Significant Improvement In Myocardial Function Research Articles

Abstract 4131409: Systemic Review and Meta-analysis of Global Longitudinal Strain Changes after Angiotensin Receptor Nephrilysin Inhibitor Initiation in Patients with Heart Failure

Angiotensin Receptor Nephrilysin Inhibitors (ARNi) have been established as a beneficial medication in patients with heart failure (HF). This class of medications has been shown to decrease HF hospitalizations and has been included as one of the pillars in guideline directed medical therapy. Recently, left ventricular (LV) global longitudinal strain (GLS) measurements on echocardiograms have become more common and provide a more precise measurement of LV function than ejection fraction. GLS is now being used as a more intricate way of monitoring improvement in the function of the myocardium, especially in patients with heart failure. This meta-analysis was conducted to determine if treatment with ARNi in HF patients significantly improves myocardial functioning measured by LV GLS. A meta-analysis of 9 studies including observational studies and randomized controlled trials found in a Pubmed search was performed and included patients with heart failure who were initiated on an ARNi for guideline directed medical therapy and had LV GLS measurements taken on an echocardiogram before and after ARNi initiation. The study included patients with heart failure with reduced ejection fraction. Studies were excluded if the patient population did not have a diagnosis of HF and if LV GLS measurements were not available before and after treatment with ARNi. This analysis was performed to determine if initiation of ARNi in patients with HF led to a significant improvement in LV GLS on echocardiography and therefore a significant improvement in myocardial function. There were 9 studies included in the analysis and 879 patients with HF who were treated with ARNi or a control. The change in LV GLS at the conclusion of the study period was measured in both treatment and control groups and the mean difference between the two groups was -1.61 with a 95% confidence interval of (-2.23, -0.98) (p <0.00001). This indicates that the ARNi treatment groups had a significant improvement in GLS compared to the control groups. ARNi initiation was found to significantly improve LV GLS and therefore myocardial function in patients with HF with reduced ejection fraction. LV GLS is a precise measurement of myocardial function. Using this form of measurement in echocardiograms can aid in determining the effect different treatments have directly on myocardial function.

The Effect of HIF1-α/NF-κB/MMP2 Signaling Pathways Mediated by ALDH2 on Chronic Intermittent Hypoxia Induced Myocardial Injury in Rats

(1) Objective: To investigate the effect of HIF1-α/NF-κB/MMP2 signaling pathways mediated by ALDH2 on chronic intermittent hypoxia induced myocardial injury in rats. (2) Methods: Thirty SD rats were randomly assigned to three groups (10 rats in each group): control group (CONTROL), chronic intermittent hypoxia group (CIH), and CIH + ALDH2 group. Rats in the CIH + ALDH2 group were established by an intraperitoneal injection of the ALDH2 activator, Alda-1 (20 mg/kg), once a day for three consecutive days. After three months, changes in ventricular function were determined by ultrasound. The expressions of HIF1-α, NF-κB, and MMP2 proteins were detected by protein blotting, and the concentration of 4-HNE in myocardial tissue was measured. (3) Results: Compared with the control group, echocardiography showed that rats in the CIH group had significantly reduced myocardial function, elevated protein levels of HIF1-α, NF-κB, and MMP2 in myocardial tissues, and increased the expression of 4-HNE in myocardial tissues (P<0.01); Compared with the CIH group, rats in the CIH + ALDH2 group showed significant improvement in myocardial function, decreased protein levels of HIF1-α, NF-κB, and MMP2 in myocardial tissue, and decreased the expression of 4-HNE in myocardial tissue (P<0.01). (4) Conclusion: Chronic intermittent hypoxia increases the expression of HIF1-α to damage the myocardium and affect cardiac function, and ALDH2 inhibits the expression of HIF1-α to protect the myocardium.

Cannabinoid Receptor Agonist WIN55, 212-2 Adjusts Lipid Metabolism in a Rat Model of Cardiac Arrest.

