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In JoVE (1)
Other Publications (22)
- Cardiovascular Drugs and Therapy / Sponsored by the International Society of Cardiovascular Pharmacotherapy
- Stem Cells (Dayton, Ohio)
- European Journal of Cell Biology
- Clinical and Experimental Pharmacology & Physiology
- Endothelium : Journal of Endothelial Cell Research
- European Journal of Cell Biology
- Wiener Medizinische Wochenschrift (1946)
- Molecular Therapy : the Journal of the American Society of Gene Therapy
- Journal of Cardiovascular Pharmacology
- Cardiology Research and Practice
- Methods in Molecular Biology (Clifton, N.J.)
- Journal of the American College of Cardiology
- American Journal of Physiology. Heart and Circulatory Physiology
- The Annals of Thoracic Surgery
- International Journal of Cardiology
- International Journal of Cardiology
- Circulation Research
- Molecular Therapy : the Journal of the American Society of Gene Therapy
- Molecular Therapy : the Journal of the American Society of Gene Therapy
- The International Journal of Cardiovascular Imaging
- Cardiovascular Therapeutics
- American Journal of Physiology. Heart and Circulatory Physiology
Articles by Dennis Ladage in JoVE
Gene Transfer for Ischemic Heart Failure in a Preclinical Model
Kiyotake Ishikawa, Dennis Ladage, Lisa Tilemann, Kenneth Fish, Yoshiaki Kawase, Roger J. Hajjar
Cardiovascular Research Center, Mount Sinai School of Medicine
A method of gene transfer for the treatment of ischemic heart failure is described using a swine model of myocardial infarction. Our simple and reproducible method enables us to readily evaluate the efficacy of various gene transfers with a very simple and reproducible way.
Other articles by Dennis Ladage on PubMed
Crataegus Special Extract WS 1442 Induces an Endothelium-dependent, NO-mediated Vasorelaxation Via ENOS-phosphorylation at Serine 1177
Cardiovascular Drugs and Therapy / Sponsored by the International Society of Cardiovascular Pharmacotherapy. Jun, 2006 | Pubmed ID: 16779533
This study investigates the influence of WS(R) 1442, a special extract of Crataegus leaves with flowers, on the relaxation of rat aorta and human mammarian artery (coronary bypass patients).
Stem Cells (Dayton, Ohio). Jul, 2006 | Pubmed ID: 16822883
Little is known about the migration of mesenchymal stem cells (MSCs). Some therapeutic approaches had demonstrated that MSCs were able to regenerate injured tissues when applied from different sites of application. This implies that MSCs are not only able to migrate but also that the direction of migration is controlled. Factors that are involved in the control of the migration of MSCs are widely unknown. The migratory ability of isolated MSCs was tested in different conditions. The migratory capability was examined using Boyden chamber assay in the presence or absence of basic fibroblast growth factor (bFGF), erythropoietin, interleukin-6, stromal cell-derived factor-beta, and vascular endothelial growth factor. bFGF in particular was able to increase the migratory activity of MSCs through activation of the Akt/protein kinase B (PKB) pathway. The results were supported by analyzing the orientation of the cytoskeleton. In the presence of a bFGF gradient, the actin filaments developed a parallelized pattern that was strongly related to the gradient. Surprisingly, the influence of bFGF was not only an attraction but also routing of MSCs. The bFGF gradient experiment showed that low concentrations of bFGF lead to an attraction of the cells, whereas higher concentrations resulted in repulsion. This ambivalent effect of bFGF provides the possibility to a purposeful routing of MSCs.
