Atherosclerotic plaque rupture is a major cause of cardiovascular events. Plaque destabilization is associated with extracellular matrix (ECM) modification involving proteases which generate protein fragments with new N-termini. We hypothesized that rupture-prone plaques would contain elevated fragment levels, and their sequences would allow identification of active proteases and target proteins. Plaques from 21 patients who underwent surgery for symptomatic carotid artery stenosis were examined in an observational/cross-sectional study. Plaques were analyzed by liquid chromatography-mass spectrometry for the presence of N-terminal fragments. 33920 peptides were identified, with 17814 being N-terminal species. 5735 distinct N-terminal peptides were quantified and subjected to multidimensional scaling analysis and consensus clustering. These analyses indicated three clusters, which correlate with gross macroscopic plaque morphology (soft/mixed/hard), ultrasound classification (echolucent/echogenic), and the presence of hemorrhage/ulceration. Differences in the fragment complements are consistent with plaque-type-dependent turnover and degradation pathways. Identified peptides include signal and pro-peptides from synthesis and those from protein fragmentation. Sequence analysis indicates that targeted proteins include ECM species and responsible proteases (meprins, cathepsins, matrix metalloproteinases, elastase, and kallikreins). This study provides a large data set of peptide fragments and proteases present in plaques of differing stability. These species may have potential as biomarkers for improved atherosclerosis risk profiling.

The development and progression of non-alcoholic steatohepatitis (NASH) are linked to oxidative stress, inflammation, and fibrosis of the liver. Chymase, a chymotrypsin-like enzyme produced in mast cells, has various enzymatic actions. These actions include activation of angiotensin II, matrix metalloproteinase (MMP)-9, and transforming growth factor (TGF)-β, which are associated with oxidative stress, inflammation, and fibrosis, respectively. Augmentation of chymase activity in the liver has been reported in various NASH models. Generation of hepatic angiotensin II and related oxidative stress is upregulated in NASH but attenuated by treatment with a chymase inhibitor. Additionally, increases in MMP-9 and accumulation of inflammatory cells are observed in NASH but are decreased by chymase inhibitor administration. TGF-β and collagen I upregulation in NASH is also attenuated by chymase inhibition. These results in experimental NASH models demonstrate that a chymase inhibitor can effectively ameliorate NASH via the reduction of oxidative stress, inflammation, and fibrosis. Thus, chymase may be a therapeutic target for amelioration of NASH.

Chymase is the most efficient Ang II (angiotensin II)-forming enzyme in the human body and has been implicated in a wide variety of human diseases that also implicate its many other protease actions. Largely thought to be the product of mast cells, the identification of other cellular sources including cardiac fibroblasts and vascular endothelial cells demonstrates a more widely dispersed production and distribution system in various tissues. Furthermore, newly emerging evidence for its intracellular presence in cardiomyocytes and smooth muscle cells opens an entirely new compartment of chymase-mediated actions that were previously thought to be limited to the extracellular space. This review illustrates how these multiple chymase-mediated mechanisms of action can explain the residual risk in clinical trials of cardiovascular disease using conventional renin-angiotensin system blockade.

Fatal hepatic disease is closely related to non-alcoholic fatty liver disease, especially non-alcoholic steatohepatitis (NASH). NASH is associated with cardiovascular events because it develops on the background of lifestyle-related diseases. Chymase-dependent angiotensin II-forming activity (dAIIFA) in circulating mononuclear leucocytes (CML) is a marker of local angiotensin II production and inflammation. This study investigated the association between CML chymase dAIIFA and NASH. Cardiovascular outpatients were recruited and the Fib4 index (F4I) was calculated. Patients with an F4I > 2.67 were classified into the high F4I group and these patients were strongly suspected to have NASH, while patients with an F4I < 1.30 were classified into the low F4I group. Patient background factors were compared between these groups. CML chymase dAIIFA was measured by ELISA using Nma/Dnp-modified angiotensin I. Among 499 patients, 16% were classified into the high F4I group. Compared with the low F4I group, the high F4I group had a significantly higher age, pancytopenia, more frequent diabetes mellitus, lower diastolic blood pressure, lower estimated glomerular filtration rate, higher brain natriuretic peptide, lower plasma aldosterone concentration, higher total AIIFA, higher CML chymase dAIIFA, and higher pulse wave velocity. Contrary to expectations, the body mass index, triglycerides, and low-density lipoprotein cholesterol were relatively low in the high F4I group. Many cardiovascular outpatients have a high F4I and can probably be categorized as NASH. The high F4I patients had few features of metabolic syndrome and were suspected to have elevated tissue chymase dAIIFA contributing to inflammation in the liver as well as in cardiovascular organs.

