Expanded extracellular volume (ECV) is an early marker of myocardial interstitial fibrosis in patients with hypertension. Animal studies suggest that surges in sympathetic nerve activity (SNA) might contribute more to the development of interstitial fibrosis than the resting level of SNA. The aim of this study was to investigate whether resting SNA or greater SNA reactivity to a stressor may be associated with expanded ECV in humans across a range of blood pressures. This was a cross-sectional study in 19 individuals with varying levels of ambulatory systolic blood pressure (111–153 mmHg, 48 ± 13 years, 26.5 ± 2.6 kg/m2, n = 10 diagnosed with hypertension and n = 9 normotensive controls). Beat-to-beat non-invasive blood pressure (Finometer), heart rate (3-lead ECG) and muscle SNA (MSNA; peroneal microneurography) were recorded simultaneously during baseline, and throughout a cold pressor test (physiological stress), with hand immersion in 3–4 °C water. LV chamber size, wall thickness and ECV were assessed using cardiac magnetic resonance imaging. Resting MSNA was not associated with cardiac ECV (B coefficient = − 0.07, 95

The underlying aetiology and pathophysiology of arterial hypertension often remain unclear. To provide a better understanding of the disease process, a more comprehensive and multisystem use of magnetic resonance imaging is advocated in the assessment of hypertensive patients, with additional novel focus on the ‘selfish brain hypothesis’. This approach may guide more individualised therapy to managing one of the most important noncommunicable causes of human morbidity and mortality.

Bicuspid aortic valve (BAV) patients develop ascending aortic (AAo) dilation. The pathogenesis of BAV aortopathy (genetic vs. haemodynamic) remains unclear. This study aims to identify regional changes around the AAo wall in BAV patients with aortopathy, integrating molecular data and clinical imaging. BAV patients with aortopathy (n = 15) were prospectively recruited to surgically collect aortic tissue and measure molecular markers across the AAo circumference. Dilated (anterior/right) vs. non-dilated (posterior/left) circumferential segments were profiled for whole-genomic microRNAs (next-generation RNA sequencing, miRCURY LNA PCR), protein content (tandem mass spectrometry), and elastin fragmentation and degeneration (histomorphometric analysis). Integrated bioinformatic analyses of RNA sequencing and proteomic datasets identified five microRNAs (miR-128-3p, miR-210-3p, miR-150-5p, miR-199b-5p, and miR-21-5p) differentially expressed across the AAo circumference. Among them, three miRNAs (miR-128-3p, miR-150-5p, and miR-199b-5p) were predicted to have an effect on eight common target genes, whose expression was dysregulated, according to proteomic analyses, and involved in the vascular-endothelial growth-factor signalling, Hippo signalling, and arachidonic acid pathways. Decreased elastic fibre levels and elastic layer thickness were observed in the dilated segments. Additionally, in a subset of patients n = 6/15, a four-dimensional cardiac magnetic resonance (CMR) scan was performed. Interestingly, an increase in wall shear stress (WSS) was observed at the anterior/right wall segments, concomitantly with the differentially expressed miRNAs and decreased elastic fibres. This study identified new miRNAs involved in the BAV aortic wall and revealed the concomitant expressional dysregulation of miRNAs, proteins, and elastic fibres on the anterior/right wall in dilated BAV patients, corresponding to regions of elevated WSS.

Arterial hypertension is a leading cause of mortality, affecting at least a quarter of the adult population, with its effects having devastating consequences to the global economy. Unfortunately, the underlying causes and pathophysiology of the disease often remain unclear. Ongoing research in this important field investigates the mechanisms involved in the genesis of hypertension. Magnetic resonance imaging is a well-established imaging technique that is widely used for anatomical organ and vascular evaluation. According to the latest European Society of Hypertension (ESC) guidelines, cardiovascular magnetic resonance can be used in the assessment of hypertensive patients. But the authors advocate a more comprehensive and multisystem use of the varied and novel sequences of MRI scanners to provide an even better understanding of the development of hypertension and its consequences. The extensive and detailed data that can be derived, with the additive focus on the concept of the ‘selfish brain hypothesis’, might further assist us in altering and providing a more individualised therapeutic approach to one of the greatest non-communicable causes of human mortality and morbidity.

