Integrating clinical cardiology and echocardiography in a single specialty to help clinical decision making from the community level, to the out patients setting, to critical care and the operating room-
- Dobutamine stress echocardiography
- Intra-operative echocardiography
- Multi-plane trans-oesophageal echocardiography
- Sequential external counter-pulsation
- Non-invasive tools for prediction of coronary artery disease
TOOLS TO PREDICT & HELP PREVENT THE CORONARY ARTERY DISEASE- METABOLIC DISEASES EPIDEMIC IN INDIA
The global burden of cardiovascular diseases (CVD) is rapidly increasing, predominantly due to a sharp rise in the incidence and prevalence of the same in the developing countries. The most important underlying reason for this has been changing lifestyle due to rapid urbanization and epidemiological shift. The lifestyle changes have resulted in decreased physical activity, faulty food habits, increasing stress, cigarette smoking etc. which together have led to increased prevalence of obesity, diabetes, hypertension, dyslipidemia and of other cardiovascular risk factors. These factors such as delayed industrialization; probable adverse cardiovascular effects of foetal under-nutrition and genetic propensity have made the matter worse.
India, a developing nation, is undergoing the same phase and is now in the middle of a coronary artery disease (CAD) epidemic. Over the past 30 years, the CAD rates have doubled in India whereas CAD rates have declined by 50% in most developed countries during the same period. Several surveys have shown the prevalence of CAD in India in urban adults aged > 35 years to be ~ 10%. In other words, while every 25th individual in 1960 was suffering from CAD, now in 2001 every 9th individual can be suspected to be having CAD. Every year 25 000 coronary bypass operations and 12000 percutaneous transluminal coronary angioplasties are being carried out in India. Coronary artery bypass grafting that accounted for less then 10% of all cardiac surgeries in 1980, today accounts for more than 60%. Deaths from coronary heart disease in India have also risen sharply from 1.17 million in 1990 to 1.59 million in 2000 and are expected to rise to 2.03 million in 2010. In 2000, CVD was estimated to have resulted in 31.7% of all deaths in India- the single most common cause of mortality.
Today in India, CAD has not only become exceedingly common, it tends to occur at a younger age and is more severe & more extensive. In India 52% of cardiovascular deaths occur below the age of 70, compared with 23% in countries with established market economies. During the past 3 decades, the average age of a first heart attack has increased by 10 years in the U.S., but has decreased by 10 years in India. About 50% of all heart attacks among Asian Indian men occur under the age of 55 and 25% under the age of 40, something that is very uncommon in any other populations. In some studies from India, the percentage of patients below the age of 45 years suffering from acute myocardial infarction (AMI) is reported as high as 25-40%. Moreover, young patients from other communities do not show extensive disease, whereas in young Indians there is often three-vessel disease with poor prognosis. The post-infarction course is also worse in Indians as compared to whites. This is reflected by three-times higher rate of re-infarction and two-times higher rate of mortality.
The reasons postulated for higher prevalence and greater severity & extent of CAD in Indians are-
- Increased genetic propensity to develop CVD and
- Increasing prevalence of cardiovascular risk factors.
It has been very well established now that Indians ethnically have greater tendency to develop CVD, possibly due to abnormalities of glucose homeostasis. Studies conducted in South Asian migrants show they have higher coronary mortality than the reference population of there adopted countries and an earlier onset of disease. The risk of CAD in Indians is 3-4 times higher than White Americans, 6-times higher than Chinese, and 20-times higher than Japanese. It appears that the increase in CAD risk from a weight gain of 10 pounds or smoking 10 cigarettes (or beedi) by Indians is similar to a 30 pound weight gain or smoking 30 cigarettes by other populations.
During the past three decades prevalence of most of the cardiovascular risk factors has increased markedly in India. India has a higher number of people with diabetes than any other country, with estimates ranging from 19.4 million in 1995 to 32.7 million in 2000. The number of people with diabetes is expected to rise by 195% in India during 1995-2025 to reach 57.2 million in 2025. It is estimated that every 16th adult individual in urban India has diabetes and an additional 16th has impaired glucose tolerance. Similarly, a meta-analysis showed an increase in the prevalence of hypertension over the years, especially of systolic blood pressure. Recent studies using the criterion of 140/90 mmHg as the cut-off point for hypertension have shown a prevalence of 10%– 30.9% in urban areas, while earlier reports since 1950 showed a prevalence of 1%–3%. Dyslipidemia, another risk factor for CVD has also become more common over past few decades. In Delhi, the mean serum cholesterol level has risen from 160 mg/dl in 1982 to 199 mg/dl in 199. Moreover, the pattern of lipid abnormality in Indians is such that it increases cardiovascular risk more than similar degree of increase in cholesterol levels in other populations. A 75% prevalence of phenotype-B (associated with increased risk of CVD) is seen in Asian Indians in contrast to 25% in White population. In Indians, both in India and abroad, the levels of lipoprotein-a are higher as compared to the whites in Great Britain, suggesting a genetic propensity. Metabolic syndrome which is a constellation of several cardiovascular risk factors viz. hypertension, obesity, impaired glucose tolerance, increased tri-glycerides; low HDL cholesterol etc. has also become very common in India.