The objective of this study was to investigate the effects of pharmacologically induced hypothermia with WIN55, 212-2 (WIN)on postresuscitation myocardial function, microcirculation, and metabolism-specific lipids in a rat cardiac arrest (CA) model. Ventricular fibrillation was electrically induced and untreated for 6 minutes in 24 Sprague-Dawley rats weighing 450-550 g. Cardiopulmonary resuscitation including chest compression and mechanical ventilation was then initiated and continued for 8 minutes, followed by defibrillation. At 5 minutes after restoration of spontaneous circulation (ROSC), animals were randomized into four groups: (1) normothermia with vehicle (NT); (2) physical hypothermia with vehicle (PH); (3) WIN55, 212-2 with normothermia (WN); and (4) WIN55, 212-2 with hypothermia (WH). For groups of WN and WH, WIN was administered by continuous intravenous infusion with a syringe pump for 4 hours. PH started at 5 minutes after resuscitation. NT maintained core temperature at 37°C ± 0.2°C with the aid of a heating blanket. Hypothermia groups maintained temperature at 33°C ± 0.5°C for 4 hours after ROSC. There was a significant improvement in myocardial function as measured by ejection fraction, cardiac output, and myocardial performance index in animals treated with WH and PH beginning at 1 hour after start of infusion. In the WH and PH groups, buccal microcirculation was significantly improved compared with NT and WN. Plasma at pre-CA and ROSC 4 hours was harvested for lipid metabolism. The WH group appeared to be closer to baseline than the other groups in lipid metabolism. lysophosphatidylcholine (LPC) 18:2, free fatty acid (FFA) 22:6, and ceramide (CER) (24:0) changed significantly among the lipidomic data compared with NT (p < 0.05). Postresuscitation hypothermia improved myocardial function and microcirculation. WH-mediated lipid metabolism had the best metabolic outcome to bring back the animals to normal metabolism, which may be protective to improve outcomes of CA. LPC 18:2, FFA 22:6, and CER (24:0) may be important predictors of outcomes of CA.

Direct intracardiac injection of umbilical cord-derived stromal cells and umbilical cord blood-derived endothelial cells for the treatment of ischemic cardiomyopathy.

The development of new therapeutic strategies is necessary to reduce the worldwide social and economic impact of cardiovascular disease, which produces high rates of morbidity and mortality. A therapeutic option that has emerged in the last decade is cell therapy. The aim of this study was to compare the effect of transplanting human umbilical cord-derived stromal cells (UCSCs), human umbilical cord blood-derived endothelial cells (UCBECs) or a combination of these two cell types for the treatment of ischemic cardiomyopathy (IC) in a Wistar rat model. IC was induced by left coronary artery ligation, and baseline echocardiography was performed seven days later. Animals with a left ventricular ejection fraction (LVEF) of ≤40% were selected for the study. On the ninth day after IC was induced, the animals were randomized into the following experimental groups: UCSCs, UCBECs, UCSCs plus UCBECs, or vehicle (control). Thirty days after treatment, an echocardiographic analysis was performed, followed by euthanasia. The animals in all of the cell therapy groups, regardless of the cell type transplanted, had less collagen deposition in their heart tissue and demonstrated a significant improvement in myocardial function after IC. Furthermore, there was a trend of increasing numbers of blood vessels in the infarcted area. The median value of LVEF increased by 7.19% to 11.77%, whereas the control group decreased by 0.24%. These results suggest that UCSCs and UCBECs are promising cells for cellular cardiomyoplasty and can be an effective therapy for improving cardiac function following IC.

Improved Cardiac and Neurologic Outcomes With Postresuscitation Infusion of Cannabinoid Receptor Agonist WIN55, 212-2 Depend on Hypothermia in a Rat Model of Cardiac Arrest*