Background: Variants in the posterior anatomy of the cerebral circulation are associated with hypertension and lower cerebral blood flow in midlife (age ≈55 years); however, whether these variants are a result of aging or long-term exposure to high blood pressure is unclear. Additionally, the role these variants play in early onset of hypertension (<40 years) and poor cerebral perfusion in this population is unknown. Methods: We retrospectively examined whether specific cerebrovascular variants (vertebral artery hypoplasia and absent/hypoplastic posterior communicating arteries (an incomplete posterior circle of Willis) measured via magnetic resonance angiography) were associated with a diagnosis of hypertension in 220 young adults (<40 years; n=164 primary hypertensive [mean age±SD, 32±6 years] and n=56 [30±6 years] normotensive adults). Whether cerebrovascular variants were associated with lower cerebral blood flow (phase-contrast angiography) was measured in the hypertensive group only (n=146). Results: Binary logistic regression (adjusted for age, sex, and body mass index) showed that vertebral artery hypoplasia with an incomplete posterior circle of Willis was associated with hypertension diagnosis ( P <0.001, odds ratio; 11.79 [95% CI, 3.34–41.58]). Vertebral artery hypoplasia plus an incomplete circle of Willis was associated with lower cerebral blood flow in young adults with hypertension ( P =0.0172). Conclusions: Vertebral artery hypoplasia plus an incomplete posterior circle of Willis independently predicts hypertension in young adults suggesting that this variant is not acquired with aging into midlife. Importantly this variant combination was associated with lower cerebral perfusion, which may have long-term consequences on cerebrovascular health in young adults with hypertension.

Arterial hypertension is a leading cause of mortality, affecting at least a quarter of the adult population, with its effects having devastating consequences to the global economy. Unfortunately, the underlying causes and pathophysiology of the disease often remain unclear. Ongoing research in this important field investigates the mechanisms involved in the genesis of hypertension. Magnetic resonance imaging is a well-established imaging technique that is widely used for anatomical organ and vascular evaluation. According to the latest European Society of Hypertension (ESC) guidelines, cardiovascular magnetic resonance can be used in the assessment of hypertensive patients. But the authors advocate a more comprehensive and multisystem use of the varied and novel sequences of MRI scanners to provide an even better understanding of the development of hypertension and its consequences. The extensive and detailed data that can be derived, with the additive focus on the concept of the ‘selfish brain hypothesis’, might further assist us in altering and providing a more individualised therapeutic approach to one of the greatest non-communicable causes of human mortality and morbidity.