Rapidly increasing prevalence of diabetes in India poses a special threat. CVD is extremely common in patients with diabetes and it is the commonest cause of morbidity & mortality in them. More than half of all deaths in diabetics are due to CVD. It has been conclusively shown that risk of having a major cardiovascular event (myocardial infarction, stroke or death) in diabetics without established CAD is similar to that in a person with established CAD. On the basis of this, American Heart Association has recently designated diabetes mellitus (DM) to be ‘CAD risk equivalent’. In other words, what it means is that every diabetic patient even in absence of CVD should be treated as a person having CVD. Hence increasing prevalence of diabetes implies even rapidly increasing burden of CVD morbidity & mortality in the community.
NEED FOR EARLY DETECTION OF CARDIOVASCULAR DISEASE
From these statistics it is evident that CVD is going to be the most important public health issue in India over the coming decades. We are already witnessing CVD epidemic and if timely action is not taken the disease is likely to assume alarming proportions very soon. It is therefore imperative for us to urgently formulate and implement an effective public health policy that focuses predominantly on early detection, prediction and prevention of disease than on treatment since prevention is the only way by which we can curb this rapidly growing epidemic. The cornerstone of prevention of CVD would be to increase awareness in the general population about healthy life-style and about avoidance and control of various cardiovascular risk factors. This undoubtedly is the most effective strategy. Another critical issue in prevention of CVD is to identify, at an early stage, those individuals who are at high risk of developing CVD and to institute aggressive preventive measures in them so as to avoid development of disease. This strategy has the potential to reduce CVD burden significantly in a very cost-effective manner since it specifically targets the population that is at the maximum risk. However, effective implementation of this strategy implies and necessitates availability of such tools that allow early and accurate identification of those individuals who are at high-risk of having CVD. Until recently, early identification of these ‘at risk’ individuals has predominantly been based on assessment of presence or absence of conventional cardiovascular risk factors. Although this still remains an effective strategy, over last few years several newer non-invasive tools have been developed that have the ability to detect high-risk individuals more accurately and with greater specificity. These include-
- Brachial artery flow-mediated vasodilatation (BaFMD)
- Carotid intima-media thickness (CIMT), and
- Pulse wave velocity (PWV).
CVD is the end result of a pathological process called arteriosclerosis. Arteriosclerosis itself is a multi-stage process that progresses through a series of structural and functional changes taking place in vessel wall culminating into manifest CVD. Endothelial dysfunction is a key early event in this process and is known to appear long before the formation of structural atherosclerotic changes. It is the final common pathway through which various cardiovascular risk factors produce their adverse vascular effects resulting in development of atherosclerotic and subsequent CVD. Long, latent phase of arteriosclerosis provides us with ample opportunity to identify this process at an early stage, thus facilitating primary prevention. This can be done either at the stage of endothelial dysfunction or at a later stage of structural atherosclerotic changes but when the disease process is still pre-occlusive (figure 1).
