Hemodynamic Loading Conditions Research Articles

Load Dependency of Ventricular Pump Function: Impact on the Non-Invasive Evaluation of the Severity and the Prognostic Relevance of Myocardial Dysfunction.

Ventricular pump function, which is determined by myocyte contractility, preload and afterload, and, additionally, also significantly influenced by heart rhythm, synchrony of intraventricular contraction and ventricular interdependence, explains the difficulties in establishing the contribution of myocardial contractile dysfunction to the development and progression of heart failure. Estimating myocardial contractility is one of the most difficult challenges because the most commonly used clinical measurements of cardiac performance cannot differentiate contractility changes from alterations in ventricular loading conditions. Under both physiological and pathological conditions, there is also a permanent complex interaction between myocardial contractility, ventricular anatomy and hemodynamic loading conditions. All this explains why no single parameter can alone reveal the real picture of ventricular dysfunction. Over time there has been increasing recognition that a load-independent contractility parameter cannot truly exist, because loading itself changes the myofilament force-generating capacity. Because the use of a single parameter is inadequate, it is necessary to perform multiparametric evaluations and also apply integrative approaches using parameter combinations which include details about ventricular loading conditions. This is particularly important for evaluating the highly afterload-sensitive right ventricular function. In this regard, the existence of certain reluctance particularly to the implementation of non-invasively obtainable parameter combinations in the routine clinical praxis should be reconsidered in the future. Among the non-invasive approaches used to evaluate ventricular function in connection with its current loading conditions, assessment of the relationship between ventricular contraction (e.g., myocardial displacement or deformation) and pressure overload, or the relationship between ejection volume (or ejection velocity) and pressure overload, as well as the relationship between ventricular dilation and pressure overload, were found useful for therapeutic decision-making. In the future, it will be unavoidable to take the load dependency of ventricular function much more into consideration. A solid basis for achieving this goal will be obtainable by intensifying the clinical research necessary to provide more evidence for the practical importance of this largely unsolved problem.

Facile fabrication of Bi-layered perfusable hydrogel tubes as biomimetic 3D arterial construct

Small-diameter arterial conduits with native physiological and biological equivalence continues to be a constant global demand posing critical challenges in fabrication. Advent of various strategies towards mimicking the structural hierarchy of a native blood vessel, often involve complex instrumentation and template-assistance with post-processing complications eventually compromising structural fidelity. In the present research, we report a template-free, facile strategy- ‘3D wet writing’ by peripheral-core differential ionic gelation to fabricate perfusable customizable constructs of any dimension, thickness and length in <5 mins. Dual-crosslinking using di-diol complexation of borax with Alginate- poly (vinyl alcohol) was performed to enhance the stability of fabricated bi-layered tubular constructs (BLT). These fabricated BLTs demonstrated non-linear mechanical characteristics of native blood vessels in withstanding physiological (120/80 mmHg) hemodynamic loading conditions with cyclic strain (5.82 ± 0.88%). The BLTs also ensured adequate longitudinal (0.176 ± 0.03 MPa) & circumferential (0.29 ± 0.012 MPa) tensile strength and burst pressure strength of 353.875 ± 22.69 mmHg. Hemocompatible characteristics of BLT were clearly evident with lower hemolytic index (0.21 ± 0.03%) and maintenance of erythrocyte structural integrity under dynamic conditions. Further, non-thrombogenic and non-inflammatory characteristics of BLTs were confirmed by in-activated platelets and monocytes under dynamic conditions. The developed wet-writing technique exhibited facile integration of layer-specific cells concurrently with the BLT fabrication. The spatial cell-specific expressions of smooth muscle (α-SMA) and endothelial (CD-31) cells in BLT were comparable to native hierarchical cellular organization with the multi-layered medial and mono-layered intimal layers. Further, ex-vivo dynamic studies on anastomotic interface between BLT and rat abdominal aorta clearly evidenced the functional efficacy of fabricated BLTs as physiologically relevant small-diameter vascular construct.

Left Ventricular Inotropic Response To An Exertional Challenge After Sympathetic Decentralization In Humans

