notes by dr Claudio Italiano
Among the most important risk factors for cardiovascular disease are diabetes mellitus, hypertension, hypercholesterolemia, smoking and abdominal obesity.
It is important to
recognize early the presence of these factors, which are often associated
together. The control of cardiovascular risk factors has a positive
impact on events if such control is adequate. It is important to know and use
the new markers for the assessment of atherosclerosis, among which the high
sensitivity PCR stands out.
Talk to your doctor and regulate the values of pressure, cholesterol,
triglycerides, diabetes control and visceral obesity. Make movement.
The consecutive evolutionary stages of atherosclerosis include the formation and
growth of atherosclerotic plaque and the subsequent destabilization predisposing
to its rupture and subsequent intravascular thrombosis.
The inflammatory process that leads to the development of atherosclerosis
recognizes several risk factors, distinct in environmental and genetic. Among
these, treatable or modifiable risk factors (such as smoking, dyslipidemia,
hypertension and diabetes) are the cornerstone of medical intervention, both
pharmacological and non-pharmacological. Among the most important risk factors
for cardiovascular disease there is certainly arterial hypertension.
The linear correlation between cardiovascular mortality and pressure increase is
now well known. For example, for each increment of 20 mmHg of systolic pressure
or 10 mmHg of diastolic pressure, the risk of cardiovascular mortality doubles.
Even small increases in pressure increase the risk: for example, 2 mmHg
increases in pressure increase the risk of coronary mortality by 7% and 10% of
strokes.
Treatment of arterial hypertension reduces cardiovascular complications. The combined results of 17 randomized trials, placebo active treatment, with an average duration of 3-5 years, showed a reduction in blood pressure of about 10-12 mmHg for systolic and 5-6 mmHg for diastolic in active treatment. These effects have led to significant benefits for all the higher end-points, but more evident in terms of reduction of heart failure and stroke.
A very recent meta-analysis of large pharmacological trials demonstrates how
important it is to reduce the pressure, regardless of the drug used. In fact,
there were no differences between the various classes of antihypertensive drugs
in terms of prevention of events, especially as regards the effect on coronary
heart disease. Even small diastolic pressure reductions in the general
population could have a major impact in terms of reduction of stroke and
coronary events.
Data from the Framingham Heart Study, longitudinal cohort study and the
National Health and Nutrition Examination Survey (NHANES II), were used to evaluate the
impact of a population strategy aimed at reducing diastolic blood pressure by an
average of 2 mmHg. This reduction has been shown to be associated with a 6%
reduction in the risk of coronary events and 15% of strokes and TIAs.
The
so-called high-normal pressure is also important, as it is associated with
increased cardiovascular risk. The association between baseline pressure and
incidence of cardiovascular events in follow-up was studied in 6,859
participants in the Framingham Heart Study initially free of hypertension and
cardiovascular disease. The 10-year cumulative incidence in subjects aged 35-64
with normal-high pressure at baseline (systolic blood pressure: 130-139 mm Hg,
diastolic blood pressure: 85-89 mm Hg) was 4% in women and 8% in men. In 65-90
year olds, the incidence of cardiovascular events was 18% in women and 25% in
men. Compared to subjects with optimal pressure, subjects with normal-high
pressure had a relative risk of 2.5 in women and 1.6 in men.
Evaluate blood pressure at each visit
Always recommend lifestyle change
Treatment goal: bring patients to target:
<140/90 mmHg; <130/80 mmHg in diabetic
patients and at elevated or very high cardiovascular risk or in the presence of
associated clinical conditions (stroke, myocardial infarction, renal damage and
proteinuria)
The combination of multiple drugs is usually necessary to obtain optimal results
on the tensile values
Take into account the need to promote patient adherence to therapy. Early
prevention of atherothrombotic disease is essential and is carried out by
controlling the main risk factors.
Cardiovascular risk factors
- Age
- Sex
- Family history of coronary artery disease or other early atherosclerotic
disease (males <55 aa, females <65 yy)
- A history of coronary artery disease or other atherosclerotic disease
- Lifestyles
- Hypercaloric diet o
- Avoid saturated fats and cholesterol. In fact, the diet must tend to reduce
the intake of foods rich in LDL cholesterol: saturated fats (<7% of total
calories), dietary cholesterol (<200 mg/day); there are also therapeutic
options for lowering LDL cholesterolemia, such as stanols and plant sterols (2 g
/ day), intake of soluble viscous fibers (10-25 g / day), weight loss (7-10% in
one year) and increased physical activity (30 min / day for 5 days / week).
