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      Paradoxical Cardiorenal Responses Following Acute Vasodilator/Natriuretic Treatment in Presystolic Heart Failure : Should We Be Surprised?

      , MD, MSCI a , , MD b ,

      JACC: Basic to Translational Science

      Elsevier

      glomerular filtration rate, natriuresis, nesiritide, systolic heart failure

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          Abstract

          The kidney is a regulatory organ and is focused on maintenance of fluid and pressure homeostasis. The kidney is equipped with many mechanisms by which to maintain volume homeostasis; it takes its cues, however, from its “marital partner,” the heart, in many circumstances and especially when the heart is failing (1). The heart and the kidney communicate through hormonal and neural systems to maintain life and organ function. The kidney is especially sensitive to changes in sodium delivery and sudden blood pressure reductions, and thus 1 needs to distinguish between immediate and long-term responses to hemodynamic changes of the kidney. What is perceived as an adverse response initially may be a beneficial response chronically, especially if the cardiovascular response is positive. The current study by Wan et al. (2) in this issue of JACC: Basic to Translational Science describes the acute cardiorenal effects of combining tadalafil, a phosphodiesterase-5 inhibitor (PDE5i), with nesiritide, a recombinant human B-type natriuretic peptide (BNP), in response to acute saline volume expansion in participants with preclinical systolic dysfunction (PSD) and stages 2 and 3A chronic kidney disease (CKD). The authors hypothesized that this combination would enhance the cardiorenal response to volume expansion in PSD compared with a PDE5i alone. Unfortunately, this was not the case. All variables reflecting cardiac performance and related compensatory hormonal changes were favorable; renal response was not. Pre-treatment with tadalafil alone increased renal plasma, urine flow, and sodium excretion. In contrast, pre-treatment with tadalafil plus nesiritide decreased renal plasma flow, glomerular filtration rate, and urine flow. Hence, addition of human BNP altered the predicted renal response. Before discussing the reasons for this paradox, it is important to note that the participants received only 1 dose of tadalafil plus nesiritide or placebo before the acute saline volume expansion. What are possible reasons for this response? First, we need to understand the neurohormonal changes that affect the heart and the kidney at this stage of heart failure in the presence of CKD. As the authors note (2), the neurohumoral profile of their cohort is reminiscent of those in the SOLVD (Studies of Left Ventricular Dysfunction) Prevention cohort; that is, mild activation of the natriuretic peptide system and no activation of the renin-angiotensin-aldosterone system. An impaired renal response to acute volume expansion in the patients with PSD compared with normal subjects is known. In addition, patients with left ventricular dysfunction who are asymptomatic or have Class II heart failure symptoms already have a decreased ability to augment plasma atrial natriuretic peptide in response to sodium loading and thus may retain sodium. The importance of the natriuretic peptide system in response to volume expansion in PSD is further underscored by data from animal studies showing significant urinary retention when the natriuretic peptide receptor-A is blocked (3). In contrast, a study randomized 36 adults with preclinical diastolic dysfunction to receive subcutaneous BNP for 12 weeks versus placebo (4). This study reported an increase in urinary cyclic guanosine monophosphate (cGMP) and natriuresis at 12 weeks with volume expansion, an effect similar to that in subjects without underlying cardiac or kidney dysfunction. Given the data from the current study (2), potential mechanisms for impaired renal response to acute volume expansion in patients with PSD include decreased plasma atrial natriuretic peptide levels, up-regulation of PDE5 leading to greater degradation of cGMP, down-regulation of natriuretic peptides in the kidney, and up-regulation of neutral endopeptidases leading to disruption of the homeostasis of natriuretic peptides with downstream effects within the nephron. This latter hypothesis seems most plausible based on data regarding cGMP levels in the combination group. As the authors speculate (2), PDE5 metabolizes cGMP, a second messenger that leads to vascular smooth muscle relaxation and subsequent vasodilation. Renal cGMP plays an important role in modulating glomerular filtration rate (GFR) and natriuresis. Chronic PDE5 inhibition for 10 days in dogs with experimental heart failure accentuated the renal actions of exogenous BNP by maximizing the cGMP system (5). The renal effect of BNP and PDE5i were synergistic compared with BNP monotherapy. This suggests that PDE5 up-regulation may contribute to natriuretic peptide desensitization. Thus, there may be a role for combined chronic treatment using both PDE5i and BNP to maximize the benefits of endogenous and exogenous natriuretic peptides. The divergent responses between the heart and the kidney in the study by Wan et al. (2) may also relate to acute hemodynamic accommodation to changes in blood pressure. Specifically, there was a large drop in systolic blood pressure within the normal range from 125 to 112 mm Hg that was not seen in the placebo group. This would have an acute effect of reducing the GFR and, to a lesser extent, reducing renal plasma flow, especially in the presence of CKD. This would contribute to decreased sodium delivery to the descending loop of Henle, and result in greater sodium reabsorption and thus less sodium excretion. Moreover, 1 should also note that although autoregulatory mechanisms in the kidney attempt to maintain a relatively constant GFR within the normal pressure range, acute reductions even within this range result in these homeostatic mechanisms being transiently overwhelmed until they re-establish homeostasis. Taken together with previous data, this study (2) helps in understanding the acute changes imposed by modifying the natriuretic peptide system in the early stage of heart failure and has clinical and therapeutic implications. Use of sacubitril/valsartan, currently approved for the treatment of advanced heart failure with reduced ejection fraction, resulted in positive renal benefits when used chronically (6). However, it should be assessed in this earlier setting of heart failure because of its potentiating effects on the natriuretic peptide pathway. Finally, these results should remind us not to make decisions about long-term outcomes from acute changes in kidney function, especially if they are understandable based on hemodynamic and neurohumoral changes. This is exemplified by the original reports 20 years ago of nephrotoxicity from angiotensin-converting enzyme inhibitors because there were acute increases of 20% to 30% in serum creatinine (1). Publication of the early reports resulted in a major hesitancy to use this class of medication in heart failure and CKD. However, use over the last 20 years has taught us that up to a 30% increase in serum creatinine translates into equal or better cardiovascular and renal outcomes. Thus, it must be remembered that the current study (2) of acute findings in the kidney may translate to beneficial long-term outcomes.