Introduction Hypertension (HTN) is a major risk factor for developing of heart failure (HF). Patients with early onset HTN (≤40 years) are at increased risk compared to those who develop HTN in later life. The transition from HTN to HF is incompletely understood but involves left ventricular (LV) changes at the cellular level. These include diffuse interstitial fibrosis, measured by extracellular volume fraction (ECV). Elevated ECV is associated with an increased risk of death and HF hospitalisation but the extent of elevated ECV in patients with early onset HTN is not known. In addition, among patients with HF with preserved ejection fraction (HFpEF), women outnumber men by a ratio of 2:1. The reasons for this are not known. We aimed to investigate cardiac MRI parameters including ECV in patients with early onset HTN who do not have HF. Methods Data from consecutive patients from a tertiary HTN clinic referred for CMR (Siemens, Germany) over a 3-year period was retrospectively analysed. Elevated ECV was defined as ≥28% as this is associated with increased HF hospitalisation. Data are mean ± SD. Alpha was set at 0.05. Results 29 patients ≤40 years underwent CMR during the study period; mean age 33±5.4 years, 15/29 (52%) female.Elevated ECV was identified in 9/29 (31%) patients ≤40 years and the majority were female (8/9, p=0.01, Fisher’s exact test). This gender difference was not seen in patients >40 years old with HTN who underwent CMR during the same period (29/59 [49%] had an elevated ECV with 14/29 female, p=0.19, Fisher’s exact test).Among patients ≤40 years, LV hypertrophy (all concentric) was more common in those with ECV ≥28% (5/9) than those with ECV <28% (2/20, p=0.02, Fisher’s exact test). Among the female patients ≤40 years, there was a trend towards increased LV mass in the 8 patients with ECV ≥28% compared to 7 with ECV <28% (78±14.4g/m2 vs 67±3.8g/m2, p=0.06, t-test).Among patients ≤40 years, there were no significant differences between the ECV ≥28% and ECV <28% groups in LV ejection fraction or LV strain, strain rate, and diastolic strain rate. There were also no differences in the parameters in table 1. Conclusions Among patients with early onset HTN, one in three had elevated ECV. This was independent of age, BMI, blood pressure (BP), and BP treatment. These patients are likely to be at increased risk of HF in later life.Patients with early onset HTN and an elevated ECV were more likely to be female. This may reflect an expected gender difference; recent studies indicate healthy females have higher ECV than healthy males, and this study further highlights the importance of separate ECV reference ranges for men and women. However it may also reflect early pathological fibrosis in response to HTN, particularly as in patients >40 years old there was no gender difference among patients with an elevated ECV. Increased LV fibrosis at a younger age may be a contributor to the increased development of HFpEF among female patients. Conflict of Interest None

It has been estimated that 20–30% of repaired aortic coarctation (CoA) patients develop hypertension, with significant cardiovascular morbidity and mortality. Vertebral artery hypoplasia (VAH) with an incomplete posterior circle of Willis (ipCoW; VAH + ipCoW) is associated with increased cerebrovascular resistance before the onset of increased sympathetic nerve activity in borderline hypertensive humans, suggesting brainstem hypoperfusion may evoke hypertension to maintain cerebral blood flow: the “selfish brain” hypothesis. We now assess the “selfish brain” in hypertension post-CoA repair. Time-of-flight cardiovascular magnetic resonance angiography from 127 repaired CoA patients (34 ± 14 years, 61% male, systolic blood pressure (SBP) 138 ± 19 mmHg, diastolic blood pressure (DBP) 76 ± 11 mmHg) was compared with 33 normotensive controls (42 ± 14 years, 48% male, SBP 124 ± 10 mmHg, DBP 76 ± 8 mmHg). VAH was defined as < 2 mm and ipCoW as hypoplasia of one or both posterior communicating arteries. VAH + ipCoW was more prevalent in repaired CoA than controls (odds ratio: 5.8 [1.6–20.8], p = 0.007), after controlling for age, sex and body mass index (BMI). VAH + ipCoW was an independent predictor of hypertension (odds ratio: 2.5 [1.2–5.2], p = 0.017), after controlling for age, gender and BMI. Repaired CoA subjects with VAH + ipCoW were more likely to have difficult to treat hypertension (odds ratio: 3.3 [1.01–10.7], p = 0.049). Neither age at time of CoA repair nor any specific repair type were significant predictors of VAH + ipCoW in univariate regression analysis. VAH + ipCoW predicts arterial hypertension and difficult to treat hypertension in repaired CoA. It is unrelated to age at time of repair or repair type. CoA appears to be a marker of wider congenital cerebrovascular problems. Understanding the “selfish brain” in post-CoA repair may help guide management. High Blood Pressure; Hypertension; Magnetic Resonance Imaging (MRI); Cardiovascular Surgery; Cerebrovascular Malformations.

