The role of whole blood viscosity in premature coronary artery disease in women

BACKGROUND: Impaired hemorheology has been demonstrated in atherosclerotic disease and has shown a relationship with classical risk factors. Blood viscosity (eta), being the ratio of shear stress over shear rate, is an important parameter of hemorheology. In women with premature coronary artery disease (CAD), the underlying risk factors are a matter of debate and the role of whole blood viscosity in its pathogenesis has not been documented. AIM: To investigate the association of whole blood viscosity with premature CAD in women, with complaints suggestive of angina pectoris. METHODS: Eighty-eight women (mean age 53 years) were divided into two groups, those with a high likelihood of CAD (LIKELI+) and those with a low likelihood of CAD (LIKELI-), based on medical history and technical investigations. Assessment of risk factors comprised smoking, diabetes mellitus, arterial hypertension, left ventricular hypertrophy (LVH), systolic and diastolic blood pressures, total low-density lipoprotein (LDL)- and high-density lipoprotein (HDL)-cholesterol, triglycerides, body mass index, menopause, hormone replacement therapy, uric acid and creatinine, and predicted 10-year cardiovascular risk according to the Framingham study was calculated. Whole blood viscosity was determined at 37 degrees C using a rotational cone-and-plate viscosimeter. RESULTS: Baseline characteristics did not differ significantly between the groups except for antiplatelet therapy (P=0.001), prevalence of diabetes mellitus (P=0.002), predicted 10-year cardiovascular risk (P=0.007), essential hypertension (P=0.02), LVH (P=0.03) and smoking habits (P=0.04). LIKELI+ women had a significantly higher whole blood viscosity at all shear rates compared with LIKELI- women (P<0.05). All blood viscosities measured from 25 to 125 s(-1) were highly significantly (P<0.0001) correlated with eta(250s(-1)). Univariate correlates with eta(250s(-1)) comprised triglycerides (P=0.006) and haematocrit (P=0.026). Binary logistic multivariate regression analysis for high likelihood of CAD revealed that only presence of arterial hypertension (P<0.0001) was predictive. Multiple regression analysis demonstrated that haematocrit (P=0.001) and likelihood of CAD (P=0.01) were the only significant determinants of eta(250s(-1)). CONCLUSION: In this study, blood viscosity did not appear as an independent risk factor for the prediction of premature CAD in women. Viscosity may act as a marker of CAD or of classical risk factors.     

Acute pulmonary hypertension causes depression of left ventricular contractility and relaxation

BACKGROUND AND OBJECTIVE: The haemodynamic effects of acute pulmonary hypertension can be largely attributed to ventricular interdependence during diastole. However, there is evidence that the two ventricles also interact during systole. The aim of the present study was to examine the effects of acute pulmonary hypertension on both components of left ventricular systole, i.e. contraction and relaxation, using load-independent indices. METHODS: Ten pigs were instrumented with biventricular conductance catheters, a pulmonary artery flow probe and a high-fidelity pulmonary pressure catheter. Haemodynamic measurements were performed in baseline conditions and during stable pulmonary vasoconstriction induced by the thromboxane analogue U46619. Contractility was quantified using the end-systolic pressure-volume and preload recruitable stroke work relationships. The tau-end-systolic pressure relationship was used to assess load-dependency of relaxation. RESULTS: Acute pulmonary hypertension caused a decrease in the slope of the left ventricular preload recruitable stroke work relationship (from 6.64 +/- 1.7 to 5.19 +/- 1.9, mean +/- SD; P < 0.05), a rightward shift of the end-systolic pressure-volume relationship (P < 0.05), and an increase in the slope of the tau-end-systolic pressure relationship (from -0.15 +/- 0.5 to 0.35 +/- 0.17; P < 0.05). The diastolic chamber stiffness constant of both ventricles increased during pulmonary hypertension (P < 0.05). CONCLUSIONS: In the present model, acute pulmonary hypertension impairs left ventricular contractile function and relaxing properties. The present study provides additional evidence that, besides the well-known diastolic ventricular cross talk, systolic ventricular interaction may play a significant role in the haemodynamic consequences of acute pulmonary hypertension.     

Long-term pressure monitoring with arterial applanation tonometry: a non-invasive alternative during clinical intervention?

Arterial tonometry is a non-invasive technique for continuous registration of arterial pressure waveforms. This study aims to assess tonometric blood pressure recording (TBP) as an alternative for invasive long-term bedside monitoring. A prospective study was set up where patients undergoing neurosurgical intervention were subjected to both invasive (IBP) and non-invasive (TBP) blood pressure monitoring during the entire procedure. A single-element tonometric pressure transducer was used to better investigate different inherent error sources of TBP measurement. A total of 5.7 hours of combined IBP and TBP were recorded from three patients. Although TBP performed fairly well as an alternative for IBP in steady state scenarios and some short-term variations, it could not detect relevant long-term pressure variations at all times. These findings are discussed in comparison to existing work. Physiological alterations at the site of TBP measurement are highlighted as a potentially important source of artifacts. It is concluded that at this point arterial tonometry remains not enough understood for long-term use during a delicate operative procedure. Physiological changes at the TBP measurement site deserve further investigation before tonometry technology is to be considered as an non-invasive alternative for long-term clinical monitoring.     

