Jeetesh V. Patel

Endothelial Dysfunction and Damage in Congestive Heart Failure. Relation of Flow-Mediated Dilation to Circulating Endothelial Cells, Plasma Indexes of Endothelial Damage, and Brain Natriuretic Peptide

Background—Congestive heart failure (CHF) is associated with endothelial perturbation (as defined by flow-mediated endothelial-dependent vasodilation [FMD, an index of endothelial dysfunction], circulating endothelial cells [CECs, an index of endothelial damage], or plasma indexes of endothelial damage/dysfunction [eg, von Willebrand factor (vWf) and soluble thrombomodulin (sTM)]) and raised plasma levels of brain natriuretic peptide (BNP, a peptide hormone associated with left ventricular systolic dysfunction and prognosis). However, the relations between these parameters are unclear. Methods and Results—To test the hypothesis that there is a relation between endothelial perturbation (defined by FMD, CECs, vWf, and sTM) and BNP in CHF, we studied these indexes in 30 patients with CHF who were compared with 20 age-matched control subjects. FMD, CECs, plasma vWf, and BNP levels (but not sTM) were all abnormal in patients with CHF. There were significant inverse correlations between FMD and vWf (P=0.001), CECs (P=0.002) and BNP (P=0.006) as well as a positive correlation between CECs and vWf (P=0.032). In multivariate analysis, BNP (P<0.001) and FMD (P<0.001) were both independently associated with CHF. Conclusions—Ample evidence of endothelial cell damage/dysfunction in CHF cannot be fully explained by the variance in plasma BNP per se. Therefore, the routes by which these indexes influence the pathophysiology of CHF as well as predict adverse outcomes may be independent.

High-Sensitivity C-Reactive Protein and Soluble CD40 Ligand as Indices of Inflammation and Platelet Activation in 880 Patients With Nonvalvular Atrial Fibrillation Relationship to Stroke Risk Factors, Stroke Risk Stratification Schema, and Prognosis

Background and Purpose— There is now considerable evidence that atrial fibrillation is associated with an inflammatory state. We tested the hypothesis that plasma levels of C-reactive protein (CRP; an index of inflammation) and soluble CD40 ligand (an index of platelet activation, with links to inflammation) could be related to 3 established stroke risk stratification schema (SPAF, CHADS2, and NICE), recognized stroke risk factors or other cardiovascular disease, and prognosis. Methods— We studied 880 subjects with atrial fibrillation recruited from subjects receiving aspirin 325 mg/d (alone or combined with fixed inefficacious doses of warfarin) from the Stroke Prevention in Atrial Fibrillation (SPAF) III clinical trial. CRP and soluble CD40 ligand were measured by enzyme-linked immunosorbent assay. Results— With respect to the SPAF III stroke risk stratification criteria, those with moderate to high risk had the highest levels of CRP (Kruskal Wallis test, P<0.001), but those with the highest risk had the lowest levels of soluble CD40 ligand (P=0.01). Similarly, CRP levels increased in a positive fashion with increasing stroke risk with respect to the CHADS2 and NICE risk stratification criteria, whereas soluble CD40 ligand levels were negatively associated with stroke risk. CRP levels were higher among those patients with raised body mass index, diabetes, hypertension, ischemic heart disease, peripheral vascular disease, and recent heart failure, but not those with thromboembolism. Patients were followed-up for a mean time of 453 (standard deviation, 229) days, and all-cause mortality (log rank test, P=0.001), and vascular events (P=0.05), but not stroke, were more common in patients with high CRP levels. Soluble CD40 ligand levels were not related to stroke, vascular events, or all-cause mortality. Conclusion— Among atrial fibrillation patients, CRP was positively correlated to stroke risk and related to stroke risk factors and prognosis (mortality, vascular events). Soluble CD40 ligand levels were lowest in those at moderate to high risk of stroke and not related to prognosis. The use of CRP in risk stratification for atrial fibrillation merits further study.

Angiogenin: a review of the pathophysiology and potential clinical applications

Summary.  Angiogenin is a member of the ribonuclease (RNase) superfamily: enzymes of innate substrate specificity, but divergent functional capacities. Angiogenin is a normal constituent of the circulation and contained in a vasculature that rarely undergoes proliferation, but in some physiological and pathological conditions its levels increase in blood, promoting neovascularization. Hence, angiogenesis is a common pathophysiological attribute of angiogenin. In malignant disease, the most studied pathological state in regard to angionenin, abnormally high levels are seen, which may be of prognostic significance. Angiogenin has also been studied in other non‐malignant pathological states. The aim of this review article is to provide an overview of the biochemistry and physiology of angiogenin, specifically in relation to the human pathological states where angiogenin has been implicated and finally, its potential clinical applications.

