Ajay Yerramasu

Osteoprotegerin as a Predictor of Coronary Artery Disease and Cardiovascular Mortality and Morbidity

Osteoprotegerin (OPG) is a glycoprotein that acts as a decoy receptor for receptor activator of nuclear factor kappaB ligand (RANKL) and tumor necrosis factor-related apoptosis-inducing ligand. The OPG/RANKL/receptor activator of nuclear factor kappaB axis plays an important regulatory role in the skeletal, immune, and vascular systems. The protective role of OPG, in animal models, against vascular calcification has not been replicated in human trials; moreover, increased OPG levels have been consistently associated with the incidence and prevalence of coronary artery disease. There seems to be some dichotomy in the role of OPG, RANKL, and tumor necrosis factor-related apoptosis-inducing ligand in atherosclerosis and plaque stability. In this review, we integrate the findings from some of the important studies and try to draw conclusions with a view to gaining some insight into the complex interactions of the OPG/RANKL/receptor activator of nuclear factor kappaB axis and tumor necrosis factor-related apoptosis-inducing ligand in the pathophysiology of atherosclerosis.

Increased volume of epicardial fat is an independent risk factor for accelerated progression of sub-clinical coronary atherosclerosis

BACKGROUND Epicardial adipose tissue (EAT), a metabolically active visceral fat depot surrounding the heart, has been implicated in the pathogenesis of coronary artery disease (CAD) through possible paracrine interaction with the coronary arteries. We examined the association of EAT with metabolic syndrome and the prevalence and progression of coronary artery calcium (CAC) burden. METHODS CAC scan was performed in 333 asymptomatic diabetic patients without prior history of CAD (median age 54 years, 62% males), followed by a repeat scan after 2.7±0.3 years. CAC progression was defined as >2.5mm(3) increase in square root transformed volumetric CAC scores. EAT and intra-thoracic fat volumes were quantified using a dedicated software (QFAT), and were examined in relation to the metabolic syndrome, baseline CAC scores and CAC progression. RESULTS Both epicardial and intra-thoracic fat were associated with metabolic syndrome after adjustment for conventional cardiovascular risk factors, but the association was attenuated after additional adjustment for body mass index. EAT, but not intra-thoracic fat, showed significant association with baseline CAC scores (odds ratio [OR] 1.13, 95% confidence interval [CI] 1.04-1.22, p=0.04) and CAC progression (OR 1.12, 95% CI 1.05-1.19, p<0.001) after adjustment for conventional measures of obesity and risk factors. CONCLUSION EAT volume measured on non-contrast CT is an independent marker for the presence and severity of coronary calcium burden and also identifies individuals at increased risk of CAC progression. EAT quantification may thus add to the prognostic value of CAC imaging.

Walking speed and subclinical atherosclerosis in healthy older adults: the Whitehall II study

Objective Extended walking speed is a predictor of incident cardiovascular disease (CVD) in older individuals, but the ability of an objective short-distance walking speed test to stratify the severity of preclinical conditions remains unclear. This study examined whether performance in an 8-ft walking speed test is associated with metabolic risk factors and subclinical atherosclerosis. Design Cross-sectional. Setting Epidemiological cohort. Participants 530 adults (aged 63±6 years, 50.3% male) from the Whitehall II cohort study with no known history or objective signs of CVD. Main outcome Electron beam computed tomography and ultrasound was used to assess the presence and extent of coronary artery calcification (CAC) and carotid intima-media thickness (IMT), respectively. Results High levels of CAC (Agatston score >100) were detected in 24% of the sample; the mean IMT was 0.75 mm (SD 0.15). Participants with no detectable CAC completed the walking course 0.16 s (95% CI 0.04 to 0.28) faster than those with CAC ≥400. Objectively assessed, but not self-reported, faster walking speed was associated with a lower risk of high CAC (odds ratio 0.62, 95% CI 0.40 to 0.96) and lower IMT (β=−0.04, 95% CI −0.01 to −0.07 mm) in comparison with the slowest walkers (bottom third), after adjusting for conventional risk factors. Faster walking speed was also associated with lower adiposity, C-reactive protein and low-density lipoprotein cholesterol. Conclusions Short-distance walking speed is associated with metabolic risk and subclinical atherosclerosis in older adults without overt CVD. These data suggest that a non-aerobically challenging walking test reflects the presence of underlying vascular disease.

