Selective improvement in renal function preserved remote myocardial microvascular integrity and architecture in experimental renovascular disease

Abstract

Aim Atherosclerotic renovascular disease (ARVD) may impair renal function and increase cardiovascular morbidity and mortality, but the mechanism by which ARVD impacts cardiovascular function is unclear. We tested the hypothesis that preservation of renal function can reverse cardiac dysfunction in ARVD. Methods and results Endothelial progenitor cells (EPC) were injected intra-renally (ARVD + EPC) after 6 weeks of swine ARVD (concurrent hypercholesterolemia and renovascular hypertension), and single kidney function and myocardial blood-flow and microvascular permeability (MP) responses to adenosine were assessed using CT 4 weeks later. Myocardial microvascular density was evaluated by micro-CT. Inflammation and oxidative-stress were assessed in kidney venous and systemic blood samples. Normal and untreated ARVD pigs served as controls. Blood pressure was similarly increased in ARVD and ARVD + EPC. Compared to normal, ARVD showed lower glomerular filtration rate, elevated renal vein and systemic oxidized LDL (ox-LDL), aldosterone, uric acid, isoprostanes, transforming growth factor (TGF)-, and interleukine-6. Renal vein ox-LDL and TGF-showed a positive gradient across the stenotic kidney, indicating increased renal oxidative stress and fibrogenic activity. Furthermore, ARVD impaired myocardial blood-flow and MP response to adenosine, decreased microvascular density, and induced myocardial fibrosis. Improvement of renal function in ARVD + EPC decreased systemic aldosterone, inflammation, and oxidative stress, and improved myocardial microvascular integrity and density. Conclusion Selective improvement in renal function, which reduced renal and systemic oxidative stress and inflammation, preserved remote myocardial microvascular function and architecture, despite enduring hypertension. These findings underscore functionally important cardiorenal crosstalk possibly mediated by renal injury signals.

Rcan1-1L overexpression induces mitochondrial autophagy and improves cell survival in angiotensin II-exposed cardiomyocytes

“…An evidence that has accumulated over the last decade indicates that activation of the renin-angiotensin II (Ang II) system is a primary cause of cardiac fibrosis and hypertrophy in hypertensive heart disease [3,4]. Accordingly, the prevalence of left ventricular (LV) hypertrophy (LVH) is higher among patients with renovascular hypertension than those with essential hypertension, possibly attributed to greater activation of angiotensin II (Ang II) [5,6].…”

Percutaneous Pericardial Resection

“…This model has been shown to display several features of human HFpEF, including elevation in LVEDP, hypertension, oxidative stress, and coronary microvascular dysfunction. 18–20, 26–29 However, we did not perform experiments to demonstrate that these animals had diastolic dysfunction or true clinical heart failure, and further study is warranted in this regard.…”

“…Animals then continue with high fat diet for an additional 10 weeks. This model has been shown to display increased LV mass, diastolic dysfunction, impaired coronary microvascular function, a pro-inflammatory milieu, and increased myocardial oxidative stress despite preserved EF, 18–20 mirroring changes seen in human HFpEF. 1–3 …”

“…18–20 In this model, domestic pigs are fed a high-fat diet (2% cholesterol and 15% lard by weight) for 6 weeks followed by surgical induction of renovascular hypertension by unilateral renal artery coiling. Animals then continue with high fat diet for an additional 10 weeks.…”

Paradigm Shifts in Atherosclerotic Renovascular Disease

“…15 For some subjects, cardiac dysfunction limits systemic pressor responses as part of a true cardiorenal syndrome. 16,17 In such patients, progressive, severe occlusion may fail to elicit hypertension altogether, despite leading to advanced parenchymal fibrosis in the affected kidney. 18 How vascular lesions develop over time may have important additional effects.…”