Reduction In Cardiac Function Research Articles

Warm fish with cold hearts: thermal plasticity of excitation–contraction coupling in bluefin tuna

Bluefin tuna have a unique physiology. Elevated metabolic rates coupled with heat exchangers enable bluefin tunas to conserve heat in their locomotory muscle, viscera, eyes and brain, yet their hearts operate at ambient water temperature. This arrangement of a warm fish with a cold heart is unique among vertebrates and can result in a reduction in cardiac function in the cold despite the elevated metabolic demands of endothermic tissues. In this study, we used laser scanning confocal microscopy and electron microscopy to investigate how acute and chronic temperature change affects tuna cardiac function. We examined the temporal and spatial properties of the intracellular Ca2+ transient (Δ[Ca2+]i) in Pacific bluefin tuna (Thunnus orientalis) ventricular myocytes at the acclimation temperatures of 14°C and 24°C and at a common test temperature of 19°C. Acute (less than 5 min) warming and cooling accelerated and slowed the kinetics of Δ[Ca2+]i, indicating that temperature change limits cardiac myocyte performance. Importantly, we show that thermal acclimation offered partial compensation for these direct effects of temperature. Prolonged cold exposure (more than four weeks) increased the amplitude and kinetics of Δ[Ca2+]i by increasing intracellular Ca2+ cycling through the sarcoplasmic reticulum (SR). These functional findings are supported by electron microscopy, which revealed a greater volume fraction of ventricular SR in cold-acclimated tuna myocytes. The results indicate that SR function is crucial to the performance of the bluefin tuna heart in the cold. We suggest that SR Ca2+ cycling is the malleable unit of cellular Ca2+ flux, offering a mechanism for thermal plasticity in fish hearts. These findings have implications beyond endothermic fish and may help to delineate the key steps required to protect vertebrate cardiac function in the cold.

Elevation of Serum NT-Pro BNP Correlates with Asymptomatic Cardiac Dysfunction Induced by Doxorubicin.

Abstract Background: Cardiac dysfunction is one of the major limitations of anthracycline treatment in cancer patients. Current reliable investigation to detect early cardiac damage from anthracycline is not available. There are several serum cardiac markers useful in other types of cardiomyopathy including NT-pro BNP, Troponin-T, and CK-MB. We chose to investigate potential application of these serum biomarkers in the cancer patients receiving anthracycline.Patients and methods: We prospectively collected data from a cohort of 52 female breast cancer patients who receiving doxorubicin and cyclophosphamide (AC) regimen every 3 weeks for 4 cycles for preoperative or postoperative adjuvant treatment. Cardiac function evaluations by echocardiography were done at baseline and post 4th cycle chemotherapy. Patients' blood samplings were serially measured for cardiac biomarkers at baseline, after 1st cycle, and after 4th cycle chemotherapy.Results: All patients were in good performance status with ECOG scale 0-1.The mean cumulative dose of doxorubicin in this study was 236.69 mg/m2. There was no symptomatic heart failure detected during study period. However, there were significant asymptomatic reductions of left ventricular ejection fraction (LVEF) from 70.73 ± 5.97% at baseline to 66.96 ± 5.48% (p<0.001). The severities of LVEF declination were 17.4% in grade1 and 3.8% in grade 2 by clinical toxicity criteria of NCI version 2. We found significant elevation of serum NT-proBNP (p = 0.044) following the first dose of chemotherapy when compared the measurements in patients who had reduction of LVEF to those with normal LVEF. Measurement of serum Troponin-T and CK-MB showed no significant correlation with changes in LVEF. Generalized-estimating-equations correlation analysis demonstrated that the reduction of fractional shortening (FS) was significantly associated with the elevation NT-pro BNP (r = -0.016, p = 0.014). At cutoff level 45 pg/mL, serum NT-proBNP had 100% sensitivity and 66.67% specificity for the detection of cardiotoxicity in patients under 50 year-old.Conclusion: Asymptomatic reductions in cardiac function are common in patients treated with doxorubicin. NT-pro BNP may serve as a potential convenient serum biomarker for early detection of cardiotoxicity induced by anthracycline. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4003.

