Hemodynamic Load Research Articles

CARDIOHEMODYNAMIC AND SECRETORY FUNCTION OF THE MYOCARDIUM IN ELITE ATHLETES DURING ADAPTATION TO COLD

Aim: To study circulatory system functioning in elite skiers during adaptation to cold. Methods: Echocardiography, electrocardiography, recording of arterial pressure and electrochemiluminescent assessment of serum B-natriuretic peptide were performed to study the functioning of the cardiovascular system in 16 skiers during the period of preparation for the national competitions in different seasons. Results. Adaptive structural and functional changes in the cardiovascular system remain during seasons. At the same time, considerable seasonal differences in the functioning of the circulatory system were found. In winter, the subjects showed lower blood pressure, larger size of the left heart cavity, an higher rate of early blood filling of the left ventricle, transtricuspid blood flow, as well as the time of hemodynamics in the root of the pulmonary artery. In the rehabilitation period after exercise in skiers background levels of serum NT-proBNP in winter were about three times lower than in summer. Conclusion. The results have shown that the cardiovascular system of elite skiers during seasonal preparation for the competition is characterized by stable adaptive structural and functional changes. Adaptation to cold increases the influence of vagus nerve on the tone of resistive vessels, increases cardiohemodynamics and decreases basal secretory function of the myocardium in response to hemodynamic loads.

Zinc binding to Muscle LIM Protein regulates its structure and interaction with binding partners

Muscle LIM protein (MLP) is a member of the cysteine‐rich protein family, localising predominantly to the Z‐disk of the myofilaments in cardiac myocytes. MLP is a mechanosensor and functions through its translocation to the nucleus from the myofilaments and through protein‐protein interactions in the cytoplasm. Mechanosensing enables the heart to adapt appropriately to alterations in hemodynamic load, whilst mutations in the MLP gene lead to cardiomyopathy and heart failure. MLP contains two LIM domains each consisting of a double zinc‐finger motif. Rather than interacting with DNA, LIM domains mediate protein‐protein interactions associated with cellular signalling.The aim of this investigation is to determine how zinc binding regulates the structure of MLP and determine the impact on its interaction with binding partners. The analysis was performed using a combination of circular dichroism (CD), bioinformatics tools and online servers. CD is the difference in absorption between left‐handed and right‐handed circularly polarised light, occurring when a molecule contains light‐absorbing groups. It can be used to study the secondary, tertiary and quaternary structure of proteins, as well as studying its conformational stability under different conditions.In this study, we used CD to determine structural changes to MLP in the presence and absence of zinc. MLP is predominantly helical (~36%) with a small percentage of beta‐strands of ~8%, 34% of unordered and 21% of turns. In the presence of excess zinc, the helical content was reduced to ~19% with a gain of beta‐strand component to 30%. The presence of EDTA caused MLP to lose some helical conformation to 22% with an increased in the beta‐strand content to 16%. These data suggest that zinc increases the structural folding and organization of MLP.The full length wildtype MLP sequence was submitted to a variety of servers along with the C58G mutation known to reduce zinc binding in the first LIM domain. This mutation in humans leads to heart failure. Heart failure is defined as a progressive condition in which the heart is unable to pump enough blood to meet the body's needs for oxygen and nutrients. Bioinformatic protein‐protein analysis indicated that the C58G mutation inhibits interaction with NRAP, TCAP, alpha‐actinin and cofilin 2 which would interfere with MLP binding to the z‐disk and the myofilaments within cardiac myocytes. This would have a significant negative impact on mechanosensing in the heart and explains why the C58G mutation in MLP leads to heart failure.Support or Funding InformationUniversity of Reading and Diamond Light SourceThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Cardiac Tissue Chips (CTCs) for Modeling Cardiovascular Disease.

