Pathways to recovery and loss of nephrons in anti-Thy-1 nephritis

The present histopathologic study of anti-Thy-1.1 models of mesangioproliferative glomerulonephritis in rats provides a structural analysis of damage development and of pathways to recovery and to nephron loss. As long as the disease remains confined to the endocapillary compartment, the damage may be resolved or recover with a mesangial scar. Irreversible lesions with loss of nephrons emerge from extracapillary processes with crucial involvement of podocytes, leading to tuft adhesions to Bowman's capsule (BC) and subsequent crescent formation. Two mechanisms appeared to be responsible: (1) Epithelial cell proliferation at BC and the urinary orifice and (2) misdirected filtration and filtrate spreading on the outer aspect of the nephron. Both may lead to obstruction of the tubule, disconnection from the glomerulus, and subsequent degeneration of the entire nephron. No evidence emerged to suggest that the kind of focal interstitial proliferation associated with the degeneration of injured nephrons was harmful to a neighboring healthy nephron.     

EGF and EGF-receptor expression in rat anti-Thy-1 mesangial proliferative nephritis

Summary: Epidermal growth factor (EGF) is a potent mesangial cell and tubular epithelial cell mitogen. Based upon the novel finding that rat mesangial cells express EGF mRNA and protein in vitro, we investigated whether renal EGF production was involved in mesangial proliferation and concomitant tubular epithelial proliferation in rat anti-Thy-1 mesangial proliferative nephritis. During the period of mesangial proliferation in anti-Thy-1 nephritis (days 4–14) no EGF immunoreactive material was detected within the glomerulus. Epidermal growth factor-receptor (EGF-R) expression, which is strong on podocytes in normal glomeruli, was notably absent from focal areas of proliferating mesangial cells, suggesting that EGF available from the circulation was not involved in mesangial cell proliferation. Concomitant with the transient decline in creatinine clearance on day 8 of disease, there was mild tubular injury and a significant increase in cortical tubular proliferation as assessed by expression of the proliferating cell nuclear antigen (PCNA). Double immunohistochemistry staining found that the increased cortical tubular proliferation on day 8 occurred in EGF^? tubules, but not EGF⁺ tubules. In contrast, there was an increase in proliferation of EGF⁺ tubules, but not EGF^? tubules, on day 28. Renal EGF mRNA and protein expression was down-regulated over days 1-14, with a rebound in expression on day 28 which correlated with proliferation of EGF⁺ tubules. Tubular EGF-R expression, which is most clearly seen on EGF⁺ tubules in normal rat kidney, was unchanged over the disease course. the potential role of EGF in tubular proliferation in normal and diseased states is discussed. In summary, this study finds no evidence to implicate EGF in mesangial cell proliferation in rat anti-Thy-1 nephritis, even though mesangial cells can express EGF in vitro, and suggests that EGF may regulate proliferation of tubular epithelial cells in different stages of disease.     

Tubular lesions and tubular cell adhesion molecules for the prognosis of lupus nephritis.

BACKGROUND: To assess the prognostic value of tubular lesions and cell adhesion molecules' expression, a retrospective study with immunohistochemistry was performed on 152 patients presenting lupus nephritis from January 1985 to December 1999. METHODS: The following clinical parameters were recorded: age, sex, race, time of systemic lupus erythematosus (SLE) diagnosis, time of the biopsy, proteinuria, creatininemia, and renal function at the end of follow-up. All biopsies were re-evaluated according to a tubular grading, an inflammatory grading, the percentage of sclerosed glomeruli, the percentage of crescents, and the current WHO classification. Immunohistochemistry was performed with anti-CD40, anti-CD44, and anti-intercellular adhesion molecule-1 (anti-ICAM-1) antibodies. RESULTS: Patients were 136 women (89.5%) and 16 men with a mean age of 31.2 years +/- 12.8 at the time of biopsy. The mean follow-up period was 94.3 months +/- 64.1. Eighty-eight biopsies (58%) showed various degrees of tubular atrophy. Males (P = 0.001) and tubular grading (P = 0.0001) were linked with renal survival in univariate and multivariate analysis. CD40 (P = 0.01) and ICAM-1 (P = 0.001) tubular expressions were linked with renal survival. ICAM-1 tubular expression provided additional information for the prognosis of the patients with biopsies showing tubular atrophy (P = 0.005) or not (P = 0.05). CONCLUSIONS: Our study shows that tubular lesions are good indicator of lupus nephritis outcome. Furthermore, tubular expression of cell adhesion molecules like ICAM-1 and CD40 also serves to predict the outcome.     