The changes in β-adrenoceptor-mediated cardiac function in experimental hypothyroidism: the possible contribution of cardiac β3-adrenoceptors

Thyroid hormone deficiency has been reported to decrease expression and function of both beta(1)- and beta(2)-adrenoceptor in different tissues including heart. The purpose of this study was to examine the possible contribution of beta(3)-adrenoceptors to cardiac dysfunction in hypothyroidism. In addition, effect of this pathology on beta(1)- and beta(2)-adrenoceptor was investigated. Hypothyroidism was induced by adding methimazole (300 mg/l) to drinking water of rats for 8 weeks. Cardiac hemodynamic parameters were measured in anesthetised rats in vivo. Responses to beta-adrenoceptor agonists were examined in rat papillary muscle in vitro. We also studied the effect of hypotyroidism on mRNA expression of beta-adrenoceptors, Gialpha, GRK, and eNOS in rat heart. All of the hemodynamic parameters (systolic, diastolic and mean arterial pressure, left ventricular pressure, heart rate, +dp/dt, and -dp/dt) were significantly reduced by the methimazole treatment. The negative inotropic effect elicited by BRL 37344 (a beta(3)-adrenoceptor preferential agonist) and positive inotropic effects produced by isoprenaline and noradrenaline, respectively, were significantly decreased in papillary muscle of hypothyroid rats as compared to those of controls. On the other hand, hypothyroidism resulted in increased cardiac beta(2)- and beta(3)-adrenoceptor, Gialpha(2), Gialpha(3), GRK3, and eNOS mRNA expressions. However, beta(1)-adrenoceptor and GRK2 mRNA expressions were not changed significantly in this pathology. These results show that mRNA expression of beta(3)-adrenoceptors as well as the signalling pathway components mediated through beta(3)-adrenoceptors are significantly increased in hypothyroid rat heart. Since we could not correlate these alternates with the decreased negative inotropic response mediated by this receptor subtype, it is not clear whether these changes are important for hypothyroid induced reduction in cardiac function.

Reduction in fragile X related 1 protein causes cardiomyopathy and muscular dystrophy in zebrafish

Lack of the FMR1 gene product causes fragile X syndrome, the commonest inherited cause of mental impairment. We know little of the roles that fragile X related (FXR) gene family members (FMR1, FXR2 and FXR1) play during embryonic development. Although all are expressed in the brain and testis, FXR1 is the principal member found in striated and cardiac muscle. The Fxr1 knockout mice display a striated muscle phenotype but it is not known why they die shortly after birth; however, a cardiac cause is possible. The zebrafish is an ideal model to investigate the role of fxr1 during development of the heart. We have carried out morpholino knockdown of fxr1 and have demonstrated abnormalities of striated muscle development and abnormal development of the zebrafish heart, including failure of looping and snapping of the atrium from its venous pole. In addition, we have measured cardiac function using high-speed video microscopy and demonstrated a significant reduction in cardiac function. This cardiac phenotype has not been previously described and suggests that fxr1 is essential for normal cardiac form and function.

Thyroid hormone analogue 3,5‐diiodothyropropionic acid (DITPA) promotes healthy vasculature in the adult myocardium independent of thyroid metabolic effects

Patients with hypothyroidism are at higher risk for coronary vascular disease. Patients with diabetes and related vascular complications also have an increased incidence of low thyroid function. While thyroid hormones (THs) may be key regulators of healthy vasculature, potential undesirable side effects hinder their use in the treatment of vascular disorders. TH analogs such as DITPA may provide a safer treatment option. We hypothesized that the vascular growth promoting effects of DITPA can be obtained with little or no effect on cardiac function and metabolism. Thyroidectomized Sprague Dawley rats were given slow‐release pellets with either thyroxine (T4, 2.7‐mg or 5.2‐mg) or DITPA (80‐mg) for 6 weeks and compared to placebo. Hypothyroidism led to reductions in cardiac function, heart mass, body temperature, and myocardial arterioles. High dose T4 prevented arteriolar loss and development of hypothyroidism. Low dose T4 partially prevented the reduction in cardiac function but had minimal effects on arteriolar loss. In contrast, DITPA treatment prevented myocardial arteriolar loss but not progression of hypothyroid‐induced changes in cardiac function and metabolism. Results suggested that DITPA can promote healthy vasculature independently from its thyroid related metabolic effects. Drugs in this class may provide new therapeutic options for patients with vascular disease.Grant Funding SourceP20RR017662 from the National Center for Research Resources