- Additional dietary factors are represented by a diet rich in polyunsaturated
fatty acids (linolenic acid n-6 and n-3) N-3 (omega 3) polyunsaturated fatty
acids, Vitamins, Antioxidants, Alcohol in small quantities such as red wine ,
oligomineral elements (sodium, potassium, calcium)
- Avoid smoking in fact The smoke risk factor is responsible for the majority of
heart attacks that strike before the age of fifty.
- It has been calculated that the presence of smoking among the risk factors of
atherosclerosis anticipates ten years of the occurrence of the first
cardiovascular event.
- Avoid excessive consumption of alcohol
- Avoiding a sedentary lifestyle
- Hypertension
-High LDL-cholesterol.
Then there is another important risk factor for cardiovascular diseases: cholesterol. From an epidemiological point of view, the correlation between increased plasma cholesterol levels and an increased likelihood of coronary events is clear and defined. In fact, most of the studies conducted show that the increase in total cholesterolemia is associated with a progressive increase in the risk of these diseases. As for the pressure, the relationship appears without a "threshold" level; in fact, there is no value of the cholesterolemia below which the correlation with the risk of coronary events is less. The correlation, therefore, is "continuous and increasing": a situation that implies a reduction of the coronary risk consequent to a reduction of cholesterolemia, whatever the starting value of the same.
Analyzed in greater detail, as is known, the correlation between cholesterol and coronary events can be decomposed into a negative component, correlated with the value of LDL atherogenic cholesterol, and in a protective vice versa, correlated to the value of HDL antagonist cholesterol. This slide, taken from observations made in the Framingham study, shows how a progressive decrease in coronary risk is associated with increasing the value of HDL cholesterol. This decrease is observed for any LDL cholesterol value, which the opposite correlates directly with the risk of disease. It is therefore necessary to take into account these two parameters at the same time to precisely define the lipid risk of coronary heart disease. HDL is highly correlated with LDL levels and cardiovascular risk. Epidemiological studies have shown a close correlation between levels of HDL cholesterolemia and risk of cardiovascular events, independent of LDL cholesterol levels. In the PROCAM study, at the same LDL cholesterol levels, the incidence of myocardial infarction at 10 years was higher in subjects with lower levels of HDL cholesterolemia. Numerous studies have shown the benefit of LDL cholesterol reduction <100 mg / dl and, in very high risk cases <70 mg / dl. These are the indications of the modern Guidelines, especially for the patient with major cardiovascular events and for the diabetic with organ complications.
It is not sufficient to act on LDL to effectively prevent cardiovascular events.
In the pathogenesis of atherosclerosis, HDLs also play a fundamental role at
different levels. Multiple atheroprotective effects have been attributed and
demonstrated against HDL over the last twenty years, some of which are
synergistic with each other.
Among the most important: 1) the central role of HDL in the process of reverse
transport of cholesterol from peripheral cells (eg macrophages in
atherosclerotic plaque) to the liver; 2) the ability of HDL to protect against
oxidative stress, which includes not only the protection of LDL from oxidative
modifications, but the protection against cellular damage caused by oxidized
LDL; 3) the anti-inflammatory effects of HDL on monocytes and more generally on
the cellular component of the vessel wall; 4) the ability of HDL to positively
influence arterial vasodilation through their prolongation action on the plasma
half-life of prostacyclin; 5) the ability of HDL to reduce platelet aggregation;
6) the ability of HDL to reduce the production of adhesion molecules by the
endothelium (VCAM-1, ICAM-1, selectin-E) and decrease the recruitment of
inflammatory cells within the arterial wall.
Accelerated atherosclerosis that characterizes diabetes mellitus begins years before a hyperglycaemia occurs More than 50% of subjects newly diagnosed with diabetes mellitus already have ischemic heart disease. The risk of adverse cardiac events is 2 to 4 times higher in diabetics than in non-diabetics. Diabetes mellitus is another important cardiovascular risk factor. Diabetes is one of the most important causes of death, but also of complications, such as nephropathy and retinopathy. It should be emphasized that vascular alterations in the diabetic start to develop even before the onset or the actual diagnosis of the disease. Atherosclerosis accounts for at least 70% of deaths in diabetes mellitus (45% for ischemic heart disease, 15% for other cardiovascular disease, 10% for stroke). Today it is recognized that all patients with atherosclerotic vascular disease should be screened for the presence of diabetes mellitus. In case of diagnostic doubt, the oral loading test with glucose must be performed, while the glycosylated hemoglobin dosage is of no use for diagnostic purposes, but it is necessary to evaluate the metabolic compensation status in the patient with diabetes mellitus. All patients with atherosclerotic vascular disease should be screened for the presence of diabetes mellitus. In case of diagnostic doubt proceed to the oral loading test with glucose. The control of glycosylated hemoglobin is not useful for diagnostic purposes, but it is necessary to evaluate the state of metabolic compensation in the patient with diabetes mellitus: the target is to keep it below 7%.
