Sharad Agarwal

The Role of Asymmetric Dimethylarginine (ADMA) in Endothelial Dysfunction and Cardiovascular Disease.

Endothelium plays a crucial role in the maintenance of vascular tone and structure. Endothelial dysfunction is known to precede overt coronary artery disease. A number of cardiovascular risk factors, as well as metabolic diseases and systemic or local inflammation cause endothelial dysfunction. Nitric oxide (NO) is one of the major endothelium derived vaso-active substances whose role is of prime importance in maintaining endothelial homeostasis. Low levels of NO are associated with impaired endothelial function. Asymmetric dimethylarginine (ADMA), an analogue of L-arginine, is a naturally occurring product of metabolism found in human circulation. Elevated levels of ADMA inhibit NO synthesis and therefore impair endothelial function and thus promote atherosclerosis. ADMA levels are increased in people with hypercholesterolemia, atherosclerosis, hypertension, chronic heart failure, diabetes mellitus and chronic renal failure. A number of studies have reported ADMA as a novel risk marker of cardiovascular disease. Increased levels of ADMA have been shown to be the strongest risk predictor, beyond traditional risk factors, of cardiovascular events and all-cause and cardiovascular mortality in people with coronary artery disease. Interventions such as treatment with L-arginine have been shown to improve endothelium-mediated vasodilatation in people with high ADMA levels. However the clinical utility of modifying circulating ADMA levels remains uncertain.

Circulating endothelial progenitor cells, endothelial function, carotid intima–media thickness and circulating markers of endothelial dysfunction in people with type 1 diabetes without macrovascular disease or microalbuminuria

Aims/hypothesisType 1 diabetes is associated with premature arterial disease. Bone-marrow derived, circulating endothelial progenitor cells (EPCs) are believed to contribute to endothelial repair. The hypothesis tested was that circulating EPCs are reduced in young people with type 1 diabetes without vascular injury and that this is associated with impaired endothelial function and increased carotid intima–media thickness (CIMT).MethodsWe compared 74 people with type 1 diabetes with 80 healthy controls. CD34, CD133, vascular endothelial (VE) growth factor receptor-2 (VEGFR-2) and VE-cadherin antibodies were used to quantify EPCs and progenitor cell subtypes using flow-cytometry. Ultrasound assessment of endothelial function by brachial artery flow-mediated dilatation (FMD) and CIMT was made. Circulating endothelial markers, inflammatory markers and plasma plasminogen activator inhibitor-1 (PAI-1) levels were measured.ResultsCD34+VE-cadherin+, CD133+VE-cadherin+ and CD133+VEGFR-2+ EPC counts were significantly lower in people with diabetes (46–69%; pu2009=u20090.004–0.043). In people with type 1 diabetes, FMD was reduced by 45% (pu2009<u20090.001) and CIMT increased by 25% (pu2009<u20090.001), these being correlated (ru2009=u2009−0.25, pu2009=u20090.033). There was a significant relationship between FMD and CD34+VE-cadherin+ (ru2009=u20090.39, pu2009=u20090.001), CD133+VEGFR-2+ (ru2009=u20090.25, pu2009=u20090.037) and CD34+ (ru2009=u20090.34, pu2009=u20090.003) counts. Circulating high-sensitivity C-reactive protein, PAI-1, interleukin-6 and E-selectin were significantly higher in the diabetes group (pu2009<u20090.001 to pu2009=u20090.049), the last two of these correlating with FMD (ru2009=u2009−0.27, pu2009=u20090.028 and ru2009=u2009−0.24, pu2009=u20090.048, respectively).Conclusions/interpretationThese findings suggest that abnormalities of endothelial function in addition to pro-inflammatory and pro-thrombotic states are already common in people with type 1 diabetes before development of clinically evident arterial damage. Low EPC counts confirm risk of macrovascular complications and may account for impaired endothelial function and predict future cardiovascular events.