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          Most cited references 6

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          Effects of Sacubitril/Valsartan Versus Irbesartan in Patients With Chronic Kidney Disease.

          Sacubitril/valsartan reduces the risk of cardiovascular mortality among patients with heart failure with reduced ejection fraction, but its effects on kidney function and cardiac biomarkers in people with moderate to severe chronic kidney disease are unknown.
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            • Article: not found

            Acute phosphodiesterase 5 inhibition mimics hemodynamic effects of B-type natriuretic peptide and potentiates B-type natriuretic peptide effects in failing but not normal canine heart.

            The aim of this work was to test whether acute phosphodiesterase 5 (PDE5) inhibition via sildenafil (SIL) mimics and/or potentiates cardiorenal effects of exogenous natriuretic peptide (NP) infusion. Heart failure (HF) is often accompanied by elevated NP secretion yet blunted responsiveness. Such NP resistance may, in part, relate to increased cyclic guanosine monophosphate (cGMP) catabolism by PDE5. Dogs (n = 7) were studied before and after tachypacing-induced HF. Animals received 30-min infusion of B-type natriuretic peptide (BNP) (2 mug/kg bolus, 0.02 mug/kg/min), and on a separate day SIL (1 mg/kg, intravenous), followed by BNP (SIL + BNP). Phosphodiesterase 5 activity was measured in lung, vasculature, and kidney. At baseline (non-failing), BNP lowered central venous, pulmonary capillary wedge, diastolic, mean pulmonary artery, and mean arterial pressure. Sildenafil had no effects, and SIL + BNP was similar to BNP alone. In contrast, SIL lowered these pressures similarly to BNP in dogs with HF, and SIL + BNP was additive in further reducing pulmonary pressures over BNP alone. Plasma cGMP/plasma BNP ratio was markedly reduced with HF, indicating NP resistance. Sildenafil plus BNP increased this ratio in HF, but had no effect in non-failing animals. Sildenafil had no independent diuretic/natriuretic effects nor did it enhance BNP effects under baseline or HF conditions. In HF, PDE5 activity was significantly increased in the systemic and pulmonary vasculature and in the kidney. The PDE5 activity in systemic and pulmonary vasculature increases in HF rendering hemodynamic responses to PDE5 inhibition identical to those from BNP infusion. Natriuretic peptide desensitization in HF relates, in part, to increased PDE5 activity, supporting a therapeutic role for PDE5 inhibition.
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              Maximizing the renal cyclic 3'-5'-guanosine monophosphate system with type V phosphodiesterase inhibition and exogenous natriuretic peptide: a novel strategy to improve renal function in experimental overt heart failure.