Introduction Synchronised DC cardioversion is a commonly used treatment option for persistent atrial fibrillation (AF). Atrial distension is a predisposing factor for AF, and fibrosis of the atrial myocardium may prevent remodelling of the atrium to normalised parameters following cardioversion, with a fibrotic atrium begetting inevitable recurrence of AF. Methods We retrospectively investigated echocardiographic appearances of 89 patients prior to elective DC cardioversion, to determine whether simple measurements of atrial dimensions in atrial systole and diastole may predict the recurrence of AF. We analysed 89 echocardiograms for patients attending for elective cardioversion, The long-term success following DC cardioversion at six months was correlated with patient demographics, biochemistry and parameters measured on echocardiogram. Results 89 patients were assessed, with age 66.6 ± 1.0 years, ejection fraction 55.2 ± 1.2%, diameter (atrial diastole) 4.6 ± .0.1, and diameter (atrial systole) 4.1 ± 0.1. Left atrial diameter in atrial diastole, and atrial distension index, derived from measurements of atrial diameter in atrial systole and diastole on M-mode parasternal long axis view, were shown to have a statistically significant correlation with successful sustained sinoversion on linear regression (F(2,83), p = 0.0176). Atrial distension index = [diameter (atrial diastole) – diameter (atrial systole)]/diameter (atrial systole). Conclusion In summary atrial distension index, derived from simple measurements of the left atrium in systole and diastole from 2D transthoracic echocardiography, may predict persistence of sinus rhythm following DC cardioversion in persistent AF.

INTRODUCTION:Arterial hypertension is often associated with a stiff aorta as a result of collagen accumulation in the aortic wall and may produce chest pain. In the present study, possible interrelationships between aortic function, collagen turnover and exercise-induced chest pain in patients with arterial hypertension and angiographically normal coronary arteries were investigated.METHODS:Ninety-seven patients with arterial hypertension, angiographically normal coronary arteries and no evidence of myocardial ischemia on nuclear cardiac imaging during exercise test were studied. Of these, 43 developed chest pain during exercise (chest pain group) while 54 did not (no chest pain group). Carotid femoral pulse-wave velocity (PWVc-f) was used to assess the elastic properties of the aorta. Amino-terminal pro-peptides of pro-collagen type I, (PINP, reflecting collagen synthesis), serum telopeptides of collagen type I (CITP, reflecting collagen degradation), pro-metalloproteinase 1 (ProMMP-1), and tissue inhibitor of metalloproteinase 1 (TIMP-1, related to collagen turnover) were measured in plasma by immunoassay.RESULTS:The chest pain group had higher PWVc-f, higher and /CITP ratio, and lower proMMP-1/ TIMP-1 ratio compared to the no chest pain group. PWVc-f (t=2.53, p=0.02) and PINP (t=2.42, p=0.02) were independently associated with the presence of chest pain in multiple regression analysis.CONCLUSIONS:Patients with arterial hypertension, exercise-induced chest pain and angiographically normal coronary arteries, without evidence of exercise-induced myocardial ischemia, had a stiffer aorta compared to those without chest pain. Alterations in collagen type I turnover that favor collagen accumulation in the aortic wall may contribute to aortic stiffening and chest pain in these patients.

BACKGROUNDAltered myocardial extracellular matrix turnover has been proposed as a major determinant of myocardial remodelling. Carboxy-terminal telopeptide of collagen type-I (CITP) represents a collagen type-I degradation-derived serum peptide. In this study we examined the independent and additive prognostic value of serum concentrations of CITP compared with well-known mortality predictors such as the N-terminal pro-brain natriuretic peptide (NT-proBNP) in chronic heart failure (CHF) patients.METHODSWe studied 196 consecutive patients (126 male, mean age 69 ± 10 years), who were admitted for acute decompensation of the CHF syndrome. The study entry point was determined at the discharge of the patients after achieving a stable compensated status. The primary endpoint was cardiac mortality during a 12-month follow-up.RESULTSIn the multivariate Cox proportional hazard model the levels of CITP remained a predictor of survival (hazards ratio 0.4 95% confidence interval 0.21-0.76, P = 0.005), independent of NT-proBNP levels. The stratified log-rank test (P < 0.001) showed that CHF patients characterized by low levels of both biomarkers had better survival (hazards ratio 0.12 95% confidence interval 0.04-0.35, P < 0.001) compared with patients characterized by high levels of both biomarkers. The negative predictive value of the combined measure for long-term adverse events was 94%.CONCLUSIONSerum levels of CITP were shown to be an independent and strong prognostic marker regarding survival in CHF patients. Furthermore, CITP levels had an additive prognostic value compared with NT-proBNP levels. These findings underline the detrimental role of myocardial fibrosis in the progression of heart failure and suggest a novel multi-marker approach for risk stratification in the CHF syndrome.