A previous clinical study revealed elevation of chymase- and cathepsin G-dependent angiotensin II-forming activity (AIIFA) in the myocardium after acute myocardial infarction (AMI). This study examined the time course of chymase- and cathepsin G-dependent AIIFA in circulating mononuclear leukocytes (CML) after AMI. Consecutive patients with AMI were recruited. Chymase- and cathepsin G-dependent AIIFA in CML were assayed using a modified angiotensin I substrate with Nma/Dnp fluorescence quenching. The changes of CML AIIFA were monitored over time in the patients. Fifteen consecutive AMI patients admitted to our hospital were recruited. At 1 day after the admission, CML chymase- and cathepsin G-dependent AIIFA were 2.9- and 1.7-fold higher than at discharge, respectively. The ratio of chymase-dependent AIIFA to total AIIFA was significantly increased. AIIFA gradually decreased over time after the admission. The peak value of chymase- and cathepsin G-dependent AIIFA was significantly correlated with the maximum levels of aspartate aminotransferase (r = 0.53, 0.64), lactate dehydrogenase (r = 0.57, 0.62), and creatine kinase (r = 0.60, 0.65). This is the first evidence that chymase- and cathepsin G-dependent AIIFA is elevated in CML after AMI. Our data suggested that chymase-dependent AIIFA is increased in CML as well as in the myocardium after AMI, and that the level of chymase-dependent AIIFA might reflect the severity of infarction.

Background and Purpose: Human chymase (h-chymase) is a serine protease that forms local angiotensin II and has been proven to be related to onset of hypertension, arteriosclerosis, and post myocardial infarction cardiac remodeling. Since no chymase inhibitor was clinically available, an extensive screening for inhibition of h-chymase in three different extracts (water, hot water,  and ethanol) of approximately 800 food ingredients had been performed and we identified Polygonum hydropiper L (Polygonum). Using a dried and powdered Polygonum, we conducted a prospective, single-arm, pilot study to investigate its safety and antihypertensive effect in subjects with normal high blood pressure to moderate hypertension.Methods: First, a single oral dose of Polygonum powder (4000 mg) was administered to assess acute toxicity. Then, a pilot study was conducted in 11 subjects using the sequence of placebo and Polygonum for 2 weeks each. The dose of Polygonum was increased sequentially (200-2000 mg/day). Home blood pressure and pulse rate were monitored.Results: Oral administration of Polygonum (4000 mg) did not cause any adverse events. In the dose-escalation phase, evening systolic blood pressure was significantly decreased at 800 mg, 2000 mg doses post-treatment (p < 0.05, and p < 0.05, respectively). Depressor responders to Polygonum intake had significantly higher salt intake in spot urine (p < 0.05). No adverse events or reactions occurred.Conclusion: This was the first investigation that an h-chymase inhibitory Polygonum intake for safety and tolerability was proven and, in addition, chymase inhibitory Polygonum appeared to have depressor effect especially in a hypertensive subject with excessive salt intake.

Chymase is a major angiotensin-converting enzyme (ACE)-independent angiotensin convertase, and its expression is upregulated in the maternal vascular endothelium in preeclampsia, a hypertensive disorder in human pregnancy. Increased chymase-dependent angiotensin II generation has been reported in several cardiovascular diseases, including atherosclerosis and aneurysmal lesions. However, it remains unclear how chymase is activated. Histone modification is an important regulatory mechanism that controls gene expression. In this study, using a chymase overexpression cell model, we investigated the mechanisms of chymase activation to test our hypothesis that histone acetylation could promote endothelial chymase expression. Human umbilical vein endothelial cells were transfected with the chymase gene. Trichostatin A was used to inhibit histone deacetylases (HDACs). The expression levels of chymase, ACE, and HDACs were determined by western blotting. Our results showed that ACE was strongly expressed in control cells, but was significantly downregulated in cells transfected to express chymase. Strikingly, we also found that HDAC inhibition resulted in a dose-dependent increase in chymase expression but a dose-dependent decrease in ACE expression in cells transfected with the chymase gene. HDAC inhibition was confirmed by the decreased expression of HDAC1 and HDAC6 in cells treated with trichostatin A. Increased chymase expression associated with reduced histone deacetylase expression was further confirmed by immunostaining of subcutaneous adipose sections from women with preeclampsia. We conclude that aberrant HDAC expression/activity could disturb the balance between ACE and chymase expression in endothelial cells. Our results support the clinical importance of chymase as a new pharmacological target for cardiovascular disorders.

