Cardiovascular (patho)physiology

Transient receptor potential channels of the ankyrin subtype-1 (TRPA1) are non-selective cation channels that show high permeability to calcium. Previous studies from our laboratory have demonstrated that TRPA1 ion channels are expressed in adult mouse ventricular cardiomyocytes (CMs) and are localized at the z-disk, costamere and intercalated disk. The functional significance of TRPA1 ion channels in the modulation of CM contractile function have not been explored. To identify the extent to which TRPA1 ion channels are involved in modulating CM contractile function and elucidate the cellular mechanism of action. Freshly isolated CMs were obtained from murine heart and loaded with Fura-2 AM. Simultaneous measurement of intracellular free Ca(2+) concentration ([Ca(2+)]i) and contractility was performed in individual CMs paced at 0.3 Hz. Our findings demonstrate that TRPA1 stimulation with AITC results in a dose-dependent increase in peak [Ca(2+)]i and a concomitant increase in CM fra...

Aims/hypothesis: The goal of this investigation was to determine whether there are sex-related differences in the development of cardiomyocyte dysfunction in prediabetic, insulin-resistant animals. Materials and methods: Male and female rats were maintained on a high-sucrose diet for 5-11 weeks, and mechanical properties of isolated ventricular myocytes were measured by high-speed video edge detection. Several in vitro interventions were used to manipulate intracellular Ca 2+ in order to determine whether altered Ca 2+ availability contributes to the cardiomyocyte dysfunction. Results: Myocyte shortening and relengthening were significantly slower in sucrose-fed (insulin-resistant) males than in starch-fed (normal) male rats, whereas only relengthening was slower in sucrose-fed females when compared with normal females. Areas under the contraction and relaxation phases for sucrose-fed males were also significantly larger than in diet-matched females, and the slowed cardiomyocyte mechanics appeared earlier in males (7 vs 10 weeks). Prolonged relaxation was ameliorated in myocytes from sucrose-fed female rats by all interventions (i.e. 10 −8 mol/l isoprenaline, elevated extracellular Ca 2+ , and higher rates of stimulation). Twice as much extracellular Ca 2+ (4 mmol/l) was required to restore normal time courses of contraction and relaxation in sucrose-fed males than in females, and mechanical responses to higher frequency stimulation remained impaired (slower) in some myocytes from sucrose-fed male rats. Conclusions/ interpretation: These data suggest that in myocytes from insulin-resistant rats altered Ca 2+ handling occurs, contributing to abnormal excitation-contraction coupling; female rats seem to have some cardioprotection during early stages in the progression towards type 2 diabetes. Females show delayed onset and milder abnormalities in metabolic status and cardiomyocyte function, but with a much tighter temporal coupling of these dysfunctions. Keywords Contraction. Insulin resistance. Relaxation. High sucrose feeding. Sex differences. Ventricular myocytes Abbreviations A C : area under the contractile phase. A R : area under the relaxation phase. β-AR: β-adrenergic receptor. CaMKII: Ca 2+ calmodulin kinase II. [Ca 2+ ] c : extracellular Ca 2+ concentration. HOMA: homeostasis model assessment. Max+dL/dt: maximum rate of contraction. Max−dL/dt: maximum rate of relaxation. PK: peak shortening amplitude. PS: peak fractional shortening. SERCA: sarco(endo)plasmic reticulum Ca 2+ ATPase

We recently identified cardiomyocyte dysfunction in the early stage of type 2 diabetes (i.e., diet-induced insulin resistance). The present investigation was designed to determine whether a variety of clinically relevant interventions are sufficient to prevent and reverse cardiomyocyte dysfunction in sucrose (SU)-fed insulin-resistant rats. Subsets of animals were allowed to exercise (free access to wheel attached to cage) or were treated with bezafibrate in drinking water to determine whether these interventions would prevent the adverse effects of SU feeding on cardiomyocyte function. After 6–8 wk on diet and treatment, animals were surgically prepared to assess whole body insulin sensitivity (intravenous glucose tolerance test), and isolated ventricular myocyte mechanics were evaluated (video edge recording). SU feeding produced hyperinsulinemia and hypertriglyceridemia, with euglycemia, and induced characteristic whole body insulin resistance. Both exercise and bezafibrate treat...