Objectives - Myocardial collagen content as a fundamental component of extracellular matrix, is altered in pathological states including heart failure (HF). Serum peptides related to myocardial collagen synthesis and degregation can be measured and may be used as indices of myocardial collagen turnover. The present study was undertaken to assess the hypothesis that resolution of acute decompensation of chronic HF is associated with changes in serum peptides related to collagen synthesis and degregation.Methods and results - Serum concentrations of the amino-terminal propetide of procollagen type I (PINP) and the carboxy-terminal telopeptide of collagen type I (CITP), indices of collagen type I synthesis and degradation, respectively, were determined at the time of admission and discharge in 156 patients (100 men, 68 10 years) with acute clecompensation of chronic HF A significant decrease (-3.5 ng/ml 95%CI -5.3/-1.6 ng/ml, P < 0.00 1) of PINP was observed whereas CITP levels were significantly increased (+0.04 ng/ml 95%CI 0.01-0.08 ng/ml, P = 0.031) at discharge compared to admission.Conclusions - Findings of the present study showed that serum indices of myocardial collagen turnover were changed significantly in a short period of time during the improvement of acute clecompensation of chronic HF.

High cholesterol content of erythrocyte membranes (CEM) levels is present in patients with acute coronary syndromes (ACS). Intraplaque hemorrhage and erythrocyte lysis contribute to the deposition of cholesterol on the atherosclerotic plaque and to plaque rupture. With the present study we assessed the effect of statin therapy on CEM levels, a novel marker of coronary artery disease (CAD) instability during a 1-year follow-up in CAD patients.

ObjectivesPresence of free cholesterol in atherosclerotic plaques is a major determinant of plaque instability. It is hypothesized that extravasated erythrocytes may contribute to free cholesterol accumulation in atherosclerotic plaques through their rich in cholesterol membrane. In this study we assessed whether cholesterol in erythrocyte membranes (CEMs), that is, free (FCEM) versus esterified (ECEM), differs in patients with chronic stable angina (CSA) compared with patients presenting with acute coronary syndromes (ACSs). MethodsConsecutive angina patients were prospectively assessed; 154 had CSA (118 men, 63 years, 56–69 years) and 164 ACS (124 men, 63 years, 55–71 years). FCEM and ECEM were measured using an enzymatic assay, and protein content was assessed by the Bradford method. ResultsFCEM was significantly higher (P<0.001) in the ACS patients group (94.1 μg/mg, IQ 71–116.5 μg/mg) compared with patients with CSA (61.9 μg/mg, IQ 49.3–73.1 μg/mg). ECEM levels were also significantly higher (P<0.001) in ACS patients (23.3 μg/mg, IQ 14.9–47.7 μg/mg) compared with CSA patients (10.8 μg/mg, IQ 8–22.3 μg/mg). In contrast, ratio of free-to-esterified cholesterol (P=0.110) as well as ratio of free-to-total CEM (P=0.109) were not different among CSA and ACS patients. ConclusionFindings of this study show that although free cholesterol is the prevailing form of CEMs, both FCEM and ECEM levels are increased in patients with ACS compared with CSA patients. These findings suggest that it is the quantity of CEM rather than the type of cholesterol present in the erythrocyte membrane that determines plaque progression.