Effects of pirfenidone on an acute phase of anti-Thy-1 nephritis

Background. 5-Methyl-1-phenyl-2-(1H)-pyridone (pirfenidone [PD]) has anti-fibrotic and anti-inflammatory effects. Previous reports have indicated that PD can prevent the progression of chronic kidney fibrosis in some animal models. It has not yet been reported, however, whether PD is capable of controlling acute inflammation of the kidney. Methods. The present study was designed to observe the effect of PD on an acute phase of anti-Thy-1 nephritis, a well known model for acute kidney inflammation. Male standard Wistar rats (specific pathogen-free [SPF] level), 7 weeks old (day −10, 141.52 ± 2.60 g) were divided into two groups. In group C (n = 7), 0.7 ml of anti-Thy-1 antibody was injected intravenously on day 0. In group P (n = 6), anti-Thy-1 antibody was injected similarly, and PD (500 mg/kg BW per day) was given daily by dietary intake starting 1 day before the first injection and continuing throughout the study. All rats were killed on day 7 and subjected to light microscopic and serum biochemical examinations. The degree of glomerular extracellular matrix (ECM) expansion was determined as a matrix score, using a semiquantitative method. Differences between the two group scores were analyzed by a non-parametric test. Results. The mean matrix score for group C was 87.6 ± 11.8, against 71.5 ± 12.5 (P < 0.05) for group P. The mean cell count for the 140 glomeruli in group C was 75.3 ± 6.1, and for the 120 glomeruli in group P it was 78.2 ± 11.6 (no significant difference). However, the possibility could not be ruled out that the degree of initial mesangiolysis in group P had been smaller than that in group C. Serum creatinine and blood urea nitrogen (BUN) levels were within the normal range in both groups. Conclusions. It is possible that PD is capable of partially controlling acute phases of anti-Thy-1 nephritis. More detailed studies in the future will establish the validity of the short-term effects of PD on this animal model. Received: February 8, 1999 / Accepted: September 5, 2000     

利多卡因抑制内皮细胞粘附因子表达进而抑制肝癌细胞粘附脐带静脉内皮细胞

【摘要】 目的 探讨利多卡因对血管内皮细胞粘附因子表达的影响。方法 采用不同浓度利多卡因预处理脐带静脉内皮细胞（HUVECs）30 min后,加入肿瘤坏死因子α（TNFα）进行刺激。通过实时荧光定量聚合酶链反应检测选择素E（CD62E）、血管细胞粘附分子-1（VCAM-1）和细胞间粘附分子-1（ICAM-1）表达量,蛋白免疫印迹分析NF-Kappa B（NF-κB）通路蛋白的改变,并通过细胞粘附实验评估利多卡因预处理对肝癌细胞（HepG2）粘附于HUVECs的影响。结果 利多卡因预处理可以明显抑制p65并抑制HepG2粘附于HUVECs。qRT-PCR结果表明利多卡因预处理可明显抑制TNF-α刺激后的CD62E、VCAM-1和ICAM-1表达水平的增高。结论 利多卡因可能通过抑制NF-κB通路进而抑制细胞粘附因子表达并抑制结肝癌细胞粘附于血管内皮细胞。     