Levels of triglycerides and free fatty acids (FFAs) are elevated in patients with diabetes and may contribute to endothelial dysfunction through renin-angiotensin system (RAS) activation and oxidative stress. The present study investigated how systemic FFA loading affected myocardial microcirculation during hyperemia via RAS.

Eight healthy men received candesartan, perindopril, or a placebo for 2 days in a double-blind crossover design, and then myocardial microcirculation during hyperemia induced by a 2-h infusion of lipid/heparin was assessed using dipyridamole stress-myocardial contrast echocardiography (MCE). Leukocyte activity and hemorheology were also assessed ex vivo using a microchannel flow analyzer, serum levels of oxidative stress markers, and IκB-α expression in mononuclear cells. Serum FFA elevation by the infusion of lipid/heparin significantly decreased myocardial capillary blood velocity and myocardial blood flow during hyperemia. Both candesartan and perindopril significantly prevented the FFA-induced decrease in capillary blood velocity and myocardial blood flow during hyperemia. Systemic FFA loading also caused an increase in the number of adherent leukocytes and prolonged the whole blood passage time. These effects were blocked completely by candesartan and partially by perindopril. Both agents prevented the FFA-induced enhancement of oxidative stress and IκB-α degradation in mononuclear cells.

Both candesartan and perindopril can prevent FFA-induced myocardial microcirculatory dysfunction during hyperemia via modulation of leukocyte activation and microvascular endothelial function.

Chymase is a potent and specific angiotensin II (Ang II)-forming enzyme in vitro. There is also strong evidence to suggest its importance in vivo. Recent clinical studies have suggested that high serum cholesterol levels are associated with increased vascular chymase activity and this may assist in the development of atherosclerosis. This clinical finding has been reproduced in hamster models. Studies with transgenic mice overexpressing the human chymase gene suggest a direct association between vascular chymase upregulation and atherogenesis. There is also increased chymase activity following various cardiac diseases such as myocardial ischaemia, volume overload cardiac failure, cardiomyopathy and viral myocarditis, suggesting that increased cardiac chymase activity appears to be involved in cardiac remodelling.

Although it is well-known that excess renin angiotensin system (RAS) activity contributes to the pathophysiology of cardiac and vascular disease, tissue-based expression of RAS genes has given rise to the possibility that intracellularly produced angiotensin II (Ang II) may be a critical contributor to disease processes. An extended form of angiotensin I (Ang I), the dodecapeptide angiotensin-(1-12) [Ang-(1-12)], that generates Ang II directly from chymase, particularly in the human heart, reinforces the possibility that an alternative noncanonical renin independent pathway for Ang II formation may be important in explaining the mechanisms by which the hormone contributes to adverse cardiac and vascular remodeling. This review summarizes the work that has been done in evaluating the functional significance of Ang-(1-12) and how this substrate generated from angiotensinogen by a yet to be identified enzyme enhances knowledge about Ang II pathological actions.

At least 468 individual genes have been manipulated by molecular methods to study their effects on the initiation, promotion, and progression of atherosclerosis. Most clinicians and many investigators, even in related disciplines, find many of these genes and the related pathways entirely foreign. Medical schools generally do not attempt to incorporate the relevant molecular biology into their curriculum. A number of key signaling pathways are highly relevant to atherogenesis and are presented to provide a context for the gene manipulations summarized herein. The pathways include the following: the insulin receptor (and other receptor tyrosine kinases); Ras and MAPK activation; TNF-α and related family members leading to activation of NF-κB; effects of reactive oxygen species (ROS) on signaling; endothelial adaptations to flow including G protein-coupled receptor (GPCR) and integrin-related signaling; activation of endothelial and other cells by modified lipoproteins; purinergic signaling; control of leukocyte adhesion to endothelium, migration, and further activation; foam cell formation; and macrophage and vascular smooth muscle cell signaling related to proliferation, efferocytosis, and apoptosis. This review is intended primarily as an introduction to these key signaling pathways. They have become the focus of modern atherosclerosis research and will undoubtedly provide a rich resource for future innovation toward intervention and prevention of the number one cause of death in the modern world.

