Offir Ertracht

The mitochondria as a target for cardioprotection in acute myocardial ischemia

The ischemic heart suffers from nutrient deprivation, lack of oxygen, metabolic acidosis, hyperkalemia and Ca(2+) overload as well as high level of reactive oxygen species (ROS) generation; these risk factors endanger the cardiomyoctes and may cause their demise. Nevertheless, the treatment of acute myocardial infarction includes reperfusion, although it can exacerbate the effects of ischemia since resumption of blood supply to the ischemic myocardium is associated with increased ROS production. In the past 20 years, preconditioning and postconditioning were revealed, directing research efforts at finding pharmacological agents that can mimic these techniques. Soon thereafter, the involvement of several molecular pathways such as the reperfusion injury salvage kinase, the ATP-sensitive K(+) channel, the survivor-activating factor enhancement and the adenosine mono phosphate activated protein kinase pathways were discovered. Further, studies have shown that these pathways convey the adverse effects of ischemia, reperfusion and the combination thereof to the mitochondria, suggesting that the death signals during ischemia and reperfusion are controllable, and can therefore be partially inhibited or even reversed. Hence, the aim of this review is to describe these signaling pathways, the established pre-clinical means to manipulate them, and their current application status in the clinic.

Layer-specific strain analysis by speckle tracking echocardiography reveals differences in left ventricular function between rats and humans

The rat heart is commonly used as an experimental model of the human heart in both health and disease states, assuming that heart function of rats and humans is alike. When studying a rat model, echocardiography is usually performed on sedated rats, whereas standard echocardiography on adult humans does not require any sedation. Since echocardiography results of sedated rats are usually inferred to alert humans, in the present study, we tested the hypothesis that differences in left ventricular (LV) function may be present between rats sedated by a low dose of ketamine-xylazine and alert humans. Echocardiography was applied to 110 healthy sedated rats and 120 healthy alert humans. Strain parameters were calculated from the scans using a layer-specific speckle tracking echocardiography program. The results showed that layer longitudinal strain is equal in rats and humans, whereas segmental strain is heterogeneous (P < 0.05) in a different way in rats and humans (P < 0.05). Furthermore, layer circumferential strain is larger in humans (P < 0.001), and the segmental results showed different segmental heterogeneity in rats and humans (P < 0.05). Radial strain was found to be homogeneous at the apex and papillary muscle levels in humans and heterogeneous in rats (P < 0.001). Additionally, whereas LV twist was equal in rats and humans, in rats the rotation was larger at the apex (P < 0.01) and smaller at the base (P < 0.001). The torsion-to-shortening ratio parameter, which indicates the transmural distribution of contractile myofibers, was found to be equal in rats and humans. Thus, when evaluating LV function of sedated rats under ketamine-xylazine, it is recommended to measure the global longitudinal strain, LV twist, and torsion-to-shortening ratio, since no scaling is required when converting these parameters and inferring them to humans.

Layer-specific assessment of left ventricular function by utilizing wavelet de-noising: a validation study

Regional myocardial function assessment is essential for diagnosis and evaluation of heart disease. The purpose of this study was to enhance the spatial resolution of a speckle tracking echocardiography approach and enable layer-specific analysis of the myocardium. Following validation with software-implemented and mechanical phantoms versus imposed values, short-axis cines were obtained from 50 rats. The cines were post-processed by a speckle tracking commercial program, and the myocardial velocities were processed by a three-dimensional wavelet de-noising program, instead of the built-in smoothing process of the commercial program. Software-implemented phantom measurements yielded rotation errors of 7.5%, 2.9%, and 3.4%, for inner, middle, and outer layers, respectively. Analysis of a shrinking/expanding mechanical phantom yielded strain errors of 3%, 5%, and 7% for the three layers. Bland–Altman analysis showed agreement between the commercial and enhanced programs. Thus, layer-specific analysis is feasible while using echocardiography even on small animals such as rats.