Cardiovascular research and regenerative strategies have been significantly limited by the lack of relevant cell culture models that can recreate complex hemodynamic stresses associated with pressure-volume changes in the heart. To address this issue, we designed a biomimetic cardiac tissue chip (CTC) model where encapsulated cardiac cells can be cultured in three-dimensional (3-D) fibres and subjected to hemodynamic loading to mimic pressure-volume changes seen in the left ventricle. These 3-D fibres are suspended within a microfluidic chamber between two posts and integrated within a flow loop. Various parameters associated with heart function, like heart rate, peak-systolic pressure, end-diastolic pressure and volume, end-systolic pressure and volume, and duration ratio between systolic and diastolic, can all be precisely manipulated, allowing culture of cardiac cells under developmental, normal, and disease states. We describe two examples of how the CTC can significantly impact cardiovascular research by reproducing the pathophysiological mechanical stresses associated with pressure overload and volume overload. Our results using H9c2 cells, a cardiomyogenic cell line, clearly show that culture within the CTC under pathological hemodynamic loads accurately induces morphological and gene expression changes, similar to those seen in both hypertrophic and dilated cardiomyopathy. Under pressure overload, the cells within the CTC see increased hypertrophic remodeling and fibrosis, whereas cells subject to prolonged volume overload experience significant changes to cellular aspect ratio through thinning and elongation of the engineered tissue. These results demonstrate that the CTC can be used to create highly relevant models where hemodynamic loading and unloading are accurately reproduced for cardiovascular disease modeling.

Comparative efficiency of continuous intensity trainings and interval loads in patients aftering myocardial infarct with a subsequent corrective coronary intervention

Aim. The purpose of the study is to conduct a comparative analysis of the effectiveness of physical aerobic training in the mode of interval and constant loads in patients who have had a myocardial infarction with subsequent percutaneous coronary intervention. Materials and methods. 35 patients aged from 46 to 67 years old were examined in the process of passing a 3-week course of physical rehabilitation in a day hospital. Of these, 18 people (group 1) performed daily training on cardiovascular machines in the mode of interval loads, 17 people (group 2) - in the mode of moderate loads with constant intensity. Results. When conducting physical training in different training regimens, both groups of patients showed an improvement in exercise tolerance. At the same time, the interval training as compared to the constant intensity training provided a more pronounced training effect on the cardiorespiratory system due to high-intensity loading phases and at the same time a low level of hemodynamic load due to the presence of relatively low-intensity phases. Conclusion. Interval training is preferred in patients who have had a myocardial infarction followed by percutaneous coronary intervention, due to their high efficacy and safety.

Hemodynamic Stimulation Using the Biomimetic Cardiac Tissue Model (BCTM) Enhances Maturation of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

Human induced pluripotent stem cell (hiPSC)-derived cardio­myocytes (hiPSC-CMs) hold great promise for cardiovascular disease modeling and regenerative medicine. However, these cells are both structurally and functionally ­immature, primarily due to their differentiation into cardiomyocytes occurring under static culture which only reproduces biomolecular cues and ignores the dynamic hemo­dynamic cues that shape early and late heart development during cardiogenesis. To evaluate the effects of hemodynamic stimuli on hiPSC-CM maturation, we used the biomimetic cardiac tissue model to reproduce the hemodynamics and pressure/volume changes associated with heart development. Following 7 days of gradually increasing stimulation, we show that hemodynamic loading results in (a) enhanced alignment of the cells and extracellular matrix, (b) significant increases in genes associated with physiological hypertrophy, (c) noticeable changes in sarcomeric organization and potential changes to cellular metabolism, and (d) a significant increase in fractional shortening, suggestive of a positive force frequency response. These findings suggest that culture of hiPSC-CMs under conditions that accurately reproduce hemodynamic cues results in structural orga­nization and molecular signaling consistent with organ growth and functional maturation.