Comparative reproducibility of dermal microvascular blood flow changes in response to acetylcholine iontophoresis, hyperthermia and reactive hyperaemia

Laser Doppler fluxmetry (LDF) can non-invasively measure skin microvascular changes in response to acetylcholine (ACh), local heating of the skin and reactive hyperaemia following arterial occlusion. Various studies have used microvascular changes in response to these stimuli, especially ACh iontophoresis and local heating, as a surrogate marker of endothelial function. There are few data in the literature regarding the comparative reproducibility of microvascular perfusion changes induced by the three stimuli. The aim of this study was to systematically assess and compare the reproducibility of skin microcirculatory function in response to each of these challenges. Ten healthy non-smoking subjects (seven males) median age 36 years (range 23-46), with no history of hypertension, diabetes, coronary artery disease or any connective tissue disorder, were studied. Changes in skin microcirculation in response to ACh iontophoresis, local heating of the skin and post-occlusive reactive hyperaemia, on two separate days (median 31, range 11-42 days), were assessed in all subjects. We measured three parameters: the change in perfusion from baseline perfusion (peak minus baseline perfusion), the relative percentage change in perfusion from baseline (peak--baseline)/baseline x 100 (%) and also the time-to-peak perfusion. The reproducibility of the change in perfusion had coefficients of variation (CV) of 9.3% for local skin heating, 19.4% for reactive hyperaemia and 25.5% for ACh iontophoresis. The relative percentage change in perfusion from baseline was more variable with CVs ranging from 23% to 39%. The coefficient of variation of time-to-peak perfusion was 7.0% for heating, 15.1% for reactive hyperaemia and 10.4% for ACh iontophoresis. We have shown that microcirculatory changes measured by the change in perfusion from baseline and time-to-peak perfusion in response to ACh, post-occlusive reactive hyperaemia and local skin heating had good reproducibility when carried out in a controlled environment with a standardized protocol. Relative change in perfusion had relatively poor reproducibility. The change in perfusion and time-to-peak perfusion for local skin heating were the most reproducible overall.

Phaeochromocytomas presenting as acute crises after beta blockade therapy

Objectiveu2002u2002 Phaeochromocytoma crisis is a life‐threatening emergency that may be undiagnosed because of its numerous, nonspecific manifestations. We analysed, retrospectively, the presentation, management and outcome of patients who were admitted to our institution with phaeochromocytoma crises over a 5‐year period.

Carotid intima-media thickness as a surrogate marker of cardiovascular disease in diabetes

Background: Diabetes mellitus is associated with a high risk of cardiovascular disease. Carotid intima-media thickness (CIMT) is increasingly used as a surrogate marker for atherosclerosis. Its use relies on its ability to predict future clinical cardiovascular end points. Methods: This review examines the evidence linking CIMT as a surrogate marker of vascular complications in people with type 1 and type 2 diabetes. We have also reviewed the various treatment strategies which have been shown to influence CIMT. Conclusions: CIMT measurement is an effective, noninvasive tool which can assist in identifying people with diabetes who are at higher risk of developing microvascular and macrovascular complications. It may also help to evaluate the effectiveness of various treatment strategies used to treat people with diabetes.

A study of endothelial function and circulating asymmetric dimethylarginine levels in people with Type 1 diabetes without macrovascular disease or microalbuminuria

BackgroundAsymmetric dimethylarginine (ADMA) is a competitive inhibitor of endothelial nitric oxide synthase (eNOS) that is associated with endothelial dysfunction, and is a risk marker for cardiovascular disease, a significant problem in Type 1 diabetes. The aim of the present study was to measure circulating ADMA, and define its association with endothelial dysfunction and endothelial markers in people with Type 1 diabetes with low likelihood of macrovascular disease.MethodsSixty-one young people with Type 1 diabetes without macrovascular disease or nephropathy and 62 healthy volunteers underwent brachial artery flow-mediated dilatation (FMD) and assay of plasma ADMA and adhesion molecules.ResultsAge, gender, BMI, lipid profile and renal function were similar in the two groups. People with Type 1 diabetes had impaired FMD compared to healthy controls (5.0 ± 0.4 vs 8.9 ± 0.4%; p < 0.001). Plasma ADMA levels were significantly lower in the people with diabetes compared to healthy controls (0.52 ± 0.12 vs 0.66 ± 0.20 μmol/l, p < 0.001). Plasma ICAM-1, E-selectin and PAI-1 levels were significantly higher in people with diabetes compared to healthy controls (median 201 (IQR 172–226) vs 180 (156–216) μg/l, p = 0.027; 44.2 (32.6–60.9) vs. 33.1 (22.4–51.0) μg/l; p = 0.003 and 70.8 (33.3–85.5) vs 46.3 (23.9–76.8) μg/l, p = 0.035). Plasma ADMA and VCAM-1 levels were positively correlated (r = 0.37, p = 0.003) in people with diabetes. There was no correlation between the plasma ADMA and FMD.ConclusionADMA levels are not associated with endothelial dysfunction in young adults with Type 1 diabetes without microalbuminuria or known macrovascular disease. This suggests that the impaired endothelial function in these individuals is not a result of eNOS inhibition by ADMA.

