CARDIOMETABOLIC SYNDROME

Transcription

1 CARDIOMETABOLIC SYNDROME Prof. Gerald Yonga FESC, FACC Dept of Medicine, Aga Khan University East Africa

2 Introduction Years after the term metabolic syndrome was first coined, controversy continues over the validity of naming and treating this clustering of certain risk factors as a separate condition. While different organizations use different definitions, metabolic syndrome is generally defined as having any three of the following: increased waist circumference, elevated triglycerides, reduced HDL cholesterol, elevated blood pressure, or elevated fasting glucose.

3 Metabolic Syndrome Controversies Is it the sum total or individual parts that are important? Is it just a pattern of risk factor clustering without a common basis or common importance? Is there sufficient evidence supporting common pathologic mechanism? Is there a genetic basis? Does it identify people for aggressive lifestyle intervention? Does it carry predictive power of CVD and diabetes over one s lifetime?

4 Definition of metabolic syndrome

5 Simmons RK et al Diabetologia 2010 Apr 53(4): The metabolic syndrome has little utility as a diagnostic or management tool. 2. The different definitions of the metabolic syndrome hamper its epidemiological utility, though it can be used as an educational concept. 3. It should not, however, be applied as a clinical diagnosis, and should instead be considered as a pre morbid condition.

6 Dr Scott Grundy (University of Texas Southwestern Medical Center, Dallas) Metabolic syndrome is a valid concept, Metabolic syndrome has not proved to be great for predicting more serious disease. "It's not meant to be a predictive tool. Over a lifetime, metabolic syndrome does carry a tremendous predictive power of cardiovascular events and of diabetes. But it shouldn't be the main predictive tool. A risk analysis based on traditional risk factors will tell us whether to prescribe statins or not. CMR is more about identifying a group of patients to whom aggressive lifestyle advice can be targeted."

7 Racial differences Patients with normal body mass indexes may still have elevated waist circumferences that meet the ATP III risk criteria for metabolic syndrome. Blacks have high rates of hypertension even without considering metabolic syndrome, and they may have more disease risk than other populations. Hispanics have an increased risk of diabetes associated with metabolic syndrome. Criteria may not be sufficient to diagnose metabolic syndrome in Asian Americans as a result of different body types.

8 Obesity & Insulin resistance In expanded adipose tissue, free fatty acids (FFA) stimulate increased production of glucose, triglycerides, LDL C, and VLDL C from the liver, along with reductions in HDL C. FFA also induce insulin resistance of skeletal muscle, inhibiting insulin mediated glucose uptake and storage as glycogen. The resulting increase in circulating glucose and FFA stimulate pancreatic insulin secretion, which enhances sodium re absorption and sympathetic nervous system drive, resulting in high blood pressure.

9 ÁDISOPATHY Adiposity may cause adipocyte and adipose tissue anatomic and functional abnormalities, termed adiposopathy Adipose opathy or sick fat, result in endocrine and immune derangements. Adiposopathy may directly contribute to CVD through pericardiac and perivascular effects on the myocardium and blood vessels. Adiposopathy may also indirectly contribute to CVD through promoting or worsening major CVD risk factors such as type 2 diabetes mellitus, high blood pressure, and dyslipidemia.

10 Pathogenic adipose tissue & CVD

11 Common embryonic origin: heart, vessels & adipose tissue

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13 Microalbuminuria, CKD, MS & CHD

14 Obesity, cardiac dysfuntion & aging Obesity associated effects on load induced, apoptotic, and mitochondrial genes observed in rat atrial cardiomyocytes reflect the situation in the ventricles. Premature cardiac aging together with premature metabolic disturbances and mitochondrial dysfunction in obesity?contribute to the development of new therapeutic strategies.

15 Inflammation in obese adipose tissue (Wellen et al J Cin Inv 2003,112;1785)

16 Genes and Environment There is evidence for a genetic contribution to CMS from observations in twins and families. In addition, single gene human models and genetic association studies have identified multiple genes associated with the phenotypic expression of CMS. However, no genomic DNA markers have been identified and no genetic test is currently available in the diagnosis or treatment of CMS. The influence of ethnicity and sex and the interaction of genes with environmental factors (calorie excess, physical inactivity) will likely influence the phenotypic expression of CMS and complicate the genetic associations that can be made.

17 CV Risk associated with Metabolic syndrome Systematic review + meta analysis of 87 studies involving >950,000 patients MS associated with 2X increase in CV outcomes (RR 2.35) MI (RR 2.0), Stroke (RR 2.3) 1.5X increase in all cause mortality (RR 1.58), 2X increase in CV mortality (RR 2.4) Studies still needed to elucidate mechanisms of the CV risk increases & if prognostic significance of MS exceeds sum of individual components. (JACC 2010, 56: )

18 Adjusted odds ratio for MI associated with metabolic syndrome or its component factors Risk factor OR (95% CI) Metabolic syndrome (WHO definition) 2.69 ( ) Metabolic syndrome (IDF definition) 2.20 ( ) Diabetes 2.72 ( ) Hypertension 2.60 ( ) Abdominal obesity (WHO definition) 1.64 ( ) Abdominal obesity (IDF definition) 1.32 ( ) Low HDL 1.30 ( ) Mente A et al. J Am Coll Cardiol 2010; 55:

