Several epidemiologic studies have illustrated the relationship between the metabolic syndrome, cardiovascular events and mortality [^9-16]; however the syndrome was criticised by the American Diabetes Association a few years ago for its modest consistency and limited clinical application [¹¹] and the use of the term metabolic syndrome was discouraged. Although the predictive performance of the syndrome for diabetes incidence has been stressed in several studies and meta-analyses [¹⁷], several issues remain unresolved including the presence of potential gender differences in the risk for incident diabetes associated with the metabolic syndrome and whether the metabolic syndrome offers additional prediction beyond its components [¹⁸]. Also, its value for both cardiovascular and all-cause mortality is questioned [¹⁷]. Hence, it is now important to look back at the issue to ensure about its consistency and usefulness. For instance, the following consideration must be taken for a new definition:

1. Insulin resistance has been presumed to be the common pathway for all features of the metabolic syndrome [¹⁹]; yet insulin related measurements are not standardized and vary widely [²⁰, ²¹]. Despite the general belief, hyperinsulinemia and insulin resistance are not equivalent terms [¹¹]. Besides, while 78% of individuals with metabolic syndrome have insulin resistance, only 48% of patients with insulin resistance have the metabolic syndrome [²²]. Therefore the association of hyperinsulinemia and other elements of metabolic syndrome are not constant and many other factors may also play important roles as underlying mechanisms in clustering the risk factors. In other words, insulin resistance may simply be one of many abnormalities linked to a more fundamental, truly unifying pathophysiology [¹¹].
2. Metabolic syndrome diagnosis is not always associated with higher cardiovascular risk, for example an increased risk was not observed in elderly diabetics, non-diabetic American Indians and women with suspected CV disease but normal angiography [¹⁷, ^23-25]. Additionally, application of different definitions of the syndrome causes 15-20% disagreement in patients classification [¹¹] and changes the predictive value of the syndrome diagnosis for CV disease and mortality [¹⁰, ¹⁵, ²⁶]. Therefore the association of the included syndrome components with CV disease and with each other is uncertain. Even reports supporting the metabolic syndrome state that “detecting the metabolic syndrome is only one part of the overall CV risk assessment and is not an adequate tool to estimate 10-year risk for coronary heart disease”[²⁷]. This is possibly because of many other related factors which have not been included as syndrome criteria. In fact, residual analysis of many longitudinal studies demonstrates a high unexplained variance (as much as 47%) when metabolic syndrome components were considered as independent variables [¹¹].
3. Although several epidemiologic studies have demonstrated the relationship between metabolic syndrome and microalbuminuria, this factor was only incorporated into the World Health Organisation criteria for the syndrome. Likewise, renal failure is now recognised as an independent CV risk factor, as is anaemia, but they have not been considered as a part of the metabolic syndrome.
4. Despite a large body of evidence of the strong and independent association of endothelioarterial dysfunction with mortality, CV disease, diabetes and renal function[^28-40], its impact has been overlooked in metabolic syndrome. Also, cardiac disease has been considered simply as an outcome of metabolic syndrome while it should be an interacting part of the syndrome.

By and large, the current evidence strongly suggests that the metabolic syndrome definition needs significant amendments, which should include the addition of other factors. Furthermore it must be standardized. Therefore, we introduce the term of “circulatory syndrome” instead as a more refined clinical construct since it is composed of many disease markers including cardiac, arterial and renal (respectively abbreviated as MARC) components as well as the traditional risk factors[⁴¹].

Circulatory (MARC) syndrome is a cluster of risk markers with synergic effects. The proposed syndrome consists of eight major components (Fig. 1):

• Abnormal glucose metabolism
• Hypertension
• Renal impairment
• Microalbuminuria
• Arterial stiffness
• Left ventricular dysfunction
• Dyslipidemia
• Anaemia

The above markers construct a network of associations while the strength of associations creates manifestation nodes. Then, the syndrome may have several facets of presentation and any given individual may exhibit some dominant features.

The above markers can be simply and non-invasively assessed in outpatient clinical settings, although more complex assessments would be necessary for additional workups.

All of these “markers” are expressed on a background of oxidative stress, inflammation, hypercoagulability and endotheliopathy (underlying factors) and can be accelerated by factors such as aging, obesity, smoking and physical inactivity (predisposing factors).

While mechanisms underlying the circulatory (MARC) syndrome are poorly understood, it must be strongly stated that vascular-endothelial pathways link all and all are of pathological significance. Activation of the renin-angiotensin system, insulin resistance and increased sympathetic activation are all by-products of the underlying pathogenic process (Fig. 2). Since these markers represent the extent of the underlying disease process, they could also manifest as risk factors for other components and thereby enhance their development. The final outcome in this model is the general circulatory health level of the individuals or the ability of the circulatory system to respond to body demands including exercise tolerance and ischemia related symptoms and signs.

