Ulf Neisius

Urinary proteomic diagnosis of coronary artery disease: identification and clinical validation in 623 individuals.

Objectives We studied the urinary proteome in a total of 623 individuals with and without coronary artery disease (CAD) in order to characterize multiple biomarkers that enable prediction of the presence of CAD. Methods Urine samples were analyzed by capillary electrophoresis coupled online to micro time-of-flight mass spectrometry. Results We defined a pattern of 238 CAD-specific polypeptides from comparison of 586 spot urine samples from 408 individuals. This pattern identified patients with CAD in a blinded cohort of 138 urine samples (71 patients with CAD and 67 healthy individuals) with high sensitivity and specificity (area under the receiver operator characteristic curve 87%, 95% confidence interval 81–92) and was superior to previously developed 15-marker (area under the receiver operator characteristic curve 68%, P < 0.0001) and 17-marker panels (area under the receiver operator characteristic curve 77%, P < 0.0001). The sequences of the discriminatory polypeptides include fragments of alpha-1-antitrypsin, collagen types 1 and 3, granin-like neuroendocrine peptide precursor, membrane-associated progesterone receptor component 1, sodium/potassium-transporting ATPase gamma chain and fibrinogen-alpha chain. Several biomarkers changed significantly toward the healthy signature following 2-year treatment with irbesartan, whereas short-term treatment with irbesartan did not significantly affect the polypeptide pattern. Conclusion Urinary proteomics identifies CAD with high confidence and might also be useful for monitoring the effects of therapeutic interventions.

Association of central and peripheral pulse pressure with intermediate cardiovascular phenoytpes

Objective We assessed the relationship between pulse pressure and intermediate cardiovascular phenotypes in a middle-aged cohort with high prevalence of hypertension. Background It has been suggested that central pulse pressure (cPP) is a better predictor of cardiovascular outcome than peripheral pulse pressure (pPP), particularly in the elderly. Yet, it is unclear if cPP provides additional prognostic information to pPP in younger individuals. Methods In 535 individuals we assessed cPP and pPP as well as the intermediate cardiovascular phenotypes pulse wave velocity (PWV; SphygmoCor, Complior, PulsePen), carotid intima-media thickness (C-IMT; carotid ultrasound), left-ventricular mass index (LVMI; echocardiography) and urinary albumin : creatinine ratio (ACR). cPP was derived noninvasively from brachial blood pressure by pulse wave analysis (PWA; SphygmoCor) based on radial pulse wave tonometry and a validated transfer function. Results The cohort contained 331 hypertensive participants of whom 84% were treated. The average age was 46 ± 16 years. When compared to pPP, cPP had stronger associations with PWV (r = 0.471 vs. r = 0.372; P < 0.01), C-IMT (r = 0.426 vs. r = 0.235; P < 0.01) and LVMI (r = 0.385 vs. r = 0.189; P < 0.01), but equal association with ACR (r = 0.236 vs. r = 0.226; P = n.s.). In contrast, after adjustment for age, mean arterial pressure, heart rate and hypertension status there was no significant difference between cPP and pPP for prediction of PWV (adjusted R2, 0.399 vs. 0.413; P = 0.066), C-IMT (adjusted R2, 0.399 vs. 0.413; P = 0.487) and LVMI (adjusted R2, 0.181 vs. 0.170; P = 0.094) in multivariate analysis. Conclusion In our middle-aged cohort with high prevalence of hypertension cPP is more closely correlated with cardiovascular phenotypes than pPP. When adjusted for relevant cofactors, however, cPP does not provide additional information beyond pPP.

Reduced LDL-cholesterol levels in patients with coronary artery disease are paralelled by improved endothelial function: An observational study in patients from 2003 and 2007