Figure 1: Process of atherogenesis & role of newer non-invasive tools for detection of endothelial dysfunction
Early detection of atherosclerotic process in coronary vessels has remained hampered by the poor access of coronary vessels to most non-invasive imaging modalities. However, realization of the fact that arteriosclerosis is a generalized process that affects all arterial beds and that the risk factors that lead to arteriosclerosis are shared by all the arterial beds, has led to development of tools that detect sub-clinical arteriosclerosis in the peripheral vessels and are used for prediction of same in the coronary vessels. Thus CIMT is a non-invasive imaging test that detects structural atherosclerotic changes in carotid arteries, BaFMD is for detection of endothelial dysfunction in brachial vessels and PWV is used for assessment of stiffness of aorta and peripheral arteries (another marker of atherosclerotic process). Results of all these tests have been shown to have an excellent correlation with future risk of adverse cardiovascular events. (33-40) Development of these tools has been a major advancement in cardiovascular imaging since these tests-
- Can reliably predict future risk of cardiovascular events and help in early identification of high-risk individuals
- Can reliably predict future risk of cardiovascular events and help in early identification of high-risk individuals
- Provide an excellent tool for cardiovascular research in the field of arteriosclerosis
Unfortunately, until recently these extremely useful techniques were unavailable for routine use in our country because of the fact that most of the work on these techniques had been done in Western population whose result could not be applied to Indian population since Indians have been shown to be different from the Western population with respect to cardiovascular risk profile as well as morbidity & mortality. Hence it was imperative that we had our own data and our own cut-off values for these tests before we could benefit from them. Over last few years, we have systematically assessed the role of these tests in early detection of endothelial dysfunction in our community, have found out values for each test that are seen in normal individuals and have determined their utility in routine clinical practice. Based on our research work, we are now able to utilize these tests for cardiovascular risk stratification on a regular basis. It has been extremely helpful in optimising treatment strategy and extending full benefit of newer anti-atherosclerotic therapeutic modalities to our patients.
BRACHIAL ARTERY FLOW-MEDIATED DILATATION (BAFMD)
As has already mentioned above, endothelial dysfunction is the key early event in the process of atherogenesis that eventually leads to clinical CVD. Vascular endothelium is a dynamic organ that produces several substances that maintain a delicate balance between vasoconstriction and vasodilatation, cell proliferation and inhibition, coagulation and anticoagulation etc. Nitric oxide (NO) is the most important molecule that is responsible for anti-atherogenic effects of endothelium and maintains normal vascular health. Deleterious effects of endothelial dysfunction are mediated predominantly by decreased production of NO.
BaFMD is a test that relies on NO secreting ability of normal endothelium. In this test, shear stress is produced on the endothelium that results in release of NO, which leads to vasodilatation. Impaired vasodilatation in response to shear stress indicates underlying endothelial dysfunction.
The patient is asked to lie supine. The sphygmomanometer cuff (usual BP cuff) is tied around the arm. The brachial artery is imaged in the ante-cubital fossa using 7.5 MHz linear array transducer attached to an Echocardiography machine and its diameter is measured. The arm is then occluded with the sphygmomanometer cuff inflated to at least 50 mm Hg above systolic blood pressure for 5 minutes. When the cuff is released, there is sudden increase in blood flow that puts shear stress on the endothelium. This causes release of NO, which leads to vasodilatation that peaks at 1 min. Hence the brachial artery diameter is measured again at 1 minute. Percentage increase in diameter from baseline is calculated and is taken as FMD. To avoid compounding influence of meals, smoking, drugs etc, the test is to be performed after overnight fasting; smoking is prohibited for at least 4 hours before the test and all the vaso-active drugs such as nitrates are withheld for 48 hours preceding the test.
As already mentioned, there was very limited data regarding role of BaFMD in Indian population. Hence we studied BaFMD in 241 individuals- 100 with established CAD and 141 without CAD. FMD was calculated as percentage increase in brachial artery diameter at 1 minute. We also calculated FMD index as the ratio of FMD and percentage increase in blood flow following cuff release. Mean FMD was found to be significantly higher in non-CAD group (8.71 4.77%) than in CAD group (3.77 2.03%; p value < 0.0001). The FMD index was also significantly higher in the non-CAD group (0.031) than in CAD group (0.021; p value 0.0117). On multiple regression analysis, FMD index was found to be significantly associated with presence of CAD (p value 0.0015), independent of conventional cardiovascular risk factors. (Journal of Indian Medical Association 2004; 102: 243-52)
This study clearly demonstrated that BaFMD is a better predictor of presence of CAD than conventional risk factors and its predictive ability is independent of these risk factors. The study also provided values of BaFMD seen in Indian patients with and without CAD.
