Cardiovascular disease is a leading cause of morbidity and mortality. Is responsible for more than 17 million deaths worldwide every year 31 of total mortality, while in Europe this percentage rises up to 42% (1,2). It's a chronic disorder and usually by the time that symptoms occurred it's in advanced stage. CV disease is strongly related to life style (smoking, physical inactivity, unhealthy diet habits and stress) (3) as well as with several risk factors such as hypertension, diabetes, dyslipidaemia, obesity, and other conditions that present increased CV morbidity and mortality and tacked into consideration such as age, family history of premature coronary heart disease and endothelial dysfunction (2). Prevention and confrontation of these risk factors represents the cornerstone of CVD treatment. Usually, different risk factors are presented in the same patient. Although hypertension represents probably the most important and frequent risk factor, only 23% of those patients is free from additional risk factors (4). The majority of patients present overlapping risk factors (4). The coexistence of different risk factors increases exponentially the risk for CV morbidity and mortality. This phenomenon is well represented in patients with metabolic syndrome since they present a clustering of different risk factors were the risk of CVD is greater than the sum of its individual components (5,6). This led the Scientific Community to introduce the term of total (or global) CV risk factor with the purpose to assess and manage all the risk factors that every patient presents. This was accomplished with the introduction of different models, scores or charts that practically estimates the CV risk of every patient under investigation. The European Society of Hypertension use a model that takes into consideration the level of blood pressure, the presence of different risk factors, Diabetes, symptomatic Cardiovascular disease and target organ damage, in order to classify those patients in to low, moderate, high and very high risk according their chance to have a CV event over 10 years (7) Fig 1.
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Classical Risk factors
Although pulse pressure, abnormal glucose tolerance test and diabetes mellitus, metabolic syndrome, obesity and obstructive sleep apnea are established risk factors affecting CV morbidity and mortality, are discussed in other chapters of this manual. All classical risk factors shares common pathways promoting oxidative and mechanical stress inflammation inducing endothelial dysfunction, atherogenesis and atherothrombosis leading to tissue injury and CV disease with increased morbidity and mortality (Fig 2).
There is overwhelming evidence demonstrating the cardiovascular hazards of smoking or passive smoking and the benefits obtained with smoking cessation. Smoking practically triggers the atherogenic cascade through the activation of endogenous source of free radicals (Xanthine oxidace, uncoupled NOS,NADPH oxidace) or other oxidants that
cigarette smoke contains in abundance (8). Moreover promotes the inflammatory response (essential component for the initiation and progression of atherosclerosis), inducing vasomotor and endothelial dysfunction, smooth muscle proliferation, platelet and thrombohemostatic dysfunction leading to atherogenesis (8). Smoking and passive smoking modificates the lipid profile. Increases oxidative modification of LDL (9), decreases plasma high lipoprotein levels (HDL) and alters the HDL/LDL, HDL and total cholesterol as well as HDL/triglycerides ratios (10,11). Moreover, smoking induces abrupt increases of blood pressure as well as heart rate and stimulates sympathetic activity (12,13). Smoking cessation decrease significantly the risk of CV morbidity and mortality and within 10-15 years the risk approach that of never smokers (2).
In the Framingham study cholesterol as well as lipoproteins (LDL,HDL) are proven to be excellent predictors of cardiovascular morbidity and mortality (14). According this study, for every 1% increase of plasma cholesterol the risk of coronary disease rose from 2 to 3% while for every 1% decrease of cholesterol, there was a 2% decrease of risk for coronary disease. The concept of lipid lowering strategy is well known since several studies proved the benefits obtained from the control of lipid profile. Reducing LDL cholesterol more than 50%, seems to stop the progression or even leading to regression of coronary atherosclerosis (15). In patients with type 2 diabetes, lowering of LDL by 2-3 mmol/L with statin therapy, reduced the 5 year incidence for heart attack, revascularization and ischaemic stroke for about 40-50% (16). The benefit of LDL lowering strategy was significant also to non diabetic patients (16). In primary prevention (Jupiter trial), patients that reached LDL< 2.0 mmol/L had the lowest CV event rate (17). Participants randomized to rosuvastatin and achieved LDL cholesterol less than 1.8 mmol/L in comparison to placebo showed a 55% reduction in vascular events (17). Hypertension and dyslipidaemia frequently coexists. Nearly 52% of dyslipidemics suffers also from hypertension (18). The prevalence of combined hypertension and dyslipidaemia is increased in patients with diabetes mellitus (41%), with metabolic syndrome (37%), and in patients with self reported cardiovascular disease (44%) (19). This combination is more frequent in hypertensives than in normotensives subjects (20). According the ESC guidelines, the primary goal is to achieve target LDL levels according the total CV risk with all means (lifestyle changes or lipid lowering agents), independently the use or not of lipid lowering agents in order to decrease CV morbidity and mortality (2).
