Myocardial energy depletion and dynamic systolic dysfunction in hypertrophic cardiomyopathy

Evidence indicates that anatomical and physiological phenotypes of hypertrophic cardiomyopathy (HCM) stem from genetically mediated, inefficient cardiomyocyte energy utilization, and subsequent cellular energy depletion. However, HCM often presents clinically with normal left ventricular (LV) systolic function or hyperkinesia. If energy inefficiency is a feature of HCM, why is it not manifest as resting LV systolic dysfunction? In this Perspectives article, we focus on an idiosyncratic form of reversible systolic dysfunction provoked by LV obstruction that we have previously termed the 'lobster claw abnormality' — a mid-systolic drop in LV Doppler ejection velocities. In obstructive HCM, this drop explains the mid-systolic closure of the aortic valve, the bifid aortic pressure trace, and why patients cannot increase stroke volume with exercise. This phenomenon is characteristic of a broader phenomenon in HCM that we have termed dynamic systolic dysfunction. It underlies the development of apical aneurysms, and rare occurrence of cardiogenic shock after obstruction. We posit that dynamic systolic dysfunction is a manifestation of inefficient cardiomyocyte energy utilization. Systolic dysfunction is clinically inapparent at rest; however, it becomes overt through the mechanism of afterload mismatch when LV outflow obstruction is imposed. Energetic insufficiency is also present in nonobstructive HCM. This paradigm might suggest novel therapies. Other pathways that might be central to HCM, such as myofilament Ca2+ hypersensitivity, and enhanced late Na+ current, are discussed

Predictors of high central blood pressure in young with isolated systolic hypertension

G D Radchenko, O O Torbas, Yu M Sirenko State Institute National Scientific Center, M.D. Strazhesko Institute of Cardiology, National Academy of Medical Science, Kyiv, Ukraine Objective: According to the European Society of Cardiology/European Society of Hypertension 2013 guidelines, evaluation of aortic blood pressure (BP) is needed in young with isolated systolic hypertension (ISH), but using special devices is not common, especially in Ukraine, where only a few centers have these devices. The purpose of our study was to identify the simple clinical predictors for differentiation (with or without elevated aortic systolic BP [SBP]) of the young with ISH without the need for further extensive work-up. Patients and methods: The study included 44 young men (mean age: 32.2±1.3 years) with office SBP ≥140 mmHg and office diastolic BP (DBP) <90 mmHg (average: 153.4±2.1 mmHg and 83.4±1.7 mmHg, respectively). The following procedures were performed in all the subjects: body weight and height evaluation; measurement of office SBP, DBP, and heart rate; ambulatory BP monitoring; measurement of pulse wave velocity in arteries of elastic and muscle types and central SBP (cSBP); biochemical blood tests; electrocardiography; echocardiography; and carotid ultrasound investigations. Step-by-step multifactor regression analyses were used for finding the predictors of high cSBP. Results: Depending on the cSBP level, all the patients were divided into two groups: first group (n=17), subjects with normal cSBP, and second group (n=27), subjects with elevated cSBP. Patients in the second group were significantly older, with less height and higher body mass index; they had significantly higher levels of office SBP and DBP. Characteristics of target organ damage were within normal limits in both groups and did not differ significantly. Only pulse wave velocity in arteries of elastic type was significantly higher in the second group. The independent predictors of increased cSBP were as follows: height ≤178 cm (β=7.038; P=0.05), body weight ≥91 kg (β=5.53, P=0.033), and the level of office DBP ≥80 mmHg (β=4.43; P=0.05). The presence of two or three of these factors increased the probability of high cSBP in more than ten times (β=10.6, P=0.001). The sensitivity and specificity were 92.6% and 88.2%, respectively. Conclusion: Thus, 38.6% of young with ISH had normal cSBP. Independent predictors of increased cSBP included height ≤178 cm, weight ≥91 kg, and the level of office DBP ≥80 mmHg. The presence of at least two of these factors indicated the need for starting the antihypertensive therapy in young with ISH. The presence of only one of these factors or none indicated the need for providing the central BP measurements in order to choose the further management strategy. Keywords: isolated systolic hypertension, young, central blood pressur

Influence of fixed-dose combination perindopril/amlodipine on target organ damage in patients with arterial hypertension with and without ischemic heart disease (results of EPHES trial)

