Comparative analysis of various prognostic nodal factors, adjuvant chemotherapy and survival among stage III colon cancer patients over 65 years: an analysis using surveillance, epidemiology and end results (SEER)-Medicare data.

AIM: The prognostic effects of chemotherapy and various lymph node measures [positive nodes, total node count and the positive lymph node ratio (PLNR)] have been established. It is unknown whether the cancer-specific survival benefit of chemotherapy differs across these nodal prognostic categories. METHOD: This retrospective analysis of linked Surveillance, Epidemiology and End Results (SEER) data and Medicare data (SEER-Medicare)included patients ≥ 65 years of age with a diagnosis of stage III colon cancer between 1997 and 2002. We grouped patients according to the number of positive nodes (N1 and N2), total node count (≥ 12 and < 12 total nodes) and PLNR (below the 75th percentile and at least at the 75th percentile of the PLNR). The end point was colon cancer-specific mortality. RESULTS: Fifty-one per cent (3701) of the 7263 patients received adjuvant therapy during the time period 1997-2002. The mean (standard deviation) number of total nodes examined was 13 (9) and the number of positive nodes identified was 3 (3). Patients with N2 disease, < 12 total nodes examined and a high PLNR had a worse survival at 2, 3 and 5 years following colectomy. Utilization of chemotherapy demonstrated a colon cancer-specific survival benefit (hazard ratio at median follow up = 0.7; P < 0.001) that was consistent and statistically significant across the three nodal prognostic categories examined. CONCLUSION: The benefit of chemotherapy did not vary based on N stage, total node count or PLNR. The results favour a broad-based approach towards increasing the chemotherapy treatment rates in stage III patients of ≥ 65 years of age, rather than an approach that targets clinical subgroups.

Regulation of calcium channel expression in neonatal myocytes by catecholamines.

Expression of the dihydropyridine (DHP) receptor (alpha 1 subunit of L-type calcium channel) in heart is regulated by differentiation and innervation and is altered in congestive heart failure. We examined the transmembrane signaling pathways by which norepinephrine regulates DHP receptor expression in cultured neonatal rat ventricular myocytes. Using a 1.3-kb rat cardiac DHP receptor probe, and Northern analysis quantified by laser densitometry, we found that norepinephrine exposure produced a 2.2-fold increase in DHP receptor mRNA levels at 2 h followed by a decline to 50% of control at 4-48 h (P < 0.02). The alpha-adrenergic agonist phenylephrine and a phorbol ester produced a decline in mRNA levels (8-48 h). The beta-adrenergic agonist isoproterenol and 8-bromo-cAMP produced a transient increase in mRNA levels. After 24 h of exposure to isoproterenol, 3H-(+)PN200-110 binding sites increased from 410 +/- 8 to 539 +/- 39 fmol/mg (P < 0.05). The number of functional calcium channels, estimated by whole-cell voltage clamp experiments, was also increased after 24 h of exposure to isoproterenol. Peak current density (recordings performed in absence of isoproterenol) increased from -10.8 +/- 0.8 (n = 23) to -13.9 +/- 1.0 pA/pF (n = 27) (P < 0.01). Other characteristics of the calcium current (voltage for peak current, activation, and inactivation) were unchanged. Exposure for 48 h to phenylephrine produced a significant decline in peak current density (P < 0.01). We conclude that beta -adrenergic transmembrane signaling increases DHP receptor mRNA and number of functional calcium channels and that alpha - adrenergic transmembrane signaling produces a reciprocal effect. Regulation of cardiac calcium channel expression by adrenergic pathways may have physiological and pathophysiological importance.

Metformin but not glyburide prevents high glucose-induced abnormalities in relaxation and intracellular Ca2+ transients in adult rat ventricular myocytes.

