| BackgroundThe prevention of cardiovascular disease (CVD) is crucial, particularly in individuals with CKD, as they are more likely to die of CVD than to reach dialysis or die due to kidney failure. A recent report suggests that CKD is a health condition equivalent to coronary heart disease (CHD) in terms of high mortality risk. Accordingly, the United States Renal Data System (USRDS) reported that cardiovascular mortality accounted for 42.2% of the 17.9 deaths per 100 patient-years at risk. On the other hand, it is now well recognized that the presence of CKD is one of the most potent known risk factors for cardiovascular disease, yielding an up to 20-fold increased risk of cardiac death. In 2003, more than 320,000 people in the United States were receiving dialysis for end-stage renal disease (ESRD), with a predicted increase to 2 million by 2030. Mortality from CVD in patients with ESRD is 10 to 30 times higher than that in the general population. Cardiovascular complications lead in all causes of mortality among patients with CKD, accounting for approximately 50% of deaths. USRDS data indicate that the mortality rate for patients on dialysis or with ESRD is remarkably higher than that of patients in the same age groups with other major diseases. In 1836 Richard Bright was the first to describe the association between CKD and CVD. However, only recently has it been understood that cardiovascular events are the major cause of death in CKD. Individuals with CKD have a substantially greater risk of cardiovascular disease compared with the general population but they have largely been excluded from clinical trials. Between the heart and the kidney there is a complex bi-directional relationship where damage to one of the two organs leads to the dysfunction of the other in a sort of vicious circle, which ultimately determines the amplification of the damage in both organs. The term "cardiorenal syndrome" has been reintroduced into the clinical and research literature with the goal of promoting research and understanding of how the heart and kidneys can both promote and promulgate disease in the reciprocal organ system. Improved understanding of the association between prevalent cardiovascular disease and progression of CKD may not only enhance prognosis for kidney disease, but also lead to future studies of the pathophysiology of these two commonly co-existent diseases. The relationship between cardiac and kidney function have generated considerable interest in the last few years, resulting in a formal classification of cardiorenal syndromes. To include the vast array of interrelated derangements, and to stress the bidirectional nature of heart-kidney interactions, we present a new classification of the CRS with 5 subtypes that reflect the pathophysiology, the time-frame, and the nature of concomitant cardiac and renal dysfunction. CRS can be generally defined as a pathophysiologic disorder of the heart and kidneys whereby acute or chronic dysfunction of 1 organ may induce acute or chronic dysfunction of the other. Type 1 CRS reflects an abrupt worsening of cardiac function (e.g., acute cardiogenic shock or decompensated congestive heart failure) leading to acute kidney injury. Type 2 CRS comprises chronic abnormalities in cardiac function (e.g., chronic congestive heart failure) causing progressive chronic kidney disease. Type 3 CRS consists of an abrupt worsening of renal function (e.g., acute kidney ischemia or glomerulonephritis) causing acute cardiac dysfunction (e.g., heart failure, arrhythmia, ischemia). Type 4 CRS describes a state of chronic kidney disease (e.g., chronic glomerular disease) contributing to decreased cardiac function, cardiac hypertrophy, and/or increased risk of adverse cardiovascular events. Type 5 CRS reflects a systemic condition (e.g., sepsis) causing both cardiac and renal dysfunction. The use of this classification can help physicians characterize groups of patients, provides the rationale for specific management strategies, and allows the design of future clinical trials with more accurate selection and stratification of the population under investigation.According to a well-established classification of cardiorenal syndrome, cardiovascular involvement in CKD is also defined as cardiorenal syndrome type 4 (chronic renocardiac). Left ventricular hypertrophy (LVH) represents the key feature in uremic cardiopathy and it is related to CRS type 4 (chronic renocardiac/cardiorenal syndrome).Cardiovascular complications can occur at any stage of CKD irrespective of glomerular filtration rate (GFR) levels. According to the