To investigate the mechanisms of improved myocardial and neurological function and survival following i.v. administration of cannabinoid receptor agonist, WIN55, 212-2 in a rat model of cardiac arrest. Prospective randomized controlled experimental study. University-affiliated research institute. Thirty male Sprague-Dawley rats. Ventricular fibrillation was electrically induced in 30 male Sprague-Dawley rats weighing between 450 and 550 g. Cardiopulmonary resuscitation was initiated after 6 minutes of untreated ventricular fibrillation. The precordial compression was performed with a pneumatically driven mechanical chest compressor. No pharmacological agent was used during cardiopulmonary resuscitation. After 8 minutes of cardiopulmonary resuscitation, up to three 2-J defibrillations were attempted. The animals were then randomized into three groups: 1) WIN55, 212-2 hypothermia, 2) WIN55, 212-2 with normal body temperature, and 3) placebo control. Either WIN55, 212-2 (1.0 mg/kg/hr) or saline placebo was continuously infused for 2 hours. Except for the WIN55, 212-2 hypothermia group, the body temperature in the other two groups was maintained at 37.0 ± 0.2°C using an external heating lamp. Postresuscitation myocardial function was measured by echocardiogram. Neurological deficit scores and survival time were observed for up to 72 hours. Blood temperatures decreased from 37°C to 33°C in 4 hours in animals in WIN55, 212-2 hypothermia group. Myocardial function, as measured by cardiac output, ejection fraction, and myocardial performance index, was significantly impaired in all animals after successful resuscitation when compared with the baseline values. There was a significant improvement in myocardial function in the animals treated with WIN55, 212-2 hypothermia beginning at 1 hour after start of infusion. However, no improvement was observed in the groups of WIN55, 212-2 with normal body temperature and placebo control. WIN55, 212-2 hypothermia group was associated with significantly improved neurologic deficit scores and survival time when compared with placebo control group and WIN55, 212-2 with normal body temperature group. In a rat model of cardiac arrest, better postresuscitation myocardial function, neurological deficit scores, and longer duration of survival were observed by the pharmacologically induced hypothermia with WIN55, 212-2. The improved outcomes of cardiopulmonary resuscitation following administration of WIN55, 212-2 appeared to be the results from its temperature reduction effects.

Myocardial regeneration by transplantation of modified endothelial progenitor cells expressing SDF‐1 in a rat model

Cell based therapy has been shown to attenuate myocardial dysfunction after myocardial infarction (MI) in different acute and chronic animal models. It has been further shown that stromal-cell derived factor-1α (SDF-1α) facilitates proliferation and migration of endogenous progenitor cells into injured tissue. The aim of the present study was to investigate the role of exogenously applied and endogenously mobilized cells in a regenerative strategy for MI therapy. Lentivirally SDF-1α-infected endothelial progenitor cells (EPCs) were injected after 90 min. of ligation and reperfusion of the left anterior descending artery (LAD) intramyocardial and intracoronary using a new rodent catheter system. Eight weeks after transplantation, echocardiography and isolated heart studies revealed a significant improvement of LV function after intramyocardial application of lentiviral with SDF-1 infected EPCs compared to medium control. Intracoronary application of cells did not lead to significant differences compared to medium injected control hearts. Histology showed a significantly elevated rate of apoptotic cells and augmented proliferation after transplantation of EPCs and EPCs + SDF-1α in infarcted myocardium. In addition, a significant increased density of CD31+ vessel structures, a lower collagen content and higher numbers of inflammatory cells after transplantation of SDF-1 transgenic cells were detectable. Intramyocardial application of lentiviral-infected EPCs is associated with a significant improvement of myocardial function after infarction, in contrast to an intracoronary application. Histological results revealed a significant augmentation of neovascularization, lower collagen content, higher numbers of inflammatory cells and remarkable alterations of apoptotic/proliferative processes in infarcted areas after cell transplantation.

Safe Genetic Modification of Cardiac Stem Cells Using a Site-Specific Integration Technique

Human cardiac progenitor cells (hCPCs) are a promising cell source for regenerative repair after myocardial infarction. Exploitation of their full therapeutic potential may require stable genetic modification of the cells ex vivo. Safe genetic engineering of stem cells, using facile methods for site-specific integration of transgenes into known genomic contexts, would significantly enhance the overall safety and efficacy of cellular therapy in a variety of clinical contexts. We used the phiC31 site-specific recombinase to achieve targeted integration of a triple fusion reporter gene into a known chromosomal context in hCPCs and human endothelial cells. Stable expression of the reporter gene from its unique chromosomal integration site resulted in no discernible genomic instability or adverse changes in cell phenotype. Namely, phiC31-modified hCPCs were unchanged in their differentiation propensity, cellular proliferative rate, and global gene expression profile when compared with unaltered control hCPCs. Expression of the triple fusion reporter gene enabled multimodal assessment of cell fate in vitro and in vivo using fluorescence microscopy, bioluminescence imaging, and positron emission tomography. Intramyocardial transplantation of genetically modified hCPCs resulted in significant improvement in myocardial function 2 weeks after cell delivery, as assessed by echocardiography (P=0.002) and MRI (P=0.001). We also demonstrated the feasibility and therapeutic efficacy of genetically modifying differentiated human endothelial cells, which enhanced hind limb perfusion (P<0.05 at day 7 and 14 after transplantation) on laser Doppler imaging. The phiC31 integrase genomic modification system is a safe, efficient tool to enable site-specific integration of reporter transgenes in progenitor and differentiated cell types.

