The Severe Cardiorenal Syndrome

In this thesis we investigated the interactions between heart and kidneys in disease in a longitudinal and integrative fashion. We developed two different rat models of the Severe Cardiorenal Syndrome and studied the effects of different interventions on progression of cardiorenal failure and on structural and functional outcome. In Part I we propose the Cardiorenal Connection (CRC) as a pathophysiological model in which the cardiorenal connectors interact and synergize to cause accelerated cardiovascular damage in the SCRS. The connectors are: (1) an imbalance between nitric oxide (NO) and reactive oxygen species (ROS), (2) activation of the sympathetic nervous system (SNS) (3) activation of the renin-angiotensin system (RAS), and (4) induction of inflammation. In Part II we describe the development of a model of combined chronic kidney disease (CKD) and heart failure (HF), and found evidence of bi-directional organ damage and the effect of interventions targeted at the CRC. We found that pre-existent CKD aggravated cardiac dilatation after MI that was associated with worsened cardiac diastolic and systolic function, and mortality. Conversely, the ensuing HF exacerbated glomerular damage in CKD rats, which was not associated with worsening of creatinine clearance or proteinuria. Blockade of all cardiorenal connectors with angiotensin receptor blockade and beta-blockade, systemic supplementation of NO, and anti-oxidant and anti-inflammatory therapy had significant beneficial effects on cardiorenal outcome: cardiac systolic function was preserved, glomerular damage was ameliorated, and tubulointerstitial damage was almost completely reversed. Blockade of 3 or 1 cardiorenal connectors resulted in a similar upholding of systolic function but had less effect on renal injury. We further described increased cardiac hepcidin expression in rats with SNX or CL, as well as in the combination. In contrast, liver hepcidin expression was not affected by both single insults but down-regulated in combined SNX and CL. Part III describes investigations into the role of nitric oxide (NO) in cardiac dysfunction in CKD. Low dose NO synthase (NOS) inhibition during CKD induced worsened proteinuria, severe cardiac dysfunction and reduced systemic NO production as compared to rats with CKD alone and controls treated with a similar dose of NOS inhibition. Furthermore, the increased protein excretion, the cardiac dysfunction and the low NO production after cessation of NOS inhibition. The mild hemodynamic effects of low dose NOS inhibition observed in controls were fully reversible. The findings of the previous study strongly suggested a causal link between NO availability and cardiac function. We investigated the effect of systemic NO supplementation with the tolerance-free NO donor molsidomine (MOLS) as a rescue therapy. MOLS significantly improved diastolic and systolic heart function, with mild effects on cardiac loading conditions and LVH, and no effects on cardiac fibrosis. Creatinine clearance and tubulo-interstitial injury improved, but no effect was seen on proteinuria. Expression of nNOS was increased compared to controls in this model of the SCRS. We assessed the effect of selective nNOS blockade in baseline and under beta-adrenergic stimulation and found that nNOS derived NO supports diastolic relaxation in CRS rats, but does not modulate the impaired beta-adrenergic respons

The nitric oxide donor molsidomine rescues cardiac function in rats with chronic kidney disease and cardiac dysfunction