Adipose tissue produces a wide range of hormones and cytokines involved in
glucose metabolism (eg adiponectin, resistin), lipid metabolism (eg ester
cholesterol transfer protein, CETP), inflammation (eg TNF-a, IL -6), coagulation
(PAI -1), blood pressure (eg angiotensinogen, angiotensin II), and in dietary
behavior (leptin) thus influencing the metabolism and function of many organs
and tissues including the muscles, the liver, the vessels, and the brain. The
synthesis of adiponectin is reduced in obese subjects, resistant to insulin,
with metabolic syndrome, and with type 2 diabetes.
Thrombogenic factors
- According to recent estimates worldwide, the mortality due to hypertension
amounts to 7.6 million people, confirming the enormous epidemiological impact of
this cardiovascular risk factor. Here are some of the so-called emerging risk
factors. Some of them are more studied and of greater weight, while others are
still objects of study. For some of them the efficacy of their reduction
determined by the therapy has not been demonstrated, for others the reference
values are missing and the target values have not been defined.
The exact physiological role of LP (a) is not yet clear: it probably has a protective function against oxidative stresses of various kinds; on the surface it is composed of apolipoprotein B-100 (Apo-B100) and would act as scavenger of oxidized LDL. In a context of chronic oxidative stress, a high circulating level of LP (a), with its oxidized lipid content, becomes pro-atherogenic. Low blood levels (genetically determined) of LP (a) were observed in the ultracentenarians (relationship with longevity?). High (genetically determined) levels of LP (a) are associated with an increased risk of cardiovascular events. In a study conducted in the USA on a large population of about 6,000 elderly subjects (> 65 aa), apparently healthy, it was found that elevated values of LP-a constitute an independent predictor of risk of cardio and cerebrovascular events in male subjects . The usefulness of the use of LP-a as a screening test to estimate the cardiovascular risk of the elderly male population is still under investigation. The figure shows precisely the Kaplan-Meier survival curves in men, based on quintiles of lipoprotein-a levels.
Homocysteine is an intermediate derivative of the methyl metabolic pathway.
The latter is an essential amino acid that, when activated at
S-adenosyl-methionine, yields methyl groups to a series of recipients -
including creatine, steroid hormones, the purine bases of DNA and RNA - coming
transformed into homocysteine. Homocysteine can, in turn, be irreversibly
trans-sulphured into cystathionine and then into cysteine, or, in methionine
deficiency taken with the diet, remitted to methionine.
A series of enzymes and cofactors regulate these metabolic pathways. For the
trans-sulphuration process, the fundamental enzyme is cystathionine β-synthase
(CBS), which requires the pyridoxal-phosphate (PLP) or vitamin B6 cofactor,
while a greater number of enzymes - and cofactors - plays a role fundamental in
the remiliation of homocysteine. The methyl donor is, in this case, the
5-methyltetrahydrofolate (MTHF), in turn regenerated by methylene
tetrahydrofolate reductase (MTHFR), and the reaction is catalyzed by the
methionine synthase (MS) which needs, as a cofactor, transcobalamin ( vitamin
B12 methylated). Since methionine synthase is inactivated during the reaction,
it is necessary the intervention of methionine synthetase reductase,
riboflavinadependent, to regenerate active methionine synthase. An alternative
route of remethylation involves betaine, as a methyl donor, and the
betaine-homocysteine methyltransferase (BHMT) enzyme. Trans-sulphuration of
homocysteine and its betaine-dependent remethyling are thought to occur
exclusively in the liver, and the pathway of remethylation-folate and vitamin
B12 dependent is the only metabolic transformation of homocysteine operating
in peripheral cellular districts. When saturation of the metabolic pathways
occurs, the excess intracellular homocysteine is exported to the circulation,
where it is bound to plasma proteins or is eliminated, mainly from the kidney.