Outcomes after Surgical Correction of Anomalous Origin of the Left Coronary Artery from the Pulmonary Artery

SUMMARY Background The anomalous origin of the left coronary artery from the pulmonary artery is a rare congenital heart defect that produces myocardial ischemia with left ventricular dysfunction and mitral regurgitation. The natural history of the disease has been modified by the current surgical techniques which establish a system with two coronary arteries. Objectives To evaluate our experience with the surgical correction of the anomalous origin of the left coronary artery from the pulmonary artery. Material and Methods A total of 13 patients underwent surgical repair of this condition from February 2000 to May 2008. Median age was 2.5 years; range 45 days to 21 years. Six patients were <1 year old. Before surgery, 61% of patients presented congestive heart failure, 69% had signs of myocardial infarction and 84% moderate to severe heart enlargement. Average shortening fraction was 26.07% and 46% of patients had moderate to severe mitral regurgitation. The diagnosis was confirmed by coronary angiography in 11 patients. The Takeuchi procedure was performed in one patient and 12 patients underwent direct anastomosis of the anomalous left coronary artery directly to the aorta. One patient underwent mitral valve repair. Perfusion of the anomalous coronary artery and cardioplegia were provided via the pulmonary artery in six patients. Results At present, after a mean follow-up of 74.76 months, mortality rate is 0%. None of the patients presented congestive heart failure at discharge. A reduction in cardiac size was observed in 9/11 patients. The average postoperative shortening fraction was 39.92%. A decrease in the severity of mitral regurgitation was observed in all patients with only one exception. None of the patients presented severe mitral regurgitation in the late postoperative period. Conclusions The outcomes of the surgical correction of the anomalous origin of the left main coronary artery from the pulmonary artery are excellent in all age groups, with significant improvement of myocardial function and reduction of the severity of mitral regurgitation in most patients

Clinical outcome of transcatheter aortic valve implantation in patients with low‐flow, low gradient aortic stenosis

Low-flow, low-gradient aortic stenosis is associated with relevant postoperative mortality whereas conservative management results in dismal prognosis. We present the initial experience of low-flow, low-gradient aortic stenosis treated with transcatheter aortic valve implantation (TAVI). From June 2008 to December 2010 167 consecutive patients with native severe aortic stenosis and an excessive operative risk underwent TAVI. Of these, 15 patients presented with low-flow, low-gradient aortic stenosis (aortic valve area < 1 cm(2) , left ventricular (LV) ejection fraction < 40%, aortic mean gradient < 40 mm Hg). The CoreValve prosthesis 18-F-generation (Medtronic, Minneapolis, Minnesota) was inserted retrograde. Clinical follow-up and echocardiography were performed 6 months after procedure. Patients with low-flow, low-gradient aortic stenosis (mean LV ejection fraction 32 ± 6%, mean aortic gradient 27 ± 7 mm Hg) had higher all-cause mortality 6 months after TAVI compared to patients without low-flow, low-gradient aortic stenosis (33% vs. 13%, P = 0.037). In the surviving 10 patients with low-flow, low-gradient aortic stenosis, LV ejection fraction increased (34 ± 6% before vs. 46 ± 11% 6 months after TAVI, p = 0.005) and more distance covered in the 6-minute walk test (218 ± 102 meters before vs. 288 ± 129 meters 6 months after TAVI, p = 0.038). Our study suggests that TAVI is feasible in patients with severe co-morbidities and low-flow, low-gradient aortic stenosis. Within the first 6 months after treatment all-cause mortality was considerable high, but the surviving patients showed symptomatic benefit and significant improvement of myocardial function and exercise capacity.