Left Atrial Function Assessment in Patients with Rheumatic Mitral Valve Diseases

AbstractBackground: The assessment of Left Atrial (LA) function is used in various cardiovascular diseases. LA plays a com-plementary role in cardiac performance by modulating Left Ventricular (LV) function. Transthoracic two-dimensional (2D) phasic volumes and Doppler echocardiography can measure LA function non-invasively. However, evaluation of LA deformation derived from 2D Speckle Tracking Echocar-diography (STE) is a new feasible and promising approach for assessment of LA mechanics. These parameters are able to detect subclinical LA dysfunction in different pathological condition.Aim of Study: To assess left atrial function by conventional echo Doppler study and tissue Doppler based strain imaging as well as global longitudinal strain in patients with rheumatic mitral valve disease.Patients and Methods: A total of 50 rheumatic mitral valve disease patients appearing consecutively for echocardi-ogram (ECHO) test at the Cardiology Department in a tertiary care hospital were recruited into the study as per the pre-set inclusion and exclusion criteria. The data were pooled using Microsoft Excel and analysed using SPSS software by appli-cation of appropriate statistical tests.Results: Of the 50 subjects, 22 had Mitral Stenosis (MS), 14 had Mitral Regurgitation (MR), and 14 of them were found to have both MS and MR. The major presenting symptom as observed in 23 patients was dyspnea. LA functions were significantly reduced in double mitral lesion group which was observed in LA indices such as LA emptying fraction, LA passive emptying fraction, atrial fraction, and LA expansion index among groups.Conclusion: LA reservoir, conduit and contractile function were significantly affected in rheumatic mitral valve disease due to increased hemodynamic load. Global longitudinal strain was significantly reduced in patients with MS and MR.

Effects of Natural Cytokine Complex on the Myocardial Blood Flow in Normal and under Conditions of Increased Hemodynamic Load.

The effects of a natural complex of cytokines IL-1, IL-2, IL-6, TNF, MIF, and GTFβ on myocardial blood flow were studied under control conditions and during acute experimental aortal stenosis. Systemic administration of the cytokine complex under control conditions led to moderate impairment of the blood flow in the myocardium associated with plethora and perivascular edema. The number of functioning vessels in the myocardium significantly increased under these conditions, which reflected enhancement of the coronary blood flow. The comparison of the myocardial blood flow under conditions of acute heart overload alone and in combination with systemic administration of the cytokine complex revealed similar changes. In both cases, moderate plethora in all compartments of the vascular network, moderate perivascular edema, and moderate blood stasis in the myocardial capillaries were seen. The only difference the increase in the density of functioning capillaries that was significantly more pronounced after cytokine administration. These data indicate that the increase in the blood cytokine level induced dilatation of myocardial vessels and intensification of blood flow in normal and under conditions of acute hemodynamic heart overload. Against the background of pronounced vasodilatation, the dyscirculatory changes in the myocardium were moderate. It was assumed that the increase in the duration or frequency of hypercytokinemia episodes can induce more severe blood flow disturbances in the myocardium.

Right ventricular remodeling in response to volume overload in fetal sheep.

The fetal myocardium is known to be sensitive to hemodynamic load, responding to systolic overload with cellular hypertrophy, proliferation, and accelerated maturation. However, the fetal cardiac growth response to primary volume overload is unknown. We hypothesized that increased venous return would stimulate fetal cardiomyocyte proliferation and terminal differentiation, particularly in the right ventricle (RV). Vascular catheters and pulmonary artery flow probes were implanted in 16 late-gestation fetal sheep: a right carotid artery-jugular vein (AV) fistula was surgically created in nine fetuses, and sham operations were performed on seven fetuses. Instrumented fetuses were studied for 1 wk before hearts were dissected for component analysis or cardiomyocyte dispersion for cellular measurements. Within 1 day of AV fistula creation, RV output was 20% higher in experimental than sham fetuses ( P < 0.0001). Circulating atrial natriuretic peptide levels were elevated fivefold in fetuses with an AV fistula ( P < 0.002). On the terminal day, RV-to-body weight ratios were 35% higher in the AV fistula group ( P < 0.05). Both left ventricular and RV cardiomyocytes grew longer in fetuses with an AV fistula ( P < 0.02). Cell cycle activity was depressed by >50% [significant in left ventricle ( P < 0.02), but not RV ( P < 0.054)]. Rates of terminal differentiation were unchanged. Based on these studies, we speculate that atrial natriuretic peptide suppressed fetal cardiomyocyte cell cycle activity. Unlike systolic overload, fetal diastolic load appears to drive myocyte enlargement, but not cardiomyocyte proliferation or maturation. These changes could predispose to RV dysfunction later in life. NEW & NOTEWORTHY Adaptation of the fetal heart to changes in cardiac load allows the fetus to maintain adequate blood flow to its systemic and placental circulations, which is necessary for the well-being of the fetus. Addition of arterial-venous fistula flow to existing venous return increased right ventricular stroke volume and output. The fetal heart compensated by cardiomyocyte elongation without accelerated cellular maturation, while cardiomyocyte proliferation decreased. Even transient volume overload in utero alters myocardial structure and cardiomyocyte endowment.