19 Data from Shepherd, J, Cobbe, SM, Ford, I, et al, N Engl J Med 1995; 333:1301.

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21 Diabetes Mellitus Insulin resistance, hyperinsulinemia, and elevated blood glucose are associated with atherosclerotic CVD The 2002 NCEP report designated DM to be a CHD equivalent

22 Diabetes and CV risk In the INTERHEART study, diabetes accounted for 10% of the population attributable risk of a first MI. In the Copenhagen Heart Study, the RR of incident of MI or stroke was increased 2 3 fold in those with type 2 diabetes, and the risk of death was increased 2 fold, independent of other CHD risk factors. A significant number of patients with an acute MI have previously undiagnosed diabetes. Diabetics have a greater burden of other atherogenic risk factors, including hypertension, obesity, increased total to HDL cholesterol ratio, hypertriglyceridemia, and elevated plasma fibrinogen

23 Blood Pressure Hypertension is a risk factor for adverse cardiovascular outcomes, including CHD mortality and stroke. In the INTERHEART study, hypertension accounted for 18% of the population attributable risk of a first MI. Systolic blood pressure and isolated systolic hypertension are major risk factors at all ages in either sex.

24 SBP Associated Risks: MRFIT SBP versus DBP in Risk of CHD Mortality CHD Death Rate Diastolic BP (mm Hg) <70 < Systolic BP (mm Hg) Adapted from Neaton JD et al. Arch Intern Med. 1992;152:56-64.

25 Chronic Kidney Disease The 2002 National Kidney Foundation/ACC/AHA task force in 2004 recommended that CKD be considered a CHD risk equivalent Mild to moderate renal dysfunction is associated with a substantial increase in CHD risk. An estimated GFR that is <60 ml/min/1.73 m2 or proteinuria >1g/day to have sufficient increased cardiovascular risk to be considered a CHD risk equivalent The ARIC study, the Cardiovascular Health Study, and the Framingham Heart and Offspring Studies demonstrated that CKD was associated with increased number of adverse cardiac outcomes

26 OTHERS Microalbuminuria reflects vascular damage and appears to be a marker of early arterial disease. A number of studies have shown that microalbuminuria is an important risk factor for CVD and early cardiovascular mortality ( HOPE, LIFE, PREVEND trials) HIV infection The risk of CVD in HIV positive patients is predominantly influenced by the presence of traditional CVD risk factors. However, studies correcting for traditional CVD risk factors have shown higher rates of CHD and MI in HIV positive patients compared to HIV negative controls. Mediastinal radiation

27 CRP The baseline level of inflammation, as assessed by the CRP, predicts the long term risk of a first MI, ischemic stroke, or peripheral arterial disease. Measurement of CRP levels improves risk stratification. A statement from the CDC and the AHA published in 2003 concluded that, in patients at intermediate risk for CHD, serum hs CRP may, at the discretion of the physician, help direct further evaluation and therapy for primary prevention. Cardiovascular risk has also been associated with a variety of other markers of inflammation, further supporting the role of inflammation in atherosclerosis.

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29 MULITIVARIATE RISK MODELS Developed for estimating the risk of cardiovascular events in apparently healthy, asymptomatic individuals based upon assessment of multiple variables. Estimate risk of an individual over the next 10 years. Many of the risk factors (eg, age, hypertension, serum LDL cholesterol) are recognized as producing a graded increase in risk. Risk factor assessment is useful in adults to guide therapy for dyslipidemia, hypertension, and diabetes

30 RISK SCORE MODELS Framingham risk scores SCORE QRISK and QRISK2 Reynolds risk score ASSIGN

31 FRAMINGHAM RISK SCORES 1998 incorporated age, gender, LDL cholesterol, HDLcholesterol, blood pressure (including whether the patient is treated or not), diabetes, and smoking to derive an estimated risk of developing CHD (MI, coronary death, and angina) within 10 years modifications include elimination of diabetes from the algorithm, since it was considered to be a CHD equivalent, broadening of the age range, and inclusion of hypertension treatment and age specific points for smoking and total cholesterol 2008 include the potential adverse consequences of atherosclerosis, such as stroke, transient ischemic attack, claudication and heart failure

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33 ATP III Framingham Risk Scoring Step 1: Age Years Points Step 2: Total Cholesterol Assessing CHD Risk in Men TC Points at Points at Points at Points at Points at (mg/dl) Age Age Age Age Age < Step 280 3: HDL-Cholesterol HDL-C (mg/dl) Points <40 2 Step 4: Systolic Blood Pressure Systolic BP Points Points (mm Hg) if Untreated if Treated < Step 5: Smoking Status Points at Points at Points at 10 Points 6% at Points at Age Age Age Age Age Nonsmoker Smoker Note: Risk estimates were derived from the experience of the Framingham Heart Study, a predominantly Caucasian population in Massachusetts, USA. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285: Step 7: CHD Risk Point Total 10-Year Risk Risk Step 6: Adding Up the Points Age Total cholesterol HDL-cholesterol Systolic blood pressure Smoking status Point total Point Total 10-Year <0 <1% 11 8% 0 1% 12 10% 1 1% 13 12% 2 1% 14 16% 3 1% 15 20% 4 1% 16 25% 5 2% 17 30% 6 2% 7 3% 8 4% 9 5%

34 SCORE RISK Recommended in the 2007 European Society of Cardiology guideline. Variables incorporated into the model included age, gender, systolic blood pressure, total cholesterol, HDL cholesterol, and cigarette smoking.