人羊水间充质干细胞的分离鉴定及其对抗Thy-1肾炎的治疗作用

探讨羊水间充质干细胞(amniotic fluid mesenchymal stem cells,AF-MSCs)对抗Thy-1肾炎模型的治疗作用。 方法采用差异性贴壁与机械性分离法从人孕中期羊水中分离出羊水间充质干细胞,流式细胞术鉴定其表面标志物,成脂、成骨诱导分化检测其分化能力。利用尾静脉注射抗Thy-1抗体建立SD大鼠抗Thy-1系膜增生性肾炎模型;将第5代羊水间充质干细胞通过尾静脉注射治疗抗Thy-1系膜增生性肾炎大鼠,检测大鼠尿蛋白的变化,PAS染色观察大鼠肾脏病理改变。 结果羊水间充质干细胞顺利分离,流式结果显示其表达间充质干细胞标志物(CD29、CD44、CD73、CD90、CD105)和胚胎干细胞标志物(SSEA-4)而不表达造血干细胞标志物(CD34、CD45、CD133),且在适当条件下能够被诱导分化为脂肪细胞和骨细胞。羊水间充质干细胞治疗后,与模型组相比,治疗组在第7、12天时24 h尿蛋白明显下降(P<0.01),且肾脏病理结果表明系膜细胞增殖减轻,系膜区细胞外基质积聚减少。 结论成功的从人孕中期羊水中分离出羊水间充质干细胞,羊水间充质干细胞治疗系膜增生性肾小球肾炎有效。     

Involvement of soluble adhesion molecules in acute pancreatitis.

The relationship between inflammatory cytokines and adhesion molecules in cases of acute pancreatitis was studied. Twenty-five patients were divided into three groups based on the severity of their disease as rated by the Ranson score. They were also divided into two groups according to the presence or absence of the complications of the multiorgan dysfunction syndrome (MODS) and the prognosis. As the severity of acute pancreatitis increased, the plasma levels of TNF-alpha, slCAM-1, sE-selectin, and sVCAM-1 also increased. The levels of all of these soluble adhesion molecules were significantly higher in the MODS-complicated group than in the non-MODS-complicated group. The levels of TNF-alpha, slCAM-1, and sVCAM-1 were significantly higher in patients who eventually died than in patients who survived. Significant correlations were observed between the levels of TNF-alpha and slCAM-1, between those of TNF-alpha and sVCAM-1, and between the levels of slCAM-1 and sVCAM-1. These results suggest that inflammatory cytokines stimulate the expression of adhesion molecules on the vascular endothelium and that mediators, including these adhesion molecules, are closely involved in the pathogenesis of acute pancreatitis. The plasma levels of these soluble adhesion molecules reliably reflected the severity of the disease.     

Cytokines and adhesion molecules in renal vasculitis and lupus nephritis

Background: Plasma levels of some pro-inflammatory cytokines and soluble adhesion molecules have been suggested to be useful parameters to assess the activity of antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis and lupus nephritis. We hypothesized that the renal activity of these diseases is better reflected by the urinary excretion and fractional excretion of these molecules. Methods: Plasma levels and urinary excretion of tumour necrosis factor-&agr; (TNF-&agr;), interleukin (IL)-6, IL-8, and the soluble cell adhesion molecules sICAM-1 and sVCAM-1 were measured by enzyme-linked immunosorbent assay (ELISA) in 15 patients with ANCA-positive renal vasculitis (eight active, ANCA-A; six in remission, ANCA-R), six patients with active lupus nephritis (LN), 15 patients with IgA nephropathy (IgAN) and nine healthy subjects. Fractional excretion of selected cytokines and adhesion molecules was also calculated. Results: Patients with ANCA-A had increased urinary excretion and fractional excretion of TNF-&agr; (9.27±3.19% vs 0.58±0.02%, P<0.01), IL-6 (120.79±65.83% vs 1.89±0.34%, P<0.01) and increased fractional excretion of IL-8 (23.34±6.38% vs 2.56±1.07%, P<0.01) and sVCAM-1 (0.81±0.33% vs 0.03±0.02%, P<0.01) compared with controls. Urinary excretion of TNF-&agr; and IL-6 and fractional excretion of TNF-&agr;, IL-6 and IL-8 were higher in ANCA-A than in ANCA-R. Patients with LN had increased plasma TNF-&agr; (20.52±2.01 pg/ml vs 12.33±0.23 pg/ml, P<0.05) and sVCAM-1 (1537.88±276.36 ng/ml vs 692.26±44.42 ng/ml, P<0.05) and increased urinary excretion of TNF-&agr; (2.81±0.51 &mgr;g/mol creat vs 0.98±0.05 &mgr;g/mol creat, P<0.01), IL-8 (35.78±14.03 &mgr;g/mol creat vs 12.46±5.19 &mgr;g/mol creat, P<0.05) and sVCAM-1 (48.98±20.20 &mgr;g/mol creat vs 2.92±1.35 &mgr;g/mol creat, P<0.01) compared with controls. Patients with IgAN had, in comparison with controls only increased plasma TNF-&agr; (18.10±0.57 pg/ml vs 12.33±0.23 pg/ml, P<0.05). Conclusions: Urinary excretion and fractional excretion, but not plasma levels of selected proinflammatory cytokines (TNF-&agr;, IL-6 and IL-8) were increased in patients with active ANCA-positive renal vasculitis, but not in ANCA positive vasculitis in remission. These parameters may be useful to monitor the activity of this disease.     