In Vitro Endothelialization of Surface-Integrated Nanofiber Networks for Stretchable Blood Interfaces.

Despite major technological advances within the field of cardiovascular engineering, the risk of thromboembolic events on artificial surfaces in contact with blood remains a major challenge and limits the functionality of ventricular assist devices (VADs) during mid- or long-term therapy. Here, a biomimetic blood-material interface is created via a nanofiber-based approach that promotes the endothelialization capability of elastic silicone surfaces for next-generation VADs under elevated hemodynamic loads. A blend fiber membrane made of elastic polyurethane and low-thrombogenic poly(vinylidene fluoride- co-hexafluoropropylene) was partially embedded into the surface of silicone films. These blend membranes resist fundamental irreversible deformation of the internal structure and are stably attached to the surface, while also exhibiting enhanced antithrombotic properties when compared to bare silicone. The composite material supports the formation of a stable monolayer of endothelial cells within a pulsatile flow bioreactor, resembling the physiological in vivo situation in a VAD. The nanofiber surface modification concept thus presents a promising approach for the future design of advanced elastic composite materials that are particularly interesting for applications in contact with blood.

Role of the cytoskeleton in the development of a hypofibrotic cardiac fibroblast phenotype in volume overload heart failure.

Hemodynamic load regulates cardiac remodeling. In contrast to pressure overload (increased afterload), hearts subjected to volume overload (VO; preload) undergo a distinct pattern of eccentric remodeling, chamber dilation, and decreased extracellular matrix content. Critical profibrotic roles of cardiac fibroblasts (CFs) in postinfarct remodeling and in response to pressure overload have been well established. Little is known about the CF phenotype in response to VO. The present study characterized the phenotype of primary cultures of CFs isolated from hearts subjected to 4 wk of VO induced by an aortocaval fistula. Compared with CFs isolated from sham hearts, VO CFs displayed a "hypofibrotic" phenotype, characterized by a ~50% decrease in the profibrotic phenotypic markers α-smooth muscle actin, connective tissue growth factor, and collagen type I, despite increased levels of profibrotic transforming growth factor-β1 and an intact canonical transforming growth factor-β signaling pathway. Actin filament dynamics were characterized, which regulate the CF phenotype in response to biomechanical signals. Actin polymerization was determined by the relative amounts of G-actin monomers versus F-actin. Compared with sham CFs, VO CFs displayed ~78% less F-actin and an increased G-actin-to-F-actin ratio (G/F ratio). In sham CFs, treatment with the Rho kinase inhibitor Y-27632 to increase the G/F ratio resulted in recapitulation of the hypofibrotic CF phenotype observed in VO CFs. Conversely, treatment of VO CFs with jasplakinolide to decrease the G/F ratio restored a more profibrotic response (>2.5-fold increase in α-smooth muscle actin, connective tissue growth factor, and collagen type I). NEW & NOTEWORTHY The present study is the first to describe a "hypofibrotic" phenotype of cardiac fibroblasts isolated from a volume overload model. Our results suggest that biomechanical regulation of actin microfilament stability and assembly is a critical mediator of cardiac fibroblast phenotypic modulation.

Real-time Imaging of an Experimental Intracranial Aneurysm in Rats.