Purpose: Cardiac sympathetic decentralization is a phenomenon in which supraspinal sympathoadrenal control to the heart is deprived. Dysfunction of the sympathetic nervous system is known to contribute to blood pressure abnormalities, arrhythmias, diminished heart rate variability, restricted peak heart rate, and decreased venous return and stroke volume. Cardiac inotropic insufficiency as a result of sympathetic dysfunction has been less frequently studied. This study aimed to characterize the change in left ventricular (LV) inotropicity from rest to a severe exercise challenge in the sympathetically decentralized heart using complete spinal cord injury (cSCI) as a model. Methods: We present two male cases with cSCI (age: 45 and 30 years, BMI 21.8 and 29.5 kg/m2) and compared them with two male sedentary otherwise healthy individuals (age: 43 and 29 years, BMI 29.2 and 25.6 kg/m2). Subjects underwent an incremental arm-ergometer exercise (iAEE) test to peak volitional exhaustion. All indices of LV inotropicity and hemodynamic loading conditions were assessed at rest, during iAEE and at peak iAEE using bioimpedance cardiography (PhysioFlow® Enduro, Manatec, France). LV inotropic response was characterized by observing the response of the acceleration index (dZ/dt2) in all subjects. Results: dZ/dt2 was observed to be impaired in subjects with cSCI compared to the healthy control counterparts (baseline: 0.39 and 0.44 vs .41 and 0.48; peak; 0.55 and 1.073. vs 0.96 and 0.97, respectively). Concomitant differences in the heart rate (HR) and cardiac output (Q) responses to maximal exercise between the cSCI and control subjects were also observed. HR baseline: 57 and 73 vs 97 and 63 bpm; peak: 123 and 99 vs 176 and 151 bpm, respectively. Q baseline: 4.38 and 6.04. vs 6.93 and 5.35 L/m; peak: 11.3 and 10.3 vs 17.06 and 13.94 L/m, respectively. Conclusions: A dichotomy in both the inotropic and chronotropic responses to exercise was apparent in the subjects with decentralizing cSCI. This preliminary data could underscore a critical dependency on heterometric autoregulation for mechanizing increases in cardiac function response to exercise in complete high-level SCI.

Abstract 12395: Nitroglycerin Reduces Pulsatile Arterial Load But Not Steady State Load In Aortic Stenosis Patients Before Or After Transcatheter Aortic Valve Implantation

Background: Pulsatile arterial load is represented by the characteristic impedance (Zc) of the ascending aorta. In aortic stenosis (AS) patients, Zc is thought to contribute significantly to left ventricular afterload in addition to aortic transvalvular gradient. We evaluated the effect of nitroglycerin, a potent vasodilator, on Zc non-invasively in AS patients before or after transcatheter aortic valve implantation (TAVI). Methods: Simultaneous aortic pressure from radial arterial tonometry and flow from cardiac magnetic resonance phase contrast imaging were obtained. Radial waveforms were converted to central aortic pressure using SphygmoCor 8.1 (AtCor Medical) and calibrated using brachial cuff values. Zc was derived from aortic pressure and flow by averaging the impedance modulus in frequency domain analysis. Data acquisition was repeated after administration of 300 micrograms of sublingual nitroglycerin to investigate its effect on pulsatile and steady state load. Results: Analysis was performed in 9 AS patients (3 female, age 68-81 years) with a left ventricular ejection fraction &gt; 55%, of whom 5 had undergone recent TAVI. When compared with baseline measurements, nitroglycerin reduced mean arterial pressure (107 ± 11 pre vs 87 ± 5 post, mmHg), central pulse pressure (67 ± 15 pre vs 48 ± 13 post, mmHg), forward stroke volume (83 ± 15 pre vs 70 ± 13 post, ml) and Zc (129 ± 42 pre vs 95 ± 32 post, dynes.cm/s 5 ). However, there was no change in compliance or steady state systemic vascular resistance (2163 ± 445 pre vs 2045 ± 485 post, dynes.cm/s 5 ). Conclusion: Nitroglycerin significantly reduces pulsatile arterial load in AS patients without reducing steady state load. Our non-invasive technique can reliably assess changes in hemodynamic loading conditions, and larger longitudinal paired analysis of nitroglycerin response before and after TAVI may help predict AS patients at risk of poorer outcomes from ventriculo-arterial coupling mismatch following treatment.

A Computational Framework to Predict and Understand in situ Heart Valve Tissue Engineering

Objective: It is widely accepted that there is a strong relation between mechanical factors due to hemodynamic loading and tissue adaptation in native and tissue-engineered heart valves (TEHVs)[1,2]. Yet, this process remains poorly understood due to complex interactions between cell-mediated tissue growth and remodeling (G&R) and the hemodynamic environment. Computational modeling can aid in understanding valve adaptation. Yet, existing models have limitations that do not allow investigating simultaneous tissue formation and scaffold degradation, which is instrumental for an in situ TEHV. Hypothesizing that G&R occurs to (re-)establish mechanical homeostasis, we aimed to develop a computational framework that enables simulation, and ultimately understanding, of in situ TEHV development under complex hemodynamic loading conditions. Methods: A valve mechanical model [3] was enriched with a G&R algorithm [4] to compute the turnover of individual constituents following [5]. This model predicts the evolution of the tissue volume (growth), composition, and microstructure (remodeling) due to changes in hemodynamic loading. Results: To demonstrate the concept, increased blood pressure is modeled by increasing tissue stretch 25% and computing the adaptation of the tissue. The elevated tissue production leads to increased tissue volume and a relative increase in collagen content (Figure 1). Both these mechanisms improve the load-bearing capacity of the tissue and enable the tissue to return to its homeostatic mechanical state. Conclusions: Computational models of heart valve G&R provide valuable insights into interactions between hemodynamics and evolving tissue properties. The presented framework allows, for the first time, simulations of evolving in situ TEHVs, which will aid in understanding experimental outcomes and rationally improving valve designs. Additionally, it enables prediction of morphology and ECM architecture after certain clinical interventions, like the Ross-Yacoub procedure.