Laser Doppler assessment of dermal circulatory changes in people with coronary artery disease.

BACKGROUNDnDermal microcirculation provides an easily accessible vasculature bed which can be used to assess endothelial mediated vasodilatation. We studied and compared microcirculatory changes in response to acetylcholine iontophoresis (ACh), local heating of the skin and reactive hyperaemia in patients with coronary artery disease (CAD).nnnMETHODS AND RESULTSnForty eight patients with CAD were studied and compared with 25 age and sex matched control subjects. Vasodilatory changes in the dermal microcirculation were assessed in response to ACh iontophoresis, local heating of the skin and reactive hyperaemia using a laser Doppler flowmeter (LDF).nnnRESULTSnBody mass index (BMI) and systolic BP were higher in people with CAD, (p=0.001, 0.043). The perfusion change (measured as absolute in agreement with our previous publish results) in response to ACh iontophoresis, local heating of the skin and reactive hyperaemia, in healthy controls was 234 (190-286), 90 (69-118), 139(106-172) arbitrary perfusion units (APU) compared to 161 (121-214), 50 (39-63), 116(77-143) APU in patients with CAD; p<0.03. The time to peak perfusion in response to reactive hyperaemia was significantly higher in patients with CAD, 14.1±4.0 vs 10.9±1.7s; p=0.001. There was a small but significant positive correlation between the perfusion change in response to ACh iontophoresis and local heating (r=0.31, p=0.035). On ROC curve analysis, perfusion changes with heating had higher sensitivity and specificity in discriminating patients with CAD from the healthy controls with an area under the curve (AUC) of 0.86, with a specificity of 92% and sensitivity of 77% compared to a perfusion changes by reactive hyperaemia, AUC of 0.68 (41% sensitivity and 91% specificity) and ACh iontophoresis, AUC of 0.76 (88% sensitivity and 60% specificity).nnnCONCLUSIONnVasodilatation in the dermal microcirculation measured by the three techniques is attenuated in patients with coronary artery disease. Local heating of the skin is a better discriminator of patients with CAD than ACh iontophoresis and reactive hyperaemia.

Assessment of functional status and quality of life after percutaneous coronary revascularisation in octogenarians

overground and treadmill walking. J Biomech Eng 2001; 123: 27–32. 10. ElHaber N, Hill KD, Cassano AT et al. Genetic and environmental influences on variation in balance performance among female twin pairs aged 21–82 years. Am J Epidem 2006; 164: 246–56. 11. Besser MP, Kmieczak K, Schwartz L, Snyderman M, Wasko J, Selby-Silverstein L. Representation of temporal spatial gait parameters using means in adults without impairment. Gait Posture 1999; 9: 113. 12. Lindemann U, Najafi B, Zijlstra W, Hauer K, Muche R, Becker C et al. Distance to achieve steady state walking speed in frail elderly persons. Gait Posture 2008; 27: 91–6. 13. Paterson KL, Hill KD, Lythgo ND, Maschette W. The reliability of spatiotemporal gait data for young and older women during continuous overground walking. Arch Phys Med Rehabil 2008; 89: 2360–5. 14. Selby-Silverstein L, Besser MP. Accuracy of the GAITRite system for measuring temporal-spatial parameters of gait. Presented at: American Physical Therapy Association Combined Annual Conference; 7 June 1999; Washington, D.C. 15. Atkinson G, Nevill AM. Statistical methods for assessing measurement error (reliability) in variables relevant to sports medicine. Sports Med 1998; 26: 217–38. 16. Perneger TV. What’s wrong with Bonferroni adjustments. BMJ 1998; 316: 1236–8. 17. Portney LG, Watkins MP. Foundations of Clinical Research: Applications to Practice, 2nd edition. Upper Saddle River, NJ: Prentice Hall Health, 2000. 18. Cohen J. Statistical Power Analysis for the Behavioral Sciences, 2nd edition. Hillsdale, NJ: Lawrence Erlbaum Associates, 1988. 19. Orendurff MS, Schoen JA, Bernatz GC, Segal AD, Klute GK. How humans walk: bout duration, steps per bout, and rest duration. J Rehabil Res Dev 2008; 45: 1077–90. 20. Griffin L, West DJ, West BJ. Random stride intervals with memory. J Biol Phys 2000; 26: 185–202. 21. Hausdorff JM, Purdon PL, Peng CK, Ladin Z, Wei JY, Goldberger AL. Fractal dynamics of human gait: stability of long-range correlations in stride interval fluctuations. J App Physiol 1996; 80: 1448–57. 22. Besser MP, Selby-Silverstein L, Prickett N. Predicting fall risk in the elderly using temporal-spatial parameters of gait. Neurol Rep 2001; 25: S3.