European Journal of Cell Biology. Nov, 2006 | Pubmed ID: 16824647
Mesenchymal stem cells (MSCs) seem to be a useful tool for cellular therapy in injured tissues, e.g. myocardial infarction or cardiomyopathies resulting in heart failure. For therapeutic approaches it is crucial that MSCs cross the endothelial barrier especially in intravascular or rather intracoronary application. Until today little is known about MSCs transmigrating across the endothelium. We performed co-culture experiments of MSCs on an endothelial monolayer to analyse direct interactions. An increasing flattened morphology of the MSCs was followed by a total integration into the monolayer after 2h. We repeated these experiments in isolated heart perfusions with gold-labelled MSCs. Using electron microscopy we detected MSCs exhibited direct cell-cell contacts. Tight junctions between the endothelial cells became abolished resulting in a distinct split between the cells. MSCs developed tight cell-cell contacts and became integrated into the endothelial wall of the capillary vessel. Finally, using confocal laser scanning microscopy, we assessed the ability of the MSCs to fully pass the endothelial barrier. Within the first 30 min, 30+/-8% of MSCs transmigrated, increasing to about half at 60 min (50+/-8%), whereas after 120 min the rate remained nearly unchanged (53+/-10%). This work demonstrates the capability of MSCs for transendothelial migration. Moreover we showed that the vast majority of MSCs migrated within 30 min, an important finding for the exposure times in clinical settings.
Mechanisms Underlying Nebivolol-induced Endothelial Nitric Oxide Synthase Activation in Human Umbilical Vein Endothelial Cells
Clinical and Experimental Pharmacology & Physiology. Aug, 2006 | Pubmed ID: 16895546
1. Nebivolol (NEB) has been shown to be a selective blocker of beta1-adrenoceptors with additional vasodilating properties that are mediated, at least in part, by an endothelial-dependent liberation of nitric oxide (NO). In the present study, we investigated the underlying mechanisms of NEB-induced vasodilation. 2. Immunohistochemical staining of endothelial nitric oxide synthase (eNOS) was performed in the absence and presence of NEB in human umbilical vein endothelial cells (HUVEC). In addition, we measured the release of nitric oxide (NO) using diaminofluorescein. Metoprolol (MET) was used for comparison. 3. Nebivolol, but not MET (each at 10 micromol/L), caused a time-dependent increase in NO release from HUVEC, as demonstrated by an increase in DAF fluorescence at 0 versus 10 min (+234 +/- 7 and 55 +/- 22% basal, respectively). Blockade of beta3-adrenoceptors by SR 59230A (1 micromol/L) partially reduced the NEB-induced increase in DAF fluorescence. Complete inhibition of NEB-induced NO liberation was achieved by the simultaneous blockade of beta3-adrenoceptors and oestrogen receptors (with 1 micromol/L ICI 182,780). 4. Application of NEB significantly increased eNOS translocation and serine 1177 phosphorylation of eNOS. However, NEB did not alter eNOS-phosphorylation at threonine 495 and at serine 114. 5. In conclusion, the endothelium-dependent NO liberation induced by NEB is due to stimulation of beta3-adrenoceptors and oestrogen receptors and coincides with eNOS translocation and a phosphorylation at eNOS-serine 1177. These characteristics of NEB may be beneficial not only when treating patients suffering from cardiovascular disease, but may also prevent further deterioration of endothelial dysfunction.
Endothelium : Journal of Endothelial Cell Research. Mar-Apr, 2007 | Pubmed ID: 17497361
Mesenchymal stem cells (MSCs) are bone marrow-derived, pluripotent cells that possess the ability to transdifferentiate into various mesenchymal tissues such as bone, endothelium, and (heart) muscle. Therefore, these cells may provide a therapeutic tool, especially for the treatment of myocardial infarction. The interaction of the MSCs with the endothelial barrier and their ability to ultimately leave blood vessels after application are crucial in this context. In this study, the authors focused on the soluble factors produced by MSCs and their effect on the intracellular signal transduction of endothelial cells. The authors performed immunohistochemical measurements on human umbilical vein endothelial cells (HUVECs) treated with conditioned stem cell medium and took measurements of the intracellular nitric oxide (NO) levels and calcium changes. After application of conditioned stem cell medium, the authors detected an increase in endothelial NO synthase (eNOS) activity by translocation (Ca(2+)) and by phosphorylation (increase of pAKT and peNOS1177). Additionally, the authors observed an upregulation of pERK within the same time. The phosphorylated eNOS forms are linked to these findings and the increase of intracellular NO in the DAF measurements. Moreover, conditioned medium also increased intracellular calcium levels in endothelial cells. Concluding, the authors postulate that MSCs emit soluble factors that alter the NO and calcium levels of endothelial cells and may be important for facilitate crossing the endothelial barrier.