1. Apparatus for recording the small tensions developed by electrically stimulated single intact myocytes of frog heart is described. A laser-light optoelectronic transducer was used. The compliance of the force probes was 10-20 nm/nN, with a frequency response of 600-900 Hz in Ringer solution. The myocyte shortening during an ordinary twitch contraction was no greater than 1% of the slack length. The overall sensitivity of the transducer system was 5-10 mV/nN, with a total noise of 0.5-1 nN peak to peak. The experiments were performed at 20-23 degrees C on either atrial or ventricular myocytes at 2.15-2.2 microns sarcomere length, in 1 mM-Ca2+ Ringer solution. 2. Isoprenaline (5 microM), increases in external Ca2+ concentration ([Ca2+]o), and shortening of stimulus interval potentiated the myocyte twitch tension. The dependence of twitch characteristics on these inotropic interventions for all the atrial and ventricular myocytes tested was comparable to that of multicellular prepar...

Contraction and intracellular free Ca2+ concentrations (Ca2+)i in ventricular myocytes from rats receiving sucrose-enriched diets (SED's) were investigated. Groups of Wistar rats received normal rat chow together with either normal drinking water or water containing 500 mM sucrose ad libitum . Experiments were performed 12-14 weeks later. Rats receiving SED's responded differently to a standard glucose tolerance test. Fasting blood glucose levels in SED and control rats were 59.4±1.3 and 58.8±1.4 mg/dl, respectively. At 30 min after intraperitoneal administration of glucose (2g/kg body weight) concentrations of blood glucose were significantly (P0.05) different when compared to initial fasting blood glucose values. Blood plasma insulin concentrations in SED and control rats were 3.01±0.55 (5) and 0.29±0.05 (5) ng/ml, respectively. Amplitude and time to peak (TPK) of ventricular myocyte shortening and Ca2+ transient were not altered by SED. Time to half (THALF) relaxation of ...

Since the mechanisms responsible for gender differences in cardiac contractile function have not been fully elucidated, we focused to determine the effect of gender difference on b-adrenergic receptors (b-ARs) signal transduction in ventricular cardiomyocytes from insulindependent diabetic (streptozotocin-induced) rats. Doseresponse curves of left ventricular developed pressure (LVDP) to isoproterenol (ISO) in females showed that there was only a~30% decrease in the maximum response without a significant shift in EC 50 in diabetic females. On the other hand, diabetes induced a clear rightward shift in the potency (5-10 folds) without a significant change in the maximum response in the males. In order to further determine of the underlying mechanism for this difference, we measured cAMP production and obtained doseresponse curves with ISO stimulation in isolated cardiomyocytes. In diabetic females, there was no obvious change in the cAMP dose-response curve. On the other hand, there was a significant decrease in the maximum response without any apparent change in the potency of diabetic males. Our findings indicate that male and female rats are affected differently by diabetes in terms of LVDP responses to bARs stimulation. Also, the difference between their bARs induced cAMP responses may underlie this disparity. Keywords Diabetes Á Gender differences Á Betaadrenergic signal transduction Á cAMP Á G-proteins Á Cardiomyopathy

An inventor creates something new of
practical value, not necessarily following
an intellectually reasoned
path; a scientist (by and large, after a
long process, whether theoretical, experimental,
or both) discovers something
new that eventually may significantly
change the course of knowledge.
Both the inventor and the scientist are
creators, but their philosophical bases
and motivations are utterly different.

The objective is to describe the first patents, key inventions and scientific papers related to glass science & technology. According to the literature and the Guinness Book of Records, the first English recorded patent was granted to John Uty-nam in England in 1449 and a second in 1552. Regarding publications, the first two papers on glass production were published in 1665 in Le Journal des Sçavans in France and the Philosophical Transactions of the Royal Society in Eng-land. We illustrate our points using landmarks that cover half a millennia and constitute advancements in modern life that are substantially connected to and dependent on glass technology.

are distinct from the Ca 2/ transport site. Recent work We have examined the possible regulatory effect of in transfected CHO cells suggests that Ca 2/ released tyrosine kinase activity on Ca 2/ transport observed in from intracellular stores binds to these sites and actithe cultured rat cortical neurons. Na / /Ca 2/ exchange vates Ca 2/ transport (5).