Flip angle optimization for dynamic contrast-enhanced MRI-studies with spoiled gradient echo pulse sequences

Spoiled gradient echo pulse (SPGRE) sequences are commonly used in dynamic contrast-enhanced MRI (DCE-MRI) studies to measure the contrast agent concentration in a tissue of interest over time. However, due to improper tuning of the SPGRE parameters, concentration uncertainty can be very high, even at high signal-to-noise ratio in the MR measurement. In this work, an optimization procedure is proposed for selecting the optimal value of the SPGRE-flip angle FA(opt), given the expected concentration range. The optimization condition ensures that every concentration in the assumed range has the lowest possible uncertainty. By decoupling the R(1)- and R*(2)-effects caused by the presence of the contrast agent, a contour plot has been generated from which FA(opt) can be read off for any study design. Investigation of ten recent DCE-MRI studies showed that improper flip angle selection unnecessarily increases the concentration uncertainty, up to 742% and 72% on average for the typical physiological concentration ranges of 0-2 mM in tumour tissue and 0-10 mM in blood, respectively. Simulations show that the reduced noise levels on the concentration curves, observed at the optimal flip angle, effectively increase the precision of the kinetic parameters estimates (up to 82% for K(trans), 82% for ν(e) and 92% for ν(p) in the case of an individually measured arterial input function (AIF), up to 53% for K(trans), 59% for ν(e) and 67% for ν(p) in the case of a standard AIF). In vivo experiments confirm the potential of flip angle optimization to increase the reproducibility of the kinetic parameter estimates.     

An Integrated Framework to Quantitatively Link Mouse-Specific Hemodynamics to Aneurysm Formation in Angiotensin II-infused ApoE −/− mice

Locally disturbed flow has been suggested to play a (modulating) role in abdominal aortic aneurysm (AAA) formation, but no longitudinal studies have been performed yet due to (a.o.) a lack of human data prior to AAA formation. In this study we made use of recent advances in small animal imaging technology in order to set up entirely mouse-specific computational fluid dynamics (CFD) simulations of the abdominal aorta in an established ApoE −/− mouse model of AAA formation, combining (i) in vivo contrast-enhanced micro-CT scans (geometrical model) and (ii) in vivo high-frequency ultrasound scans (boundary conditions). Resulting areas of disturbed flow at baseline were compared to areas of AAA at end-stage. Qualitative results showed that AAA dimension is maximal in areas that are situated proximal to those areas that experience most disturbed flow in three out of four S developing an AAA. Although further quantitative analysis did not reveal any obvious relationship between areas that experience most disturbed flow and the end-stage AAA dimensions, we cannot exclude that hemodynamics play a role in the initial phases of AAA formation. Due to its mouse-specific and in vivo nature, the presented methodology can be used in future research to link detailed and animal-specific (baseline) hemodynamics to (end-stage) arterial disease in longitudinal studies in mice.     

Endogenous inhibitors of hypertrophy in concentric versus eccentric hypertrophy

Left ventricular (LV) hypertrophy (LVH) is an adaptive response to hemodynamic overload, but also contributes to the pathogenesis of heart failure. LVH can be concentric (cLVH) but subsequent dilatation and progression to eccentric hypertrophy (eLVH) may lead to global pump failure. Recently, several endogenous molecular inhibitors of hypertrophy have been identified. Using real-time PCR, we compared the myocardial mRNA expression of these inhibitors in pressure-overload induced cLVH (severe aortic stenosis) and in volume overload-induced eLVH (severe mitral regurgitation) in patients, and during the progression from cLVH to eLVH in pressure overload in rat. Each of these genes showed a unique temporal expression profile. Strikingly, except for SOCS-3, changes in gene expression of these negative regulators in rat cLVH and eLVH vs sham were recapitulated in human cLVH and eLVH. In particular, VDUP-1 and MCIP-1 were high in cLVH but expression levels were normal in eLVH, both in rat and human. These data indicate that during the progression of LVH, both in pressure and volume overload, expression levels of endogenous inhibitors of hypertrophy are modified and that these changes may have pathophysiological significance. In particular, MCIP-1 (the endogenous calcineurin inhibitor) and VDUP-1 (the endogenous inhibitor of thioredoxin) are potential molecular switches in the progression of LV hypertrophy.     

Design of protein membrane interaction inhibitors by virtual ligand screening, proof of concept with the C2 domain of factor V

Most orally bioavailable drugs on the market are competitive inhibitors of catalytic sites, but a significant number of targets remain undrugged, because their molecular functions are believed to be inaccessible to drug-like molecules. This observation specifically applies to the development of small-molecule inhibitors of macromolecular interactions such as protein-membrane interactions that have been essentially neglected thus far. Nonetheless, many proteins containing a membrane-targeting domain play a crucial role in health and disease, and the inhibition of such interactions therefore represents a very promising therapeutic strategy. In this study, we demonstrate the use of combined in silico structure-based virtual ligand screening and surface plasmon resonance experiments to identify compounds that specifically disrupt protein-membrane interactions. Computational analysis of several membrane-binding domains revealed they all contain a druggable pocket within their membrane-binding region. We applied our screening protocol to the second discoidin domain of coagulation factor V and screened >300,000 drug-like compounds in silico against two known crystal structure forms. For each C2 domain structure, the top 500 molecules predicted as likely factor V-membrane inhibitors were evaluated in vitro. Seven drug-like hits were identified, indicating that therapeutic targets that bind transiently to the membrane surface can be investigated cost-effectively, and that inhibitors of protein-membrane interactions can be designed.