Characterisation of the Interaction Between Circulating and in Vitro Cultivated Endothelial Progenitor Cells and the Endothelial Barrier
European Journal of Cell Biology. Feb, 2008 | Pubmed ID: 17945378
In vitro cultured endothelial progenitor cells (cEPC) are used for intracoronary cell therapy in cardiac regeneration. The aim of this study was to investigate whether cEPC and circulating mononuclear cells (MNC), which include a small number of in vivo circulating EPC, are able to transmigrate through the endothelial barrier into the cardiac tissue. MNC and EPC were isolated from the peripheral blood from healthy male volunteers (n = 13, 25+/-6 years) and stained with a fluorescent marker. The cells were perfused in vitro through organs with endothelial layers of different phenotypes (rat aorta, human umbilical vein, isolated mouse heart). The endothelium and the basal lamina were then stained by immunofluorescence and the cryo-sections analysed using a confocal laser scanning microscope. After perfusion through the rat aorta, an adhesion/integration of MNC was observed at the endothelial layer and the basal lamina beneath endothelial cells. However, no migration of MNC over the endothelial barrier was found. This remained true even when the cell numbers were increased (from 0.5 to 10 million cells/h), when the time of perfusion was prolonged (1.5-4 h) and when the aorta was cultivated for 24 h. In the Langendorff-perfused mouse heart with intact endothelium, no migration of MNC (1 x 10(7)) or cEPC (1 x 10(6)) was observed after 0.5 and 2 h. In conclusion, MNC and cEPC do not possess any capacity to transmigrate the endothelial barrier. In the context of stem cell therapy, these cells may therefore serve as endothelial regenerators but not as cardiomyocyte substitutes.
Wiener Medizinische Wochenschrift (1946). 2009 | Pubmed ID: 19412697
Nebivolol (Nomexor) is a third generation, vasodilating beta-blocker with a high beta(1)-adrenoceptor selectivity. Nebivolol acts as an agonist at the beta(3) adrenoceptor as well as the estrogen receptor thereby releasing nitric oxide in blood vessels via eNOS. Pleiotropic effects of nebivolol furthermore include a positive influence on cholesterol and triglycerides and a decrease in thrombocyte activity. Nebivolol is recommended in the guidelines of the European cardiac society (ESC) for patients with metabolic syndrome. Nebivolol's main properties in combination with its broad range of beneficial pleiotropic effects allow it to be clearly distinguished from other second and third generation beta-blockers.
Molecular Therapy : the Journal of the American Society of Gene Therapy. Jul, 2010 | Pubmed ID: 20461063
Congestive heart failure (HF) is associated with impaired endothelium-dependent nitric oxide-mediated vasodilatation. The aim of this study was to examine the effects of sarco/endoplasmic reticulum (ER) Ca(2+)-ATPase 2a (SERCA2a) gene transfer on endothelial function in a swine HF model. Two months after the creation of mitral regurgitation to induce HF, the animals underwent intracoronary injection of adeno-associated virus (AAV) carrying SERCA2a (n = 7) or saline (n = 6). At 4 months, coronary flow (CF) was measured in the mid-portion of the left anterior descending (LAD) artery. In the failing animals, CF was decreased significantly; SERCA2a gene transfer rescued CF to levels observed in sham-group [ml/min/g, 0.47 +/- 0.064 saline versus 0.89 +/- 0.116, SERCA2a; P < 0.05; 1.00 +/- 0. 185 sham P = NS (nonsignificant)]. In coronary arteries from HF animals, SERCA2a and endothelial isoform of nitric oxide synthase (eNOS) protein expression were decreased, but restored to normal levels by SERCA2a gene transfer. In human coronary artery endothelial cells (HCAECs), SERCA2a overexpression increased eNOS expression, phosphorylation, eNOS promoter activity, Ca(2+) storage capacity, and enhanced histamine-induced calcium oscillations, eNOS activity, and cyclic guanosine monophosphate (cGMP) production. Thus, SERCA2a gene transfer increases eNOS expression and activity by modulating calcium homeostasis to improve CF. These findings suggest that SERCA2a gene transfer improves vascular reactivity in the setting of HF.