Subarachnoid hemorrhage due to rupture of a pre-existing intracranial aneurysm has quite a poor outcome in spite of intensive medical care. Hemodynamic stress loaded on intracranial arterial walls is considered as a trigger and a regulator of formation and progression of the disease, but how intracranial arterial walls or intracranial aneurysm walls behave under hemodynamic stress loading remains unclear. The purpose of this study was to visualize and analyze the wall motion of intracranial aneurysms to detect a pathological flow condition. We subjected a transgenic rat line, in which endothelial cells are specifically visualized by expression of a green fluorescent protein, to an intracranial aneurysm model and observed a real-time motion of intracranial arterial walls or intracranial aneurysm walls by a multiphoton laser confocal microscopy. The anterior cerebral artery–olfactory artery bifurcation was surgically exposed for the monitoring. First, we observed the proper flow-dependent physiological dilatation of a contralateral intracranial artery in response to increase of blood flow by one side of carotid ligation. Next, we observed intracranial aneurysm lesions induced in a rat model and confirmed that a wall motion of the dome was static, whereas that of the neck was more dynamic in response to pulsation of blood flow. We successfully monitored a real-time motion of intracranial aneurysm walls. Findings obtained from such a real-time imaging will provide us many insights especially about the correlation of mechanical force and the pathogenesis of the disease and greatly promote our understanding of the disease.

Analysis of indicators of daily blood pressure profile in patients wi th type 1 diabetes, depending on the course of the disease

The aim: to study the features of daily profile and circadian rhythm of blood pressure (BP) in groups of patients with type 1 diabetes mellitus (T1DM), depending on glycemic control. Materials and methods: 63 patients with T1DM, age: 18-45 years without hypertension were examined. Patients were divided into groups: Group 1 — HbA1c≤7.0% (n=21), Group 2 — HbA1c&gt;7.0% (n=42). 10 sex- and agematched healthy controls were included. Results: Patients with T1DM had a significantly higher pulsatile blood pressure (PBP) per night, higher daily systolic blood pressure (SBP) variability, compared with healthy controls, and significantly higher daily SBP area index (SPAI24), daily SBP time index (SPTI24), daily diastolic blood pressure (DBP) area index (DPAI24), daily DBP time index (DPTI24). The double product (DP) was higher in patients with T1DM in the daytime and within 24 hours compared to control (p=0.002) and (p=0.001) respectively. Pathological profiles of daily blood pressure were found. In group 1, according to the dipping in SBP 28.57% of patients were non-dippers, 4.76% were extreme dippers. In group 2, the non-dipper profile had 33.33%, the reverse dipper had 2.38%, and extreme dipper had 11.90% of patients. According to the dipping in DBP: in group 1 33.33% were non-dippers, and 9.53% were extreme dippers. In group 2 non-dippers — 19.04%, extreme dippers — 2.38%, extreme dippers — 38.10%. HbA1c directly correlates with: (DPAI24) (ρ=0,301; р=0,014), DPAI night (ρ=0,292; р=0,010), DPTI24 (ρ=0.292; p=0.012), DPTI night (ρ=0.268; p=0.018). Conclusions. The daily blood pressure profile in patients with T1DM without arterial hypertension is characterized by insufficient decrease in BP at night, an increase in the average daily DBP, PBP, as well as DPAI24, DPTI24, DP and the variability of the average daily SBP. Poor glucose control led to led to an increase in hemodynamic load. It is the risk factor cardiovascular complications in patients with T1DM.

The challenge of cardiomyopathies and heart failure in pregnancy.

To discuss the risk preexisting or new onset cardiomyopathy/heart failure (CMP/heart failure) in pregnant woman, and recent insights regarding their management and therapy. Recent data from the European Registry on Pregnancy and Heart disease of the European Society of Cardiology (ROPAC) suggest that, after an adequate prepregnancy evaluation in specialized centres, the vast majority of pregnancies are safe for both mother and foetus. A tailored approach is required according to cardiac phenotype (i.e. type of cardiomyopathy), clinical and functional status, and new potential treatments (i.e. bromocriptine in patients with peripartum cardiomyopathy). In clinical practice, prepregnancy cardiac evaluation is mandatory, including evaluation of the clinical status, standard ECG (and 24-48 h monitoring, whenever required), and imaging, to define the individual risk profile. In presence of severe symptoms (advanced New York Heart Association class), cardiac dysfunction (moderate-severe reduced ejection fraction), haemodynamic load (left ventricular outflow tract obstruction, pulmonary hypertension), pregnancy is contraindicated. A tailored monitoring is warranted in other cases (mild-moderate risk pregnancies). Likewise, in women who develop PPCM, a risk stratification and tailored monitoring and therapy should be achieved by an expert, multidisciplinary team, including cardiologists, gynaecologists, obstetricians, genetic counsellor, and psychologists.