Objective Recent guidelines recommend more aggressive lipid-lowering in secondary prevention protocols. We examined whether this resulted in improved endothelial function. Methods We studied saphenous vein specimens of patients undergoing surgical coronary revascularisation in 2007 and compared results with those of patients examined in 2003. Endothelium-dependent vasodilation was assessed by relaxation to calcium ionophore A23187, and vascular superoxide production by lucigenin enhanced chemiluminescence. Results Statin dose increased from 26 ± 16 mg/d in 2003 to 37 ± 17 mg/d in 2007 (P < 0.001), and total (4.0 ± 0.9 mmol/L vs 4.8 ± 1.0 mmol/L) and LDL-cholesterol levels (2.0 ± 0.7 mmol/L vs 3.0 ± 0.9 mmol/L) were lower in 2007 compared to 2003 (P < 0.001; n = 90 each). Endothelium-dependent vasodilation was greater in 2007 (44 ± 15%) compared to 2003 (28 ± 12%; n = 36 each; P < 0.001). Vascular superoxide derived from endothelial NO synthase (eNOS) was lower in 2007 than in 2003 (reduction by NG-nitro-l-arginine-methyl ester, 0.29 ± 0.21 nmol/(mg min) vs 0.09 ± 0.20 nmol/(mg min); P = 0.002). In linear regression analysis, LDL-cholesterol levels have been shown to be the major determinant of endothelial function in the combined 2003 and 2007 cohort. Conclusion Intensive lipid-lowering is associated with improved endothelial function and reduced superoxide production from eNOS. Further improvement in vascular function could be achieved by targeting other sources of superoxide including xanthine oxidase.

Proteomics in hypertension and other cardiovascular diseases

Hypertension is a major cardiovascular risk factor with a multifactorial pathogenesis, including genetic and environmental factors. In addition to hypothesis-driven strategies, unbiased approaches such as genomics, proteomics, and metabolomics are useful tools to help unravel the pathophysiology of hypertension and associated organ damage. During development of cardiovascular disease the key organs and tissues undergo extensive functional and structural changes that are characterized by alterations in the amount and type of proteins that are expressed. Proteomic approaches study the expression of large numbers of proteins in organs, tissues, cells, and body fluids. A number of different proteomic platforms are available, many of which combine two methods to separate proteins and peptides after an initial digestion step. Identification of these peptides and changes in their expression in parallel with disease processes or medical treatment will help to identify as yet unknown pathophysiological pathways. There is also potential to use proteomic signatures as biomarkers of cardiovascular disease that will contribute to population screening, diagnosis of diseases and their severity, and monitoring of therapeutic interventions.

Pulse wave analysis for the prediction of preeclampsia

Preeclampsia is associated with a number of changes to maternal vascular function. Assessment of arterial stiffness using pulse wave analysis (PWA) has been proposed as a means of predicting preeclampsia before the onset of clinically detectable disease. One hundred and eighty women with ⩾2 risk factors for preeclampsia were examined at gestational weeks 16 and 28, of whom 17 (9.4%) developed preeclampsia. To study the effects of pregnancy itself women were also examined at 6–9 months post-natally; an additional 30 healthy non-pregnant women were also examined. PWA was performed using SphygmoCor; augmentation index (AIx), a marker of arterial wave reflection, was also measured using EndoPAT-2000. Women who developed preeclampsia were more likely to be overweight and had a higher brachial and central diastolic BP at gestational week 16 than those who remained normotensive. There was no difference in any parameter of arterial wave reflection between non-pregnant and pregnant women, nor between those who developed preeclampsia and those who remained normotensive, when examined at weeks 16 and 28 or post-natally. In this cohort of women with risk factors for preeclampsia, PWA did not provide additional information beyond brachial blood pressure and maternal risk factor profile about the risk of future development of preeclampsia.

Fabry Disease in Families With Hypertrophic Cardiomyopathy: Clinical Manifestations in the Classic and Later-Onset Phenotypes.