Nebivolol Lowers Blood Pressure and Increases Weight Loss in Patients with Hypertension and Diabetes in Regard to Age
Journal of Cardiovascular Pharmacology. Sep, 2010 | Pubmed ID: 20571428
In patients with diabetes mellitus type 2 and arterial hypertension, the control of systolic and diastolic blood pressure is essential to reduce the risk of adverse events. The present study investigates the effect of treatment with the third-generation beta-blocker nebivolol, in female and male patients of different ages.
Cardiology Research and Practice. 2010 | Pubmed ID: 20981290
Although ischemic cardiomyopathy is commonly caused by chronic obstructive coronary disease, the mechanism of the cause is still under investigation. We present echocardiographic strain, magnetic resonance, and histology findings in a chronic ischemia model in preclinical study. This case illustrates the features of multimodality imaging in chronic obstructive coronary disease and gives us great insight into understanding the mechanism of ischemic cardiomyopathy.
Methods in Molecular Biology (Clifton, N.J.). 2011 | Pubmed ID: 21194040
Cardiovascular disease is a major cause of morbidity and mortality in contemporary societies. While progress in conventional treatment modalities is making steady and incremental gains to reduce this disease burden, there remains a need to explore new and potentially therapeutic approaches. Gene therapy, which was initially envisioned as a treatment strategy for inherited monogenic disorders, has been found to hold broader potential that also includes acquired polygenic diseases, such as atherosclerosis, arrhythmias, and heart failure. Advances in the understanding of the molecular basis of conditions such as these, together with the evolution of increasingly efficient gene transfer technology, have placed some cardiovascular pathophysiologies within the reach of gene-based therapy. In fact, gene therapy holds great promise as a targeted treatment for cardiovascular diseases. One of the major hurdles for effective cardiovascular gene therapy is the delivery of the viral vectors to the heart. In this chapter, we will present the various types of delivery techniques in preclinical, large animal models of cardiovascular diseases.
Journal of the American College of Cardiology. Mar, 2011 | Pubmed ID: 21371634
Congestive heart failure is a major cause of morbidity and mortality in the United States. Although progress in conventional treatments is making steady and incremental gains to decrease heart failure mortality, there is a critical need to explore new therapeutic approaches. Gene therapy was initially applied in the clinical setting for inherited monogenic disorders. It is now apparent that gene therapy has broader potential that also includes acquired polygenic diseases, such as congestive heart failure. Recent advances in understanding of the molecular basis of myocardial dysfunction, together with the evolution of increasingly efficient gene transfer technology, have placed heart failure within the reach of gene-based therapy. Furthermore, the recent successful and safe completion of a phase 2 trial targeting the sarcoplasmic reticulum Ca(2+) ATPase pump along with the start of more recent phase 1 trials are ushering in a new era of gene therapy for the treatment of heart failure.