Association of Inadequately Low Left Ventricular Mass with Enhanced Myocardial Contractility in Severe Degenerative Aortic Stenosis.

Background: Left ventricular hypertrophy (LVH), traditionally considered an adaptive mechanism that is aimed at the maintenance of LV systolic function, is absent in 10%–35% of patients with severe aortic stenosis (AS). Our aim was to estimate the clinical and hemodynamic characteristics in patients with severe AS and absent LVH, or inadequately low LV mass (i-lowLVM) relative to an individual hemodynamic load. Methods: We retrospectively analyzed in-hospital records of 100 patients with pure severe degenerative AS, preserved LV systolic function and without relevant coexistent diseases, except for well-controlled hypertension or diabetes. Results: Clinical characteristics were similar in patients with and without LVH, as well as those with and without i-lowLVM, except for slightly lower GFR at i-lowLVM. When compared to their counterparts, subjects without LVH or with i-lowLVM had smaller LV cavities, decreased LV wall thicknesses and higher EF. There were no significant differences in stenosis severity and indices of afterload (valvulo-arterial impedance and circumferential end-systolic LV wall stress), according to the presence or absence of either LVH or i-lowLVM. However, LV fractional shortening at the midwall level was elevated only in patients with i-lowLVM, but not in those without LVH, compared to the remainder (15.8 ± 3.3 vs. 12.9 ± 3.2%, p < 0.001 for those with and without i-lowLVM, respectively; 13.7 ± 3.7 vs. 13.8 ± 3.6% for LVH presence and absence, p = 0.9). Conclusions: Inadequately low LVM relative to the individual hemodynamic load could potentially reflect a different mode of the LV response to severe AS, associated with enhanced load-independent LV systolic performance, i.e., better LV contractility. If confirmed in a large series of patients, our small preliminary study may add to the possible mechanisms of a previously reported counterintuitive tendency of a lower, not higher, risk of adverse outcome in patients with low LV mass despite severe AS. Prospective studies are warranted, in order to determine a potential utility of LVM inadequacy in the risk stratification of patients with AS.

Diffuse myocardial fibrosis in adolescents operated with arterial switch for transposition of the great arteries - A CMR study

Diffuse myocardial fibrosis in adolescents operated with arterial switch for transposition of the great arteries - A CMR study

Abstract 17349: The Biomimetic Cardiac Tissue Model (BCTM) Reproduces the Pathological Remodeling Seen in Hypertrophic and Dilated Cardiomyopathy

Introduction: Cardiovascular research and regenerative strategies have been significantly limited by the lack of relevant cell culture systems that can recreate complex hemodynamic stresses associated with pressure-volume changes in the heart. To address this issue, we designed a Biomimetic Cardiac Tissue Model (BCTM) where encapsulated cardiac cells can be cultured in 3D fibers and subjected to hemodynamic loading to mimic pressure-volume changes seen in the left ventricle. Hypothesis: We tested the hypothesis that stimulation under hemodynamic loads as seen in pressure and volume overload is capable of reproducing the pathological remodeling seen in vivo. Methods: The 3D fibers are suspended between two posts within a pumping chamber that is integrated within a flow loop. Various parameters associated with heart function like heart rate, peak-systolic pressure, end-diastolic pressure and volume, end-systolic pressure and volume, and duration ratio between systolic and diastolic can all be precisely manipulated allowing culture of various cardiac cell types under developmental, normal, and disease states. Using the BCTM we reproduced the pathophysiological mechanical stresses of pressure overload and volume overload. Results: Using H9c2 cells, a cardiomyogenic cell line, our results clearly show that culture within the BCTM under pathological hemodynamic loads accurately induces morphological and gene expression changes similar to those seen in both hypertrophic and dilated cardiomyopathies in vivo . Cells within the BCTM under pressure overload see increased hypertrophic remodeling and fibrosis whereas cells subject to prolonged volume overload experience significant changes to cellular aspect ratio through thinning and elongation of the engineered tissue. Conclusions: These results clearly demonstrate that the BCTM can accurately reproduce pathological remodeling and create highly relevant models for cardiovascular disease modeling.