Ischemic Stroke in South Asians A Review of the Epidemiology, Pathophysiology, and Ethnicity-Related Clinical Features

Within the United Kingdom, mortality from stroke is higher among South Asians compared to European whites. The reasons for this excess cerebrovascular risk in South Asians remain unclear. The aim of this review is to present a comprehensive and systematic overview of the available literature relating to ischemic stroke among South Asian populations identifying distinct features of stroke epidemiology in this group. Summary of Review— A high frequency of lacunar strokes is a familiar pattern among South Asians, which suggests a greater prevalence of small-vessel disease in South Asians. This may be a consequence of abnormal metabolic and glycemic processes. In addition, stroke mortality among South Asians appears to be explained by glycemic status, which is an independent predictor of long-term stroke mortality. Within India, there is a perceptible rural–urban gradient in stroke prevalence, underlying the dangers of the rapid transition in socioeconomic circumstances seen across the Indian subcontinent. Conclusions— This review emphasizes the importance of further research into ischemic stroke for South Asians given their higher cardiovascular disease burden and necessity for targeted healthcare approaches.

Role of microRNAs in cardiac remodelling: New insights and future perspectives

Cardiac remodelling is a key process in the progression of cardiovascular disease, implemented in myocardial infarction, valvular heart disease, myocarditis, dilated cardiomyopathy, atrial fibrillation and heart failure. Fibroblasts, extracellular matrix proteins, coronary vasculature, cardiac myocytes and ionic channels are all involved in this remodelling process. MicroRNAs (miRNAs) represent a sizable sub-group of small non-coding RNAs, which degrade or inhibit the translation of their target mRNAs, thus regulating gene expression and play an important role in a wide range of biologic processes. Recent studies have reported that miRNAs are aberrantly expressed in the cardiovascular system under some pathological conditions. Indeed, in vitro and in vivo models have revealed that miRNAs are essential for cardiac development and remodelling. Clinically, there is increasing evidence of the potential diagnostic role of miRNAs as potential diagnostic biomarkers and they may represent a novel therapeutic target in several cardiovascular disorders. This paper provides an overview of the impact of several miRNAs in electrical and structural remodelling of the cardiac tissue, and the diagnostic and therapeutic potential of miRNA in cardiovascular disease.

Characterisation and validity of inflammatory biomarkers in the prediction of post-operative atrial fibrillation in coronary artery disease patients

Atrial fibrillation (AF) is a common complication of coronary artery bypass grafting (CABG). We sought to determine the diagnostic validity of plasma biomarkers of i) inflammation (marked by interleukin-6 [IL-6] and high-sensitivity C-reactive protein [hs-CRP]), ii) extracellular matrix remodelling (matrix metalloproteinase [MMP-9], tissue inhibitor of matrix metalloproteinase [TIMP-1]) and iii) the prothrombotic state (tissue factor and von Willebrand factor [vWF]) in the risk prediction of post-operative AF. Samples were obtained preoperatively from peripheral/femoral vein and from intracardiac chambers (right atrium [RA], the right atrial appendage [RAA], the left atrium [LA] and the left atrial appendage [LAA]) amongst 100 consecutive patients free of AF and inflammatory disease undergoing elective CABG. Biomarker concentrations were related to incident AF (30 days). At 30 days post CABG, 30 patients were proven to have had AF. Concentrations of tissue factor (TF) and vWF were unrelated to postoperative AF. Peripheral (p=0.018), and intracardiac levels (RAA (p=0.029) and LA (p=0.026)) of hs-CRP were associated with the presence of AF after CABG. Intracardiac levels of IL-6 in samples from the RAA (p=0.031), LA (p=0.042) and LAA (p=0.006), and MMP-9 in the LAA sample were also associated with AF (p=0.007). Our data suggest that an intra-cardiac inflammatory environment that is manifest peri-operatively may predispose to the development of post-operative AF. This intracardiac inflammatory state was reflected by increased peripheral hs-CRP levels. These differences may indicate local substrate abnormalities contributing to the development of AF post-operatively.

Angiopoietin‐2 levels as a biomarker of cardiovascular risk in patients with hypertension

Background. Abnormal angiogenesis is a pathophysiological component of cardiovascular disease (CVD), where circulating biomarkers of angiogenesis are associated with increased CVD risk in hypertension. We hypothesized that raised levels of angiopoietin (Ang)‐1 and ‐2 would predict events in patients with hypertension treated for CVD. Methods. We measured angiopoietin levels by enzyme‐linked immunosorbent assay (ELISA) in 251 hypertensive participants (85% male; mean age 63.5 years; 192 free of previous CVD events). Plasma angiopoietin levels were related to the subsequent CVD events over a mean follow‐up period of 57.1 (SD 11) months. Results. There were 11 cases of myocardial infarction (MI) and 18 cases of stroke during follow‐up. Ang‐2 was a significant predictor of MI, stroke, and composite CVD events, with the greatest event‐free survival amongst those in the lower tertile (all P<0.05). Ang‐1 was not predictive of CVD outcomes. Of CVD risk factors at recruitment (blood pressure, body mass index, plasma glucose, serum and high‐density lipoprotein (HDL)‐cholesterol), Ang‐2 was the only discriminator of incident MI (area under curve (AUC) = 73%, P = 0.013), where a value >4.3 ng/mL optimized specificity and sensitivity. On Cox regression analysis (CVD treatments and risk factors), raised Ang‐2 was an independent predictor of MI, P<0.05, but not stroke or composite outcomes. Conclusions. Among patients with hypertension, raised levels of Ang‐2 were predictive of MI, and further study is warranted to evaluate the use of this biomarker in CVD management, risk stratification, and prevention.