Diagnostic role of coronary calcium scoring in the rapid access chest pain clinic: prospective evaluation of NICE guidance

BACKGROUND Coronary artery calcium (CAC) imaging by unenhanced computed X-ray tomography (CT) is recommended as an initial diagnostic test for patients with stable chest pain symptoms but a low likelihood (10-29%) of underlying obstructive coronary artery disease (CAD) after clinical assessment. The recommendation has not previously been tested prospectively in a rapid access chest pain clinic (RACPC). METHODS We recruited 300 consecutive patients presenting with stable chest pain to the RACPC of three hospitals. All patients underwent CAC imaging, followed by invasive coronary angiography (ICA) in patients with CAC ≥ 1000 Agatston units (Au) and CT coronary angiography (CTCA) in those with CAC <1000. Patients with 50-70% stenosis on CTCA underwent myocardial perfusion scintigraphy (MPS) while those with ≥ 70% stenosis underwent ICA. Obstructive CAD was defined as ≥ 70% stenosis on ICA or the presence of inducible ischaemia on MPS. Patients were followed up clinically for a mean of 17 (SD 6) months. RESULTS The mean patient age was 60.6 (SD 9.6) years and 48% were males. Obstructive CAD was found in 56 (19%) patients, of whom 42 (14%) underwent revascularization. CAC was zero in 131 (44%) patients, of whom two (1.5%) had obstructive CAD and one (0.8%) underwent revascularization. The sensitivity, specificity, negative predictive value, and positive predictive value of CAC ≥ 1 for detection of obstructive CAD were 96, 53, 32, and 98%, respectively. None of the 57 patients with low pre-test probability of CAD and zero CAC had obstructive CAD or suffered a cardiovascular event during the follow-up. CONCLUSION Patients with stable chest pain symptoms but a low likelihood of CAD can safely be diagnosed as not having obstructive CAD in the absence of detectable coronary calcification by unenhanced CT. Patients with CAC >400 Au have a high prevalence of obstructive CAD and further investigation with ICA or functional imaging may be warranted rather than CTCA. These findings support NICE guidance for the investigation of stable chest pain. ClinicalTrials gov identifier: NCT01464203.

Radiation dose of CT coronary angiography in clinical practice: Objective evaluation of strategies for dose optimization

BACKGROUND CT coronary angiography (CTCA) is an evolving modality for the diagnosis of coronary artery disease. Radiation burden associated with CTCA has been a major concern in the wider application of this technique. It is important to reduce the radiation dose without compromising the image quality. OBJECTIVES To estimate the radiation dose of CTCA in clinical practice and evaluate the effect of dose-saving algorithms on radiation dose and image quality. METHODS Effective radiation dose was measured from the dose-length product in 616 consecutive patients (mean age 58 ± 12 years; 70% males) who underwent clinically indicated CTCA at our institution over 1 year. Image quality was assessed subjectively using a 4-point scale and objectively by measuring the signal- and contrast-to-noise ratios in the coronary arteries. Multivariate linear regression analysis was used to identify factors independently associated with radiation dose. RESULTS Mean effective radiation dose of CTCA was 6.6 ± 3.3 mSv. Radiation dose was significantly reduced by dose saving algorithms such as 100 kV imaging (-47%; 95% CI, -44% to -50%), prospective gating (-35%; 95% CI, -29% to -40%) and ECG controlled tube current modulation (-23%; 95% CI, -9% to -34%). None of the dose saving algorithms were associated with a significant reduction in mean image quality or the frequency of diagnostic scans (P = non-significant for all comparisons). CONCLUSION Careful application of radiation-dose saving algorithms in appropriately selected patients can reduce the radiation burden of CTCA significantly, without compromising the image quality.

Cardiac computed tomography and myocardial perfusion imaging for risk stratification in asymptomatic diabetic patients: A critical review