Sarcolemmal Alterations in Unloaded Rat Heart after Heterotopic Transplantation.

Following heterotopic transplantation, the rat heart undergoes atrophy and exhibits delayed cardiac relaxation without any changes in contraction and systolic Ca 2+ transients. Furthermore, the sarcoplasmic reticular Ca 2+ uptake and release activities were reduced and Ca 2+ influx through L-type Ca 2+ channels was increased in the atrophied heart. Since Ca 2+ movements at sarcolemma are intimately involved in the regulation of intracellular Ca 2+ concentration, the present study was undertaken to test if sarcolemma plays any role to maintain cardiac function in the atrophied heart.The characteristics of sarcolemmal Ca 2+ pump and Na + -Ca 2+ exchange activities were examined in 8 weeks heterotopically isotransplanted rat hearts which did not support hemodynamic load and underwent atrophy. Sarcolemmal ATP (adenosine triphosphate)-dependent Ca 2+ uptake and Ca 2+ -stimulated ATPase (adenosine triphosphatase) activities were increased without any changes in Na + -K + ATPase activities in the transplanted hearts. Although no alterations in the Na + -dependent Ca 2+ uptake were evident, Na + -induced Ca 2+ release was increased in the transplanted heart sarcolemmal vesicles. The increase in Na + -induced Ca 2+ release was observed at different times of incubation as well as at 5, 20, and 40 mM Na + . The sarcolemma from transplanted hearts also showed higher contents of phosphatidic acid, sphingomyelin, and cholesterol.These results indicate that increases in the sarcolemmal, Ca 2+ transport activities in unloaded heart may provide an insight into adaptive mechanism to maintain normal contractile behavior of the atrophic heart.

Cmah-dystrophin deficient mdx mice display an accelerated cardiac phenotype that is improved following peptide-PMO exon skipping treatment.

Duchenne muscular dystrophy (DMD) is caused by loss of dystrophin protein, leading to progressive muscle weakness and premature death due to respiratory and/or cardiac complications. Cardiac involvement is characterized by progressive dilated cardiomyopathy, decreased fractional shortening and metabolic dysfunction involving reduced metabolism of fatty acids—the major cardiac metabolic substrate. Several mouse models have been developed to study molecular and pathological consequences of dystrophin deficiency, but do not recapitulate all aspects of human disease pathology and exhibit a mild cardiac phenotype. Here we demonstrate that Cmah (cytidine monophosphate-sialic acid hydroxylase)-deficient mdx mice (Cmah−/−;mdx) have an accelerated cardiac phenotype compared to the established mdx model. Cmah−/−;mdx mice display earlier functional deterioration, specifically a reduction in right ventricle (RV) ejection fraction and stroke volume (SV) at 12 weeks of age and decreased left ventricle diastolic volume with subsequent reduced SV compared to mdx mice by 24 weeks. They further show earlier elevation of cardiac damage markers for fibrosis (Ctgf), oxidative damage (Nox4) and haemodynamic load (Nppa). Cardiac metabolic substrate requirement was assessed using hyperpolarized magnetic resonance spectroscopy indicating increased in vivo glycolytic flux in Cmah−/−;mdx mice. Early upregulation of mitochondrial genes (Ucp3 and Cpt1) and downregulation of key glycolytic genes (Pdk1, Pdk4, Ppara), also denote disturbed cardiac metabolism and shift towards glucose utilization in Cmah−/−;mdx mice. Moreover, we show long-term treatment with peptide-conjugated exon skipping antisense oligonucleotides (20-week regimen), resulted in 20% cardiac dystrophin protein restoration and significantly improved RV cardiac function. Therefore, Cmah−/−;mdx mice represent an appropriate model for evaluating cardiac benefit of novel DMD therapeutics.