Human chymase, an angiotensin II-forming chymotrypsin-like serine proteinase, posses various biological actions mediating through local angiotensin II formation in the tissue level of many cardiovascular organs. Our previous experimental data have shown that chymase inhibitor increased a survival rate of the hamster post-myocardial infarction model with concomitant improvements of the cardiac function and hypertrophy, decreased hamster aortic atherosclerotic lesion induced by a high fat diet and improved hamster diabetic nephropathy decreasing the proteinuria and increased renal antiotensin II levels. Although chymase inhibitor has not yet been applied for clinical use, clinical cardiovascular diseases above mentioned appear to be the target of chymase inhibitor. The related basal and clinical circumstances are discussed in this review article for chymase inhibitor.

Enhanced production of angiotensin II and excessive release of norepinephrine in the ischemic heart are major causes of arrhythmias and sudden cardiac death. Mast cell-dependent mechanisms are pivotal in the local formation of angiotensin II and modulation of norepinephrine release in cardiac pathophysiology. Cardiac mast cells increase in number in myocardial ischemia and are located in close proximity to sympathetic neurons expressing angiotensin AT1- and histamine H3-receptors. Once activated, cardiac mast cells release a host of potent pro-inflammatory and pro-fibrotic cytokines, chemokines, preformed mediators (e.g., histamine) and proteases (e.g., renin). In myocardial ischemia, angiotensin II (formed locally from mast cell-derived renin) and histamine (also released from local mast cells) respectively activate AT1- and H3-receptors on sympathetic nerve endings. Stimulation of angiotensin AT1-receptors is arrhythmogenic whereas H3-receptor activation is cardioprotective. It is likely that in ischemia/reperfusion the balance may be tipped toward the deleterious effects of mast cell renin, as demonstrated in mast cell-deficient mice, lacking mast cell renin and histamine in the heart. In these mice, no ventricular fibrillation occurs at reperfusion following ischemia, as opposed to wild-type hearts which all fibrillate. Preventing mast cell degranulation in the heart and inhibiting the activation of a local renin-angiotensin system, hence abolishing its detrimental effects on cardiac rhythmicity, appears to be more significant than the loss of histamine-induced cardioprotection. This suggests that therapeutic targets in the treatment of myocardial ischemia, and potentially congestive heart failure and hypertension, should include prevention of mast cell degranulation, mast cell renin inhibition, local ACE inhibition, ANG II antagonism and H3-receptor activation.

Chymase converts angiotensin I to angiotensin II and it can also convert precursors of TGF-β and MMP-9 to their active forms. Therefore, diseases related to angiotensin II TGF-β, and MMP-9 could potentially be treated with chymase inhibitors.

This review discusses the appropriate targets and safety of chymase inhibitors. Six diseases with notable mortality or morbidity as targets of chymase inhibitors are focused on; abdominal aortic aneurysms (AAAs), nephropathy and retinopathy, cardiomyopathy, nonalcoholic steatohepatitis (NASH), organ fibrosis and intestinal diseases.

If chymase inhibition proves to be a useful strategy for the attenuation of angiotensin II, TGF-β and MMP-9 in vivo, the application of chymase inhibitors is likely to become widespread in various diseases in the clinical setting. Chymase inhibitors are anticipated not to interfere with the homeostasis of resting tissues, that is, those not affected by injury or inflammation.

The renin angiotensin system (RAS) is important for fluid and blood pressure regulation. Recent studies suggest that an overactive RAS is involved in the metabolic syndrome. This article discusses recent advances on how genetic alteration of the RAS affects cardiovascular and metabolic phenotypes, with a special emphasis on the potential role of angiotensin-independent effects of renin.