Thyroid hormone analog 3,5-diiodothyropropionic acid promotes healthy vasculature in the adult myocardium independent of thyroid effects on cardiac function

Patients with hypothyroidism are at a higher risk for coronary vascular disease. Patients with diabetes and related vascular complications also have an increased incidence of low thyroid function. While thyroid hormones (THs) may be key regulators of a healthy vasculature, potential undesirable side effects hinder their use in the treatment of vascular disorders. TH analogs such as 3,5-diiodothyropropionic acid (DITPA) may provide a safer treatment option. However, the relative potency of DITPA on vascular growth, cardiac function, and metabolism is poorly understood. We hypothesized that the vascular growth-promoting effects of DITPA can be obtained with a minimum effect on cardiac function. Thyroidectomized Sprague-Dawley rats were given slow-release pellets with either thyroxine (T4, 2.7 or 5.2 mg) or DITPA (80 mg) for 6 wk and were compared with placebo. Heart mass, body mass, body temperature, serum THs, cardiac function (echocardiograms and hemodynamics), and myocardial arteriolar density were determined. Hypothyroidism led to reductions in cardiac function, heart mass, body temperature, and myocardial arterioles. High-dose T4 prevented arteriolar loss and the development of hypothyroidism. Low-dose T4 partially prevented the reduction in cardiac function but had minimal effects on arteriolar loss. In contrast, DITPA treatment prevented myocardial arteriolar loss but not the progression of hypothyroid-induced changes in cardiac function. The results suggested that DITPA can promote a healthy vasculature independently from its thyroid-related metabolic effects. Drugs in this class may provide new therapeutic options for patients with vascular disease.

Novel antioxidant therapeutic strategies for cardiovascular dysfunction associated with ageing

Overproduction of free radicals in ageing tissues induces nitro-oxidative stress, which has been implicated in the functional decline of the cardiovascular system at old age. Toxic oxidants like hydrogen peroxide or peroxynitrite damage proteins and DNA and activate several pathways causing tissue injury, including the poly(ADP-ribose) polymerase (PARP) pathway. First, we tested whether the inhibition of PARP can improve endothelial dysfunction induced by hydrogen peroxide in an in vitro model of vascular oxidative stress. In turn, our main aim was to investigate the effects of acute PARP inhibition and catalytic peroxynitrite decomposition on ageing-associated cardiac and endothelial dysfunction. In vascular reactivity measurements on isolated rat aortic rings, we investigated the endothelium-dependent and -independent vasorelaxation by using acetylcholine and sodium nitroprusside. Endothelial dysfunction was induced by hydrogen peroxide. In the treatment group, rings were preincubated with a PARP-inhibitor. In the in vivo rat model of ageing-associated cardiovascular dysfunction, young and ageing rats were treated with a single dose of PARP-inhibitor, or with the peroxynitrite decomposition catalyst FP15. Using a pressure-conductance catheter, left ventricular pressure-volume analysis was performed to study cardiac function. Endothelium-dependent and -independent relaxation of aortic rings were investigated. Immunohistochemical analysis was performed to study the changes on the cellular and tissue level. In our in vitro model, hydrogen peroxide caused a dose-dependent impairment of endothelium-dependent vasorelaxation of aortic rings which was significantly improved by PARP-inhibition. Ageing rats showed a marked reduction of cardiac function and loss of endothelium-dependent relaxant responsiveness of aortic rings. Both acute PARP-inhibition and FP15-treatment improved cardiac performance and endothelial function. Immunohistochemistry confirmed enhanced nitro-oxidative stress and PARP-activation in ageing rats, which were reversed in the treatment groups. Our results demonstrate the importance of endogenous peroxynitrite-overproduction and the activation of the PARP pathway in the age-related functional decline of the cardiovascular system. Catalytic peroxynitrite decomposition and PARP-inhibition may represent novel antioxidant therapeutic utilities to improve ageing-associated cardiovascular dysfunction.