Myocardial work – new insights from deformation imaging in patients with advanced heart failure

Abstract Background The evaluation of myocardial contractility appears to be a major determinant for the prognosis and allocation of treatment strategies in advanced systolic heart failure (HFrEF). Non-invasive measurement of myocardial work is currently emerging as a new promising method for the assessment of myocardial contractility, as it additionally accounts for hemodynamic loading conditions of the ventricle. Objectives This study sought to assess the prognostic impact of myocardial work in patients with advanced heart failure and to compare it with routinely used deformation imaging parameters. Methods We included 234 patients with HFrEF under guideline directed therapy and comprehensively assessed myocardial work, as well as global longitudinal strain (GLS) by speckle tracking echocardiography. The primary endpoint was all-cause mortality. Results Median age of the patients was 68 years (IQR 60–75) and 78% were male. Over a 5-year follow-up period, 107 patients died. Median GWI was 526 mmHg% (IQR 366–779) and median GCW was 730 mmHg% (IQR 523–988). Parameters of myocardial work displayed a strong and independent association with long-term mortality, even after careful adjustment for clinical and echocardiographic confounders (Table 1). Additionally, we observed a significantly better calibration towards long-term mortality for GCW compared to GLS as the current golden standard for myocardial deformation imaging (AUC 0.63 vs. 0.60; P=0.007). Conclusion This is the first study to comprehensively assess global myocardial work in patients with advanced heart failure. Important treatment decisions rely on the assessment of myocardial contractility and risk stratification, specifically in late stages of the disease where exact guiding of treatment success and timely allocation of more aggressive treatment strategies are warranted. By incorporating loading conditions, myocardial work seems to be able to sensitively detect changes in myocardial contractility thath predict a dismal course of the disease. Furthermore, our data suggests that global constructive work is a more sensitive parameter to predict long-term outcome compared to the currently used echocardiographic deformation imaging parameters (i.e. GLS). Funding Acknowledgement Type of funding source: None

Sex differences in patients with repaired tetralogy of Fallot support a tailored approach for males and females: a cardiac magnetic resonance study

Purpose Substantial differences between sexes exist with respect to cardiovascular diseases, including congenital heart disease. Nevertheless, clinical decisions in the long-term follow-up of patients with repaired tetralogy of Fallot (rTOF) are currently based on unisex thresholds for cardiac magnetic resonance (CMR) measurements. This study aimed to assess whether sex differences exist in cardiac adaptation to hemodynamic loading conditions in patients with rTOF. Methods and Results This cross-sectional, two-center, combined pediatric and adult cohort included 320 rTOF patients (163 males, 51%) who underwent routine CMR. Despite similar age (median and interquartile range [m + IQR] 23.4 [15.2–34.4] years), surgical history, and hemodynamic loading, males with rTOF demonstrated higher biventricular CMR-derived volumes and masses, indexed for body surface area, compared to females (e.g. m + IQR right ventricular (RV) end-diastolic volume: males 123 [100–151] mL/m2, females 114 [94–131] mL/m2, P = 0.007). Sex-specific Z-scores of biventricular volumes and masses were similar for males and females. RV volumes and masses correlated with hemodynamic loading, but these relations did not differ between sexes. Biventricular ejection fraction (EF) appeared to be lower in male patients, compared to female patients (e.g. m + IQR RVEF: males 48 [43–54]%, females 52 [46–57]%, P < 0.001). Conclusion Indexed ventricular volumes and masses are higher in males with rTOF, compared to females, similar to the healthy population. RV hypertrophy and dilatation correlated to loading conditions similarly for both sexes. However, under comparable loading conditions, males demonstrated more severe functional impairment. These results indicate that sex-differences should no longer be ignored in treatment strategies, including timing of pulmonary valve replacement.