Bongartz LG, Braam B, Verhaar MC, Cramer MJ, Goldschmeding R, Gaillard CA, Steendijk P, Doevendans PA, Joles JA. The nitric oxide donor molsidomine rescues cardiac function in rats with chronic kidney disease and cardiac dysfunction. Am J Physiol Heart Circ Physiol 299: H2037-H2045, 2010. First published September 17, 2010; doi: 10.1152/ajpheart.00400.2010.-We recently developed a rat model of cardiorenal failure that is characterized by severe left ventricular systolic dysfunction (LVSD) and low nitric oxide (NO) production that persisted after temporary low-dose NO synthase inhibition. We hypothesized that LVSD was due to continued low NO availability and might be reversed by supplementing NO. Rats underwent a subtotal nephrectomy and were treated with low-dose NO synthase inhibition with N-omega-nitro-L-arginine up to week 8. After 3 wk of washout, rats were treated orally with either the long-acting, tolerance-free NO donor molsidomine (Mols) or vehicle (Veh). Cardiac and renal function were measured on weeks 11, 13, and 15. On week 16, LV hemodynamics and pressure-volume relationships were measured invasively, and rats were killed to quantify histological damage. On week 15, blood pressure was mildly reduced and creatinine clearance was increased by Mols (both P < 0.05). Mols treatment improved ejection fraction (53 +/- 3% vs. 37 +/- 2% in Veh-treated rats, P < 0.001) and stroke volume (324 +/- 33 vs. 255 +/- 15 mu 1 in Veh-treated rats, P < 0.05). Rats with Mols treatment had lower end-diastolic pressures (8.5 +/- 1.1 mmHg) than Veh-treated rats (16.3 +/- 3.5 mmHg, P < 0.05) and reduced time constants of relaxation (21.9 +/- 1.8 vs. 30.9 +/- 3.3 ms, respectively, P < 0.05). The LV end-systolic pressure-volume relationship was shifted to the left in Mols compared with Veh treatment. In summary, in a model of cardiorenal failure with low NO availability, supplementing NO significantly improves cardiac systolic and diastolic function without a major effect on afterload

The nitric oxide donor molsidomine rescues cardiac function in rats with chronic kidney disease and cardiac dysfunction

Bongartz LG, Braam B, Verhaar MC, Cramer MJ, Goldschmeding R, Gaillard CA, Steendijk P, Doevendans PA, Joles JA. The nitric oxide donor molsidomine rescues cardiac function in rats with chronic kidney disease and cardiac dysfunction. Am J Physiol Heart Circ Physiol 299: H2037-H2045, 2010. First published September 17, 2010; doi: 10.1152/ajpheart.00400.2010.-We recently developed a rat model of cardiorenal failure that is characterized by severe left ventricular systolic dysfunction (LVSD) and low nitric oxide (NO) production that persisted after temporary low-dose NO synthase inhibition. We hypothesized that LVSD was due to continued low NO availability and might be reversed by supplementing NO. Rats underwent a subtotal nephrectomy and were treated with low-dose NO synthase inhibition with N-omega-nitro-L-arginine up to week 8. After 3 wk of washout, rats were treated orally with either the long-acting, tolerance-free NO donor molsidomine (Mols) or vehicle (Veh). Cardiac and renal function were measured on weeks 11, 13, and 15. On week 16, LV hemodynamics and pressure-volume relationships were measured invasively, and rats were killed to quantify histological damage. On week 15, blood pressure was mildly reduced and creatinine clearance was increased by Mols (both P < 0.05). Mols treatment improved ejection fraction (53 +/- 3% vs. 37 +/- 2% in Veh-treated rats, P < 0.001) and stroke volume (324 +/- 33 vs. 255 +/- 15 mu 1 in Veh-treated rats, P < 0.05). Rats with Mols treatment had lower end-diastolic pressures (8.5 +/- 1.1 mmHg) than Veh-treated rats (16.3 +/- 3.5 mmHg, P < 0.05) and reduced time constants of relaxation (21.9 +/- 1.8 vs. 30.9 +/- 3.3 ms, respectively, P < 0.05). The LV end-systolic pressure-volume relationship was shifted to the left in Mols compared with Veh treatment. In summary, in a model of cardiorenal failure with low NO availability, supplementing NO significantly improves cardiac systolic and diastolic function without a major effect on afterload.Cardiac Dysfunction and Arrhythmia

The nitric oxide donor molsidomine rescues cardiac function in rats with chronic kidney disease and cardiac dysfunction