Reactive oxygen species (ROS) such as hydrogen peroxide (H(2)O(2)), O(*-)(2) and OH(*) participate in the pathogenesis of ischemia/reperfusion injury, inflammation and atherosclerosis. Our previous studies have suggested that increased angiotensin II (Ang II)-forming chymase may be involved in the development of atherosclerosis. However, the regulatory mechanism of chymase expression has not yet been clarified. In this study, we tested whether oxidative stress upregulates mouse mast cell proteinase chymase, mouse mast cell proteinase (MMCP)-5 or MMCP-4. We also examined the expression and activity of these proteins after treatment. Cultured mouse mastocytoma cells (MMC) displaying chymase-dependent Ang II-forming activity were treated with H(2)O(2) and several aminothiols with or without anti-oxidants. The levels of MMCP-5 and MMCP-4 expression were determined by quantitative RT-PCR; the level of chymase-dependent Ang II-forming activity was measured by high performance liquid chromatography using Ang I as a substrate. Treatment of MMC with homocysteine (0.1-3 mmol l(-1)) significantly increased MMCP-5 and MMCP-4 expression, as well as Ang II-forming activity. These effects were significantly inhibited by the addition of catalase and further suppressed by the combination of catalase and superoxide dismutase. Incubation with hydrogen peroxide alone caused a significant increase in Ang II-forming activity, which was completely suppressed by co-treatment with catalase. Furthermore, MMCP-5 and MMCP-4 expression levels were drastically suppressed and chymase induction by homocysteine was diminished under the GATA-inhibited condition. Homocysteine increased mast cell chymase expression and activity through the mechanism of oxidative stress. Our results suggest that there is a biochemical link between oxidative stress and the local Ang II-forming system.

It is no a secret that we are confronted by an alarmingly increasing number of patients with progressive renal disease. There is ample evidence for the notion that angiotensin II (Ang II) is a major culprit in progression. The vasopeptide Ang II turned out to have also multiple nonhemodynamic pathophysiologic actions on the kidney, including proinflammatory and profibrogenic effects. Diverse complex Ang II generating systems have been identified, including specifically local tissue-specific renin-angiotensin systems (RAS). For example, proximal tubular cells have all components required for a functional RAS capable of synthesizing Ang II. On the other hand, Ang II is not the only effector of the RAS and other peptides generated by the RAS influence renal function and structure as well. Moreover, the discoveries that Ang II can be generated by enzymes other than angiotensin-converting enzyme (ACE) and that Ang II and other RAS derived peptides bind to various receptors with different functional consequences have further added to the complexity of this system. Several major clinical trials have clearly shown that ACE inhibitor treatment slows the progression of renal diseases, including in diabetic nephropathy. Well-controlled studies demonstrated that this effect is in part independent of blood pressure control. More recently, with Ang II type 1 receptor (AT(1)) receptor antagonists a similarly protective effect on renal function was seen in patients with type 2 diabetes. Neither ACE inhibitor treatment nor AT(1) receptor blockade completely abrogate progression of renal disease. A recently introduced novel therapeutic approach is combination treatment comprising both ACE inhibitor and AT(1) receptor antagonists. The rationale for this approach is based on several considerations. Small-scale clinical studies, mainly of crossover design, documented that combination therapy is more potent in reducing proteinuria in patients with different chronic renal diseases. Blood pressure as an important confounder was, however, significantly lower in the majority of this studies in the combination treatment arms compared to the respective monotherapies. In a recent prospective study Japanese authors avoided this confounder and demonstrated that combination therapy reduced hard end-points (end stage renal failure or doubling of serum creatinine concentration) by 50% compared to the respective monotherapies. This effect could not be explained by a more pronounced reduction of blood pressure in the combination therapy group. Although these results are encouraging, administration of combination therapy should be reserved currently to special high risk groups. Further studies are necessary to confirm these promising results. It is possible that combination therapy may increase the risk of hyperkalemia, particularly when with coadministered with medications such as nonsteroidal anti-inflammatory drugs (NSAIDs) or spironolactone. In our opinion patients with proteinuria >1 g/day despite optimal blood pressure control under RAS-blocking monotherapy are a high-risk group which will presumably benefit from combination therapy.