Clinical Significance of Cardiac Damage and Changes in Function after Exercise

Acute bouts of ultraendurance exercise may result in the appearance of biomarkers of cardiac cell damage and a transient reduction in left ventricular function. The clinical significance of these changes is not fully understood. There seems to be two competing issues to be resolved. First, could prolonged endurance exercise produce a degree of cardiac stress and/or damage that results, during the short or long term, in deleterious consequences for cardiac health. Second, there is a clear need to educate those responsible for the medical care of endurance athletes about the possibility of a transient reduction in cardiac function and the appearance of cTnT/cTnI after an exercise. Minor elevations in cardiac troponins are commonplace after an endurance exercise in elite and recreational athletes and may occur alongside exercise-associated collapse. Misdiagnosis of myocardial injury and subsequent mismanagement can be unnecessarily expensive and psychologically damaging to the athlete. Diagnosis of myocardial injury after prolonged exercise should be made on the basis of all available information and not blood tests alone. The clinical significance of chronic exposure to endurance exercise is unknown. The development of myocardial fibrosis has been suggested as a long-term outcome to chronic exposure to repetitive bouts of endurance exercise and has been linked to an exercise-induced inflammatory process observed in an animal model. This hypothesis is supported by a limited number of studies reporting postmortem studies in athletes and an increased prevalence of complex arrhythmia in veteran athletes. Care is warranted in promoting this hypothesis without further detailed work, given the unequivocal link between exercise and mortality and morbidity. It would seem erroneous, however, to assume that a linear relationship exists between exercise volume and cardiac health.

Myocardial Strain Analysis Following the Western States 100-Mile Mountain Race

Transient reductions in cardiac function have been documented following prolonged strenuous exercise lasting between two and twelve hours. Less information exists regarding the cardiac consequences of ultra-endurance events lasting in excess of 20 hours where exercise intensity is reduced as duration is extended. Ultra-endurance events may also alter blood volume and distribution complicating the assessment of post-exercise cardiac function. Therefore, the use of less load-dependent indices of cardiac function such as speckle-tracking derived myocardial displacements, velocities and strain measurements are likely to be informative. PURPOSE: The aim of this investigation was to examine indices of systolic and diastolic function following the Western States 100-mile endurance race (WSER) using 2-D echocardiography with speckle-tracking analysis. METHODS: 32 individuals participating in the WSER completed two echocardiographic assessments: 1) before the race; 2) immediately post-race. Cardiac function was assessed in the apical 4-chamber and short axis views. Offline speckle-tracking analysis was conducted using EchoPac software (General Electric). Measurements of myocardial displacement, velocity, and peak strain in systole, early diastole and during atrial contraction were recorded. RESULTS: 12 participants completed the race and had echocardiographic images that were suitable for analysis. The average race finishing time was 25.5 ± 0.3 hours. Basal radial (6.6 ± 2.6 mm vs. 3.9 ± 1.7 mm) and longitudinal (septal: 19.1 ± 2.7 mm vs. 13.7 ± 3.1 mm, lateral: 15.1 ± 3.6 mm vs. 10.2 ± 3.6 mm) displacements were significantly reduced pre vs. post race (p<0.05). Longitudinal myocardial velocity during early diastole in both the basal septum (-10.3 ± 1.1 cm·s−1 vs. −9.0 ± 1.8 cm·s−1) and basal lateral wall (-9.2 ± 1.5 cm·s−1 vs. -6.8 ± 2.2 cm·s−1) were also reduced following the race (p<0.05). Peak radial basal strain (41.7 ± 10.2 % vs. 29.9 ± 15.8 %) as well as basal (-17.7 ± 1.9 % vs. -11.9 ± 3.8 %) and apical (-20.1 ± 4.2% vs. -15.0 ± 3.2%) circumferential strain were diminished post race (p<0.05). CONCLUSION: The present findings suggest that novel measures of systolic and diastolic function were reduced across all planes of LV motion following a 100-mile mountain run.

Hypothyroidism-induced myocardial damage and heart failure: an overlooked entity

Hypothyroid state may induce cardiac muscle impairment such as diastolic dysfunction and abnormal relaxation time. Advanced heart failure in hypothyroid patients has been described only in severe symptomatic cases, mostly during myxedematous coma. We describe an unusual case of asymptomatic patient with hypothyroidism who presented with severely reduced cardiac function with elevated cardiac enzymes reflecting significant myocardial injury. Comprehensive evaluation for heart failure was suggestive only for long-standing untreated hypothyroidism. Endomyocadial biopsy demonstrated unique histological findings of mucopolysaccharide accumulation attributed to hypothyroid state. Asymptomatic hypothyroidism may cause severe reduction in cardiac function accompanied with elevated cardiac enzymes. To our knowledge, this is the first description of human myocardial biopsy revealing mucopolysaccharide accumulation attributed to hypothyroid state.