American Journal of Physiology. Heart and Circulatory Physiology. Aug, 2011 | Pubmed ID: 21551276
A number of promising therapies for ischemic cardiomyopathy are emerging, and the role of translational research in testing the efficacy and safety of these agents in relevant clinical models has become important. The goal of this study was to develop a chronic model of ischemic cardiomyopathy in a large animal model. In this study, 40 consecutive pigs were initially enrolled. To induce progressive stenosis, a plastic occluder with a fixed diameter of 1.0 mm fitted with an 18-gauge copper wire was placed around the proximal left anterior descending (LAD) coronary artery. Coronary angiography, hemodynamic measurements, and echocardiography were performed at 2 wk and 1, 2, and 3 mo. Overall mortality was 26% at 3 mo, and up to 80% of the pigs showed total occlusion of LAD at 1 mo. A significant depression of peak LV pressure rate of rise (+dP/dt(max)) was observed in the animals showing total artery occlusion throughout the study. Left ventricular ejection fraction was also impaired, and the left ventricular volumes tended to be larger in the pigs with occlusion. Approximately 10% of scar tissue was found in the LAD occluded pigs, whereas the coronary flow pattern in the rest of the area took the pattern of hibernating myocardium. At the same time, histological and protein analysis established the presence of fibrosis and ongoing apoptosis in the ischemic area. In this model, the timing and incidence of total occlusion and low mortality offer significant advantages over other ischemic cardiomyopathy models in conducting preclinical studies.
Staged Approach Prevents Spinal Cord Injury in Hybrid Surgical-endovascular Thoracoabdominal Aortic Aneurysm Repair: an Experimental Model
The Annals of Thoracic Surgery. Jul, 2011 | Pubmed ID: 21718839
In a porcine model, we investigated the impact of sudden stent graft occlusion of thoracic intercostal arteries after open lumbar segmental artery (SA) ligation.
International Journal of Cardiology. Jul, 2011 | Pubmed ID: 21764470
BACKGROUND: Treatment of heart failure patients with aldosterone antagonists has been shown to reduce the occurrence of sudden cardiac death. Therefore we aimed at determining the consequences of chronic exposure to aldosterone and the aldosterone antagonists eplerenone and spironolactone on the electrophysiological properties of the heart in a rat model. METHODS AND RESULTS: Male Wistar rats were chronically treated (4weeks) with aldosterone (ALD) via an osmotic minipump. Spironolactone (SPI) or eplerenone (EPL) was administered with the rat chow. ALD treated animals developed left ventricular hypertrophy, prolonged QT-intervals, a higher rate of ventricular premature beats and non-sustained ventricular tachycardia despite normal blood pressure values. Spironolactone and eplerenone were both able to inhibit the alterations. Left-ventricular mRNA expressions of Kv4.2 and Kv4.3 (I(to)), Kv1.5 (I(Kur)), Kir2.1 and Kir2.3 (I(K1)) and of Ca(v)1.2 (L-type Ca(2+) channel) were significantly down-regulated in ALD. Correspondingly, the protein expressions of subunits Kv1.5, Kir2.3 and Cav1.2 were significantly decreased. A diminished calcineurin activity and mRNA expression of the Aß subunit of calcineurin were found in ALD, which was insensitive to aldosterone antagonists. CONCLUSIONS: Chronic aldosterone-overload induces blood pressure independent structural and electrical remodeling of the myocardium resulting in an increased risk for malignant ventricular arrhythmias.
Hyperaldosteronism is Associated with a Decrease in Number and Altered Growth Factor Expression of Endothelial Progenitor Cells in Rats
International Journal of Cardiology. Jun, 2011 | Pubmed ID: 20116868
Aldosterone plays a role in hypertension, the pathogenesis of heart failure and vascular injury. However, little information exists about the possible influence of aldosterone on bone marrow derived endothelial progenitor cells (EPC), which are involved in the repair of damaged endothelium. This study was designed to determine the long- term in vivo influence of aldosterone on the number of EPC.
Inhibition of PKCα/β with Ruboxistaurin Antagonizes Heart Failure in Pigs After Myocardial Infarction Injury
Circulation Research. Dec, 2011 | Pubmed ID: 21998327
Protein kinase Cα (PKCα) activity and protein level are induced during cardiac disease where it controls myocardial contractility and propensity to heart failure in mice and rats. For example, mice lacking the gene for PKCα have enhanced cardiac contractility and reduced susceptibility to heart failure after long-term pressure overload or after myocardial infarction injury. Pharmacological inhibition of PKCα/β with Ro-32-0432, Ro-31-8220 or ruboxistaurin (LY333531) similarly enhances cardiac function and antagonizes heart failure in multiple models of disease in both mice and rats.