              Type V phosphodiesterase (PDE V) metabolizes cyclic guanosine monophosphate (cGMP) and is abundant in the kidney and vasculature and was found recently in the heart. Sildenafil is a PDE V inhibitor that is used clinically for erectile dysfunction. Brain natriuretic peptide (BNP) is a cardiac peptide with vasodilating, lusitropic, and natriuretic properties that are mediated via cGMP. It was hypothesized that chronic inhibition of PDE V (PDE VI) will enhance the renal actions of exogenous BNP by potentiating the renal cGMP. The cardiorenal and humoral function was determined at baseline in two groups of dogs with pacing-induced overt chronic heart failure (CHF; 240 bpm for 10 d): Group 1 (n = 6) received Sildenafil 50 mg orally three times daily during the 10 d of pacing, and group 2 (n = 5) received no PDE V inhibitor. The response to acute subcutaneous BNP (5 microg/kg) administration also was compared in both groups on day 11. The GFR was assessed by inulin clearance (P < 0.05). There was no improvement of renal function in group 1 after 10 d of PDE VI as compared with group 2, despite having higher cardiac output (P < 0.05). Group 1 had significantly higher plasma (44 +/- 2 versus 21 +/- 3 pmol/ml; P < 0.05) and urinary cGMP (4219 +/- 900 versus 1954 +/- 300 pmol/min; P < 0.05) as compared with group 2. With acute subcutaneous BNP administration, group 1 had a natriuretic and diuretic response that was associated with an increase in GFR (30 +/- 6 to 45 +/- 6 ml/min; P < 0.05) and that was not observed in group 2 (25 +/- 6 to 29 +/- 4 ml/min). Plasma BNP increased to a similar extent in both groups with subcutaneous BNP. In contrast, group 1 had a much greater urinary cGMP excretion (4219 +/- 900 to 8600 +/- 1600 pmol/min; P < 0.05) as compared with group 2 (1954 +/- 300 to 3580 +/- 351 pmol/min; P < 0.05). In experimental overt CHF, chronic administration of PDE V inhibitor did not enhance renal function despite an improvement in cardiac output. However, chronic PDE VI significantly enhanced the renal hemodynamic and excretory responses to exogenous BNP. This study supports a role for PDE V as contributing to renal maladaptation in a model of experimental overt CHF and the strategy of maximizing the renal cGMP system by combined PDE VI and natriuretic peptides in CHF to improve renal function.
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                Author and article information

                Contributors
                Journal
                JACC Basic Transl Sci
                JACC Basic Transl Sci
                JACC: Basic to Translational Science
                Elsevier
                2452-302X
                23 December 2019
                December 2019
                23 December 2019
                : 4
                : 8
                : 973-975
                Affiliations
                [a ]Department of Medicine, Section of Cardiology, University of Chicago Medicine, Chicago, Illinois
                [b ]American Heart Association Comprehensive Hypertension Center, Section of Endocrinology, Diabetes and Metabolism, University of Chicago Medicine, Chicago, Illinois
                Author notes
                [] Address for correspondence: Dr. George L. Bakris, American Heart Association Comprehensive Hypertension Center, University of Chicago Medicine, 5841 South Maryland Avenue, MC 1027, Chicago, Illinois 60637. gbakris@ 123456uchicago.edu
                [∗]

                Editorials published in JACC: Basic to Translational Science reflect the views of the authors and do not necessarily represent the views of JACC: Basic to Translational Science or the American College of Cardiology.

                Article
                S2452-302X(19)30357-2
                10.1016/j.jacbts.2019.11.002
                6938987
                © 2019 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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