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Marked to Standard
Kidney disease is a world wide public health problem with increased morbidity and mortality. The definition of kidney disease is based on the presence of A) anatomical or structural component (markers of kidney damage, including albuminuria), (B) functional component (based on GFR), and (C) a temporal component (at least 3 months' duration of structural and/or functional alterations) (21).
Its association with increased CV events is well known from 4 decades (22). Evidence for this association was first recognized in dialysis patients were the incidence of CV death was extremely high (23,24). Patients with end stage renal disease (ESRD) showed 15 to 30 folds higher CV mortality than general population (23) and the percentage of death in this population reached approximately the 50% (23). However further studies, showed the magnitude of the problem since the presence of even minor renal dysfunction (expressed by the decrease of Glomerular Filtration Rate (GFR) and/or trace of microalbuminuria or proteinuria) increase the risk for CV events. The Joint National Committee (JNC-7) as well as the European Society of Hypertension-European Society of Cardiology (ESH-ESC) recognized as risk factors the estimated GFR (eGFR) value <60 ml/min per 1.73 m2 and microalbuminuria. (25,7). There are several studies affirming that these two factors have a major impact on CV events. In low risk patients, a study enrolled more than 1 million patients, was observed and independent graded association between eGFR and the risk of CV events, highlighting the clinical and public importance of renal impairment (26).
One in 13 hypertensive patients progress to hypercreatininemia every year (27).In patients with hypertension, data from HOT trial showed that patients with eGFR <60 ml/min per 1.73 m2 presented almost double CV events in comparison with patients with eGFR >60 ml/min per 1.73 m2 (28). In LIFE study, microalbuminuria was associated with increased CV events while during follow up, subjects with lowest CV events rates, presented a grater reduction of microalbuminurua after treatment. (29).In the Hoorn study, the relative risk of a CV death increased by 26% per 5 mL/min/1.73m2 lower GFR. (30). Regarding high risk patients, the HOPE trial showed a significant association between CV event and serum creatinine concentration. Patients with serum creatinine from 1.4 to 2.0 showed a higher hazard ratio (HR) by 40%, the presence of microalbuminuria increased the HR by 59%, and presence of both increased the HR by 108% (31). In heart failure patients, data from the PRIME II study showed that baseline GFR was a significant predictor of CV mortality, stronger and independent than impaired ejection fraction or NYHA class (32).
Patients with impaired renal function usually present multiple co morbidities and risk factors. Those patients present accelerated atherosclerotic disease, while the presence of diabetes or hypertension can be the cause or the consequence (for the last one) leading to an increased risk for CV morbidity and mortality. In addition, there is an activation of sympathetic nervous system with increased catecholamine turnover leading to increased CV events (33).Moreover, worsening of kidney disease is associated with changes in lipid profiles with increased oxidation of LDL, increased levels of triglycerides and decrease levels of HDL leading to dyslipidaemia (34). Kidney disease is associated with endothelial dysfunction were microalbuminuria also reflects this impairment (35).
Although there is overwhelming evidence associating renal impairement to increased CV risk there are also some concerns. In clinical practice, creatinine clearance is measured with 24-h urine collection. GFR can be estimated from serum creatinine levels using prediction equations like Cockroft-Gault or Modification of Renal Disease (MDRD), that take age, sex, race, and body weight into account. However, MDRD formula underestimates true GFR above 60 ml/min/1.73 m2 (36) while Cockroft-Gault equation overestimates measured GFR in people with normal renal function (37). Recent meta analysis investigating several blood pressure level targets in patients with CKD failed to demonstrate definite benefits in terms of renal or CV outcomes (38,39). Finally, it's uncertain if the reduction of albuminuria at least in individuals without markedly reduced GFR improves clinical outcomes (40-42).
The sympathetic nervous system (SNS) plays a significant role in cardiovascular homeostasis. Exerts long term circulatory control and affects regional blood flow however, inappropriate activation increases cardiovascular morbidity and mortality (43).