Folic acid mitigated cardiac dysfunction by normalizing the levels of tissue inhibitor of metalloproteinase and homocysteine-metabolizing enzymes postmyocardial infarction in mice

Myocardial infarction (MI) results in significant metabolic derangement, causing accumulation of metabolic by product, such as homocysteine (Hcy). Hcy is a nonprotein amino acid generated during nucleic acid methylation and demethylation of methionine. Folic acid (FA) decreases Hcy levels by remethylating the Hcy to methionine, by 5-methylene tetrahydrofolate reductase (5-MTHFR). Although clinical trials were inconclusive regarding the role of Hcy in MI, in animal models, the levels of 5-MTHFR were decreased, and FA mitigated the MI injury. We hypothesized that FA mitigated MI-induced injury, in part, by mitigating cardiac remodeling during chronic heart failure. Thus, MI was induced in 12-wk-old male C57BL/J mice by ligating the left anterior descending artery, and FA (0.03 g/l in drinking water) was administered for 4 wk after the surgery. Cardiac function was assessed by echocardiography and by a Millar pressure-volume catheter. The levels of Hcy-metabolizing enzymes, cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 5-MTHFR, were estimated by Western blot analyses. The results suggest that FA administered post-MI significantly improved cardiac ejection fraction and induced tissue inhibitor of metalloproteinase, CBS, CSE, and 5-MTHFR. We showed that FA supplementation resulted in significant improvement of myocardial function after MI. The study eluted the importance of homocysteine (Hcy) metabolism and FA supplementation in cardiovascular disease.

Endothelial Progenitor Cell Targeting to Ischemic Myocardium Attenuates Hypoxia and Enhances Cardiomyocyte Viability and Function

Introduction: Ischemic cardiomyopathy is a global health concern. Endothelial progenitor cell (EPC) upregulation with granulocyte-monocyte colony stimulating factor (GMCSF) followed by stromal-cell derived factor-1a (SDF) directed EPC chemokinesis is a means of myocardial revascularization.We recently reported upregulated EPCs, enhanced neovasculogenesis and increased myocardial perfusion with this therapy. To further investigate the biologic mechanisms we studied hypoxia attenuation, myocardial preservation, and function. Hypothesis: Neovasculogenic therapy with SDF/GMCSF enhances myocardial function by attenuating hypoxia and preserving myocardium. Methods: Lewis rats underwent LAD coronary ligation and progressed into heart failure. At 3wks the animals were randomized to intramyocardial SDF and subcutaneous GMCSF injections as therapy or saline as control. 6wks post-ligation borderzone vascular endothelial growth factor (VEGF) levels were quantified by western blot analysis. Endogenous VEGF is produced in response to tissue ischemia, thereby serving as a marker for hypoxia. Myocardial viability was determined by apoptosis as measured by caspase-3 activity levels and preservation of myocardial mass. Myocardial function was measured by echocardiography. Results: This therapy attenuated hypoxia as evidenced by decreased VEGF production. Enhanced myocardial preservation was noted by diminished apoptosis and enhanced myocardial to body mass ratio. There was a significant improvement in myocardial function with SDF/GMCSF therapy. Conclusions: GMCSF EPC upregulation and SDF mediated EPC chemokinesis enhances myocardial function by reversing myocardial ischemia and enhancing myocardial viability.

Changes of Myocardial Function after Combined Coronary Revascularization and Mitral Valve Downsizing in Patients with Ischemic Mitral Regurgitation and Advanced Cardiomyopathy