Sarcalumenin plays a critical role in age‐dependent reduction in cardiac function and SERCA2a activity

Sarcalumenin (SAR), a Ca2+‐binding protein located in the longitudinal sarcoplasmic reticulum (SR), interacts with cardiac SR Ca2+‐ATPase(SERCA2a) to modulate its activity and expression. We have demonstrated that SAR deficiency resulted in mild cardiac dysfunction in young mice (JBC 2005). Since it is well known that SERCA2a activity is decreased with aging, we examined the effects of aging on cardiac function in SAR knockout mice (SAR‐KO). Cardiac function assessed by in vivo hemodynamic study and the expression levels of SERCA2a protein were progressively decreased in senescent SARKO (n=13) when compared with senescent wild‐type (WT) (n=12) or young SARKO (4month old, n=12). LV dp/dtmax (mmHg/s) was 3897 ± 134, 7091 ± 657, and 6836 ± 298 in senescent SARKO, senescent WT, and young SARKO, respectively. The expression levels of SERCA2a protein (% of young WT) were 28 ± 8, 84 ± 17, and 44 ± 17 in senescent SARKO, senescent WT, and young SARKO, respectively. Interestingly, downregulation of SAR preceded downregulation of SERCA in aging cardiac muscles of wild‐type mice. These findings indicated that SAR plays a critical role in age‐dependent reduction in cardiac function and SR Ca2+ reuptake.

Molecular adsorbents recirculating system (MARS) and the failing liver: A negative editorial for a positive trial?

We read with interest the article by Hassanein et al.1 and the editorial by Ferenci and Kramer2 and found the editorial too negative for a positive trial. A frequent problem in the assessment of artificial liver support systems (ALSSs) is that they are unconsciously compared to the artificial renal support systems (ARSSs). This has no justification. First, although we are in the golden era of ARSS, the molecular adsorbents recirculating system (MARS) had been introduced only a few years ago. We still do not know the best indication, time of application, and treatment schedule for this device. Second, whereas chronic liver failure (CLIF) is an extremely complex syndrome, chronic renal failure (CRF) is the result of a single defect, an intense reduction in glomerular filtration rate leading to retention of water-soluble substances that are easily removed with current technology. Finally, we have excellent markers of CRF that facilitate indication and dosing of ARSS. However, this is not the case for CLIF. CLIF involves not just impaired liver excretory function but also reduced hepatic synthetic function. Moreover, most problems associated with CLIF are related to a circulatory dysfunction due to splanchnic arterial vasodilation and reduction in cardiac function.3 There is marked stimulation of the renin-angiotensin and sympathetic nervous systems and vasopressin, which maintain arterial pressure by producing vasoconstriction in extrasplanchnic organs.4 Renal vasoconstriction causes hepatorenal syndrome. Cerebral vasoconstriction may contribute to cerebral dysfunction.5, 6 Relative adrenal insufficiency is also a common event in CLIF.7 Intrahepatic vasoconstriction leading to increase in portal pressure and decrease in hepatic blood flow has been reported in CLIF.3, 8 Finally, the increased sympathetic activity impairs intestinal motility and induces bacterial overgrowth, translocation of bacterial products, and chronic inflammatory reaction.9 The observation that parameters estimating systemic hemodynamics are better markers of CLIF severity than those estimating hepatic function is a clear indication of the complexity of the syndrome. Which parameters should then be used to evaluate ALSS? Survival is important. In fact, one of the arguments given by Ferenci and Kramer to suggest a lack of benefit of MARS was the similar mortality observed by Hassanein et al. in the MARS and standard medical therapy (SMT) groups. However, the design of the trial was to assess the effect of MARS on hepatic encephalopathy and not on survival. It would have been a miracle to get differences in survival after a mean of 2.7 dialysis sessions in the MARS group. A second approach is to assess the effect of MARS on complications associated with CLIF, and here we have evidence that we are dealing with a potentially effective device. Despite the methodological criticisms raised by Ferenci and Kramer, the study by Hassanein et al. supports a significant benefit of MARS on encephalopathy. There were more patients responding in the MARS group and they improved faster. Arguments given by Ferenci and Kramer to negate a benefit of MARS were weak and could be used in the opposite sense. For example, they consider that the longer period on SMT prior to randomization in the MARS group (5.6 versus 2.6 days) could partially account for the better response of encephalopathy in this group. However, because all patients had grade III-IV encephalopathy at randomization, an alternative possibility is that there were more patients with encephalopathy refractory to SMT in the MARS group. MARS treatment is also associated with clear improvement in cardiovascular function (increase in arterial pressure and vascular resistance and suppression of renin, noradrenaline, and vasopressin).10-12 Finally, MARS removes water-soluble substances and can replace renal function in severe hepatorenal syndrome. In summary, treatment of CLIF is more complex than treatment of CRF. In addition to extracorporeal devices to replace the hepatic excretory function, it is important to treat the impaired synthetic function and multiorgan failure associated with CLIF. We need more research on CLIF to identify potential targets for treatment. MARS, in addition to being a potentially useful device, could be an important tool to explore the pathogenesis of CLIF. Vicente Arroyo*, Javier Fernandez*, Antoni Mas*, Angels Escorsell*, * Liver Unit, Hospital Clinic, University of Barcelona, Spain.