Intercellular adhesion molecules and vascular cell adhesion molecule-1 and the kidney.

Adhesion molecules such as intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 are expressed in the kidney and are regulated by proinflammatory cytokines. These adhesion molecules play an important role in the binding and activation process of leukocytes and are of importance in inflammatory kidney diseases. This review article describes current knowledge regarding the structure, expression, and functional role of adhesion molecules and their significance in immune-mediated renal diseases.     

Microarray analysis of a reversible model and an irreversible model of anti-Thy-1 nephritis

A single intravenous injection of anti-Thy-1 monoclonal antibody (mAb) 1-22-3 is known to cause reversible mesangial proliferative glomerulonephritis. However, mAb 1-22-3 injection followed by unilateral nephrectomy leads to progressive glomerulosclerosis and tubulointerstitial change with an irreversible course. To identify genes that play an important role in the irreversible progression of renal injury, we used microarray technology to identify differences in gene expression between these models. Rats were intravenously injected with mAb 1-22-3 1 week after unilateral nephrectomy (irreversible model) or a sham operation (reversible model), and rats were killed on days 4, 7, 14, 42, and 56 after the injection. complementary DNA probes prepared from kidney messenger RNAs were hybridized with oligonucleotide microarrays containing 4854 rat genes. The microarray identified 189 differentially expressed genes, having at least a two-fold difference in expression level between the two models, and they were classified into five clusters. One of the clusters consisted of genes whose expression was markedly upregulated in the irreversible model. This cluster included the genes encoding osteopontin, kidney injury molecule-1, and thymosin beta10. Increased expression of thymosin beta10 was localized mainly in macrophages in the fibrotic interstitium, and upregulation of thymosin beta10 expression was also observed in a unilateral ureteral obstruction model. The microarray analysis yielded information on the molecular mechanisms responsible for the difference in disease progression between the reversible and irreversible model of anti-Thy-1 nephritis. Thymosin beta10 may play an important role in the progression of kidney disease.     

Hypoxia and reoxygenation do not upregulate adhesion molecules and natural killer cell adhesion on human endothelial cells in vitro

Objectives: Ischemia/reperfusion injury is characterized by endothelial cell activation leading to increased expression of adhesion molecules such as inter-cellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, endothelial- and platelet-selectin (E- and P-selectin), and to the subsequent recruitment of leukocytes. The aim of the present study was to investigate the respective effects of a proinflammatory cytokine (tumor necrosis factor alpha , TNF-), hypoxia and/or reoxygenation on adhesion molecule expression and natural killer (NK) cell adhesion in an in vitro model of I/R. Methods: Human aortic endothelial cells (HAEC) were stimulated in vitro for 8h with TNF- (1000 U/ml) and exposed to hypoxia (1% O₂), reoxygenation (21% O₂) or different combinations thereof. Cell surface expression of ICAM-1, VCAM-1 and E-/P-selectin on HAEC was analyzed by flow cytometry, and culture supernatants were tested for soluble adhesion molecules by ELISA. Rolling adhesion of NK cells on HAEC was determined using a rotating assay. Results: Untreated HAEC constitutively expressed ICAM-1 on their surface but neither expressed E-/P-selectin, VCAM-1, nor shedded soluble adhesion molecules. Exposure of HAEC to hypoxia or hypoxia and reoxygenation did not upregulate cell surface expression or shedding of adhesion molecules. In contrast, TNF- significantly upregulated cell surface expression of ICAM-1, VCAM-1, and E-/P-selectin and led to the shedding of ICAM-1 and E-selectin. Combined treatment of HAEC with TNF-, hypoxia and reoxygenation reduced E-/P-selectin surface expression and enhanced E-selectin shedding, but did not further influence ICAM-1 and VCAM-1. Soluble VCAM-1 was not detected. NK cell adhesion on HAEC increased 4-fold after TNF- stimulation, but was not affected by hypoxia or hypoxia and reoxygenation. Conclusions: Both the expression of endothelial adhesion molecules and rolling NK cell adhesion was upregulated by TNF- but not by hypoxia alone or hypoxia followed by reoxygenation supporting the view that anti-inflammatory treatment may reduce ischemia/reperfusion injury.     