At present not much data is available on changes in myocardial function after combined coronary artery bypass grafting (CABG) and downsizing of the mitral valve (MV) by restrictive prosthetic ring annuloplasty in patients with chronic ischemic mitral regurgitation (IMR) and advanced cardiomyopathy. 63 patients with coronary artery disease, chronic IMR grade 3 - 4+, ischemic cardiomyopathy and reduced left ventricular (LV) function (LV ejection fraction [LVEF] of 30 +/- 9 %; range 12 - 45 %) underwent combined CABG and MV downsizing. Clinical follow-up and serial echocardiographic studies were performed to assess survival, New York Heart Association (NYHA) class, mitral regurgitation (MR), leaflet coaptation height (LCH), left atrial (LA) and LV end-systolic/end-diastolic dimensions/volumes and volume indices (LVESD, -EDD; LVESV, -EDV; LVESVI, -EDVI), fractional shortening (FS) and LVEF to evaluate the changes in myocardial function after surgery. Early mortality (< 30 days) was 1.6 %, survival at follow-up was 95 % (3 +/- 1 months) and 83 % (2 +/- 1 years), respectively. Functional class improved significantly after surgery; recurrence of relevant MR was absent in all patients. In general, LA/LV dimensions/volumes and volume indices, FS and LVEF improved significantly, even in patients with already severely reduced preoperative LV function (LVEF </= 25 %, n = 23), a significant improvement of myocardial function was observed. Combined MV downsizing and CABG surgery can be performed with low early and late mortality, resulting in a significant improvement of myocardial function and without MR recurrence at short-term and mid-term follow-up.

Significant improvement of myocardial function following cardiac support device implantation: Illustration by two-dimensional strain

Cardiac support devices (CSD) offer a new therapeutic alternative to patients with end-stage refractory heart failure and severe left ventricle (LV) dilatation. Passive mechanical constraint has been shown to reduce LV dilatation as well as to improve LV function and patient symptoms. Using a new echocardiographic technique to evaluate myocardial strain from bidimensional acquisitions, we describe the case of a patient with significant improvement in global and regional LV functions, as well as LV dyssynchrony following CSD implantation.

Autologous intracoronary mononuclear bone marrow cell transplantation in chronic ischemic cardiomyopathy in humans

Background Recent data suggest that transplantation of autologous bone marrow cells (BMC) may contribute to myocardial repair after acute myocardial infarction. We hypothesized that patients with chronic ischemic cardiomyopathy could also benefit from autologous BMC transplantation in addition to established heart failure therapy. Methods and results Five patients with chronic ischemic cardiomyopathy caused by anterior myocardial infarction, 1.3±0.5 years ago and open infarct artery, received autologous mononuclear BMC transplantation via balloon catheter in the target vessel at the site of previous occlusion. Patients were followed up at 3 months (left heart catheterisation, 2D-echocardiography, dobutamine stress echocardiography, cardiopulmonary exercise testing) and at 12 months (2D-echocardiography, cardiopulmonary exercise testing). Follow-up examination showed no significant improvement neither in global, regional, and microvascular function, nor in physical performance. Conclusions In this pilot trial intracoronary transplantation of autologous, mononuclear BMC did not lead to any significant improvement in myocardial function and physical performance of patients with chronic ischemic heart disease.

The role of bridge to transplantation: should LVAD patients be transplanted?

The decrease in useable donor organs means an increasing number of patients are requiring support with a left ventricular assist device (LVAD) for survival when their clinical status deteriorates before transplantation. We address whether these patients should be transplanted, if so, with what priority, and when and if they are not transplanted, what are the alternatives? The perioperative mortality and morbidity of LVAD insertion remains high. Infection and device failure still limit the safety of long periods of bridging and might necessitate earlier transplantation. Early results suggest that the smaller impeller pumps may be associated with a lower incidence of device failure and infection, but with more thromboembolic and hemorrhagic complications. Transplantation of LVAD patients results in survival rates as good as those with conventional transplantation, and the survival benefit is better than for non-LVAD-supported patients. A small number of LVAD patients have shown a significant improvement in myocardial function, sufficient enough to allow explantation of the device. The proportion of these patients has previously been reported to be as low as 5%, but a strategy to maximize recovery has allowed pump removal in approximately two thirds of dilated cardiomyopathy patients. In a recent destination therapy trial, survival in LVAD patients was superior to those on medical therapy, but the frequency of infection, bleeding, and malfunction of the device was higher. LVAD technology is continuing to evolve quickly, while transplantation is here to stay. The interaction between these two powerful modalities requires continued thoughtful evaluation for maximal benefit to patients.