Computational fluid–structure interaction analysis of blood flow on patient-specific reconstructed aortic anatomy and aneurysm treatment with Dacron graft

We use the fluid–structure interaction (FSI) capability in Abaqus to evaluate radial displacements, von Mises stresses and wall shear stresses (WSS) on the human aorta in response to the blood flowing through it. Complications arise when aneurysm is detected and causes the wall to thinner so much that rupture may result. We use the Materialise suite, a specialty software to reconstruct a three-dimensional geometry of the aorta from two-dimensional computerized axial tomography (CAT) images. Results are compared to those obtained on a healthy individual. Blood is assumed to be a Newtonian and incompressible medium and the blood flow is taken as pulsatile, fully developed and turbulent. The model used for aorta is Holzapfel–Gasser–Ogden (HGO), a sophisticated hyperelastic model that can describe biological tissues. We also study the behavior of Dacron, a polyester fabric used as graft in aortic surgical repair. Here, Dacron is represented by a neo-Hookean (isotropic) hyperelastic model. Time-dependent pressure conditions are assumed at the inlet and outlet of the resulting structure. Results indicate that using a patient-specific geometry for the aorta yields additional insight on the state of the stresses applied on the aortic walls. In addition, stress contours on the Dacron are comparable to those obtained on a healthy patient and stresses evaluated at the interface of the biological tissues and the fabric, provide useful information regarding the suture strength needed during surgery. In the case of aneurysm, our simulation results agree well with experimental data taken from the literature particularly with regard to WSS which can be used to assess the seriousness of the aneurysm condition. If an idealized cylindrical shell is used in place of the reconstructed anatomy, the von Mises stress values do not differ much but it underestimates the values of WSS which could interpreted as the presence of an aneurysm when there is not. Among the novel contributions, the present FSI model has the ability to predict the Dacron’s response to realistic hemodynamic loading conditions.

Heart Failure With Preserved, Mid-Range, and Reduced Ejection Fraction

The European Society of Cardiology (ESC) recently published new guidelines for the diagnosis and treatment of acute and chronic heart failure (HF).1 The new nomenclature includes separating patients with HF into 3 distinct groups depending on the left ventricular ejection fraction (LVEF): preserved LVEF (≥50%), mid-range LVEF (40–49%), and reduced LVEF (≤40%). Although there have been several studies that argue for and against stratifying HF patients by LVEF, the latest guidelines continue to focus mainly on the LVEF as the central determinant of prognosis in HF. However, further characterization of HF phenotype using etiology, comorbidities, and nonresponse to therapy among the 3 proposed groups are not incorporated into the definition. It is important to identify pathophysiological mechanisms and specific etiologies that underlie the clinical status, beyond the simplistic definition of preserved, mid-range, and reduced LVEF. Moreover, the term “preserved” could be misleading and confusing: quite comforting and mistakenly reassuring. As observed in the literature and in clinical practice, patients with preserved LVEF may have worse prognosis in terms of rehospitalization and mortality. Furthermore, it is necessary to highlight that the determination of LVEF from 2D echocardiographic images with Simpson’s biplane technique is relatively unreliable, with intra and interobserver variability of up to 13% and 15%, respectively, because of foreshortened views and geometric assumptions.2 Moreover, LVEF calculation is sensitive to changes in hemodynamic loading conditions. This is what occurs in patients with mitral regurgitation who have preserved LVEF despite severe ventricular dysfunction.3,4 The consequence of such variability in measurement and sensitivity to loading conditions may lead to a significant overlap among the 3 proposed categories that are separated by only a few percentage points. Moreover, calculating LVEF is considered a simple method to estimate ventricular function, but in fact it may be too simplistic. In the management of HF patients, it is more important to focus on ventricular function estimated by chamber volumes and pressures, as well as by Doppler flows and tissue Doppler imaging (TDI). In fact, in our opinion, the key means by which to determine the prognosis of HF patients involves establishing the presence or absence of ventricular dysfunction, that could be (1) systolic, ie, with increased ventricular volumes; (2) diastolic, ie, with abnormalities in transmitral and pulmonary veins flows, in TDI mitral annular velocities, and in left atrium volume; or (3) systo-diastolic, ie, including features of both systolic and diastolic dysfunction. The presence of systolic, diastolic, or systo-diastolic ventricular dysfunction determines low cardiac output, which is the crucial pathophysiological element of HF.

Functional significance of the discordance between transcriptional profile and left ventricular structure/function during reverse remodeling.