Chronic anti-Thy-1 nephritis is aggravated in the nonclipped but not in the clipped kidney of Goldblatt hypertensive rats

BACKGROUND: We have previously shown that renovascular hypertension does not inhibit healing of the acute Thy-1 nephritis. To test whether a chronic model of the Thy-1 nephritis is more susceptible to high blood pressure, the repetitive hit model was evaluated in rats with 2-kidney, 1-clip Goldblatt hypertension. METHODS: Six weeks after initiation of 2-kidney, 1-clip hypertension, chronic Thy-1 glomerulonephritis was induced in hypertensive rats by four consecutive injections of rabbit antiserum in weekly intervals. Renal structure and function were examined two weeks after the last injection. Glomerular binding of rabbit IgG as well as expression of transforming growth factor-beta (TGF-beta), alpha-smooth muscle actin (alpha-SMA) and cyclooxygenase (COX)-1 and -2 were evaluated by Western blotting. RESULTS: Similar glomerular deposition of rabbit IgG was detected in normotensive rats and in both kidneys of Goldblatt hypertensive rats indicating similar delivery and binding of the heterologous antibody. Induction of the repetitive Thy-1 model significantly enhanced glomerular damage in the nonclipped kidney and increased albuminuria. Surprisingly, no glomerular damage developed in the clipped kidney of nephritic hypertensive rats. In contrast, increased glomerular volume and increased expression of TGF-beta, alpha-SMA as well as COX-1 and COX-2 were found in normotensive nephritic rats and in both kidneys of nephritic hypertensive rats. CONCLUSION: Glomerular and tubulointerstitial damage of the chronic Thy-1 model is dramatically enhanced in the nonclipped kidneys of Goldblatt hypertensive rats. In contrast, the clipped kidney is completely protected from this immunological injury despite similar activation of glomerular cells, induction of TGF-beta, COX-1 and COX-2 and glomerular hypertrophy.     

The leukotriene B4 receptor antagonist ONO-4057 inhibits mesangioproliferative changes in anti-Thy-1 nephritis.

OBJECTIVE: ONO-4057 is a specific leukotriene B4 (LTB4) receptor antagonist which inhibits human neutrophil aggregation, chemotaxis and degranulation induced by LTB4. This study was conducted to evaluate the role of LTB4 in glomerulonephritis, and to examine whether ONO-4057 moderated anti-Thy-1 nephritis. METHODS: Experiment 1: Sixty Wistar rats were divided into three groups. Rats of Group A (n = 20) underwent intraperitoneal administration of placebo as a control group, rats of Group B (n = 20) first underwent intraperitoneal administration of 100 mg/kg ONO-4057 and rats of Group C (n = 20) first underwent intraperitoneal administration of 300 mg/kg ONO-4057 daily from day 3 before anti-Thy-1 antibody (OX7) injection to day 14 after OX7 injection, respectively. Experiment 2: Forty rats were divided into two groups. ONO-group (n = 20) was treated with 300 mg/kg BW of ONO-4057 and placebo-group (n = 20) with placebo daily from days 1 to 13 after OX7 injection. Urine and blood samples were collected and the kidneys were extirpated from five rats of each group sacrificed at 3 h, 24 h, day 7 or day 14 after the injection of OX7 in both experiments. Urinary protein excretion, renal function and pathological findings were analysed in each group of both experiments. RESULTS: (1) Glomerular infiltration by polymorphonuclear leucocytes (PMNs) and macrophages at 3 h was less in Groups B and C than in Group A, and matrix scores at day 7 were lower in Groups B and C than in Group A. Injury scores did not differ among the groups. (2) Urinary protein excretion at day 7 was less in Group C than in Group A. (3) Neither pathological findings nor urinary protein excretion differed between ONO-group and placebo-group. CONCLUSION: These results suggest that LTB4 is associated not with the pathogenesis of complement-dependent mesangial cell lysis but with that of mesangial proliferative change in anti-Thy-1 nephritis.     