As mentioned above, American Heart Association has recently designated diabetes mellitus (DM) to be ‘CAD risk equivalent’. However it had not been determined what exactly was the pathological basis for the ‘CAD risk equivalent’ status of diabetes. As we had already established that impaired BaFMD was an excellent surrogate marker for CAD, we conducted this study to find out whether similar degree of impairment of endothelial function occurred in patients with DM and CAD that could account for this ‘risk equivalence’. One hundred and ninety eight individuals were included in the study and divided into four groups:- Group 1 – patients with risk factors for CAD, but no DM or CAD; Group 2 – patients with DM but no CAD; Group 3 – patients with CAD but no DM and Group 4 – patients with both DM and CAD. Brachial artery FMD assessment was performed in all subjects and FMD was calculated as percentage increase in brachial artery diameter in response to increase in brachial artery flow. Mean FMD was significantly higher in Group 1 (7.032.87%) compared to the other three groups. Mean FMD in Group 2 (5.512.12%) was similar to that in Group 3 (4.562.70%; p value 0.195) but significantly higher than that in Group 4 (4.261.93%; p value 0.038). There was no statistically significant difference in mean FMD in Group 3 and Group 4 (p value 0.65). Thus, we found maximum FMD in patients without CAD or diabetes and impaired but equal FMD in patients with CAD alone or diabetes alone. The patients who had both CAD and diabetes had the least FMD. (JAPI 2003; 51: 355-358)
This study for the first time showed that similar degree of impairment in endothelial function occurs in diabetics without CAD and non-diabetic patients having CAD that could explain ‘CAD risk equivalence’ of diabetes. The data re-emphasizes the fact that detection of endothelial dysfunction can provide extremely valuable insight into the ongoing vascular damage at a very early stage in the pathogenesis. Utility of BaFMD in routine cardiac practice cannot be overstated.
CAROTID INTIMA-MEDIA THICKNESS (CIMT)
Since arteriosclerosis is a generalized process that affects all vascular beds sooner or later, it is assumed that detection of arteriosclerosis in one vascular bed should predict involvement of the other. CIMT is based on the same premise. In this test, combined thickness of intima and media is measured in the carotid arteries and the values thus obtained are used for extrapolation of extent of arteriosclerosis in coronary vessels and thus for prognostication of cardiovascular risk. CIMT is the only test that actually images ongoing atherosclerotic process.
Figure 2 A. Ultrasound Image showing IMT, 2 B. Schematic diagram showing layers of the arterial wall and segments of carotid artery where IMT measurements are taken
CCA: common carotid artery, ICA: internal carotid artery, ECA: external carotid artery
For measurement of CIMT, carotids arteries are imaged using 7.5 MHz linear arrays probe. Thickness of combined intima and media is measured as the distance between the leading edge of the first echogenic line of the far wall of carotid artery (lumen-intima interface) & leading edge of the second echogenic line (media–adventitia interface). The measurements are taken in the distal common carotid artery, carotid bulb and proximal internal carotid artery. Average of all the values is calculated that gives us average CIMT. (Figure 2A & 2B)
As with FMD, there was very limited data regarding the role of carotid IMT in CAD in Indians. Hence we conducted this study to assess the association of carotid IMT and CAD in Indian population and to define its utility in prediction of CAD. Carotid IMT was measured in patients with and without CAD. Measurements were taken at three predefined sites on each side. Average and maximum IMT were considered for further analysis. The maximum carotid IMT was significantly higher in the CAD group (mean 1.02 mm) compared to non-CAD group (mean 0.80 mm; p < 0.0001). The average IMT was also significantly higher in the CAD group (mean 0.82 mm) than the non-CAD group (mean 0.67 mm; p < 0.0001). On multivariate logistic regression analysis, only carotid IMT was found to be independent predictor of presence of CAD out of all the variables studied. Moreover, it was found that higher the number of conventional cardiovascular risk factors in an individual, higher was the IMT (r = 0.22, p less than 0.001 for average IMT and r = 0.28, p less than 0.001 for maximum IMT) in the combined study population. (Asian Cardiovasc Thorac Ann 2003; 11:217–21)
The result of this study indicated that raised average and maximum Carotid IMT were indeed the most important and independent predictors of CAD in Indians. The findings of this study are in concordance with the editorial in European Heart Journal that stated-“…common CCA IMT is nearly as predictive of future CV events as all of the following nine risk factors combined together- Age, sex, previous MI & stroke, DM, smoking, SBP, DBP, TC, HDL…” and also that “If you knew nothing else about an individual except the IMT value of CCA, you would be able to correctly identify the same fraction of subjects as you could by assembling a risk estimate from the combined total of nine other risk factors..” Our study also showed that a maximum IMT value > 1.0 mm was very likely to indicate presence of CAD, a finding of great significance in assessment of patients suspected to be having CAD.
ARTERIAL PULSE WAVE VELOCITY (PWV)
Arterial pulse wave velocity is the velocity of propagation of pulse wave along the arterial wall. It is a measure of arterial compliance and elasticity. Since stiff arteries transmit the pulse wave at faster speed, increased pulse wave velocity indirectly reflects increased stiffness of the arterial system. As endothelial dysfunction is one of the mechanisms of arterial stiffness, PWV can be used for detection of endothelial dysfunction and prediction of future risk of cardiovascular events.