Mobilization of stem cells by granulocyte colony-stimulating factor for the regeneration of myocardial tissue after myocardial infarction

BACKGROUND AND OBJECTIVE Animal data suggest that mobilized bone marrow cells (BMC) may contribute to tissue regeneration after myocardial infarction (MI). However the safety, feasibility and efficacy of treatment with granulocyte colony-stimulating factor (G-CSF) to mobilize BMC after acute myocardial infarction in patients is unknown. We analysed cardiac function and perfusion in 5 patients who were treated with G-CSF in addition to standard therapeutical regimen. METHODS AND RESULTS 48 h after successful recanalization and stent implantation in 5 patients with acute MI, the patients received 10 micro g/kg bodyweight/day G-CSF subcutaneously for a mean treatment duration of 7.6+/-0.5 days. Peak value of CD34 (+) cells, a multipotent subfraction of bone marrow cells, was reached after 5.0+/-0.7 days. After 3 months of follow-up global left ventricular ejection fraction (determined by radionuclid-ventriculography) increased significantly from 42.2+/-6.6 % to 51.6+/-8.3 % (P<0.05). The wall motion score and the wall perfusion score (determined by ECG gated SPECT) decreased from 13.5+/-3.6 to 9.9+/-3.5 (P<0.05) and from 9.6+/-2.9 to 7.0+/-4.5 (P<0.05), respectively, indicating a significant improvement of myocardial function and perfusion. No severe side effects of G-CSF treatment could be observed. Malignant arrhythmias were not observed either. CONCLUSION In patients with acute MI, treatment with G-CSF to mobilize BMC appears to be well tolerable under clinical conditions. Improved cardiac function and perfusion may be attributed to BMC-associated promotion of myocardial regeneration and neovascularization.

Usefulness of Coenzyme Q 10 in clinical cardiology: A long-term study

Over an eight year period (1985–1993), we treated 424 patients with various forms of cardiovascular disease by adding coenzyme Q 10 (CoQ 10) to their medical regimens. Doses of CoQ 10 ranged from 75 to 600 mg/day by mouth (average 242 mg). Treatment was primarily guided by the patient's clinical response. In many instances, CoQ 10 levels were employed with the aim of producing a whole blood level greater than or equal to 2.0 μg/ml (average 2.92 μg/ml, n=297). Patients were followed for an average of 17.8 months, with a total accumulation of 632 patient years. Eleven patients were omitted from this study: 10 due to non-compliance and one who experienced nausea. Eighteen deaths occurred during the study period with 10 attributable to cardiac causes. Patients were divided into six diagnostic categories: ischemic cardiomyopathy (ICM), dilated cardiomyopathy (DCM), primary diastolic dysfunction (PDD), hypertension (HTN), mitral valve prolapse (MVP) and valvular heart disease (VHD). For the entire group and for each diagnostic category, we evaluated clinical response according to the New York Heart Association (NYHA) functional scale, and found significant improvement. Of 424 patients, 58 per cent improved by one NYHA class, 28% by two classes and 1.2% by three classes. A statistically significant improvement in myocardial function was documented using the following echocardiographic parameters: left ventricular wall thickness, mitral valve inflow slope and fractional shortening. Before treatment with CoQ 10, most patients were taking from one to five cardiac medications. During this study, overall medication requirements dropped considerably: 43% stopped between one and three drugs. Only 6% of the patients required the addition of one drug. No apparent side effects from CoQ 10 treatment were noted other than a single case of transient nausea. In conclusion, CoQ 10 is a safe and effective adjunctive treatment for a broad range of cardiovascular diseases, producing gratifying clinical responses while easing the medical and financial burden of multidrug therapy.

Comparison of Functional and Metabolic Assessments in Preservation Techniques for Heart Transplantation