The present study was undertaken to assess the effect of statins on collagen type I degradation and C-reactive protein in patients with coronary artery disease and atrial fibrillation. One hundred six patients with coronary artery disease and atrial fibrillation were studied: 40 (36 men, mean age 72 +/- 8 years) treated with a statin and 66 (48 men, mean age 74 +/- 9 years) not treated with a statin. Serum concentrations of carboxy-terminal telopeptide of collagen type I, an index of collagen type I degradation, and high-sensitivity C-reactive protein were measured in all patients. Carboxy-terminal telopeptide of collagen type I levels were significantly higher (p <0.001) in statin-treated patients (0.64 ng/ml, 95% confidence interval [CI] 0.57 to 0.71) compared with nonstatin-treated patients (0.38 ng/ml, 95% CI 0.31 to 0.44). These changes were independent of cholesterol levels (before or after. therapy). Statin-treated patients had significantly lower (p <0.001) C-reactive protein levels (0.25 mg/dl, 95% CI 0.23 to 0.28) compared to statin nonusers (1.1 mg/dl, 95% CI 0.92 to 1.25). In conclusion, this study suggests that therapy with statins in patients with coronary artery disease and atrial fibrillation is associated with an increase in collagen degradation and an attenuation of inflammation, independently of cholesterol lowering. (C) 2008 Elsevier Inc. All rights reserved.

BACKGROUND:Chronic heart failure (CHF) induces peripheral vasoconstriction, endothelial dysfunction and arterial stiffness by activation of various neurohormonal pathways. The abnormal collagen turnover observed in CHF may be attributed not only to myocardial remodelling, but also to vascular remodelling. However, the effect of collagen metabolism on progressive large artery stiffening in the setting of CHF is understudied. AIMS:The present study was undertaken to investigate the association between circulating markers of collagen turnover and vascular stiffness in patients with CHF. METHODS:Eighty patients (mean age 65+/-11 years, 68 men) with stable CHF and in sinus rhythm, were studied. Serum concentrations of carboxy-terminal telopeptide of collagen type I (CITP) and amino-terminal propetide of procollagen type I (PINP), markers of collagen type I degregation and synthesis respectively, were measured in all patients. Pulse wave velocity (PWV) and augmentation index (AIx) of aortic pulse wave form, markers of arterial stiffness, were also determined by applanation tonometry. RESULTS:Peripheral PWV was inversely associated with serum CITP levels (r=-0.585, p<0.001). AIx although weakly was negatively correlated with serum CITP levels (r=-0.285, p=0.01). Multiple regression analysis showed that peripheral PWV remained independently associated with serum CITP levels after adjustment for all confounding variables. CONCLUSIONS:Findings from the present study imply a possible link between altered collagen metabolism and peripheral vascular stiffness in CHF.

AIMS Studies have shown that erythrocyte membranes are present within necrotic cores in atherosclerotic plaques, and that circulating erythrocytes in patients with acute coronary syndrome (ACS) have increased total cholesterol content (CEM). Interleukin-8 (IL-8) binds to erythrocytes and during intraplaque haemorrhage it is released into the plaque and thus may contribute to inflammatory cascade and atherosclerotic plaque instability. The present study was undertaken to test the hypothesis that erythrocyte membrane IL-8 is elevated in patients with ACS compared with those with chronic stable angina (CSA). METHODS AND RESULTS Consecutive patients who presented with CSA (n = 120, 92 men, 62 +/- 9 years), ACS (n = 118, 90 men, 62 +/- 10 years) or with chest pain who had normal coronary arteries (n = 36, 26 men, 60 +/- 7 years), were studied prospectively. IL-8 concentrations in erythrocyte membranes (rIL-8) and in plasma (pIL-8), C-reactive protein (CRP) and CEM were measured. rIL-8 levels [mean +/- 1 SD (standard deviation)] were higher in ACS (102.9 +/- 70.1 pg/mL) compared with CSA (44.7 +/- 22.8 pg/mL) (P < 0.001). No difference in pIL-8 levels between the two coronary artery disease groups was observed (P = 0.280). Serum CRP levels were correlated with rIL-8 levels (r = 0.294, P < 0.001); no association was found between CRP and pIL-8 levels (r = 0.025, P = 0.706). Further, rIL-8 had an independent association with ACS, when CRP and CEM were taken into consideration. CONCLUSION This study shows for the first time that rIL-8 content was significantly higher in ACS, compared with CSA. These findings endorse results from our previous studies suggesting that erythrocytes may play an important role in the development of unstable atherosclerotic plaque.