Carotid atherosclerosis is associated with inflammation and endothelial cell adhesion molecules in chronic haemodialysis patients.

BACKGROUND: Recently emerging evidence suggests that endothelial adhesion molecules may participate in atherogenesis. The aim of the present report was to investigate the probable association of circulating ICAM-1, VCAM-1 and E-selectin with atherosclerotic disease in chronic haemodialysis (HD) patients. METHODS: One hundred and twelve HD patients and 50 age- and sex-matched healthy normotensive controls participated in the study. Atherosclerotic disease in both groups was assessed by measuring intima-media thickness (IMT) and plaque score of the common carotid arteries using an ultrasound scanner. In addition, in a follow-up study, the survival of 81 patients after a mean period of 26 months was analysed in relation to ICAM-1 and VCAM-1 levels. RESULTS: IMT and plaque score were significantly higher in HD patients compared with control subjects (P < 0.001 and P < 0.0001, respectively). The above ultrasonographic indices were correlated with age both in controls (P = 0.0001 and P = 0.002, respectively) and HD patients (P = 0.0001 and P = 0.0001, respectively). A significant relationship was observed between IMT and systolic blood pressure (BP) both in controls and in HD patients (P = 0.002 and P = 0.01, respectively). In HD patients, plaque score was also correlated with systolic BP (P = 0.02). In HD patients, IMT and plaque score were correlated significantly with log CRP values (P = 0.01 and P = 0.01, respectively). Multivariate analysis showed that log CRP values were a strong independent contributor to plaque score (P = 0.01). IMT was significantly correlated with ICAM-1 and VCAM-1 concentrations (P = 0.0001 and P = 0.003, respectively). Multivariate analysis showed that ICAM-1 concentrations were a strong independent correlate of IMT (P = 0.001). E-selectin concentrations did not show any relation with IMT or plaque score. During the follow-up period, 13 of the 81 patients died. Survival analyses showed that patients with increased ICAM-1 had a shorter survival than patients with normal ICAM-1 values and that serum ICAM-1 levels were a strong predictor of death. CONCLUSIONS: In HD patients, carotid atherosclerosis is associated with inflammation and circulating levels of soluble adhesion molecules ICAM-1 and VCAM-1. The correlations between serum ICAM-1 and IMT and ICAM-1 and survival may indicate that this molecule could be a marker of a process that contributes to the high mortality of HD patients.     

Upregulation of endothelial adhesion molecules in hearts with congestive and ischemic cardiomyopathy: immunohistochemical evaluation of inflammatory endothelial cell activation.

OBJECTIVE: In recent years many data emphasized, that inflammatory reactions seem to be involved in the pathogenesis of ischemic (ICM) and congestive (CCM) heart disease. Since, it is well known that endothelial adhesion molecules play a pivotal role in the initiation and maintenance of inflammatory reactions we therefore, evaluated the endothelial expression of a wide variety of different adhesion molecules in hearts suffering from ICM and CCM. METHODS: Tissue samples from coronary arteries, and left and right ventricle myocardium originating form heart with ICM and CCM were evaluated. Tissue samples from healthy human donor hearts, which were not transplanted, served as controls. Evaluated adhesion molecule expression: selectin-family ELAM-1, CD62, immunoglobulin-supergene-family PECAM-1, ICAM-1, VCAM-1, integrin-family VLA-1,-2,-3,-4,-5, and -6, complementary-adhesion-molecules CD34, CD44 and the von-Willebrand-factor (vWF). RESULTS: While endocardial surfaces and coronary arteries revealed only little differences when comparing tissue samples originating from healthy donor hearts and those suffering from ICM and CCM, significant differences were found within the myocardial microvasculature. Both kinds of diseased hearts showed stronger expressions for CD62, ELAM-1, ICAM-1 and VCAM-1 (only CCM) than controls. More and above, integrin molecules showed differential expressions too. Whereas, VLA-1 showed stronger expressions in diseased hearts, VLA-3,-5, and -6 were expressed much weaker in those hearts. Complementary adhesion molecules (CD34/CD44) did not show significant differences and the vWF was not found in any sample. CONCLUSIONS: Inflammatory reactions play a pivotal role in the propagation and maintenance of both these cardiac detoriating diseases.