definition of CRS type 4, kidney disease is detected before the development of heart failure. Trial and registry data have documented that in dialysis patients, sudden cardiac death(SCD) and heart failure-not myocardial infarction-are the prevailing modes of cardiovascular death. Therefore treatment modalities should not only focus on ischemic myocardial events, but should also deal with the ill defined "cardiomyopathy" of renal failure which is further rendered complex by uremia-associated "microinflammation," comorbidities, such as diabetes, chronic hypervolemia, and others. This short review will therefore go beyond coronary heart disease and focus on the specific cardiac pathology in renal failure (heart failure, LVH; sudden death; ischemia intolerance) and will, against this background, discuss and summarize the contemporary diagnostic workup and therapeutic strategies in ESRD.In dialysis patients, LVH is almost invariably present. At least in experimental models, it occurs even in the absence of hemodynamic stimuli (increased preloadand or afterload) suggesting an inappropriate hypertrophic remodeling process of the heart. LVH is a powerful indicator of mortality. According to the Framingham Heart Study the hazard ratio for sudden death is 1.45 per 50 g/m2 LV mass. Several studies show that up to 80% of dialysis patients have LVH, equally split between concentric and dilated hypertrophy. Hypertension, neuro-humoral activation, volume expansion, and anemia are important factors in the genesis of LVH while in the specific milieu of uremia further nonclassical factors such as oxidative stress and hyperparathyroidism supervene. It is quite important to appreciate that hypertrophic remodeling comprises not only cardiomyocyte hypertrophy, but also interstitial fibrosis and micro-vessel disease. This constellation of different abnormalities of the myocardium compromises not only systolic contractile and diastolic function, but also causes electrical instability, metabolic abnormalities (e.g., insulin resistance)and reduced ischemia tolerance. So the prevention of LVH is very important.Even if the risk factors and the pathophysiological mechanisms that bind CKD to CV disease are not yet wholly understood, and the weight that each one can have in the various CKD stages is not clear, some general considerations can nonetheless be formulated to account for the surplus of CV morbidity and mortality observed in CKD patients:Framingham’s traditional cardiovascular risk factors are highly represented in patients with CKD, but alone they are not sufficient to justify the excess CV morbidity and the reduced life expectancy. Alongside age, hypertension, diabetes, obesity and dyslipidaemia,we find non-traditional factors (endothelial dysfunction tied with an excess of inducers of inflammation/oxidation, anaemia, alterations of mineral metabolism and vascular calcifications, hyperactivity of the sympathetic system) and factors closely related to renal insufficiency strictly speaking (volume expansion, new uremic toxins). The latter seem to have a pre-eminent role in the more advanced phases of CKD. It is likely that traditional and non-traditional factors do not act separately, but that there exists.a continuous interplay and that the prevalence of one upon the other may vary depending on the disease stage andt he age of the patients.Traditional and non-traditional risk factors may negatively act in conditioning either vascular damage or heart muscle damage.Many epidemiological studies above all in these past few years have confirmed the association between CV diseases and CKD, but above all they have allowed us to establishthat the bond between the two pathologies is not solely due to the fact that many risk factors(smoke, obesity, hypertension, dyslipidaemia and diabetes) are in common or simply reflectsa longer duration or severity of traditional CVD risk factors. There is evidence to support both blood pressure and cholesterol reduction in the CKD population. However, thereare mechanisms and risk factors that are specific to CKD, capable of triggering a vascular pathology and that justify the surplus of CV morbidity in CKD patients and that require we consider CKD as a CV risk factor per se. Despite this understanding, the CV diseases in CKD patients are often inadequately investigated and end up being underestimated. The risk of bleeding with antiplatelet drugs is high in CKD and these should be used with duecaution. Although there has been recent interest in targeting non-classical cardiovascular risk factors in CKD. few trials have demonstrated any significant