Pulmonary artery sarcomas (PASs) are rare tumors of the vasculature of the lung that usually present as a thromboembolism. Failure of anticoagulant therapy to relieve all of a patient's symptoms suggests the diagnosis. Approximately 75% of patients with PAS present with dyspnea, and slightly > 50% also experience chest pain or cough. Imaging studies (chest computed tomography with 3-dimensional reconstruction, magnetic resonance imaging, perfusion lung scan, and pulmonary angiogram) are usually unspecific. A definitive diagnosis requires pathologic examination of tissue obtained by intravascular, percutaneous, or surgical biopsy. Treatment of primary PAS is usually surgical with or without adjuvant chemotherapy or radiation therapy. Because these tumors are rare, data from large randomized trials are not available. Palliative chemotherapy with anthracyclines and ifosfamide is the usual treatment in advanced disease, with response rates of approximately 50%. The mean survival time ranges from 14 months to 18 months. We report 3 cases of PAS treated with surgery and chemotherapy (anthracyclines and ifosfamide) with different outcomes.

Although extremely rare, the group of primary malignant tumors of the aorta (PMTA) exhibits enormous histologic heterogeneity. In most cases, diagnosis is established late in the course of the disease; the median survival time is only a few months. We present the case of a 75-year-old patient with an intimal angiosarcoma of the infrarenal abdominal aorta and discuss the clinical presentation, histopathologic diagnosis, and classification of primary aortic sarcomas. A critical review of the diagnostic and therapeutic management in this case revealed that the atypical aortic thrombus should have prompted a comprehensive preoperative diagnostic work-up, specifically with magnetic resonance tomography of the aorta and bone scintigraphy. ( J Vasc Surg 2004;40:548-53.) From the Departments of Vascular Surgery a and Surgical Pathology, b University of Wuerzburg. Competition of interest: none.

We describe a case of 63-year-old woman with pulmonary artery sarcoma successfully treated with chemotherapy. She developed acute shortness of breath, and left chest and shoulder pain. Although a diagnosis of acute pulmonary embolism was made at a local hospital and she received anticoagulation and thrombolysis therapy, no improvement was achieved. Thereafter, she underwent a pulmonary thromboectomy in our hospital, and the histological diagnosis was intimal sarcoma of the pulmonary artery. Since post-operative computed tomography (CT) scans of the chest showed obvious persistence of an intraluminal hypoattenuated area in the left main pulmonary artery, the patient was treated with four cycles of a doublet chemotherapy consisting of ifosfamide (2.5 g/m 2 /day) on days 1-5 and epirubicin (45 mg/m 2 /day) on days 2 and 3. CTscans of the chest after four cycles showed marked regression of the intraluminal hypoattenuated area in the left main pulmonary artery. This is the first case of pulmonary artery sarcoma responding to chemotherapy. Surgical resection is currently the most hopeful treatment for pulmonary artery sarcoma. However, intensive chemotherapy is worth trying in unresectable patients.

Intimal sarcoma of the pulmonary artery is commonly misdiagnosed as chronic pulmonary embolism. Rarely, it can involve the right ventricular outflow tract and the pulmonary valve. We report a patient who was treated surgically for an intimal sarcoma of the pulmonary artery involving the right ventricular outflow tract and the pulmonary valve. The sarcoma recurred in about 8 weeks. It responded favorably to chemoradiation therapy and shows some signs of regression.