To elucidate the mechanisms for reverse LV remodeling, we generated a conditional (doxycycline [dox] off) transgenic mouse tetracycline transactivating factor-TRAF2 (tTA-TRAF2) that develops a dilated heart failure (HF) phenotype upon expression of a proinflammatory transgene, TNF receptor-associated factor 2 (TRAF2), and complete normalization of LV structure and function when the transgene is suppressed. tTA-TRAF2 mice developed a significant increase in LV dimension with decreased contractile function, which was completely normalized in the tTA-TRAF2 mice fed dox for 4 weeks (tTA-TRAF2dox4W). Normalization of LV structure and function was accompanied by partial normalization (~60%) of gene expression associated with incident HF. Similar findings were observed in patients with dilated cardiomyopathy who underwent reverse LV remodeling following mechanical circulatory support. Persistence of the HF gene program was associated with an exaggerated hypertrophic response and increased mortality in tTA-TRAF2dox4W mice following transaortic constriction (TAC). These effects were no longer observed following TAC in tTA-TRAF2dox8W, wherein there was a more complete (88%) reversal of the incident HF genes. These results demonstrate that reverse LV remodeling is associated with improvements in cardiac myocyte biology; however, the persistence of the abnormal HF gene program may be maladaptive following perturbations in hemodynamic loading conditions.

In Vivo Collagen Remodeling in the Vascular Wall of Decellularized Stented Tissue-Engineered Heart Valves.

Decellularized tissue-engineered heart valves (TEHVs) are under investigation as alternative for current heart valve prostheses with the potential to rapidly repopulate with cells within the body. Ideally, these valves are stented for transapical or minimally invasive delivery. It is unclear if and how the matrix of these valves remodels under in vivo hemodynamic loading conditions and in the presence of a stent. Here, we study the evolution of collagen orientation and tissue maturation in the wall of stented decellularized TEHVs with time after implantation. In a previous study, stented TEHVs based on rapidly degrading scaffolds were cultured in bioreactors, decellularized, and transapically implanted as pulmonary valve replacement in sheep. In the present study, collagen (re)orientation in the initially isotropic valvular wall was assessed using a fluorescent collagen probe combined with confocal imaging and image analysis of explanted tissue at 8, 16, and 24 weeks following implantation. Collagen tortuosity or waviness in the explants, as a measure of matrix maturity, was quantified using a Gabor wavelet method and compared with tortuosity in native sheep vascular wall tissue. Results indicate that on the luminal side of the valvular wall, fibers became aligned in circumferential direction, while tortuosity increased with implantation time, showing striking similarities with the native collagen structure after 24 weeks. On the outside of the wall, where the engineered tissue touches the stent, collagen fibers in the vicinity of the struts aligned along the struts, whereas collagen fibers in between struts were randomly oriented. Immunohistochemistry was performed to evaluate the presence of elastin and collagen type I and III. After 8 weeks, collagen types I and III were mostly present at the luminal side of the wall, whereas at 16 and 24 weeks, a homogenous distribution of collagen I and III was observed throughout the wall. Elastin was mostly expressed at the luminal side after 24 weeks. Biochemical assays showed that the amount of DNA (as a measure of cell number) increased significantly after 8 and 24 weeks, glycosaminoglycans increased significantly after 8, 16, and 24 weeks, and hydroxyproline, as a measure of collagen amount, increased significantly after 24 weeks compared to the controls. The collagen matrix in the wall of decellularized TEHVs shows clear structural remodeling and maturation with time. While collagen orientation rapidly remodels toward a native anisotropic architecture on the luminal side of the engineered valvular wall, it is dominated and guided by stent geometry on the outer side of the wall. Collagen tortuosity was increased with implantation time and was accompanied by an increase in elastin, especially on the luminal side of the vessel.

The Echocardiographic Tei-index Compared to Transpulmonary Thermodilution Measurement With Different Hemodynamic Biomodels

Objective: To compare Doppler flow Tei-indexes with standard intermittent transpulmonary thermodilution measurement with different hemodynamic loading conditions. Materials and methods: Total 48 piglets (6 weeks old, average weight 23kg) under general anesthesia, were divided into groups under cardiac loading conditions (at rest, with increased left ventricular afterload, with increased right ventricular preload). At 60 and 120 minutes the animals were examined by echocardiography and simultaneously transpulmonary thermodilution was used to measure cardiac output. Tei-indexes data were compared with invasively monitored haemodynamic data. Results: A total of 1632 parallel data were obtained. Correlation was found between values of right Tei-index and changes in right ventricular preload (p<0.05) and afterload ( p<0.01). Correlation was also found between left Tei-index values and changes of left ventricular preload (p<0.001), afterload ( p<0.001), stroke volume (p<0.01), and cardiac output (p<0.01). Conclusions: Tei-index as global myocardial performance selectively for the right and left ventricle can be recommended for monitoring of circulation and cardiac performance.