35 QRISK & QRISK2 The QRISK and the updated QRISK2 algorithms were developed to predict cardiovascular risk in patients from different ethnic groups living in England and Wales. The QRISK2 algorithm included risk predictors used in the modified Framingham/ATP III model, as well as ethnicity, socioeconomic status, family history, and other medical variables such as DM, CKD, atrial fibrillation, and RA. QRISK2 more accurately identified those at risk than the modified Framingham/ATP III model in this population.

36 REYNOLDS RISK SCORE It includes all the variables in the Framingham risk scores as well as the level of high sensitivity C reactive protein (hs CRP) and parental history of MI before age 60. In addition to MI, coronary revascularization and cardiovascular death, the patient important outcome of stroke is counted.

37 Primary Prevention Strategy Recognition that : a)major risk factors for CVD are preventable. b)atherosclerosis is Inflammatory process with potential targets halt or modify the process. Cholesterol lowering Smoking cessation Hypertension control Physical activity

38 AHA Guidelines for Primary Prevention of CVD and Stroke: 2002 Update Risk Assessment Beginning age 20: Circulation 2002; 106: Regularly assess family history, smoking status, diet, alcohol intake, and physical activity BP, BMI, waist circumference, pulse assessed at last every 2 years; fasting lipid profile and glucose measured every 5 years (2 yrs if other risk factors present. Beginning age 40: Assess 10 year risk of CHD using a multiple risk factor score (start younger if 2+ risk factors present); those at greater than 20% risk considered CHD risk equivalent

39 Screening for CVD in asymptomatic adults 1 (Berger et al JACC 2010, 55: Greenland et al JACC 2010, Nov 15 th ) Lifetime risk of atheroslerotic CVD for persons aged 50yrs is estimated at averages of 52% for men and 39% for women Framingham risk score of probabilty of CV events over 10yrs does not take into account other risk markers (e.g. FH, hscrp,), varies in low high risk cohorts & inaccurate for Asians & Europeans. Other risk score exist (Renolds, ASSIGN, QRISK, MESA etc) CV testing (ABI, CAC, Carotid IMT, stress ECG) may be of value in supplememting risk stratification in individual patients In the absence of inflammatory disorders, CRP may be useful in men >50 yrs & women >60yrs with LDL C <3.4mmol/L to decide on statins & those at intermediate risk (10 20%) to further risk stratify.

40 Screening for CVD in asymptomatic adults 2 (Berger et al JACC 2010, 55: Greenland et al JACC 2010, Nov 15 th ) HBA1c testing may be used in adults without diabetes Microalbuminuria testing can be used for CV risk assessment in intermediate risk, HTN & Diabetics Echo may be considered to asses LVH in adults with HTN Resting ECG recommended in adults with HTN or diabetes, & EST in intermediate risk, particularly sedentary ones planning to start exercise CAC measurement & carotid IMT may be useful at intermediate risk &CAC may also be helpful low intermediate risk (6 10%) and diabetics >40yrs old. Stress MPI considered for advanced CV risk assessment diabetics, strong family hx & if other testing suggest high risk (e.g. CAC score >400 ). No evidence to support genomic testing, CAC score in v. low risk; CTCA or MRCA plaque imaging for risk assesment; stress echo or stress MPI in low or intermediate risk.

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42 Use of Aspirin in Diabetes Patients Experiencing Cardiovascul ar Events (%) % 4% 22% 18% 12% 9% 0 Placebo ASA Placebo ASA Placebo ASA US MDs* APT ETDRS * Physician s Health Study (US MDs); relative risk (RR) = 0.39 (NS), NEJM 1989 Antiplatelet Trialists Collaboration (APT); 2 P < 0.002, BMJ 1994 Early Treatment Diabetes Retinopathy Study (ETDRS); relative risk (RR) = 0.83 (P = 0.04), JAMA 1992

43 n=1,564 University of Pennsylvania Alumnae Risk of CVD 16% 33% < 3 Miles per Week Am J Epidemiol 150: , Miles per Week > 6 Miles per Week

44 Conclusions The cardio metabolic metabolic syndrome consists of a constellation of metabolic abnormalities that confer increased risk of cardiovascular disease (CVD) It is a useful predictor of lifetime risk Identifies patients who will benefit from aggressive risk factor control Various risk models are used to estimate CVS events Local risk models & intervention strategies need to be developed

45 Conclusion! You gotta be crazy to imagine that obesity, dyslipidaemia, diabetes and hypertension have nothing in common! Not to have a strategy to deal with cardiometabolic risk is simply criminal! It is against the new constitution of the Republic of Kenya Love you, Gerald