In a prospective cohort study, the association between homocysteine and
mortality was investigated: homocysteine levels> 9 μmol / L correlate with an
increased risk of death for both cardiovascular and non-cardiovascular causes,
in men and women: therefore homocysteine it is a nonspecific predictor of
mortality. Furthermore, in two large prospective studies, the administration of
B12, B6, folic acid in subjects with hyperhomocysteinemia did not reduce the
incidence of cardiovascular events (in particular, coronary).
PCR is a marker of inflammation.
The definition of the pathophysiological role of PCR has enabled the clinician to improve the management of the patient at cardiovascular risk. In fact, high values of hs-PCR (≥2 mg / L) correlate positively with an increase in cardiovascular risk; inserting this parameter within the Framingham algorithm improves its prognostic value; recently it has been clearly demonstrated that inflammation at the arterial level is a key element of the atherosclerotic process. In the last thirty years, the events involving the formation of lesions and the progression towards clinical outcome have been clarified at the molecular and biological level. PCR is a strongly predictive marker of cardiovascular events. PCR and LDL cholesterol are complementary markers for the identification of cardiovascular risk subjects.
The addition of PCR to the Framingham algorithm improves its prognostic value. PCR adds prognostic information to the risk levels defined by the Framingham algorithm. The PCR has been studied for the research of possible associations with the development of coronary artery disease. In this analysis performed in the "Women's Health Study" both the Framingham score and the PCR level were predictors independent of the coronary risk. High levels of PCR were predictors of the development of coronary artery disease in all categories of global risk. Participants in the Women's Health Study are a very low risk population of coronary artery disease (2% in the 10 years of follow-up).
The association of
high levels of PCR and high levels of LDL confers the worst risk. Therefore, the
determination of PCR. It should be used predominantly in intermediate risk
subjects, such as the American Heart Association and Centers for Disease Control
and Prevention recommended in their guidelines published in 2003. Recent
evidence from an Italian epidemiological study confirms the importance of PCR as
a marker for systemic inflammation and atherosclerosis, especially when
associated with obesity. In the InChianti study, which enrolled 1,044 elderly
aged ≥65 years, high values of PCR-hs (> 3 mg / L) were found more frequently
in subjects with metabolic syndrome (55 vs. 41% of subjects without metabolic
syndrome). It seems that in elderly individuals the metabolic syndrome is
associated with a slight degree of systemic inflammation; It is interesting to
note that among the various components of the metabolic syndrome the most
important determinant of systemic inflammation is an increased abdominal
circumference, that is fat visceral obesity.
- In particular, the key role played, in all process evolution, has emerged from
the PCR involved starting from the initial phases of atherosclerosis where it
sustains endothelial dysfunction to arrive at the acute clinical event (plaque
rupture and formation of the thrombus).
- Infections
- Environmental pollution
The presence of metabolic syndrome has a predictive value on cardiovascular
mortality. The high abdominal circumference,> 94 cm in men,> 80 cm in women (in
Europe), and at least two of the following factors:
- Triglycerides ≥ 150 mg / dL
- HDL cholesterol
- Men <40 mg / dL
- Women <50 mg / dL
- Arterial pressure ≥ 130 / ≥85 mm Hg
- FPG ≥ 100 mg / dL, or diabetes
- Fibrinogen. Fibrinogen is a recognized independent factor of increased
risk of cardiovascular events. A meta-analysis, including 31 studies, on
fibrinogen and cardiovascular events did not allow to identify target levels of
fibrinogen beyond which to initiate therapeutic intervention. The debate on the
type of therapeutic intervention to be implemented remains open.
Summing up and raising the risk.
As demonstrated by the InterHeart study, the association between several risk
factors considerably increases the risk of myocardial infarction (Odds Ratio =
13.01; 99% CI: 10.69-15.83) compared to those who are not exposed and together
explains 53% of population attributable risk (PAR) for heart attack. The
addition of abdominal obesity (the two upper tertiles vs. the inferior tertile)
or psychosocial factors (PS) further increased the PAR).
If all nine independent risk factors were encompassed (smoking, history of diabetes or hypertension, abdominal obesity, psychosocial factors, occasional consumption of fruit and vegetables, absence of alcohol consumption, lack of regular exercise and hyperlipidemia) could be explained completely the risk of myocardial infarction in the observed population. In this study, it would seem that the risk doubles for each new additional risk factor starting from the first three (smoking, hypertension, diabetes); however the 5 main risk factors (smoking, hyperlipidemia, hypertension, diabetes and obesity, or rather abdominal adiposity), present in most individuals, explained over 80% of the population risk