Journal of Cardiothoracic-Renal Research

Rapid progression and recovery of hypertrophic obstructive cardiomyopathy during tacrolimus therapy

Duncan W. Motherwell, Adrian J.B. Brady — 2006-09-01

A 29-year-old man was being screened for a kidney transplant, following a diagnosis of end stage renal failure (urea 33.5mmol/l and creatinine 739μmol/l) presumed secondary to hypertension. He was noted to be hypertensive (BP of 170/100mmHg), on atenolol 25mg BD, and had a harsh ejection systolic murmur on examination. Echocardiography confirmed a diagnosis of hypertrophic cardiomyopathy (HCM) with asymmetrical left ventricular hypertrophy and a septal thickness of 20mm. The peak left ventricular outflow tract (LVOT) gradient was 60mmHg, and there was systolic anterior motion of the mitral valve. A subsequent 24h ECG revealed no ventricular arrhythmia and he managed 12min on a standard Bruce protocol exercise test with no significant ECG changes. Family screening was negative.

In vitro stem cell differentiation into cardiomyocytes: Part 1. Culture medium and growth factors

2006-09-01

Summary: Recent developments in the field of regenerative stem cell therapy for ischaemic heart disease have lead to an explosion in the clinical trial realm. At present no consensus exists regarding, amongst others, the optimal cell type as well as the underlying mechanism of action for any clinical improvement observed. As de novo reconstitution of myocardial tissue from multipotent stem cells is one of the working theories, the transdifferentiation potential of cellular populations under investigation into cardiomyocyte lineage phenotypes must ideally be assessed in preclinical bench work. Culture medium composition and a variety of growth factors are crucial determinants in this process. We discuss all relevant data acquired from in vitro work.

In vitro stem cell differentiation into cardiomyocytes: Part 2: Chemicals, extracellular matrix, physical stimuli and coculture assays

2006-09-01

Summary: Encouraged by the initial in vivo and clinical data on cardiac stem cell transplantation, the number of conducted clinical studies has increased exponentially. Pre-transplantation differentiation may provide, beyond proof of principal, more efficient cellular repopulation. This review concerns parameters implicated in transdifferentiation in vitro, besides cell medium composition and cytokines/growth factors. These include various chemicals, extracellular matrix cues, coculture assays and physical stimuli. Identification of all determinants in this process and possible interactions will augment in developing efficient protocols for targeted stem cell differentiation towards the cardiomyocyte lineage prior to transplantation.

Increased ERK activation and decreased MKP-1 expression in human myocardium with congestive heart failure

Yafeng Dong, Daqing Gao, Lei Chen, Ruxian Lin, John V. Conte, Chiming Wei — 2006-09-01

Summary: Mitogen-activated protein kinase (MAPK), also known as the extracellular signal regulated protein kinase (ERK), is a member of a family of serine/threonine kinases which are activated by various growth factors. To date, the activity of ERK and the nuclear dual-specificity tyrosine/threonine protein phosphatase MKP-1, a principal inactivating phosphatase of ERK1/ERK2 in many cell types, in human myocardium with congestive heart failure (CHF) remain undefined. Therefore, the current study was designed to investigate ERK and MKP-1 expression in CHF patients. Cardiac tissue from normal subjects (n=5) and end-stage CHF patients (n=5) were obtained during cardiac transplantation. ERK and MKP-1 expression were determined by immunohistochemical staining (IHCS). The staining score (0–4) and positive staining area (0–100%) were determined. Both ERK and MKP-1 were expressed in nuclear and perinuclear regions of cardiomyocytes. In CHF patients, ERK phosphorylation IHCS score and positive staining area were significantly increased in right atrium (RA), left atrium (LA), right ventricle (RV), and left ventricle (LV) compared with normal subject RA, LA, and RV (normal LV tissue was not available). In contrast, MKP-1 IHCS score and positive staining area were significantly decreased in CHF patients RA, LA, RV, and LV myocardium compared with normal subjects. The cardiomyocyte diameter determined by BioQuant system was significantly increased in CHF myocardium compared with normal subjects. These studies suggest that activation of ERK and inhibition of MKP-1 may play a significant pathophysiological role in progression of cardiac hypertrophy and congestive heart failure.

Is there a role for free radicals in the systemic inflammatory reaction?

Maqsood M. Elahi, Bashir M. Matata — 2006-09-01

Summary: This communication provides an insight that there is a differential response to stress by blood, which may directly reflect upon the induction of a proinflammatory state, with the goal of defining the sequence of oxido-inflammatory events that occur during extracorporeal circulation (ECC). In particular, we discussed if oxidative stress per se is one of the earliest pathophysiological events that occurs in ECC even before the inflammatory process sets in. The mechanism might involve the early activation of neutrophils, the most likely source of free radicals during the initial stages of ECC. However, the early increase in the oxidative stress (formation of 3-nitrotyrosine and lipid peroxidation) even before the initiation of ECC at a time when neutrophils are not yet to be activated, may suggest the existence of other factors responsible for the early oxidative stress.