The present study compares simple hypothermic storage and hypothermic perfusion in a swine model of heart transplantation using metabolic and functional assessments. In both groups the hearts were initially protected with iso-osmolar potassium Tyers' cardioplegia. The donor hearts of group A were placed in simple hypothermic storage for 5 h. The donor hearts of group B were placed onto a perfusion apparatus for 5 h with perfusion pressure maintained at 28 cm of H2O and a myocardial temperature of 8-10 degrees C. The perfustate consisted of Tyers' solution with the addition of 2 mg/L of mannitol, 12.5 mg/L of glucose, 5 units/L of insulin, and 95% oxygen. The ischemic interval within both groups was 6 h, including orthotoipic transplantation. Investigation was conducted at three time periods: prepreservation (T1) in the donor, and postpreservation (T2) and immediately after loading (T3) in the recipient. Following volume loading for the hypothermic perfusion group there was significant improvement of myocardial function (cardiac index, p less than .05; stroke index, p less than .05) with no significant change in systemic vascular resistance, systemic blood pressure, and heart rate. There was also significant improvement in myocardial performance (p less than .05) for the hypothermic perfusion group following volume loading. Results of fatty acid turnover using 15-p-iodo (123I)-phenylpentodecanoic acid indicate significantly greater increase in metabolic rate for the perfusion group than for the hypothermic storage group. (p less than .05). This indicates improved metabolic status of the heart treated with the hypothermic perfusion technique. We conclude that a combination of functional and metabolic assessments is a good method for deduction of ischemic-reperfusion injury. We also conclude that hypothermic perfusion is superior to hypothermic storage for in vitro preservation of hearts for heart transplantation.

Long-term efficacy and safety of coenzyme Q 10 therapy for idiopathic dilated cardiomyopathy

Coenzyme Q 10 (CoQ 10) occurs in the mitochondria of human cells. It is 2,3-dimethoxy-5-methyl-6-decaprenyl-l,4-benzoquinone and functions as a cofactor in several enzyme systems related to energy conversion. As such, it is essential for human life to exist. Since mitochondria are very abundant in myocardial cells and because of their huge energy needs, a deficiency of CoQ 10 could have a particularly severe effect on myocardial function. In 1981 we chose cardiomyopathy for clinical study because it has been a disease of unknown cause, which has been apparently limited to the myocardium and has been without effective treatment. A short-term doubleblind cross-over study of 19 patients with cardiomyopathy (New York Heart Association classes III and IV) was completed in 1982. Control subjects' CoQ 10 levels that were in the deficiency range were increased into the normal range by oral replacement therapy. This paralleled significant improvement in myocardial function and clinical status. There was no intolerance of the treatment. 1 A long-term open-label study was begun in November 1982 with the goal of determining if tolerance of CoQ 10 and clinical improvement were maintained over long periods of time. From our observations with untreated control subjects in the short-term study and those of Mortensen et al, 2 we thought it improper to use untreated control subjects in a long-term study. Myocardial function entails active energy input in both the contracting and relaxing phases, which may not be equally involved in clinical heart disease. Since precise measurement of each phase of myocardial function remains developmental, long-term survival figures could be finite and meaningful.

Prevention of diabetes-induced myocardial dysfunction in rats by methyl palmoxirate and triiodothyronine treatment

Diabetes results in myocardial functional alterations which are accompanied by a depression of biochemical parameters such as myosin ATPase and calcium uptake in the sarcoplasmic reticulum. Methyl palmoxirate, a fatty acid analog, is reported to decrease circulating glucose levels by inhibiting fatty acid metabolism, thus forcing carbohydrate utilization. In the present study, we attempted to prevent streptozotocin diabetes-induced myocardial alterations in the rat. Using the isolated working heart preparation, we observed a depression of myocardial function in rats 6 weeks after the induction of diabetes, which was characterized by the inability of these hearts to develop left ventricular pressures and rates of ventricular contraction and relaxation as well as control hearts at higher left atrial filling pressures. Methyl palmoxirate treatment (25 mg kg-1 day-1 po daily) was unable to control diabetes-induced changes in plasma glucose, triglycerides, insulin, and total lipids. Also, the functional depression seen in diabetic rat hearts was present despite the treatment. However, depression of calcium uptake and elevation of long chain acyl carnitines seen in sarcoplasmic reticulum (SR) prepared from diabetic rat hearts could be prevented by the treatment. As triiodothyronine (T3) treatment has been shown to normalize depression of cardiac myosin ATPase in diabetic rats, we repeated the study using a combination of T3 (30 micrograms kg-1 day-1 sc daily) and methyl palmoxirate. While diabetic rats treated with T3 alone did not show significant improvement of myocardial function when compared with untreated diabetics, the function of those treated with both T3 and methyl palmoxirate was not significantly different from that in control rat hearts.(ABSTRACT TRUNCATED AT 250 WORDS)