Tissue Doppler–Derived Contractile Reserve Is a Simple and Strong Predictor of Cardiopulmonary Exercise Performance across a Range of Cardiac Diseases

Resting echocardiographic measures of cardiac function such as left ventricular ejection fraction correlate poorly with exercise capacity. Assessment during exercise using measures less dependent on hemodynamic loading conditions, such as tissue Doppler imaging (TDI), may more accurately characterize the relationship between cardiac function and exercise capacity. One hundred one subjects with various cardiac diagnoses underwent exercise stress echocardiography with simultaneous cardiopulmonary gas exchange analysis. Standard two-dimensional, Doppler and spectral TDI parameters were assessed at both rest and peak exercise. Across all subjects the strongest relationship with peak oxygen uptake (pVO2 ) was with peak left ventricular systolic tissue velocity (S') during exercise (r = 0.84, P < 0.001). The strength of the relationship was greater than that observed with any other common echocardiographic measure of systolic or diastolic cardiac function. There is a very strong relationship between measurements of S' during exercise and exercise capacity. The previously observed poor correlation with standard measures of systolic and diastolic cardiac function may be explained both by the load dependence of parameters such as ejection fraction and by reliance on resting as opposed to exercise assessment.

Radial and Longitudinal Strain and Strain Rate Assessed by Speckle‐Tracking Echocardiography in Dogs with Myxomatous Mitral Valve Disease

Assessment of left ventricular (LV) function using conventional echocardiographic methods is difficult in mitral regurgitation (MR) owing to altered hemodynamic loading conditions. Newer methods such as speckle-tracking echocardiography (STE) provide assessment of LV strain (St) and strain rates (SR). Global St and SR are 1) decreased in dogs with clinical signs of congestive heart failure (CHF) due to myxomatous mitral valve disease (MMVD) compared with clinically healthy dogs, and are 2) associated with conventional echocardiographic indices of MMVD severity. The study subjects were 93 privately owned dogs with different MMVD severities. Prospectively recruited dogs were grouped according to MMVD severity based on echocardiographic evaluation of MR and presence of clinical signs. Global radial and longitudinal St, SR, and indices of LV dyssynchrony were assessed. On group-wise comparisons, dogs with CHF had increased global longitudinal St, global longitudinal and radial SR in systole (SRs), and early diastole (SRe) compared with dogs with no or minimal MR (all P < .04). On multiple regression analyses, these global STE variables increased with degree of MR, but associations with left atrial-to-aortic root ratio (LA/Ao) were best described by second-order polynomial equations. Thus, curvilinear relationships were found for LA/Ao and longitudinal St, SRs, and SRe (all P < .002) and radial St and SRe (all P < .001). Assessed by STE, LV function appeared to be augmented in moderate-to-severe disease. However, at CHF stages with greatly enlarged atria, a decrease to levels comparable to dogs with no or minimal MR was observed.

A Clinical Commentary on the Articles “Strategies for Tissue Engineering Cardiac Constructs to Affect Functional Repair Following Myocardial Infarction” and “Stem Cell-Based Cardiac Tissue Engineering”

Heart failure is a major cause of global morbidity and mortality. Over 24 million individuals worldwide have been diagnosed with heart failure with the number of affected individuals projected to approach 20 million by the year 2020 in the USA alone [1–3]. Historically, therapies for heart failure have focused on modulating hemodynamic loading conditions to ameliorate symptoms with salutary effects on cardiac remodeling that improve survival. Surgical advances have also led to improved outcomes after cardiac transplantation; however, the limited number of donor hearts available has driven future therapies into two arenas: biomechanical and biomolecular. The promise of mechanical support devices (MSDs) for end-stage heart failure is being realized; however, this option remains costly and invasive while demonstrating only a limited long-term survival benefit [4]. Furthermore, the long-term impact of device-based ventriculo-vascular coupling remains poorly understood as these devices have altered the overall pattern of circulation to non-pulsatile flow in recipients of MSDs. Over the past two decades, cell-based approaches for heart failure have emerged on a wave of scientific evidence supporting the possibility of generating cells that communicate, conduct, and contract. Two reviews in this edition of the Journal of Cardiovascular Translational Research provide insight into the complexity of cytotherapy from the biomedical engineering perspective. Nunes et al. provide a comprehensive overview of stem cell-based cardiac tissue engineering. Their review highlights the challenges of cell injection and tissue replacement strategies, and then examines the role of embryonic and adult stem cells. As highlighted by their review, one of the major issues facing scientists and physicians in this arena is the ability to accurately gauge improvement in cardiac function after cell therapy. Left ventricular ejection fraction (LVEF) measured by echocardiography or magnetic resonance imaging may not be sensitive enough to detect ultrastructural and physiologic improvements in cardiovascular function. For example, many patients with heart failure and severely impaired LVEF (<30%) continue to lead active lives and demonstrate normal cardiac filling pressures with normal stroke volume. In similar fashion, preclinical and clinical studies of cell-based therapies should extend their evaluation of cardiac function beyond LVEF and begin to examine whether cell strategies impact hemodynamic function as measured by a conductance catheter in the pressure volume loop plane. Notably, a majority of preclinical studies also do not provide data regarding survival outcomes. Since many drug strategies improve survival, demonstrating an incremental benefit of cytotherapy over existing therapies in the heart failure population may prove challenging. In the second review, Ye et al. examine strategies for tissue engineering after myocardial infarction by providing a comprehensive analysis of biomaterials and culture This article is a commentary on the following articles: 10.1007/ s12265-011-9303-1 and 10.1007/s12265-011-9307-x