β-adrenergic receptor desensitisation – a mechanism for post-exercise reductions in cardiac function

β-adrenergic receptor desensitisation – a mechanism for post-exercise reductions in cardiac function

Transcatheter cryoablation with 3-D mapping of an atrial ectopic tachycardia in a pediatric patient with tachycardia induced heart failure

Atrial ectopic tachycardias (AET) are often resistant to medical management and can lead to a significant reduction in cardiac function. Transcatheter cryoablation, a definitive therapy, to our knowledge has yet to be described in the pediatric population. A three-year-old male presented with AET induced heart failure which persisted despite medical management. Management was complicated by worsening heart failure and propylene glycol intoxication. He underwent transcatheter cryoablation using a 3-D navigation system with an initially successful elimination of the arrhythmia. After a late recurrence (15 months) of the AET he underwent epicardial transcatheter ablation using cryotherapy with successful elimination of the arrhythmia.

The Effects of Endurance Exercise TVaining on Cardiac Function in VLCAD -/- and LCAD -/- Mice.

Fatty acid oxidation is a crucial pathway for energy production in the heart during strenuous activity. Work in our lab has shown that exercise causes a decline in skeletal muscle function in very-long-chain acyl CoA deficient mice. The affect on cardiac function is not known. PURPOSE: The purpose was to examine the effects of endurance training on cardiac function in long-chain acyl-CoA dehy drogenase(L CAD -/-) and very-long-chain acyl-CoA dehydrogenase (VLCAD -/-) deficient mice. METHODS: Male mice were used and grouped as follows: 1) VLCAD -/-, non-exercised (n=8); 2)VLCAD -/-, exercised (n=6); 3) LCAD -/-, non-exercised (n=12); 4) LCAD -/-, exercised (n=6). Mice were trained by forced running on a treadmill for eight weeks. Twenty-four hours after the final exercise bout, the mice were anesthetized using 40 mg.Kg-1 sodium pentobarbital (i.p.) for determination of cardiac dimensions, fractional shortening, and ejection fraction using transthorasic echocardiography. Data were collected prior to and after injection with 20ng.g-1 isoproterenol and were analyzed using ANOVA of data in a 2 (training) × 2 (stress) factorial design. All comparisons were made at the 0.05 level of significance. RESULTS: Trained mice weighed significantly (p < 0.05) less than untrained mice. The weight for LCAD -/- mice tended to be higher than that of VLCAD -/- mice but not significantly. Trained mice and LCAD -/- mice had significantly (p < 0.05) larger heart weights. Training did not significantly affect cardiac dimensions. LCAD -/- mice had higher fractional shortening (FS) and a higher ejection fraction (EF). Isoproterenol improved FS% and EF with trained VLCAD -/- mice displaying a greater response. CONCLUSION: The results indicate that VLCAD deficiency caused a greater reduction in cardiac function but that the response of VLCAD -/- mice to exercise training was greater than that observed in LCAD -/- mice.