reduction in cardiovascular risk. Smoking cessation remains important but is poorly studied in CKD with many dialysis patients still smoking. Future work should focus on new management strategies and drug combinations that tackle the classical risk factors as well as better designed longitudinal andrandomized controlled trials aimed at non-classical risk factors. Patients with CKD shouldbe included in all cardiovascular intervention studies, given their poor outcomes without interventions.Heart failure is a major cause of morbidity and mortality in CKD. Rather than merely secondary to traditional vascular factors, CKD is also an independent risk factor for heart failure, termed uremic cardiomyopathy (UCM).Echocardiography commonly reveals structural left ventricular hypertrophy in CKD, without clarifying whether it is adaptive or maladaptive. Corresponding functional assessments have been mostly conducted at rest. To unravel the extents and mechanisms UCM, a next step involves the adoption of direct measurements of CKD-induced cardiac pumping incapacity at peak exercise. This could potentially lead to future novel interventions to ameliorate or reverse UCM. CKD carries a high burden of morbidity and mortality. Recent registry data from the URDS show that >40% of end stage renal disease (ESRD) deaths were due to CVD).Indeed,50% of ESRD patients suffer from heart failure (HF), thus forming the predominant cardiac abnormality observed in CKD. It is a common perception that HF in CKD is secondary to vascular comorbid conditions such as ischemic heart disease (IHD), hypertension and diabetes mellitus, but it is becoming apparent that primary CKD is an independent risk factor for incident HF even in nondiabetic and normotensive patients. It is also becoming clearer that CVD in CKD is more than just accelerated atherosclerosis. Thus, nontraditional risk factors such as uremic toxins, anemia, calcium phosphate imbalance, renin-angiotensin-aldosterone system(RAAS) activation, sympathetic activation, inflammation and oxidative stress are gaining recognition for their roles in the pathogenesis of cardiac disease in CKD. A recent Kidney Disease:Improving Global Outcome report emphasized the need for improving our understanding of cardiac dysfunction in CKD and highlighted the need for research that is capable of evaluating asymptomatic left ventricular (LV) dysfunction. Of the five subtypes of cardiorenal syndromes so far classified, it is the fourth subtype, CKD directly leading to cardiac dysfunction, which will form the focus of this brief editorial, and for simplicity, we shall ascribe the term UCM to this type of dysfunction. Structural & ultrastructural abnormalities of UCM By far the commonest, easily accessible method of studying the structural abnormalities of UCM is echocardiography, with which it is observed that a predominant feature in CKD is LVH. A recent large observational study has demonstrated a graded relationship between the severity of CKD and the prevalence and severity of LVH. The prevalence increased from 32 to 75% as one moved from patient groups with estimated glomerular filtrationrate (eGFR)>60 to <30 ml/min. The corresponding mean left ventricular mass increased from 46.1 to 57.8 g/m2.Perhaps, because CKD is closely associated with hypertension and LVH is arecognized consequence of chronic hypertension, no evidence has so far been proffered to establish whether LVH is a direct outcome of primary CKD rather than due solely to associated hypertension. A study using cardiac MRI with gadolinium contrast showed evidence of diffuse myocardial fibrosis in uremic patients, different in distribution to the subendocardial fibrosis observed in IHD.Histopathological examination of postmortem cardiac tissue samples in hemodialysis patients showed increased cardiomyocyte diameter, reduced capillary length density and increased interstitial volume. Although the above studies offer insight into the structural abnormalities of UCM, information on the functional consequences of such changes is still lacking. In order to understand whether these hypertrophic changes are adaptive or maladaptive, it is essential to study their functional correlates. Pathophysiological consequences of UCM Studies reporting functional abnormalities in UCM have mostly employed resting echocardiography.Parameters such as left ventricular ejection fraction, left ventricular fractional shortening and midwall fractional shortening have been used to assess systolic dysfunction, while transmitral flow velocity has been used to assess diastolic dysfunction. In a recent large