Bongartz LG, Braam B, Verhaar MC, Cramer MJ, Goldschmeding R, Gaillard CA, Steendijk P, Doevendans PA, Joles JA. The nitric oxide donor molsidomine rescues cardiac function in rats with chronic kidney disease and cardiac dysfunction. Am J Physiol Heart Circ Physiol 299: H2037-H2045, 2010. First published September 17, 2010; doi: 10.1152/ajpheart.00400.2010.-We recently developed a rat model of cardiorenal failure that is characterized by severe left ventricular systolic dysfunction (LVSD) and low nitric oxide (NO) production that persisted after temporary low-dose NO synthase inhibition. We hypothesized that LVSD was due to continued low NO availability and might be reversed by supplementing NO. Rats underwent a subtotal nephrectomy and were treated with low-dose NO synthase inhibition with N-omega-nitro-L-arginine up to week 8. After 3 wk of washout, rats were treated orally with either the long-acting, tolerance-free NO donor molsidomine (Mols) or vehicle (Veh). Cardiac and renal function were measured on weeks 11, 13, and 15. On week 16, LV hemodynamics and pressure-volume relationships were measured invasively, and rats were killed to quantify histological damage. On week 15, blood pressure was mildly reduced and creatinine clearance was increased by Mols (both P < 0.05). Mols treatment improved ejection fraction (53 +/- 3% vs. 37 +/- 2% in Veh-treated rats, P < 0.001) and stroke volume (324 +/- 33 vs. 255 +/- 15 mu 1 in Veh-treated rats, P < 0.05). Rats with Mols treatment had lower end-diastolic pressures (8.5 +/- 1.1 mmHg) than Veh-treated rats (16.3 +/- 3.5 mmHg, P < 0.05) and reduced time constants of relaxation (21.9 +/- 1.8 vs. 30.9 +/- 3.3 ms, respectively, P < 0.05). The LV end-systolic pressure-volume relationship was shifted to the left in Mols compared with Veh treatment. In summary, in a model of cardiorenal failure with low NO availability, supplementing NO significantly improves cardiac systolic and diastolic function without a major effect on afterload.Cardiac Dysfunction and Arrhythmia

Lack of Fibronectin-EDA Promotes Survival and Prevents Adverse Remodeling and Heart Function Deterioration After Myocardial Infarction

Rationale: The extracellular matrix may induce detrimental inflammatory responses on degradation, causing adverse cardiac remodeling and heart failure. The extracellular matrix protein fibronectin-EDA (EIIIA; EDA) is upregulated after tissue injury and may act as a "danger signal" for leukocytes to cause adverse cardiac remodeling after infarction. Objective: In the present study, we evaluated the role of EDA in regulation of postinfarct inflammation and repair after myocardial infarction. Methods and Results: Wild-type and EDA(-/-) mice underwent permanent ligation of the left anterior coronary artery. Despite equal infarct size between groups (38.2+/-4.6% versus 38.2+/-2.9% of left ventricle; P=0.985), EDA(-/-) mice exhibited less left ventricular dilatation and enhanced systolic performance compared with wild-type mice as assessed by serial cardiac MRI measurements. In addition, EDA(-/-) mice exhibited reduced fibrosis of the remote area without affecting collagen production, cross-linking, and deposition in the infarct area. Subsequently, ventricular contractility and relaxation was preserved in EDA(-/-). At tissue level, EDA(-/-) mice showed reduced inflammation, metalloproteinase 2 and 9 activity, and myofibroblast transdifferentiation. Bone marrow transplantation experiments revealed that myocardium-induced EDA and not EDA from circulating cells regulates postinfarct remodeling. Finally, the absence of EDA reduced monocyte recruitment as well as monocytic Toll-like receptor 2 and CD49d expression after infarction. Conclusions: Our study demonstrated that parenchymal fn-EDA plays a critical role in adverse cardiac remodeling after infarction. Absence of fn-EDA enhances survival and cardiac performance by modulating matrix turnover and inflammation via leukocytes and fibroblasts after infarction. (Circ Res. 2011; 108: 582-592.)Vascular Surger