PWV can now be easily measured non-invasively using an automated machine—VP 1000 (Colin Corporation) ABI/PWV analyser. The machine records pulse wave contours in different arterial segments on the basis of volume plethysmography. The patient is asked to lie supine and sphygmomanometer cuffs, which are attached to the machine, are tied around both the arms just above the elbows and both the legs just above the ankles. The cuffs are automatically inflated and deflated and pulse wave contours in both the brachial and both the posterior tibial arteries are recorded simultaneously. Pulse transit time between brachial and ankle regions is calculated from these pulse wave recordings. Dividing the distance between these segments with the pulse transit time gives the PWV for that particular segment. Since brachial-ankle PWV has been shown to have a good correlation with aortic PWV measured invasively, the same is used for clinical purpose.
With availability of multiple tools for detection of sub clinical arteriosclerosis, it becomes essential to determine how to interpret results of one test in view of the results of others since all these tests are used for the same purpose i.e. prediction of future risk of cardiovascular events. Since endothelial dysfunction is the earliest step in atherogenesis, it can be presumed that impaired BaFMD could exist in presence of normal IMT or PWV. However, relative importance of CIMT and PWV was not established. While carotid IMT is a marker of structural aspect of arteriosclerosis, PWV reflects its functional consequences. Studies conducted till date that had evaluated inter-relationship of these two markers of structural and functional aspects of arteriosclerosis had shown inconsistent results. Hence, we conducted this study to assess the correlation between carotid IMT and arterial PWV in patients with and without established CAD. Sixty-four patients with angiographicaly proven coronary artery disease and 84 age-matched individuals without coronary artery disease but having one or more conventional cardiovascular risk factors were included in the study. Individuals with established cerebral-vascular disease and peripheral vascular disease were excluded from the study. Carotid intima-media thickness of far wall was measured at three predefined sites (distal common carotid, carotid bifurcation and proximal internal carotid artery) on each side. Brachial-ankle pulse wave velocity was measured non-invasively using VP 1000 (Colin Corporation) automated ABI/ PWV analyser. There was no significant difference in gender and presence of cardiovascular risk factors in the two groups. Mean and maximum carotid intima-media thickness and brachial-ankle pulse wave velocity were all significantly higher in coronary artery disease patients as compared to patients without coronary artery disease (0.842 v. 0.657 mm, p less than 0.0001; 1.076 v. 0.795 mm, p less than 0.0001; 1708.63 v. 1547.26 cm/s, p less than 0.0004 respectively). There was a significant correlation between brachial-ankle pulse wave velocity and both mean and maximum carotid intima-media thickness in patients with coronary artery disease (r =0.47, p less than 0.0001 and r=0.41, p < 0.0008 respectively) but not in individuals without coronary artery disease (r=0.01 and -0.1 respectively). (Indian Heart Journal 2004; 56: 117-122)
This study clearly showed that the correlation between carotid intima-media thickness and brachial-ankle pulse wave velocity becomes stronger with increasing extent of arteriosclerosis. In other words, if both CIMT and PWV are increased, patient can confidently be suspected of harbouring CVD. But when only one of these two parameters are abnormal the likelihood of having CVD cannot be predicted.
It is evident that burden of CVD is rapidly increasing in India and has already developed into an epidemic. Prevention of CVD should therefore be given highest priority in delivery of healthcare in our country. Lack of adequate infrastructure, poor access of majority of Indian population to health care facilities, extremely poor awareness among general population about healthy life style, and almost total lack of scientific data about cardiovascular prevention in India have been the major obstacles. Our unique community outreach program through which we have organized hundreds of free heart camps to increase health care awareness in the community has been a major endeavor in this direction. This has been amply complemented by our research work that included development of strategy for early detection of high-risk individuals, assessment of the prevalence of cardiovascular risk factors in community and in patients having coronary artery disease and determination of their relative importance in causation of disease. Based on our research work, we have been able to define the importance of newer non-invasive techniques in prediction of CVD and their role in risk stratification of the individuals. Today, we are the only center in India to have a systematic, organized early detection set-up for cardiovascular diseases that includes state-of-the-art techniques such as carotid intima-media thickness, brachial artery flow-mediated dilatation and arterial pulse wave velocity. Even the best of labs abroad do not routinely perform these tests.