observational study evaluating cardiac structure and function in CKD, despite a clear association between LVH and renal dysfunction, no association between systolic or diastolic cardiac function and renal function was demonstrated. In contrast, it is not uncommon to find normal or enhanced echocardiographic indices of resting cardiac function in the presence of LVH. It is, however, now well established that merely assessing the resting, unstressed heart can provide unrepresentative or misleading information about true cardiac function, unless in cardiogenic shock. Stress echocardiography(via exercise or pharmacological challenge) and cardiopulmonary exercise tests (CPXs) are some of the tools available to evaluate cardiac dysfunction. Unfortunately, because recommendationson’appropriateness criteria for stress echocardiography excluded patients with renal diseases, very limited information is so far available on stress echocardiography in CKD patients Assessment of myocardial contractile reserve in pediatric CKD patients, using exercise echocardiography, has shown that contractile reserve is impaired even when resting parameters arenormal. In another study of pediatric CKD patients, peakoxygen consumption, a measure of physical functional reserve and a surrogate for peak cardiac performance, is shown to be impaired compared with healthy controls.Since these pediatric populations are assumed to have minimal atherosclerosis, the findings suggest that CKD per se may have direct deleterious effects upon cardiac function. However, results from pediatric patients may not translate fully to adults. Therefore, studies specifically designed to evaluate cardiac reserve in adult CKD patients without comorbid atherosclerosis substrates are needed to obtain useful insights into UCM.A CPX study in ESRD patients has shown impaired physical functional reserve and a negative survival impact. However, this study did not exclude patients with IHD, diabetes mellitusor pre-existing HF, and therefore, it is difficult to ascertain whether the observations were due to primary CKD or secondary to CVDs. Moreover, other comorbid factors including anemia, peripheral vascular disease, hypertension and skeletalmyopathy in CKD patients would contribute variably to theVO2max and anaerobic threshold values obtained. These considerations highlight the importance of patient selection and the choice of optimum parameters to measure cardiac dysfunction arising directly from primary CKD.Traditional Chinese Medicine(TCM) as treasure of our national medicine is effective to treat with UCM.Zhenwutang(ZWT) is one classic agents of 《Shang Han Lun》, which was written by Zhang zhong jing. We often use it to treat with patients who are heart dysfunction or kidney dysfunction. There is no report about UCM treated with zhenwutang until now. So we decided to use ZWT to cure mice which were taken subtotal nephrectomy operation and observed the changes of function and structure of their hearts to evaluate the effects of ZWT on UCM.PurposeTo investigate the protective effects of ZWT on the hearts of UCM mice.MethodUremic cardiomyopathy mice were induced by subtotal nephrectomy (STNx).C57BL/6 mice were randomly divided into sham-operation group(n=10); STNx group(n=10)and ZWT group(n=10).ZWT group mice were treated with ZWT after STNx. Sham group and STNx group mice were treated with equal quantity distilled water. Echocardiography, HE staining and biochemical assay were used to evaluate the change of heart function, structure and renal function respectively. Western blotting were used to evaluate the expression level of adenosine monophosphate activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) in heart tissues.ResultCompared with sham group,the body weight (BW) were significantly lower,heart weight(HW),heart index(HW/BW),left ventricular posterior wall thickness in diastole(LVPWd),left ventricular posterior wall thickness in systole (LVPWs),blood urea nitrogen(BUN) and serum creatinine(Scr) were significantly higher in UCM mice (P<0.05).Pathological examination of the heart tissues in UCM group showed myocardial hypertrophy.The expression levels of p-AMPK was markedly decreased and p-mTOR was significantly increased. After ZWT treatment, HW, HW/BW, LVPWd, LVPWs and expression level of p-mTOR was significantly decreased. The expression level of p-AMPK was significantly increased.The heart histological injury in UCM group was significantly ameliorated.ConclusionZWT might protect heart against STNx-induced injury via AMPK-mTOR signal pathway. |
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