Brief Ischemia-Reperfusion Performed After Prolonged Ischemia (Ischemic Postconditioning) Can Terminate Reperfusion Arrhythmias With no Reduction of Cardiac Function in Rats

Recently, it has been reported that ischemic postconditioning, a brief episode of ischemia-reperfusion performed after prolonged ischemia, can reduce ischemic myocardial injury. However, the effects of ischemic postconditioning on ischemia/reperfusion injury remain unclear. We investigated the effects of brief ischemia-reperfusion before (ischemic preconditioning) and after (ischemic postconditioning) prolonged ischemia on myocardial ischemia/reperfusion injury, especially reperfusion arrhythmias. Adult male Sprague-Dawley rats weighing about 400-500 g were used. The isolated heart was perfused using a working heart method (Krebs-Henseleit bicarbonate buffer). In the control group, after stabilization, diastolic global ischemia for 15 minutes was produced by a one-way ball valve with electrical pacing (330 bpm, 2.0 V). After ischemia, the heart was reperfused for 20 minutes. In the preconditioning and postconditioning groups, 5-minute global ischemia was produced before and after ischemia for 15 minutes with a 1 minute interval. An electrocardiogram was performed and left ventricular pressure (LVP, +dP/dt, -dP/dt) and CK activity in coronary effluent were measured during the protocol. Ischemic preconditioning did not affect the incidence or duration of reperfusion ventricular arrhythmias. Ischemic postconditioning could terminate reperfusion ventricular arrhythmias completely and reduced the duration of reperfusion ventricular arrhythmias significantly (P < 0.01). Furthermore, the recovery ratio of +dP/dt at 20 minutes after initial reperfusion was significantly higher in the postconditioning group than in the other groups. These results suggest that ischemic postconditioning can terminate reperfusion arrhythmias with no reduction of cardiac function, and may be useful for correcting stunned myocardium.

Can diesel particulate matter directly activate cardiac mast cells?

Rats subjected to inhaled diesel exhaust particles (DEP) developed a significant reduction in cardiac function. Histological examination of their hearts demonstrated a significant increase in cardiac mast cell (CMC) density coupled with increased matrix metalloproteinase activity. Pretreatment with a mast cell stabilizing compound prevented these effects on cardiac function indicating that they were mast cell-mediated. However, it was not clear if this mast cell activation was the result of a direct interaction of DEP with CMCs. The purpose of this study was to determine if DEP can directly activate CMCs. CMCs were isolated from rats and exposed to DEP or the mast cell secretagogue 48/80. 48/80 treatment triggered a significant histamine release above that of controls (80.5% and 26.1% of total histamine, respectively). However, exposure to DEP did not result in histamine release above that seen in controls (26.8%). Retained histamine levels were comparable for the control and DEP-exposed cells, ~50 ng/ml. These findings indicate that the DEP effects on cardiac function are not due to a direct action of DEP on CMCs. However, given the ability of endothelin-1 (ET-1) to stimulate mast cell activation in the whole heart and peritoneal mast cells, a DEP-induced ET-1 release from the lungs and subsequent paracrine activation of CMCs represents a plausible mechanism. Support: AHA 0435298N (JDG), EPA RD-83195301-0 (GLB)

MgSO 4 prevents left ventricular dysfunction in an animal model of preeclampsia

We hypothesized that cardiac function would be reduced in a pregnant rat model of preeclampsia induced by L-NAME, a NOS inhibitor, and be reversed with magnesium sulfate prophylaxis. Female Sprague-Dawley rats were bred in-house. On gestational day 17, rats were anesthetized and osmotic minipumps were implanted to continuously deliver saline, L-NAME, or L-NAME and MgSO4. On gestational day 21, hearts were isolated and perfused in the working mode using Krebs Henseleit buffer. Pregnant rats treated with L-NAME displayed significant hypertension compared to the saline-treated controls (P < 0.05). Moreover, cardiac output and cardiac work were significantly reduced in the L-NAME-treated rats compared to controls (P < 0.05). In the L-NAME-treated rats given MgSO4, cardiac function remained normal. Cardiac function is depressed in an animal model of preeclampsia induced by L-NAME infusion. MgSO4 prevented the reduction in cardiac function and is clearly beneficial in preserving normal heart function in preeclampsia.