Molecular Therapy : the Journal of the American Society of Gene Therapy. Jan, 2012 | Pubmed ID: 21915102
Adeno-associated virus (AAV)-based vectors are promising gene delivery vehicles for human gene transfer. One significant obstacle to AAV-based gene therapy is the high prevalence of neutralizing antibodies in humans. Until now, it was thought that, except for nonhuman primates, pre-existing neutralizing antibodies are not a problem in small or large animal models for gene therapy. Here, we demonstrate that sera of several animal models of cardiovascular diseases harbor pre-existing antibodies against the cardiotropic AAV serotypes AAV1, AAV6, and AAV9 and against AAV2. The neutralizing antibody titers vary widely both between species and between serotypes. Of all species tested, rats displayed the lowest levels of neutralizing antibodies. Surprisingly, naive mice obtained directly from commercial vendors harbored neutralizing antibodies. Of the large animal models tested, the neutralization of AAV6 transduction by dog sera was especially pronounced. Sera of sheep and rabbits showed modest neutralization of AAV transduction whereas porcine sera strongly inhibited transduction by all AAV serotypes and displayed the largest variation between individual animals. Importantly, neutralizing antibody titers as low as 1/4 completely prevented in vivo transduction by AAV9 in rats. Our results suggest that prescreening of animals for neutralizing antibodies will be important for future gene transfer experiments in these animal models.
Concomitant Intravenous Nitroglycerin With Intracoronary Delivery of AAV1.SERCA2a Enhances Gene Transfer in Porcine Hearts
Molecular Therapy : the Journal of the American Society of Gene Therapy. Jan, 2012 | Pubmed ID: 22215018
SERCA2a gene therapy improves contractile and energetic function of failing hearts and has been shown to be associated with benefits in clinical outcomes, symptoms, functional status, biomarkers, and cardiac structure in a phase 2 clinical trial. In an effort to enhance the efficiency and homogeneity of gene uptake in cardiac tissue, we examined the effects of nitroglycerin (NTG) in a porcine model following AAV1.SERCA2a gene delivery. Three groups of Göttingen minipigs were assessed: (i) group A: control intracoronary (IC) AAV1.SERCA2a (n = 6); (ii) group B: a single bolus IC injection of NTG (50 µg) immediately before administration of intravenous (IV) AAV1.SERCA2a (n = 6); and (iii) group C: continuous IV NTG (1 µg/kg/minute) during the 10 minutes of AAV1.SERCA2a infusion (n = 6). We found that simultaneous IV infusion of NTG and AAV1.SERCA2a resulted in increased viral transduction efficiency, both in terms of messenger RNA (mRNA) as well as SERCA2a protein levels in the whole left ventricle (LV) compared to control animals. On the other hand, IC NTG pretreatment did not result in enhanced gene transfer efficiency, mRNA or protein levels when compared to control animals. Importantly, the transgene expression was restricted to the heart tissue. In conclusion, we have demonstrated that IV infusion of NTG significantly improves cardiac gene transfer efficiency in porcine hearts.