Background— The screening of Icelandic patients clinically diagnosed with hypertrophic cardiomyopathy resulted in identification of 8 individuals from 2 families with X-linked Fabry disease (FD) caused by GLA(&agr;-galactosidase A gene) mutations encoding p.D322E (family A) or p.I232T (family B). Methods and Results— Familial screening of at-risk relatives identified mutations in 16 family A members (8 men and 8 heterozygotes) and 25 family B members (10 men and 15 heterozygotes). Clinical assessments, &agr;-galactosidase A (&agr;-GalA) activities, glycosphingolipid substrate levels, and in vitro mutation expression were used to categorize p.D322E as a classic FD mutation and p.I232T as a later-onset FD mutation. In vitro expression revealed that p.D322E and p.I232T had &agr;-GalA activities of 1.4% and 14.9% of the mean wild-type activity, respectively. Family A men had markedly decreased &agr;-GalA activity and childhood-onset classic manifestations, except for angiokeratoma and cornea verticillata. Family B men had residual &agr;-GalA activity and developed FD manifestations in adulthood. Despite these differences, all family A and family B men >30 years of age had left ventricular hypertrophy, which was mainly asymmetrical, and had similar late gadolinium enhancement patterns. Ischemic stroke and severe white matter lesions were more frequent among family A men, but neither family A nor family B men had overt renal disease. Family A and family B heterozygotes had less severe or no clinical manifestations. Conclusions— Men with classic or later-onset FD caused by GLA missense mutations developed prominent and similar cardiovascular disease at similar ages, despite markedly different &agr;-GalA activities.

The heart in an airbag: spontaneous pneumopericardium in a young lady.

Pneumopericardium is a rare but potentially life-threatening clinical condition that must be considered in the differential diagnosis of chest pain. It is usually associated with chest trauma, infections, invasive procedures or mechanical ventilation. We report a case of pneumopericardium in a 25-year-old woman following a recent episode of forceful vomiting possibly acting as trigger factor. The diagnosis was made by posteroanterior chest radiography and confirmed with computed tomography. Contrast swallow test failed to detect oesophagopericardial fistulae and the patient was managed conservatively without further complication.

Black blood myocardial T2 mapping

To develop a black blood heart‐rate adaptive T2‐prepared balanced steady‐state free‐precession (BEATS) sequence for myocardial T2 mapping.

Automated Cardiac MR Scar Quantification in Hypertrophic Cardiomyopathy Using Deep Convolutional Neural Networks

Scar volume quantified by cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE) is a novel imaging biomarker for risk stratification in patients with hypertrophic cardiomyopathy (HCM) [(1)][1]. In current practice, scar quantification often relies on manual delineation of

Evaluation of the systemic micro- and macrovasculature in stable angina: a case-control study

Aims The diagnosis of stable angina involves the use of probability estimates based on clinical presentation, age, gender and cardiovascular risk factors. In view of the link between the cardiac and systemic vasculature we tested whether non-invasive measures of systemic micro- and macrovascular structure and function differentiate between individuals with flow-limiting coronary artery disease (CAD) and those with normal coronary arteries (NCA). Methods and results We recruited 84 patients undergoing elective coronary angiography for investigation of symptoms of stable angina. Patients were selected for either having significant CAD or NCA (n = 43/41; age, 56±7 vs 57±7 years, P = 0.309). Only microvascular endothelial function, measured using the Endo-PAT2000 device to determine reactive hyperaemia index (CAD vs. NCA; 1.9 [1.5; 2.3] vs. 2.1 [1.8; 2.4], P = 0.03) and sonographic carotid plaque score (CAD vs. NCA; 3.0 [1.5; 4.5] vs. 1.2 [0; 2.55], P<0.001) were significantly different between patients with CAD and NCA. No significant differences were detected in reflection magnitude (CAD vs. NCA; 1.7 [1.5; 1.8] % vs 1.7 [1.5; 1.9] %, P = 0.342), pulse wave velocity (CAD vs. NCA; 7.8±1.4 m/sec vs. 8.3±1.5 m/sec, P = 0.186), carotid intima-media thickness (CAD vs. NCA; 0.73±0.10 mm vs. 0.75±0.10 mm, P = 0.518) or carotid distensibility (CAD vs. NCA; 3.8±1.2 10-3/kPa vs. 3.4±0.9 10-3/kPa, P = 0.092). Also, the c-statistic of the pre-test probability based on history and traditional risk factors (c = 0.665; 95% CI, 0.540–0.789) was improved by the addition of the inverse RHI (c = 0.720; 95% CI, 0.605–0.836), carotid plaque score (c = 0.770, 95% CI, 0.659–0.881), and of both markers in combination (c = 0.801; 95% CI, 0.701–0.900). Conclusion There are distinct differences in the systemic vasculature between patients with CAD and NCA that may have the potential to guide diagnostic and therapeutic decisions. Carotid artery plaque burden and microvascular function appear to be most promising in this context.