Ganna D Radchenko, Liliya O Mushtenko, Yuriy M Sirenko State Institute “National Scientific Center “Institute of Cardiology named after acad.M.Strazhesko” of Ukrainian National Academy of Medical Science, Kyiv, Ukraine Background: The EPHES trial (Evaluation of influence of fixed dose combination Perindopril/amlodipine on target organ damage in patients with arterial HypErtension with or without iSchemic heart disease) compared the dynamics of target organ damage (TOD) in hypertensive patients with and without ischemic heart disease (IHD) treated with the fixed-dose combination (FDC) perindopril + amlodipine. Methods: The analysis included 60 hypertensive patients (aged >30 years): 30 without IHD and 30 with IHD. At randomization, FDC was administered at a daily baseline dose of 5/5 mg with uptitration to 10/10 mg every two weeks. If target blood pressure (BP<140/90 mmHg) was not achieved after six weeks, indapamide 1.5 mg was added to the regimen. All patients underwent body mass index measurements, office and ambulatory BP measurements, pulse wave velocity (PWVe) and central systolic BP evaluation, augmentation index adjusted to heart rate 75 (Aix@75) evaluation, biochemical analysis, ECG, echocardiography with Doppler, ankle-brachial index measurement, and intima-media thickness measurement. The follow-up period was 12 months. Results: Therapy based on FDC perindopril/amlodipine was effective in lowering BP (office, ambulatory, central) in both groups. We noted significant decrease in Aix@75 with the therapy in both groups, but ΔAix@75 was lesser in the group with IHD than the group without IHD. FDC provided significant improvement in PWVe and left ventricular diastolic function, and decrease in albuminuria, left ventricular hypertrophy (LVH), and left atrium size. ΔPWVe was significantly (P<0.005) less in patients without IHD than those with IHD (2.5±0.2 vs 4.4±0.5 m/s, respectively). In spite of almost equal LVH regression, the positive dynamics of ΔE/A and ΔE/E´ were more in patients with IHD than those without IHD (64.4% and 54.1% vs 39.8 and 23.2%, respectively; P<0.05 for both comparisons). Adverse reactions were in 2 (6.5%) patients without IHD and 3 (10%) with IHD (P=NS). In the group with IHD, we noted significant decrease in angina episode rate – from 2.5±0.4 to 1.2±0.2 (P<0.01) per week. Conclusion: Thus, treatment based on FDC was effective in decreasing BP and TOD regression in both patients with and without IHD. However, the dynamics of changes in TOD were different between the two groups, which should be taken into consideration during management of patients with and without IHD. Keywords: arterial hypertension, ischemic heart disease, target organ damage regression, fixed-dose combination, prospective observation, perindopril, amlodipin

Comparative effectiveness of a fixed-dose combination of losartan + HCTZ versus bisoprolol + HCTZ in patients with moderate-to-severe hypertension: results of the 6-month ELIZA trial

GD Radchenko, YM Sirenko, SM Kushnir, OO Torbas, AS DobrokhodSecondary Hypertension Department, National Scientific Center, Strazhesko Institute of Cardiology, Kiev, UkraineBackground: The aim of this study was to compare the antihypertensive efficacy of losartan 100 mg + hydrochlorothiazide (HCTZ) 25 mg versus bisoprolol 10 mg + HCTZ 25 mg and their influence on arterial stiffness and central blood pressure (BP).Methods: Of 60 patients with a mean BP of 173.3 &plusmn; 1.7/98.4 &plusmn; 1.2 mmHg, 59 were randomized to losartan + HCTZ (n = 32) or bisoprolol + HCTZ (n = 27). Amlodipine was added if target BP was not achieved at 1 month, and doxazosin was added if target BP was not achieved after 3 months. Body mass index, office and 24-hour ambulatory BP, pulse wave velocity (carotid-femoral [PWVE] and radial [PWVM]), noninvasive central systolic BP, augmentation index (AIx), laboratory investigations, and electrocardiography were done at baseline and after 6 months of treatment.Results: Losartan + HCTZ was as effective as bisoprolol + HCTZ, with target office BP achieved in 96.9% and 92.6% of patients and target 24-hour BP in 75% and 66.7% of patients, respectively, after 6 months. Effective treatment of BP led to significant lowering of central systolic BP, but this was decreased to a significantly (P < 0.05) greater extent by losartan + HCTZ (-23.0 &plusmn; 2.3 mmHg) than by bisoprolol + HCTZ (-15.4 &plusmn; 2.9 mmHg) despite equal lowering of brachial BP. Factors correlated with central systolic BP and its lowering differed between the treatment groups. Losartan + HCTZ did not alter arterial stiffness patterns significantly, but bisoprolol + HCTZ significantly increased AIx. We noted differences in &Delta;PWVE, &Delta;PWVM, and &Delta;AIx between the groups in favor of losartan + HCTZ. Decreased heart rate was associated with higher central systolic BP and AIx in the bisoprolol + HCTZ group, but was not associated with increased AIx in the losartan + HCTZ group.Conclusion: Although both treatments decreased both office and 24-hour BP, losartan + HCTZ significantly decreased central systolic BP and had a more positive influence on pulse wave velocity, with a less negative effect of decreased heart rate on AIx and central systolic BP.Keywords: arterial hypertension, combination therapy, central blood pressure, arterial stiffnes