The biological actions of angiotensin II (ANG), the most prominent hormone of the renin-angiotensin-aldosterone system (RAAS), may promote the development of atherosclerosis in many ways. ANG aggravates hypertension, metabolic syndrome, and endothelial dysfunction, and thereby constitutes a major risk factor for cardiovascular disease. The formation of atherosclerotic lesions involves local uptake, synthesis and oxidation of lipids, inflammation, as well as cellular migration and proliferation--mechanisms that may all be enhanced by ANG via its AT1 receptor. ANG may also increase the risk of acute thrombosis by destabilizing atherosclerotic plaques and enhancing the activity of thrombocytes and coagulation. After myocardial infarction, ANG promotes myocardial remodeling and fibrosis, and its many pathological mechanisms deteriorate the prognosis of these high-risk patients in particular. Therapeutically, inhibitors of the angiotensin I-converting enzyme (ACEI) and AT1 receptor blockers (ARB) are available to suppress the generation and cellular signaling of ANG, respectively. Despite major differences in the efficacy of ANG suppression and the modulation of other hormones and receptors, both classes of drugs are generally effective in attenuating numerous pathomechanisms of ANG in vitro, and in diminishing the development of atherosclerotic lesions and restenosis after angioplasty in various animal models. In clinical therapy, ACEI and ACE are well-tolerated antihypertensive drugs that also improve the prognosis of heart failure patients. After myocardial infarction and in stable coronary heart disease, ACEI have been shown to reduce mortality in a manner independent of hemodynamic alterations. However, there is little evidence that inhibitors of the RAAS may be effective against arterial restenosis, and a possible benefit of these substances compared to other antihypertensive drugs in the primary prevention of coronary heart disease in hypertensive patients is still a matter of debate, possibly depending on the specific substance and condition being investigated. As such, the general clinical efficacy of ACEI and ARB may be due to a positive influence on hemodynamic load, vascular function, myocardial remodeling, and neuro-humoral regulation, rather than to a direct attenuation of the atherosclerotic process. Further therapeutic advances may be achieved by identifying optimum drugs, patient populations, and treatment protocols.

Chymase activates not only angiotensin I to angiotensin II but also latent transforming growth factor-beta-binding protein to transforming growth factor-beta. In dog grafted veins, chymase activity and angiotensin II concentration along with vascular proliferation were significantly increased, while they were significantly suppressed by a chymase inhibitor. After balloon injury in dog arteries, chymase activity was significantly increased in the injured artery, and a chymase inhibitor and an angiotensin AT(1) receptor antagonist were effective in preventing the vascular proliferation, but an angiotensin-converting enzyme inhibitor was ineffective. In fibrotic models, the tissue fibrosis was reduced by chymase inhibitors. In adhesion models, the transforming growth factor-beta concentration and adhesion formation were suppressed by chymase inhibitors. Therefore, chymase inhibitors may be useful for preventing cardiovascular diseases and fibrosis via inhibition of angiotensin II formation and transforming growth factor-beta activation.

Inhibition of angiotensin II action or its formation by angiotensin-converting enzyme has been highly successful in the treatment of cardiovascular diseases. Since the identification of chymase as a major angiotensin II-forming enzyme in the human heart and its vessels more than a decade ago, numerous studies have sought to understand the importance of this enzyme in tissue angiotensin II formation and in the pathogenesis of hypertension, congestive heart failure, and vascular disease. Recent studies show that chymase and angiotensin-converting enzyme regulate angiotensin II production in distinct tissue compartments and that, in the pathogenesis of cardiovascular diseases, chymase-dependent effects extend beyond its ability to regulate tissue angiotensin II levels.

Angiotensin II is known to stimulate proliferation of fibroblasts and smooth muscle cells and enhance the atherosclerotic process in native coronary arteries. The impact of genetic polymorphisms of the renin-angiotensin-aldosterone system on coronary bypass graft degeneration is unknown.

We examined polymorphisms of four genes (AGTR1, CYP11B2, ACE, CMA) in 101 patients who had follow-up coronary angiography due to symptoms 88 +/- 52 months after coronary artery bypass graft surgery. Bypass degeneration was determined with quantitative coronary angiography and an adjusted Gensini score.

Homozygosity for the G allele of the CMA-1905 polymorphism was associated with a higher degree of bypass degeneration (Bypass Gensini score CMA AA 21.4 +/- 39; AG 24.2 +/- 39.8; GG 27.8 +/- 42.3; NS-time adjusted Gensini bypass scores CMA AA 0.25 +/- 0.68; AG 0.57 +/- 1.82; GG 3.25 +/- 13.2; P = 0.005). No association could be detected for the AGTR1, CYP11B2 or ACE polymorphism.

The CMA allele G is a genetic risk factor for atherosclerosis in venous coronary artery bypass grafts. Its importance has to be shown in further studies. Other polymorphisms of the renin-angiotensin-aldosterone system do not seem to play a role in bypass degeneration.