Peroxisome Proliferator-activated Receptor (PPAR) Gene Profiling Uncovers Insulin-like Growth Factor-1 as a PPARα Target Gene in Cardioprotection

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor family of ligand-activated transcription factors and consist of the three isoforms, PPARα, PPARβ/δ, and PPARγ. Considerable evidence indicates the importance of PPARs in cardiovascular lipid homeostasis and diabetes, yet the isoform-dependent cardiac target genes remain unknown. Here, we constructed murine ventricular clones allowing stable expression of siRNAs to achieve specifically knockdown for each of the PPAR isoforms. By combining gene profiling and computational peroxisome proliferator response element analysis following PPAR isoform activation in normal versus PPAR isoform-deficient cardiomyocyte-like cells, we have, for the first time, determined PPAR isoform-specific endogenous target genes in the heart. Electromobility shift and chromatin immunoprecipitation assays demonstrated the existence of an evolutionary conserved peroxisome proliferator response element consensus-binding site in an insulin-like growth factor-1 (igf-1) enhancer. In line, Wy-14643-mediated PPARα activation in the wild-type mouse heart resulted in up-regulation of igf-1 transcript abundance and provided protection against cardiomyocyte apoptosis following ischemia/reperfusion or biomechanical stress. Taken together, these data confirm igf-1 as an in vivo target of PPARα and the involvement of a PPARα/IGF-1 signaling pathway in the protection of cardiomyocytes under ischemic and hemodynamic loading conditions.

Local angiotensin II aggravates cardiac remodeling in hypertension

Angiotensin II (ANG II) contributes to hypertension, cardiac hypertrophy, fibrosis, and dysfunction; however, it is difficult to separate the cardiac effect of ANG II from its hemodynamic action in vivo. To overcome the limitations, we used transgenic mice with cardiac-specific expression of a transgene fusion protein that releases ANG II from cardiomyocytes (Tg-ANG II) and treated them with deoxycorticosterone acetate (DOCA)-salt to suppress their systemic renin-angiotensin system. Using this unique model, we tested the hypothesis that cardiac ANG II, acting on the angiotensin type 1 receptor (AT(1)R), increases inflammation, oxidative stress, and apoptosis, accelerating cardiac hypertrophy and fibrosis. Male Tg-ANG II mice and their nontransgenic littermates (n-Tg) were uninephrectomized and divided into the following three groups: 1) vehicle-treated normotensive controls; 2) DOCA-salt; and 3) DOCA-salt + valsartan (AT(1)R blocker).Under basal conditions, systolic blood pressure (SBP) and cardiac phenotypes were similar between strains. In DOCA-salt hypertension, SBP increased similarly in both n-Tg and Tg-ANG II, and cardiac function did not differ between strains; however, Tg-ANG II had 1) greater ventricular hypertrophy as well as interstitial and perivascular fibrosis; 2) a higher number of deoxynucleotidyl-transferase-mediated dUTP nick end labeling-positive cells and infiltrating macrophages; 3) increased protein expression of NADPH oxidase 2 and transforming growth factor-β(1); and 4) downregulation of phosphatidylinositol 3-kinase (PI 3-kinase) and protein kinase B (Akt) phosphorylation. Valsartan partially reversed these effects in Tg-ANG II but not in n-Tg. We conclude that, when hemodynamic loading conditions remain unchanged, cardiac ANG II does not alter heart size or cardiac functions. However, in animals with hypertension, cardiac ANG II, acting via AT(1)R, enhances inflammation, oxidative stress, and cell death (most likely via downregulation of PI 3-kinase and Akt), contributing to cardiac hypertrophy and fibrosis.

Determinants of coronary microvascular dysfunction in symptomatic hypertrophic cardiomyopathy