The cardioprotective efficacy of TVP1022 in a rat model of ischaemia/reperfusion

Because myocardial infarction is a major cause of morbidity and mortality worldwide, protecting the heart from the ischaemia and reperfusion (I/R) damage is the focus of intense research. Based on our in vitro findings showing that TVP1022 (the S‐enantiomer of rasagiline, an anti‐Parkinsonian drug) possesses cardioprotective effects, in the present study we investigated the hypothesis that TVP1022 can attenuate myocardial damage in an I/R model in rats.

Layer-specific strain analysis: investigation of regional deformations in a rat model of acute versus chronic myocardial infarction

Myocardial infarction (MI) injury extends from the endocardium toward the epicardium. This phenomenon should be taken into consideration in the detection of MI. To study the extent of damage at different stages of MI, we hypothesized that measurement of layer-specific strain will allow better delineation of the MI extent than total wall thickness strain at acute stages but not at chronic stages, when fibrosis and remodeling have already occurred. After baseline echocardiography scans had been obtained, 24 rats underwent occlusion of the left anterior descending coronary artery for 30 min followed by reperfusion. Thirteen rats were rescanned at 24 h post-MI and eleven rats at 2 wk post-MI. Next, rats were euthanized, and histological analysis for MI size was performed. Echocardiographic scans were postprocessed by a layer-specific speckle tracking program to measure the peak circumferential strain (S(C)(peak)) at the endocardium, midlayer, and epicardium as well as total wall thickness S(C)(peak). Linear regression for MI size versus S(C)(peak) showed that the slope was steeper for the endocardium compared with the other layers (P < 0.001), meaning that the endocardium was more sensitive to MI size than the other layers. Moreover, receiver operating characteristics analysis yielded better sensitivity and specificity in the detection of MI using endocardial S(C)(peak) instead of total wall thickness S(C)(peak) at 24 h post-MI (P < 0.05) but not 2 wk later. In conclusion, at acute stages of MI, before collagen deposition, scar tissue formation, and remodeling have occurred, damage may be nontransmural, and thus the use of endocardial S(C)(peak) is advantageous over total wall thickness S(C)(peak).

TVP1022: A Novel Cardioprotective Drug Attenuates Left Ventricular Remodeling After Ischemia/Reperfusion in Pigs.

Background: The current cornerstone treatment of myocardial infarction (MI) is restoration of coronary blood flow by means of thrombolytic therapy or primary percutaneous coronary intervention. However, reperfusion of ischemic myocardium can actually provoke tissue damage, defined as “ischemia–reperfusion (I/R) injury.” TVP1022 [the S-isomer of rasagiline (Azilect), FDA-approved anti-Parkinsons drug] was found to exert cardioprotective activities against various cardiac insults, such as chronic heart failure and I/R, in rat models. Therefore, we tested the hypothesis that TVP1022 will provide cardioprotection against I/R injury and post-MI remodeling in a pig model. Methods: For inducing MI, we used an I/R model of midleft anterior descending artery occlusion for 90 minutes followed by follow-up for 8 weeks in 18 farm pigs (9 pigs in each group, MI + TVP1022 or MI + Vehicle). Echocardiographic measurements were performed and cardiac scar size was calculated using histopathological methods. For fibrosis evaluation, we measured the interstitial collagen volume fraction in the remote noninfarcted tissue. Results: TVP1022 administration significantly decreased cardiac scar size, attenuated left ventricular dilation, and improved cardiac function assessed by segmental circumferential strain analysis. Furthermore, TVP1022 significantly reduced myocardial fibrosis 8 weeks post-MI. Conclusions: Collectively, these findings indicate that TVP1022 provides prominent cardioprotection against I/R injury and post-MI remodeling in this I/R pig model.

The cardioprotective efficacy of TVP1022 against ischemia/reperfusion injury and cardiac remodeling in rats.