SNS activity is more pronounced in patients with arterial hypertension, kidney disease, obesity, metabolic syndrome and sleep apnea syndrome. SNS overactivity holds also a key physiopathological role in heart failure, acute coronary syndromes and arrhythmias (44-47). Sympathetic overactivity can be the cause or the consequence of these conditions and the trigger effect cannot be easily distinguished. Inhibition of sympathetic overactivity by various means, including central SNS suppressing drugs, peripheral alpha- and beta- adrenergic receptor blockers, or novel approaches as renal sympathetic denervation have been used successfully in the treatment of all these disorders. In 1940s ganglionic blocking drugs were used as alternatives to sympathectomy (48) and becomes the first effective antihypertensive drug cluss (49). Subsequently and until the era of inhibition of the rennin-angiotensin-aldosterone system (RAAS), primary treatment of hypertension was based on central sympathetic inhibitors clonidine, reserpine and alpha methyldopa, followed by the alpha and beta adrenergic receptor (AR) blockers (49). The emergence of newer antihypertensive drugs placed the central acting drugs to the sidelines however there are several conditions were therapy decrease also sympathetic activity with an additional benefit since SNA plays an important role in the development and the progression of the diseases mentioned above. Although evidence concerning the benefits of alpha blockers and central acting agents are limited seems to have favorable metabolic effects and decrease blood pressure adequately (50) however they don't represent the 1st choice for antihypertensive treatment. B blockers blocks alpha and beta adrenoreceptors (depends from cardioselectivity) modulating sympathetic activity (51). In hypertension are used alone or in combination reducing CV morbidity and mortality. In a meta analysis that included STOP hypertension -2 (diuretics or b-blockers vs. ACE-inhibitors vs. dihydropiridine calcium channel blockers), (UKPDS) (atenolol vs. captopril), NORDIL (thiazide or b-blocker vs. diltizem) and (CAPP (diuretics or b-blockers vs. captopril) b blockers offered similar CV protection when compared with ACE inhibitors, diuretics or calcium channel blockers (52). Moreover, b blockers are used in a variety of diseases (Ischemic heart disease, Heart failure, Arrhythmias) decreasing CV morbidity and mortality (51). The decrease of sympathetic activity is used also in other therapeutic practices like renal denervation and carotid baroreceptor stimulation decreasing blood pressure in those patients. In the simplicity HTN-1 and HTN-2 study, renal denervation decreased significantly blood pressure in patients with resistant hypertension demonstrating the significant role of sympathetic activity in hypertension (53,54). Carotid baroreceptor stimulation also decreases sympathetic activity with sustained changes on blood pressure and heart rate variability. Several studies induced in patients with resistant hypertension showed the beneficial effect of this method decreasing sympathetic activity however further studies are needed to demonstrate the beneficial effect beyond blood pressure control of these methods (55,56).
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SNA can be decreased also non invasively using devices like nasal C-Pap in patients with Obstractive Sleep Apnea (OSA). Several studies showed that the use of nC-PAP decrease sympathetic activity as well as blood pressure (57-60). In a study enrolled more that 1500 patients with OSA and followed up for about 10 years, the use of nasal cPAP decreased significantly the risk of CV events in patients with severe OSA (60). The decrease of CV events are attributed also to the decrease of inflammation and endothelial dysfunction were however SNA plays a significant role (59).
Risk factors and concerns
In general, risk factors not only have to prove their prognostic importance, they must have an addictive value and improve the accuracy to quantify future CV events.
C reactive protein (CRP) is considered as an important inflammatory risk factor, associated with increased CV morbidity and mortality (61).Jupiter trial provided evidence for the stability of hsCRP over the time on moth to moth or year to year basis similar to that of LDLc fact that has been observed also in other studies (17,62,63). In addition Jupiter trial showed that low on treatment levels of hsCRP is associated with better clinical outcome (17). In a sub study o LIFE trial, hsCRP had a significant prognostic value but it wasn't independent from urine albumin/creatinine ratio (29). However, there are several concerns. In the Framingham study (64), CRP and other inflammatory markers didn't showed a considerable improvement in the assessment of total CV risk. In general this risk factor seems to have low specificity, is costly (compared with others biological risk factors), doesn't have any specific agents (targeting CRP) that decrease CV events and have many confounders (2).
According to National Academy of Clinical Biochemistry hsCRP assessment should be done in patients with metabolically stable state, free of infection or acute illness, while hsCRP measurement might be useful for further stratification into a higher or lower risk category in intermediate risk patients (10%-20%) with uncertainty as to the use of preventive therapies such as statins or aspirin (65)
Homocystein is a marker of endothelial function and oxidant stress. Several studies associate increased levels of homocystein with increased CV events (66). However, there are several confounder parameters (lifestyle, metabolic, nutritional)(2). Moreover, there are several causes that can increase homocystein like vitamin deficiency (B12, B6, folic acid), the use of certain medications, impaired renal function and smoking (67-69).