmol/mL). In ADHF patients with low plasma ANP (16.8±4.4 pg/mL) and BNP (47.4 ±7.5 pg/mL), human plasma generated a cGMP concentration significantly lower than the combined synthetic ANP and BNP (9.5 pmol/mL vs. 15.7 pmol/mL, p=0.03). Similarly, plasma from ADHF patients with markedly elevated ANP (350±57.2 pg/mL) and BNP (1225.7±290.1 pg/mL) generated a cGMP concentration markedly lower than that of combined synthetic ANP and BNP (23.5 pmol/mL vs. 117.5 pmol/mL, p=0.03). The novel designer GC-A peptide, MANP, significantly activated cGMP (>8x) in our potency assay when added to both normal and ADHF plasma.
Conclusion: The cardiac NP/GC-A/cGMP system is impaired in HF through a reduction in peptide potency and subsequent impaired GC-A/cGMP activation, despite marked ANP and BNP peptide elevation. This cardiac endocrinopathy in ADHF warrants NP replacement therapy through novel GC-A activators such as MANP, which is now in human clinical trials to rescue this impaired NP state.
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