Prediction of bending stiffness and deformed shape of non-axially compressed microtubule by a semi-analytical approach

The bending stiffness of a microtubule is one of the most important parameters needed in the analysis of microtubule deformation. In this study, a semi-analytical approach is developed to predict the bending stiffness and deformed shape of a non-axially compressed microtubule in an explicit closed form. By using the solution presented in this paper and the experimentally observed values given in the literature, both the deformed configuration and bending stiffness of a single microtubule are determined. The proposed method is validated by comparing the obtained results with available data in the literature. The comparison shows that the present semi-analytical formulation provides the same accuracy with reduced numerical effort

Coupled oscillations of a protein microtubule immersed in cytoplasm: an orthotropic elastic shell modeling

Revealing vibration characteristics of sub-cellular structural components such as membranes and microtubules has a principal role in obtaining a deeper understanding of their biological functions. Nevertheless, limitations and challenges in biological experiments at this scale necessitates the use of mathematical and computational models as an alternative solution. As one of the three major cytoskeletal filaments, microtubules are highly anisotropic structures built from tubulin heterodimers. They are hollow cylindrical shells with a ∼ 25 nm outer diameter and are tens of microns long. In this study, a mechanical model including the effects of the viscous cytosol and surrounding filaments is developed for predicting the coupled oscillations of a single microtubule immersed in cytoplasm. The first-order shear deformation shell theory for orthotropic materials is used to model the microtubule, whereas the motion of the cytosol is analyzed by considering the Stokes flow. The viscous cytosol and the microtubule are coupled through the continuity condition across the microtubule–cytosol interface. The stress and velocity fields in the cytosol induced by vibrating microtubule are analytically determined. Finally, the influences of the dynamic viscosity of the cytosol, filament network elasticity, microtubule shear modulus, and circumferential wave-number on longitudinal, radial, and torsional modes of microtubule vibration are elucidated

Molecular structural mechanics model for the mechanical properties of microtubules

The aim of this paper was to develop a structural mechanics (SM) model for the microtubules (MTs) in cells. The technique enables one to study the configuration effect on the mechanical properties of MTs and enjoys greatly improved computational efficiency as compared with molecular dynamics simulations. The SM model shows that the Young’s modulus has nearly a constant value around 0.83 GPa, whereas the shear modulus, two orders of magnitude lower, varies considerably with the protofilament number NN and helix-start number SS . The dependence of the bending stiffness and persistence length on the MT length and protofilament number NN is also examined and explained based on the continuum mechanics theories. Specifically, the SM model is found to be in good agreement with available simulation and experiment results, showing its robustness in studying the static deformation of MTs and the potential for characterizing the buckling and vibration of MTs as well as the mechanical behaviour of intermediate and actin filaments

Creation of a library of induced pluripotent stem cells from Parkinsonian patients

Induced pluripotent stem cells (iPSCs) are becoming an important source of pre-clinical models for research focusing on neurodegeneration. They offer the possibility for better understanding of common and divergent pathogenic mechanisms of brain diseases. Moreover, iPSCs provide a unique opportunity to develop personalized therapeutic strategies, as well as explore early pathogenic mechanisms, since they rely on the use of patients' own cells that are otherwise accessible only post-mortem, when neuronal death-related cellular pathways and processes are advanced and adaptive. Neurodegenerative diseases are in majority of unknown cause, but mutations in specific genes can lead to familial forms of these diseases. For example, mutations in the superoxide dismutase 1 gene lead to the motor neuron disease amyotrophic lateral sclerosis (ALS), while mutations in the SNCA gene encoding for alpha-synuclein protein lead to familial Parkinson's disease (PD). The generations of libraries of familial human ALS iPSC lines have been described, and the iPSCs rapidly became useful models for studying cell autonomous and non-cell autonomous mechanisms of the disease. Here we report the generation of a comprehensive library of iPSC lines of familial PD and an associated synucleinopathy, multiple system atrophy (MSA). In addition, we provide examples of relevant neural cell types these iPSC can be differentiated into, and which could be used to further explore early disease mechanisms. These human cellular models will be a valuable resource for identifying common and divergent mechanisms leading to neurodegeneration in PD and MSA