THORACIC AORTIC ANEURYSM GROWTH IN PATIENTS WITH BICUSPID AORTIC VALVES: ROLE OF AORTIC STIFFNESS AND PULSATILE HEMODYNAMICS

Bicuspid aortic valve (BAV) is the most common congenital cardiac abnormality, and the second most common etiology for thoracic aortic aneurysm (TAA) formation. Among BAV patients, risk of aortic dissection is increased 8-fold, and 25-year risk of aortic surgery is 25%. However, there are no clinical predictors of aneurysm growth for risk stratification. Since the health of the aortic wall is directly reflected in its stiffness, which increases pulsatile hemodynamic load due to impairment of the aorta’s pressure buffering function, we evaluated whether measures of aortic stiffness and hemodynamic load are associated with TAA growth in patients with BAV. Twenty nine participants with TAA due to BAV who had serial imaging were recruited. Aneurysm size was measured systematically by an imaging cardiologist blinded to hemodynamics, and growth rate was calculated in mm/year. Central arterial hemodynamics were non-invasively determined with validated methods that integrate arterial tonometry with echocardiography, yielding measures of aortic stiffness (aortic pulse wave velocity, aPWV), steady (systemic vascular resistance) and pulsatile hemodynamic load [aortic characteristic impedance (Zc), proximal aortic (PAC) and total arterial (TAC) compliances, central systolic (cSBP) and pulse pressures, forward (Pf) and reflected pressure wave amplitudes]. Spearman correlation coefficients were calculated between TAA growth rate and brachial blood pressure, as well as the aforementioned central hemodynamic measures. Multivariable linear regression adjusted for potential confounders (Table 1 legend) assessed the independent associations of hemodynamic variables with TAA growth. Sixty six percent of participants were men. Mean±standard deviation (SD) age, baseline aneurysm size and follow-up time were 57.2±8.3 years, 46.9±3.6 mm and 2.9±3.3 years, respectively. There were significant correlations between several measures of aortic stiffness and pulsatile arterial load with TAA growth (Table1, top). There were no significant correlations between brachial blood pressure parameters or steady hemodynamic load with TAA growth (P>0.05 for each). In multivariable linear regression, measures of aortic stiffness (aPWV) and pulsatile hemodynamic load (Zc, PAC, TAC) remained independently associated with aneurysm growth (Table 1, bottom). Other hemodynamic measures were not independently associated with TAA growth. In patients with TAA due to BAV, greater aortic stiffness and central pulsatile hemodynamic load are associated with faster aneurysm growth; while brachial blood pressure and steady hemodynamic load are not. Our findings suggest that evaluating aortic stiffness and pulsatile arterial load could be useful for risk stratification of subjects with TAA due to BAV, and may provide a therapeutic target for this disease.

Left ventricular twist before and after haemodialysis: an analysis using speckle-tracking echocardiography.

SummaryBackgroundThe most commonly used parameter of cardiac function in the chronic kidney disease (CKD) patient is ejection fraction (EF), using transthoracic echocardiography (TTE). EF is a highly load-dependent measurement, which varies considerably in CKD patients undergoing haemodialysis. The aim of this pilot study was to evaluate a novel measure of myocardial function, left ventricular twist, which is defined as the ‘wringing action of the heart’, using speckletracking echocardiography in CKD patients before and after haemodialysis.MethodsTwenty-six patients were recruited from the Chris Hani Baragwanath Hospital haemodialysis unit. TTE was performed according to a detailed standardised protocol before and after a single haemodialysis session. Echocardiography was also performed on 26 age- and gendermatched healthy subjects.ResultsThe mean age of the control versus CKD group was 44 ± 11.4 and 43.4 ± 12.2 years, respectively; 46% were male. Apical rotation was diminished in CKD patients compared to controls (4.83 ± 2.3 vs 6.31 ± 1.6 °; p = 0.01) despite no difference in EF (61.7 ± 6.2 vs 58.8 ± 13; p = 0.68). There were no differences in the components of twist: apical rotation, basal rotation and net twist before and after dialysis, despite an increase in EF (58.8 ± 13.7 vs 61.2 ± 13.6; p = 0.02) following dialysis.ConclusionUnlike EF, the components of twist are relatively independent of changes in haemodynamic load seen during dialysis. The decrease in apical rotation may represent an early marker of cardiac pathology in the late-stage CKD patient.