Angiotensin II-mediated apoptosis on human vascular smooth muscle cells

Hong Song, Daqing Gao, Lei Chen, Koichi Seta, Joseph S. McLaughlin, Chiming Wei — 2006-09-01

Summary: While previous studies demonstrated that angiotensin II is a potent vasoconstrictor and mitogenic factor, the effect of angiotensin II on apoptosis in vascular smooth muscle cells remain controversial. Therefore, the current study was designed to investigate the action of angiotensin II on apoptosis in human vascular smooth muscle cells. Human saphenous vein was obtained from coronary artery bypass surgery (n=6) and was minced and incubated in the special tissue culture system in the absence or presence of angiotensin II (10−7M) for 24h. These studies were repeated with co-incubation of losartan (AT-1 receptor antagonist, 10−6M) or PD-123319 (AT-2 receptor antagonist, 10−6M). To detect the in situ DNA fragmentation, TUNEL staining was performed. TUNEL staining demonstrated that angiotensin II increased apoptosis in human vascular smooth muscle cells. This action of angiotensin II was enhanced by losartan and attenuated by PD-123319. Furthermore, co-incubation with both losartan and PD-123319 significantly reduced apoptosis levels. In conclusion, these data demonstrated that angiotensin II has potent apoptotic effect in human vascular smooth muscle cells through both AT-1 and AT-2 receptors. Furthermore, angiotensin II through AT-2 receptor has more potent apoptotic action in human vascular smooth muscle cells. This study indicated that angiotensin II plays an important role in the processes of apoptosis via angiotensin II receptors in human vascular smooth muscle cells.

DNA damage and repair in human spinal cord following ischemia–reperfusion injury

2006-09-01

Summary: Spinal cord ischemia leading to paraplegia is a rare, sporadic, but devastating complication of surgery on the thoracoabdominal aorta. Our patient, a 69-year-old man, succumbed from a stroke on the third hospital day following surgical repair. He also had bilateral leg paralysis. At autopsy done 4h after death there were remarkable differences between the thoracic or normally perfused spinal cord and the lumbar potentially ischemia or reperfused spinal cord. The measurements of injury were small in the thoracic spinal cord and extensive in the lumbar spinal cord DNA D/R. Apoptotic cell numbers and apoptosis-related enzymes such as caspase-3 were increased in the lumbar spinal cord. These findings duplicated those we reported in the rabbit subjected to 30min of aortic occlusion and reperfusion injury. This is the first report in humans documenting DNA oxidative injury and apoptosis in ischemia–reperfusion injury of the spinal cord.

DNA damage and mismatch repair pathway in lung ischemia and reperfusion injury

2006-09-01

Summary: Background: Oxidative damage induced by reperfusion is responsible for increased morbidity and mortality following lung transplantation. A stable and deleterious DNA adduct, 8-oxogaunine (8-oxoG) results due to oxidative DNA damage. Mut-Y homologue (MYH) is a DNA repair enzyme promoting DNA reconstruction through the mismatch repair pathway to repair 8-oxoG lesion. We investigated the role of DNA mismatch repair pathway mediated by MYH in the setting of lung ischemia and reperfusion.Methods: Left lungs of the adult Sprague Dawley rats were subjected to 1h ischemia and 2 and 4h reperfusion. Un-operated animals served as controls. Quantification of 8-oxoG was performed using immunohistochemistry (IHC) and MYH was analyzed by Western blot. Apoptosis was assessed by caspase-3 levels.Results: Indices of inflammation and permeability were raised in both reperfusion groups. There was significant increase in DNA damage as reflected by positive 8-oxoG staining in 2h (22% increase) and 4h reperfusion (31% increase) compared to control (p<0.01). MYH staining by IHC was significantly reduced in 2 and 4h reperfusion compared to controls (p<0.05). Down regulation of DNA repair enzyme (MYH) was mirrored functionally by decreased protein levels in lung tissues subjected to reperfusion compared to controls. Increasing apoptosis was detected in the reperfusion groups as reflected by caspase-3 IHC and protein estimation by Western blot.Conclusion: Reperfusion leads to increased DNA damage and down regulation of DNA mismatch repair pathway in a model of ischemia and reperfusion in lungs. Gene therapy targeted at this pathway may prove an attractive therapeutic intervention to reduce reperfusion injury in lung transplantation.

Quantitative tissue hemoglobin oxygen saturation measurement in decompensated heart failure

2006-09-01

Summary: Background: This study determined if patients with acutely decompensated heart failure (HF) have abnormal regional tissue oxygenation when compared with stable outpatients and if values change with treatment.Methods: We prospectively used differential absorption spectroscopy to measure the subcutaneous tissue hemoglobin oxygen saturation (StO2), both at presentation and discharge in patients admitted with acutely decompensated systolic HF. These values were compared with a convenience sample of stable HF patients to determine if admitted patients have different StO2 values that, after undergoing inpatient treatment, approach those of the stable HF population.Results: Stable outpatients (n=45) had significantly higher StO2 values than inpatients (n=20), both at admission (p<0.006) and discharge (p<0.0002). There were no significant differences in the discharge and admission StO2 values. Four inpatients died of HF related causes and 6 were readmitted with HF within 6 months.Conclusions: Patients with acutely decompensated HF have significantly decreased tissue oxygenation that is lower than those found in the stable outpatient population and does not respond to inpatient treatment. Measurement of subcutaneous tissue hemoglobin oxygen saturation may enable clinicians to diagnose and treat HF more effectively.

Instructions to authors

2006-09-01

Contents continued

2006-09-01

OBC - Contents

2006-09-01