Diabetes and abnormalities in glucose metabolism are well known risk factors for cardiac, arterial and renal disease as well as anemia [⁴², ⁴³]. Although insulin resistance and hyperinsulinemia can be attributed to these complications, they may occur with or without insulin resistance because several other mechanisms including advanced glycation end products, autonomic nervous instability, imbalance between the renin-angiotensin system and nitric oxide, hemodynamic changes and endothelial dysfunction with subsequent ADMA accumulation (an inhibitor for nitric oxide synthesis) and adiponectin deficiency also contribute in the process [^44-46].

Dyslipidemia including increased LDL and TG as well as low HDL is a major risk in patients with chronic renal disease, hypertension and diabetes[¹⁴, ^47-49]. Genetic variants of lipoprotein lipase correlate with the presence and degree of albuminuria [⁵⁰]. Dyslipidemia is an independent determinant of progression toward chronic kidney disease and is a known cardiac risk factor [⁵¹, ⁵²]. It also contributes to arterial micro-inflammation and atherosclerosis[⁵³]. From different perspective, the correction of lipid abnormalities can reduce albuminuria in subjects with the metabolic syndrome [⁵⁴], decrease inflammatory markers[⁵⁵], improve renal function[⁵⁶], increase arterial compliance[⁵⁷], improve left ventricular function [⁵⁵] and prevent CV events[⁵³]. It is noteworthy that obesity was not incorporated into our criteria since there is an opposite relationship between BMI and survival in CKD (reverse epidemiology) [⁵⁸] and therefore less obese patients with CKD reach to ESRD.

Hypertension is introduced as the leading risk factor of death according to WHO report of global health [⁵⁹].Hypertension and altered blood pressure circadian rhythm are common co-morbidities with diabetes and pre-diabetic states as well as kidney disease[⁶⁰]. BP is strongly associated with arterial stiffness and promotes left ventricular dysfunction[⁶¹] . In the setting of insulin resistance the vasodilatory effect of insulin can be lost but its renal sodium reabsorption stimulation is preserved. In addition, insulin-induced sympathetic activity increases the prevalence of hypertension in the metabolic syndrome [⁴⁴]. Furthermore, while salt sensitivity is associated with impaired glucose metabolism, oxidative stress, dyslipidemia and insulin resistance [⁶², ⁶³] ,it also increases efferent glomerular arteriolar tone and thereby raises glomerular capillary pressure and proteinuria [⁶⁴]. Moreover, salt sensitivity induces blood pressure abnormalities via renal sodium reabsorption and sympathetic overactivity[⁶⁵]. Therefore, the interlinking of salt-sensitivity and insulin resistance mechanisms with the clinical outcomes raises the possibility of another underlying mechanism joining these together.

Decreased arterial compliance is influenced by both atherosclerosis and arteriosclerosis, as well as functional arterial abnormalities [⁶¹, ⁶⁶]. It occurs very early in the process of kidney disease and DM [⁶⁷, ⁶⁸], even preceding microalbuminuria [⁶⁹] and has also been observed in normal individuals with a close family history of DM [⁶⁸]. Recent studies have illustrated that increased central arterial stiffness in hypercholesterolemia, even in newly diagnosed individuals, is associated with low-grade systemic inflammation [⁷⁰, ⁷¹]. Arterial stiffness in turn increases LV load and leads to ventricular stiffness and diastolic dysfunction [⁷², ⁷³]. It has also been suggested as the linking factor between renal impairment and CV diseases [⁷⁴]. Of great importance, decreased arterial compliance predicts mortality in variant patient groups, independently from other risk factors [^75-78].

Furthermore, albuminuria, arterial stiffness and intima media thickness increase with the increasing number of metabolic syndrome components even before fulfilling the diagnostic criteria for the syndrome, particularly amongst subjects with type 2 DM [⁷⁹]. In addition, alterations in BP circadian rhythm and BP profile including non-dipper nocturnal BP is now considered as a manifestation of arterial remodelling and is associated with other manifestation of endothelial dysfunction including mA and arterial stiffness.

is now accepted as a marker of renal, cardiac and arterial damage being predictive for the further development of CV events, renal failure and DM [⁴⁹, ⁷⁴]. It is also closely associated with the prevalence of anaemia [⁴³] , hypertension [⁸⁰] and metabolic syndrome components [⁷⁹]. Microalbuminuria commonly occurs early in subjects with abnormal glucose metabolism [⁶⁷, ⁸¹] and is correlated with dyslipidemia [⁸²], arterial stiffness [⁸³, ⁸⁴] and increased coagulability [⁸⁵] as well as inflammatory markers [⁸⁶, ⁸⁷]. Furthermore the presence of microalbuminuria predicts ventricular dysfunction, coronary heart disease and exercise intolerance [⁸⁸, ⁸⁹].