Coronary artery spasm and ventricular arrhythmias

Coronary artery spasm (CAS) is characterised by chest pain at rest and transient ST segment elevation on the ECG. The natural history of variant angina is not fully understood. Patients with CAS are younger, mostly female subjects and usually do not have traditional cardiovascular risk factors other than cigarette smoking. Cardiac arrhythmias are known to be associated with CAS. Ventricular arrhythmia is a well-recognised complication and sudden cardiac death has also been documented. The most important diagnostic tool in CAS is coronary angiography. 24u2005h ECG Holter monitoring can be very useful in the diagnosis of ventricular arrhythmias caused by CAS. The mainstay therapy for CAS is calcium channel blockers and nitrates. The use of β-blockers, especially the non-selective group, can promote attacks or prolong vasospastic state. The indication for implantable cardioverter defibrillator (ICD) implantation in a patient with CAS is still not clearly established. The role of primary prevention with the use of ICD is controversial; however, ICD implantation should be considered in high risk patients despite optimal medical treatment.

Predicting the development of macrovascular disease in people with type 1 diabetes: A 9-year follow-up study.

Abstract:u2002 The aim of the article was to use prospectively collected data on people with type 1 diabetes to assess which routinely collected clinical measures predict the development of macrovascular disease in people with type 1 diabetes. Data have been collected in a structured format at an annual review since 1985. For this study, all people with type 1 diabetes in the database in both 1992 and 2001 were ascertained. Data were extracted for a diagnosis of coronary artery disease, stroke, and peripheral vascular disease (macrovascular complications). Presence of other microvascular complications was also ascertained. Forty‐one of 404 (10.1%) people had macrovascular disease at the index visit in 1992 and 61 others developed macrovascular complications during follow‐up. People who developed macrovascular complications were older (48 ± 12 versus 36 ± 11 [SD] years; P= 0.000), had longer duration of diabetes (28 ± 12 versus 18 ± 11 years; P= 0.000), higher BMI (26.7 ± 4.6 versus 25.4 ± 3.6 kg/m2; P= 0.041), higher base line serum cholesterol (5.9 ± 1.7 versus 5.2 ± 1.1 mmol/L, P= 0.007), higher median base line triglyceride levels (1.5 [IQ range 0.9–2.6] versus 1.1 [0.8–1.7] mmol/L; P= 0.002), higher systolic BP (145 ± 21 versus 129 ± 20 mmHg; P= 0.000), and higher serum creatinine (102 ± 57 versus 86 ± 17 μmol/L; P= 0.038) than those who did not. We found no significant difference in the base line glycated hemoglobin in the two groups. The multivariate model showed that age, duration of diabetes, systolic BP, and serum cholesterol and creatinine levels predicted the development of macrovascular complications, which were also associated with the later development of microalbuminuria. Macrovascular complications developed in 16.8% of people with type 1 diabetes over a 9‐year follow‐up, and were predicted by potentially modifiable factors including higher BP, BMI, and serum triglyceride and cholesterol levels.