Impaired hyperemic myocardial blood flow (MBF) in hypertrophic cardiomyopathy (HCM), despite normal epicardial coronary arteries, results in microvascular dysfunction. The aim of the present study was to determine the relative contribution of extravascular compressive forces to microvascular dysfunction in HCM. Eighteen patients with symptomatic HCM and normal coronary arteries and 10 age-matched healthy volunteers were studied with PET to quantify resting and hyperemic MBF at a subendocardial and subepicardial level. In HCM patients, MRI was performed to determine left ventricular (LV) mass index (LVMI) and volumes, echocardiography to assess diastolic perfusion time, heart catheterization to measure LV outflow tract gradient (LVOTG) and LV pressures, and serum NH(2)-terminal pro-brain natriuretic peptide (NT-proBNP) as a biochemical marker of LV wall stress. Hyperemic MBF was blunted in HCM vs. controls (2.26 +/- 0.97 vs. 2.93 +/- 0.64 ml min(-1) g(-1), P < 0.05). In contrast to controls (1.38 +/- 0.15 to 1.25 +/- 0.19, P = not significant), the endocardial-to-epicardial MBF ratio decreased significantly in HCM during hyperemia (1.20 +/- 0.11 to 0.88 +/- 0.18, P < 0.01). This pattern was similar for hypertrophied septum and lateral wall. Hyperemic MBF was inversely correlated with LVOTG, NT-proBNP, left atrial volume index, and LVMI (all P < 0.01). Multivariate regression analysis, however, revealed that only LVMI and NT-proBNP were independently related to hyperemic MBF, with greater impact at the subendocardial myocardial layer. Hyperemic MBF is more severely impaired at the subendocardial level in HCM patients. The level of impairment is related to markers of increased hemodynamic LV loading conditions and LV mass. These observations suggest that, in addition to reduced capillary density caused by hypertrophy, extravascular compressive forces contribute to microvascular dysfunction in HCM patients.

The Transforming Growth Factor-β/Smad3 Pathway

Myocardial infarction (MI) is followed by a well-described sequence of events known as postinfarction ventricular remodeling, a process that involves both the infarct scar itself and the residual surviving myocardium.1 The net results of infarct remodeling are changes in chamber size, function, and geometry. Furthermore, the remodeled ventricle becomes a substrate for both heart failure and sudden cardiac death. The elements of post-MI remodeling include infarct expansion, neurohormonal activation, myocardial hypertrophy, myocardial fibrosis, and cellular apoptosis. Article p 2127 These are linked physiological responses that attempt to compensate for the sudden decrease in contractility resulting from acute myocardial cell death.2 Infarct expansion is the thinning of the infarcted segment from slippage and stretching of myocytes and cell rupture. It is highly influenced by hemodynamic loading conditions.3 The prototypic pathways that participate in post-MI remodeling include the autonomic nervous system and renin-angiotensin-aldosterone system, which may be an attempt to maintain blood pressure and cardiac output.4 Over time, however, elevated adrenergic activity may lead to further myocardial cell loss from apoptosis,5 and both adrenergic and renin-angiotensin-aldosterone system upregulation have an adverse impact on cardiac hemodynamics. Myocardial hypertrophy, fibrosis, and apoptosis are primarily seen in the noninfarcted regions of the heart, particularly within the peri-infarct zones.2,6–8 Hypertrophy occurs in response to the increased workload for the surviving myocardiocytes, especially under suboptimal hemodynamic conditions. Myocardial hypertrophy, fibrosis, and apoptosis in the noninfarcted regions are believed to result, in part, from the neurohormonal activation of the sympathetic nervous system, renin-angiotensin-aldosterone system and cytokine cascades. The effect of these processes is to further compound the myocardial damage sustained during the initial acute injury. The end result of these remodeling responses is global ventricular dilatation, which is a significant predictor of dysfunction and future mortality.9 Understanding the components of remodeling …

The reduction of hemodynamic loading assists self-regeneration of the injured heart by increasing cell proliferation, inhibiting cell apoptosis, and inducing stem-cell recruitment

Mitotic cardiomyocytes and cardiac stem cells have been identified recently in adult hearts, and both have been found to be increased in acute infarcted myocardium. Although these findings suggest potential self-repair of the heart after injury, obvious self-regeneration of the injured heart has never been observed clinically. We hypothesized that hemodynamic loading impairs myocardial repair. Myocardial infarction was induced in C57BL/6 mice by ligating the left anterior descending artery. After 60 minutes, either the infarcted heart was transplanted heterotopically into a healthy recipient C57BL/6 mouse to remove the ventricular hemodynamic loading (unloading group) or it was left as an infarcted heart under normal hemodynamic loading conditions in the same mouse (loading group). The infarcted hearts were dissected for histologic analysis after 3, 7, 14, and 28 days. Histologic analysis showed that the wall thickness of the infarcted left ventricle was significantly greater and the area of infarction was significantly smaller in the unloading group than in the loading group. Immunostaining analysis revealed significantly more Ki-67-positive cells and significantly fewer apoptotic cells in the infarcted myocardium in the unloading group than in the loading group. There were also significantly more c-kit- and Sca-1-positive stem cells in the infarcted myocardium in the unloading group than in the loading group. Our findings suggest that hemodynamic unloading assists self-regeneration of the injured heart by increasing cell proliferation, inhibiting cell apoptosis, and inducing stem-cell recruitment.