Temporal Changes of Strain Parameters in the Progress of Chronic Ischemia: with Comparison to Transmural Infarction
The International Journal of Cardiovascular Imaging. Jan, 2012 | Pubmed ID: 22231467
The aim of this study was to reveal the temporal and spatial changes of strain parameters during the progression of chronic coronary ischemia. Fourteen pigs received occluder implantation to create gradual ischemia (CI), while six pigs underwent a sham surgery (Control). Six pigs after myocardial infarction were also studied (MI). Strain analysis was performed using a speckle-tracking algorithm. Eleven of the 14 animals with occluder implantation had total occlusion of the left anterior descending artery with collaterals at 1 month (early occlusion group), whereas three pigs had occlusion at 3 months (late occlusion group). Both radial strain (RS) and circumferential strain (CS) of ischemic area deteriorated at 1 month in the early occlusion group and remained at the same level throughout the remaining 2 months of the experiment. In the late occlusion group, RS gradually declined, while CS took the same course as Control until the 2 month time point. Thereafter, both metrics reached the same level as the early occlusion group at the time of occlusion. Interestingly, RS in the remote area decreased moderately, whereas CS remained normal in CI pigs. The comparison between CI and MI revealed preserved CS at the ischemic area in CI pigs. Both RS and CS deteriorate by the time total coronary occlusion was established and remain at the same level thereafter. Altered RS in the remote area may be an indicator of remodeling in the non-ischemic area, whereas CS may be useful for distinguishing between transmural and non-transmural scar.
Cardiovascular Therapeutics. Jan, 2012 | Pubmed ID: 22279967
SUMMARY For the past 40 years, beta-blockers have been widely used in cardiovascular medicine, reducing morbidity as well as mortality. Beta-blockers are currently used in a number of cardiovascular conditions such as systolic heart failure, postmyocardial infarction, and in prevention and treatment of arrhythmias. They are not recommended as the first line antihypertensive therapy, particularly in the elderly, unless there are specific indications. Despite the benefits of beta-blockers, tolerability concerns in patients with co-morbidities have limited their use. Some of these problems were overcome with the discovery of cardioselective beta-blockers. The third generation beta-blockers have additional properties of vasodilatation and advantages in terms of minimizing the adverse effects of beta-blockers. Some of the advantages include improvement of insulin resistance, decrease in cholesterol as well as alleviation of erectile dysfunction. Acute treatment with beta-blockers modifies local muscular metabolic properties and impairs endurance exercise capacity whereas the influence of chronic is debated controversially.
Assessing Left Ventricular Systolic Dysfunction After Myocardial Infarction: Are the Ejection Fraction and the DP/dt Maximum Complementary or Redundant?
American Journal of Physiology. Heart and Circulatory Physiology. Feb, 2012 | Pubmed ID: 22307667
Background: Among the various cardiac contractility parameters, left ventricular (LV) ejection fraction (EF) and dP/dt maximum (dP/dt max) are the simplest and most used. However, these parameters are often reported together and it is not clear if they are complementary or redundant. We sought to compare the discriminative value of EF and dP/dt max in assessing systolic dysfunction after myocardial infarction (MI) in swine. Methods and Results: A total of 220 measurements were obtained. All the measurements included LV volumes and EF analysis by left ventriculography, invasive ventricular pressure tracings, and echocardiography. Baseline measurements were performed in 132 pigs, and 88 measurements were obtained at different time points after MI creation. Receiver operator characteristic (ROC) curves to distinguish the presence or absence of MI revealed a good predictive value for EF (area under the curve (AUC)=0.998), but not by dP/dt max (AUC=0.69, P<0.001 vs. EF). Dividing dP/dt max by the LV end diastolic pressure (EDP) and the heart rate (HR) significantly increased the AUC to 0.87 (p<0.001 vs dP/dt max, p<0.001 vs EF). In naive pigs, the coefficient of variation of dP/dt max was twice than EF (22.5% vs 9.5%, respectively). Furthermore, in n=19 pigs, dP/dt max increased after the MI. However, echocardiographic strain analysis of 23 pigs with EF ranging only from 36% to 40% after MI revealed significant correlations between dP/dt max and strain parameters in non-infarct area (circumferential strain: r=0.42, P=0.05, radial strain: r=0.71, P<0.001). Conclusions: EF is a more accurate measure of systolic dysfunction than dP/dt max in a swine model of MI. Despite the variability of dP/dt max both in naive pigs and after MI, it may sensitively reflect the small changes of myocardial contractility.