Ventricular dysfunction in type 2 diabetic patients is becoming apparent early after diagnosis of diabetes, but the cellular mechanisms contributing to this dysfunction are not well established. Our group has recently identified cardiomyocyte dysfunction in diet-induced insulin resistant rats that have not developed type 2 diabetes. The present investigation was designed to determine cellular mechanisms contributing to slowed cardiomyocyte relaxation in sucrose (SU)-fed rats. SU-feeding was used to induce whole-body insulin resistance. After 9-12 weeks on diet, isolated ventricular myocyte shortening/relengthening were slower in SU-fed adult male Wistar rats (42-63%) compared to starch (ST)-fed controls. Cytosolic Ca 2+ removal attributable to Na + /Ca 2+ exchange (NCX) and to sarco(endo)plasmic reticulum Ca 2+ -ATPase (SERCA) was evaluated with fluo-3/AM. Caffeine-releasable Ca 2+ and cytosolic Ca 2+ clearing through NCX were normal, whereas Ca 2+ uptake by SERCA was significantly slower in SU myocytes (330 ± 29 ms) compared to ST cells (253 ± 16 ms). Protein levels for SERCA, NCX and phospholamban were not affected by SU-feeding. Manipulating intracellular Ca 2+ with various positive inotropic interventions (e.g. post-rest potentiation, isoproterenol) and changes in stimulus frequency demonstrated that mechanical properties can be improved in subsets of myocytes. Thus, we conclude that impaired SERCA activity (with normal protein content) contributes to cardiomyocyte dysfunction in insulin resistant animals, whereas NCX function and expression are normal. These results suggest that subtle changes in Ca 2+ regulation which occur prior to overt ventricular dysfunction/failure, may be common to early stages of a number of disorders involving insulin resistance (e.g. diabetes, obesity, syndrome X and hypertension).

Aims/hypothesis: The goal of this investigation was to determine whether there are sex-related differences in the development of cardiomyocyte dysfunction in prediabetic, insulin-resistant animals. Materials and methods: Male and female rats were maintained on a high-sucrose diet for 5-11 weeks, and mechanical properties of isolated ventricular myocytes were measured by high-speed video edge detection. Several in vitro interventions were used to manipulate intracellular Ca 2+ in order to determine whether altered Ca 2+ availability contributes to the cardiomyocyte dysfunction. Results: Myocyte shortening and relengthening were significantly slower in sucrose-fed (insulin-resistant) males than in starch-fed (normal) male rats, whereas only relengthening was slower in sucrose-fed females when compared with normal females. Areas under the contraction and relaxation phases for sucrose-fed males were also significantly larger than in diet-matched females, and the slowed cardiomyocyte mechanics appeared earlier in males (7 vs 10 weeks). Prolonged relaxation was ameliorated in myocytes from sucrose-fed female rats by all interventions (i.e. 10 −8 mol/l isoprenaline, elevated extracellular Ca 2+ , and higher rates of stimulation). Twice as much extracellular Ca 2+ (4 mmol/l) was required to restore normal time courses of contraction and relaxation in sucrose-fed males than in females, and mechanical responses to higher frequency stimulation remained impaired (slower) in some myocytes from sucrose-fed male rats. Conclusions/ interpretation: These data suggest that in myocytes from insulin-resistant rats altered Ca 2+ handling occurs, contributing to abnormal excitation-contraction coupling; female rats seem to have some cardioprotection during early stages in the progression towards type 2 diabetes. Females show delayed onset and milder abnormalities in metabolic status and cardiomyocyte function, but with a much tighter temporal coupling of these dysfunctions.

Intimal sarcoma of the pulmonary artery is commonly misdiagnosed as chronic pulmonary embolism. Rarely, it can involve the right ventricular outflow tract and the pulmonary valve. We report a patient who was treated surgically for an intimal sarcoma of the pulmonary artery involving the right ventricular outflow tract and the pulmonary valve. The sarcoma recurred in about 8 weeks. It responded favorably to chemoradiation therapy and shows some signs of regression.

We describe the case of a 42-year-old man who presented with dyspnea on exertion and a history of anticoagulation therapy for what was thought to be pulmonary arterial thromboembolism. He underwent surgery for obstruction of the right ventricular outflow tract. This is a very rare case of an intimal sarcoma of the pulmonary artery, which we confirmed by pathologic studies.