Increased 5-year mortality in the migrant South Asian stroke patients with diabetes mellitus in the United Kingdom: the West Birmingham Stroke Project.

Background:  Stroke is a major cause of premature mortality in Britain, but its burden is markedly greater amongst South Asians. Because of the paucity of data in this area, we investigated the magnitude and impact of risk from cardiovascular comorbidities on survival amongst South Asian stroke patients.

Abnormal soluble CD40 ligand and C-reactive protein concentrations in hypertension: relationship to indices of angiogenesis.

Background Abnormal inflammation, platelets and angiogenesis are involved in the pathophysiology of cardiovascular disease (CVD). Objective To test the hypothesis that concentrations of high sensitive C-reactive protein (CRP, an index of inflammation) and soluble CD40 ligand (sCD40L, an index of platelet activation) would be abnormal in hypertension, and in turn, be related to plasma indices of angiogenesis, the angiopoietins-1 and -2, and vascular endothelial growth factor (VEGF), in addition to the presence or absence of CVD. Methods Using a cross-sectional approach, we measured plasma concentrations of CRP, sCD40L, VEGF, and angiopoietins-1 and -2 in 147 patients with hypertension (85 with a history of CVD event/s, 62 CVD event-free) and 68 age- and sex-matched healthy controls. Results Concentrations of sCD40L (P = 0.039), CRP (P < 0.001), angiopoietin-1 (P < 0.001), angiopoietin-2 (P = 0.003) and VEGF (P < 0.001) were all greater amongst hypertensive patients than in controls. There were no significant differences in sCD40L and VEGF concentrations between hypertensive individuals with and without CVD events, but CRP and angiopoietin-1 concentrations were significantly greater amongst those with CVD events. On multiple regression analysis, sCD40L was associated with angiopoietin-2 (P = 0.01) and VEGF (P = 0.007) in hypertensive individuals, but no such associations were found within the healthy control group. Conclusion In patients with hypertension, sCD40L was associated with increased circulating markers of abnormal angiogenesis (angiopoietin-2, VEGF). The interaction between sCD40L and angiogenesis may contribute to the pathophysiology of CVD in hypertension.

Soluble, platelet-bound, and total P-selectin as indices of platelet activation in congestive heart failure

Background. Many complications associated with congestive heart failure (CHF) have a thrombosis-related aetiology. Platelets play an important role in thrombogenesis, but it is not clear whether circulating platelets actively participate in thrombosis-related complications associated with CHF. Objective. To determine whether soluble P-selectin, platelet surface P-selectin, and total platelet P-selectin as indices of platelet activation in CHF patients—compared to ‘disease controls’ and ‘healthy controls’—and to assess their prognostic value in CHF. Methods. We measured soluble P-selectin (sP-sel, by enzyme-linked immunosorbent assay, ELISA), total platelet P-selectin (pP-sel, by a novel ‘platelet lysate’ assay), platelet surface P-selectin (CD62P%G) and platelet surface CD63 (CD63%G) expression by flow cytometry—in 108 patients with stable congestive heart failure (all with left ventricular ejection fraction (LVEF) <50%). Levels were compared with 50 healthy controls and 70 ‘disease controls’ (patients with coronary artery disease with normal left ventricular systolic function). Results. CHF patients and disease controls had higher sP-sel, CD62P%G and CD63%G than healthy controls. There were no significant correlations between sP-sel, pP-sel, CD62P%G and CD63%G with ejection fraction (all P>0.05). There were no differences in these markers when ischaemic and non-ischaemic aetiologies of CHF were compared. After a median follow-up of 490 days (range 340–535), there were 7 deaths, 15 hospitalizations for worsening heart failure, 1 for cardiac resynchronization therapy, 4 for revascularizations, 4 for myocardial infarctions, and 1 stroke. None of the platelet markers were predictive of the composite end-point at follow-up. Conclusions. Patients with stable CHF exhibit evidence of abnormal platelet activation, despite usage of antiplatelet agents. These abnormalities did not determine prognosis and were broadly similar to those seen in ‘disease controls’ indicating that platelet abnormalities in CHF may simply be related to associated comorbidities.