Kidney function can not be isolated from the health of the heart and arteries and is also associated with the metabolic syndrome components. Alterations in glomerular structure are seen very early in the obesity-mediated metabolic syndrome[⁹⁰] . Renal hemodynamic reserve is already impaired in patients with asymptomatic left ventricular dysfunction [⁹¹]. In addition, the kidney has an important role in insulin and glucose metabolism [⁹²]and insulin resistance has a predictive value for chronic kidney disease[⁴, ⁹⁰]. Renal function has been called the Cinderella of CV risk profile [⁹³] and the impact of even minor renal dysfunction on CV function is now well established [⁷⁴] with endothelial cell dysfunction is likely to be the linking factor between renal and cardiac disease[⁴⁹, ⁷⁴, ⁹⁴]. However endothelial dysfunction in turn is a consequence of inflammation and oxidative stress and is accelerated by these phenomena[⁹⁵] and is also correlated with a number of the metabolic syndrome components [⁷⁹]. Decreased arterial compliance increases ventricular wall tension and stiffness and consequently diastolic dysfunction[⁷³]. This in turn may lead to partial renal ischemia, followed by activation of the renin-angiotensin system and tubulointerstitial damage[⁹⁴]. On the other hand, hyperfiltration which is observed in the early stages of diabetic nephropathy and hypertension [⁹⁶, ⁹⁷], leads to increased glomerular pressure and resultant sclerosis which in turn accelerates hypertension[⁶⁰].

Anemia is a common finding in DM and has multifactorial mechanisms[⁴³]. Early tubulointerstitial occurs which disease decreases EPO production and moreover inflammatory cytokines reduce EPO responsiveness leading to anaemia[⁹⁸]. It is also associated with the level of albuminuria[⁴³] .Anaemia in turn, increases the progression toward CKD, oxidative stress, tissue ischemia, ventricular stress and mortality[^99-101]. Of interest, a recent study demonstrated the contribution of anemia to the frequent diastolic dysfunction in DM, as well as its association with brain natriuretic peptide (BNP) and suggested using this factor to identify diabetic patients at increased risk of cardiac dysfunction [⁹⁹]. Therefore, accumulating evidence has introduced anemia as an important risk factor for the circulatory system. On the other hand, correction of anemia improves the prognosis in chronic kidney disease, heart failure and DM and its complications as well as decreasing mortality [^101-103]

In contrast to the metabolic syndrome, ventricular function is proposed as an interactive part of the circulatory syndrome. This idea is supported by reports of a lack of a relationship between the metabolic syndrome and mortality in individuals who have good cardiorespiratory fitness [¹⁰⁴]. On the other hand even a mild stage of ventricular failure, as manifested by impaired exercise response is predictive for mortality [¹⁰⁵, ¹⁰⁶]. Ventricular function determines blood pressure and renal perfusion and in turn is influenced by kidney function, anemia and arterial stiffness and microalbuminuria [⁷³, ¹⁰⁷]. Diastolic dysfunction occurs early in DM, is correlated with arterial stiffness and affects exercise response [¹⁰⁸]. Furthermore, it has been reported that asymptomatic patients with type 2 DM have subclinical ventricular dysfunction which is related to glycated hemoglubin and LDL cholesterol [¹⁰⁹]. Also a recent in vitro study demonstrated that myocyte relaxation and Ca²⁺ handling are abnormal in early uremia, leading to uremic cardiomyopathy [¹¹⁰].

It is of great interest that some hypoglycaemic agents reduce blood pressure via suppression of the renin-angiotensin system and some ACE inhibitors can reduce insulin resistance in addition to reducing microalbuminuria and arterial stiffness, which raises the possibility of the presence of a common pathway for the adverse effects of hyperglycemia and hypertension[^111-113]. Likewise, some lipid lowering agents may exhibit mild anticoagulant and hypotensive effects [¹¹⁴] and angiotensin inhibitors have anti-inflammatory actions [¹¹⁵] which also indicate a possible common source of these abnormalities.

It could be expected that genetic predisposition including nephron underdosing, ACE gene polymorphism, congenital tubular defects and also some other factors such as aging, obesity and smoking produce organ damage susceptibility [⁴⁸, ^116-118].

The above evidence suggests that a genetic profile or a common pathologic process induces a network of metabolic (including alterations in glucose, salt, insulin and lipid metabolism) and hemodynamic abnormalities ( due to renin-angiotensin system stimulation, sympathetic overactivity and decreased nitric oxide bioavailability) which are followed by anaemia, hypercoagulability, tissue ischemia, arterial stiffness, hypertension, renal and cardiac dysfunction, the other features of the circulatory syndrome (Fig. 2).