Diabetes is a major cause of mortality and morbidity worldwide, and its prevalence is increasing at alarming proportions. Coronary artery disease (CAD) accounts for 70% of the deaths among diabetic patients. Patients with diabetes have a 2-to-4-fold higher risk of cardiac events than their nondiabetic counterparts. In fact, the risk of myocardial infarction in diabetic patients without previous CAD is comparable to the risk of reinfarction in nondiabetic subjects with previous CAD. Furthermore, patients with diabetes are less likely to survive a first myocardial infarction (MI) than those without diabetes, and those who survive the first MI face a higher risk of reinfarction. Hence it is crucial to diagnose CAD at an early subclinical stage in patients with diabetes, so that high-risk patients can be targeted for aggressive management. The search for a robust, noninvasive technique to screen asymptomatic diabetic patients has been a focus of research, and the potential role of noninvasive techniques such as coronary artery calcium (CAC) imaging and myocardial perfusion imaging (MPI) has triggered controversy and several interesting debates. On the one hand, any strategy involving the use of screening may spiral healthcare budgets out of control, and there is no strong evidence from prospective, randomized trials that a particular strategy can improve clinical outcomes. Diamond et al, in their recent essay on this controversial subject, highlighted the great difficulty in conducting a prospective, randomized trial to evaluate the cost-effectiveness of screening asymptomatic diabetic subjects. They estimated that such a trial would require the randomization of 80,000 subjects followed for 5 years, i.e., a huge investment of resources in view of the small differences in projected outcomes. On the other hand, in diabetic patients, CAD is often asymptomatic and can be well-advanced by the time of presentation. Therefore, it may be negligent to ignore these patients when diabetes is considered a “surrogate” for CAD. It is worth noting here that lack of evidence of effect does not necessarily imply evidence of lack of effect. In the absence of prospective trials exploring the clinical effectiveness and cost-effectiveness of screening strategies for asymptomatic diabetic subjects, we examined the available evidence from several studies that may provide a basis for future trials.

Evolving role of cardiac CT in the diagnosis of coronary artery disease

Non-invasive assessment of coronary artery patency has been attempted with different imaging modalities over the last few decades. The continuous motion of the heart, the respiratory movement, together with the small and tortuous nature of the coronary arteries, made this a technically challenging task. Over the last decade, significant advances in computed tomography (CT) technology helped CT coronary angiography (CTCA) to evolve as a non-invasive alternative to conventional catheter based coronary angiography. Clinical experience with CTCA has since grown rapidly and led to its acceptance as a useful diagnostic technique for coronary artery disease in certain patient populations. Recently, there has been exponential growth in the availability and use of CTCA in several centres across the world. In order to appreciate the potential impact of CTCA on current clinical practice, it is important to understand its advantages and limitations and its clinical performance in comparison with established techniques.

Abnormal myocardial perfusion in the absence of anatomically significant coronary artery disease: Implications and clinical significance

Myocardial Perfusion Scintigraphy (MPS) has dominated the field of noninvasive cardiac imaging for over three decades now and continues to do so largely due to the unparalleled evidence supporting its diagnostic and prognostic value in the management of coronary artery disease (CAD). In recent years, there has been a dramatic rise in the number of cardiac imaging procedures that are being undertaken. In the USA alone, over 10 million myocardial perfusion scans are being performed annually. This is driven by a need to be able to better risk stratify patients with suspected CAD, particularly those in the intermediate risk group in whom the clinical management decisions are often unclear. From a clinician’s standpoint, the value of MPS lies in its ability to clearly guide decisions regarding coronary revascularization; hence the clinical interest in this technique remains unabated over the years. Two of the most important factors affecting prognosis of patients with CAD are: the extent of myocardium at risk and left ventricular function. MPS by gated Single Photon Emission Computed Tomography (SPECT) is uniquely placed to provide important prognostic data on both these parameters. In patients with suspected CAD, MPS acts as an useful gatekeeper to invasive coronary angiography and has been shown to be cost-effective for this purpose. MPS also yields independent and incremental prognostic information to that obtained from clinical and stress ECG data. The prognostic value of the extent of myocardium at risk (as assessed by extent of reversible perfusion defects with Tl-201), and its subsequent relationship with cardiac death was initially described in a study of 100 patients with no known history of myocardial infarction who presented for evaluation of chest pain. Since then, there have been a multitude of studies documenting the ability of abnormal MPS in predicting future cardiac deaths, nonfatal myocardial infarction and revascularization. Equally, a negative/ normal MPS was shown to be associated with a good prognostic outcome. Of note, majority of the data regarding the diagnostic and prognostic utility of MPS comes from studies that included patients with significant CAD (either [50% or [70% luminal stenosis in major epicardial vessels).

An evaluation of coronary artery plaque burden in asymptomatic type 2 diabetics using dual-source CT coronary angiography

Current International Diabetes Federation (IDF) and American Diabetes Association (ADA) guidelines advocate investigation for coronary artery disease (CAD) in only those patients who have either typical/atypical cardiac symptoms or an abnormal resting ECG. As it is well established that diabetics with CAD may be asymptomatic, we hypothesised that a large proportion of asymptomatic diabetics may have coronary arterial plaques causing significant stenosis which goes undetected with current guidelines.