Cardiac Patch Constructed from Human Fibroblasts Attenuates Reduction in Cardiac Function after Acute Infarct

The current experiments used a scaffold-based, three-dimensional, human dermal fibroblast culture (3DFC) as a cardiac patch to stimulate revascularization and preserve left ventricular (LV) function of the infarcted LV in severe combined immunodeficient (SCID) mice. The 3DFC contains viable cells that secrete angiogenic growth factors and has been previously shown to stimulate angiogenesis. The hypothesis tested was that a 3DFC cardiac patch would attenuate a reduction in LV function of infarcted hearts. Five groups of mice were studied, including normal SCID mice (n = 13), normal SCID mice with 3DFC (n = 6), infarcted SCID mice (n = 6), infarcted mice with nonviable 3DFC (n = 6), and infarcted SCID mice with 3DFC (n = 6). An occlusion of a branch of the left anterior descending (LAD) coronary artery was performed by thermal ligation, and 3DFC was sized to the damaged area and implanted onto the epicardium at the site of tissue injury. Fourteen days postsurgery, LV mechanics were characterized with the Millar conductance catheter system (CCS). The data demonstrated that 3DFC-treated infarcted myocardium had significantly higher ejection fractions (EFs) compared with infarct-only mice (58.9 +/- 10.8 versus 31.0 +/- 5.8%, respectively; p < 0.05). Preload recruitable stroke work (PRSW) parameters were significantly higher in 3DFC-treated mice compared with infarct-only mice (64.6 +/- 11.9 versus 36.8 +/- 6.4 mmHg, respectively; p < 0.05). These results show that the 3DFC as a cardiac patch functioned to attenuate further loss of LV function accompanying acute myocardial infarct and that this may be related in part to myocardial revascularization.

DIASTOLIC PERFORMANCE AFTER PROLONGED EXERCISE

Dear Editor-in-Chief: We thank Dr. Kasikcioglu for his comments regarding our recent paper titled “Altered Cardiac Function and Minimal Cardiac Damage during Prolonged Exercise” (8). Within the paper we reported evidence of a reduction in cardiac function (both systolic and diastolic) concomitant with evidence of minimal cardiac damage, following prolonged exercise in a group of highly trained male triathletes. Dr. Kasikcioglu largely appears to agree with our findings. We do believe however, there are a number of points raised within the letter of Dr. Kasikcioglu that need to be addressed. Dr. Kasikcioglu suggests that few studies have demonstrated changes in diastolic function following prolonged exercise. Within the literature, however, there are numerous studies (3,4,5,6,7,9) demonstrating altered diastolic function following prolonged exercise, some of which demonstrate altered diastolic function in the absence of changes in systolic function (3,9). Dr. Kasikcioglu also makes recognition of the problems associated with the use of standard Doppler techniques in the assessment of diastolic function (load dependence, heart rate) with which we concur. Recent data from our laboratory employing Tissue Doppler Imaging (TDI) further support the notion of altered diastolic function following prolonged exercise. TDI is a novel, relatively load-independent ultrasound technique that may be used to assess cardiac function. Employing TDI, we have recently demonstrated altered diastolic function in the absence of changes in systolic function in a heterogeneous group of athletes following the London Marathon (unpublished findings), thus supporting earlier work employing standard Doppler techniques. Dr. Kasikcioglu suggests that the observed reduction in cardiac function following prolonged exercise is akin to “myocardial stunning.” Myocardial stunning has been widely observed within the clinical setting (2), however, its etiology is yet to be confirmed, and at present without further work we do not believe that myocardial stunning can be compared to exercise induced cardiac fatigue (EICF). Although myocardial stunning is preempted by a period of ischemia, at present the evidence does not support ischemia within the etiology of EICF. Within the available literature no study examining EICF has reported ECG evidence of ischemia preceding cardiac fatigue. In addition to ECG examination, recent work from Apple et al. (1), supported by unpublished data from our laboratory, demonstrates no evidence of ischemia immediately following a marathon using the newly developed ischemia modified albumin (IMA) assay. Further work is required to elucidate the mechanisms responsible for EICF; however, myocardial ischemia is presently not a strong candidate. Robert Shave Department of Sport Science, Brunel University, Uxbridge, United Kingdom Gregory Whyte Olympic Medical Institute, London, United Kingdom Keith George Research Institute for Sport and Exercise Science, John Moores University, Liverpool, United Kingdom