Following acute myocardial infarction (MI), early and successful reperfusion is the most effective strategy for reducing infarct size and improving the clinical outcome. However, immediate restoration of blood flow to the ischemic zone results in myocardial damage, defined as “reperfusion‐injury”. Whereas we previously reported that TVP1022 (the S‐isomer of rasagiline, FDA‐approved anti‐Parkinson drug) decreased infarct size 24 h post ischemia reperfusion (I/R) in rats, in this study we investigated the chronic cardioprotective efficacy of TVP1022 14 days post‐I/R. To simulate the clinical settings of acute MI followed by reperfusion therapy, we employed a rat model of left anterior descending artery occlusion for 30 min followed by reperfusion and a follow‐up for 14 days. TVP1022 was initially administered postocclusion–prereperfusion, followed by chronic daily administrations. Cardiac performance and remodeling were evaluated using customary and advanced echocardiographic methods, hemodynamic measurements by Millar Mikro‐Tip® catheter, and histopathological techniques. TVP1022 administration markedly decreased the remodeling process as illustrated by attenuation of left ventricular enlargement and cardiac hypertrophy (both at the whole heart and the cellular level). Furthermore, TVP1022 inhibited cardiac fibrosis and reduced ventricular BNP levels. Functionally, TVP1022 treatment preserved cardiac wall motion. Specifically, the echocardiographic and most of the direct hemodynamic measures were pronouncedly improved by TVP1022. Collectively, these findings indicate that TVP1022 provides prominent cardioprotection against I/R injury and post‐MI remodeling in this I/R model.

High-Intensity Training Improves Global and Segmental Strains in Severe Congestive Heart Failure

BACKGROUND High-intensity training (HIT) is superior to moderate aerobic training (MAT) for improving quality of life in congestive heart failure (CHF) patients. Speckle-tracking echocardiography (STE) has recently been suggested for estimation of left ventricle global and regional function. We evaluated the utility of STE for characterizing differences in cardiac function following MAT or HIT in a CHF rat model. METHODS AND RESULTS After baseline physiologic assessment, CHF was induced by means of coronary artery ligation in Sprague-Dawley rats. Repeated measurements confirmed the presence of CHF (ejection fraction 52 ± 10%, global circumferential strain (GCS) 10.5 ± 4, and maximal oxygen uptake (V˙O2max) 71 ± 11 mL⋅min-1⋅kg-1; P < .001 vs baseline for all). Subsequently, rats were divided into training protocols: sedentary (SED), MAT, or HIT. After the training period, rats underwent the same measurements and were killed. Training intensity improved V˙O2max (73 ± 13 mL⋅min-1⋅kg-1 in MAT [P < .01 vs baseline] and 82 ± 6 mL⋅min-1⋅kg-1 in HIT [P < .05 vs baseline or SED] and ejection fraction (50 ± 21% in MAT [P < .001 vs baseline] and 66 ± 7% in HIT [P > .05 vs baseline]). In addition, strains of specific segments adjacent to the infarct zone regained basal values (P > .05 vs baseline), whereas global cardiac functional parameters as assessed with the use of 2-dimensional echocardiography did not improve. CONCLUSIONS High-intensity exercise training improved function in myocardial segments remote from the scar, which resulted in compensatory cardiac remodeling. This effect is prominent, yet it could be detected only with the use of STE.

Detection of small subendocardial infarction using speckle tracking echocardiography in a rat model.

It is challenging to detect small nontransmural infarcts visually or automatically. As it is important to detect myocardial infarction (MI) at early stages, we tested the hypothesis that small nontransmural MI can be detected using speckle tracking echocardiography (STE) at the acute stage.

Strain Measurements Relative to Normal State Enhance the Ability to Detect Non-Transmural Myocardial Infarction

Noa Bachner-Hinenzon1,*, Offir Ertracht2, 3,*, Zvi Vered4,5, Marina Leitman4,5, Nir Zagury1, Ofer Binah2,3 and Dan Adam1 1Faculty of Biomedical Engineering 2Department of Physiology 3Ruth and Bruce Rappaport Faculty of Medicine, Rappaport Family Institute for Research in the Medical Sciences Technion-Israel Institute of Technology, Haifa, 4Department of Cardiology, Assaf Harofeh Medical Center, Zerifin, 5Sackler School of Medicine Tel Aviv University Israel