We have recently demonstrated that adult rat ventricular myocytes maintained in a high glucose (HG) culture medium exhibit abnormalities in excitation-contraction coupling similar to myocytes from diabetic rats. Metformin, an insulin-sensitizing biguanide, enhances peripheral insulin action and lowers blood pressure in hyperinsulinemic animals, but its direct impact on cardiac function is not fully understood. To examine the role of metformin on HG-induced cardiac dysfunction at the cellular level, normal adult ventricular myocytes were cultured for 1 day in a serum-free insulin-containing medium with either normal glucose (5.5 mmol/l glucose) or HG (25.5 mmol/l glucose) in the presence or absence of metformin or the sulfonylurea glyburide. Mechanical properties were evaluated using a high-speed video-edge detection system, and intracellular Ca2+ transients were recorded in fura-2-loaded myocytes. As previously reported, culturing myocytes in HG depresses peak shortening, prolongs time to 90% relengthening, and slows Ca2+ transient decay. Culturing cells with metformin (50 micromol/l) prevented the HG-induced abnormalities in relaxation without ameliorating depressed peak-shortening amplitudes. Incubation of the cells with metformin also prevented slower intracellular Ca2+ clearing induced by HG. However, the HG-induced relaxation defects were not improved by glyburide (50-300 micromol/l). Interestingly, metformin also improved HG-induced relaxation abnormalities in the absence of insulin, whereas it failed to protect against HG in the presence of the tyrosine kinase inhibitor genistein (50 micromol/l). These data demonstrate that, unlike glyburide, metformin provides cardioprotection against HG-induced abnormalities in myocyte relaxation, perhaps through tyrosine kinase-dependent changes in intracellular Ca2+ handling, independent of its insulin sensitizing action.

Cardiomyocyte dysfunction in sucrose-fed rats is associated with insulin resistance.

Diabetes is associated with impaired cardiac dysfunction in both humans and animals. Specific phenotypic changes-prolonged action potentials, slowed cytosolic Ca2+ clearing, and slowed relaxation-that contribute to this whole heart dysfunction occur in isolated ventricular myocytes. The present study was designed to determine whether cardiomyocyte abnormalities occur early in the development of type 2 diabetes (in this case, insulin resistance) and whether an insulin-sensitizing drug (metformin) is cardioprotective. In the study, high-sucrose feeding was used to induce whole-body insulin resistance. Wistar rats were maintained for 7-10 weeks on a starch (ST) diet, sucrose (SU) diet, or diet supplemented with metformin (SU + MET). Whole-body insulin resistance was measured in SU and SU + MET rats by performing euglycemic-hyperinsulinemic clamps. Mechanical properties of isolated ventricular myocytes were measured by high-speed video edge detection, and [Ca2+]i transients were evaluated with Fura-2 AM. Untreated SU rats were insulin-resistant (glucose infusion rate [GIR] = 14.5 +/- 1.1 mg.kg(-1).min(-1)); metformin treatment in SU + MET rats prevented this metabolic abnormality (GIR = 20.0 +/- 2.2 mg.kg(-1).min(-1)). Indexes of myocyte shortening and relengthening were significantly longer in SU rats (area under the relaxation phase [AR/peak] = 103 +/- 3 msec) when compared to ST and SU + MET rats (AR/peak = 73 +/- 2 and 80 +/- 1 msec, respectively). The rate of intracellular Ca2+ decay and the integral of the Ca2+ transient through the entire contractile cycle were significantly longer in myocytes from SU than from ST rats (Ca2+ signal normalized to peak amplitude = 152 +/- 8 vs. 135 +/- 5 msec, respectively). Collectively, our data showed the presence of cardiomyocyte abnormalities in an insulin-resistant stage that precedes frank type 2 diabetes. Furthermore, metformin prevented the development of sucrose-induced insulin resistance and the consequent cardiomyocyte dysfunction.

Troglitazone attenuates high-glucose-induced abnormalities in relaxation and intracellular calcium in rat ventricular myocytes.

Diabetes is associated with impaired cardiac diastolic dysfunction. Isolated ventricular myocytes from diabetic animals demonstrate impaired relaxation concomitant with prolonged intracellular Ca2+ transients. We have recently shown that maintaining normal adult rat ventricular myocytes in a "diabetic-like" culture medium (low insulin and high glucose) produces abnormalities in excitation-contraction coupling similar to in vivo diabetes. Troglitazone (TRO), a novel insulin-sensitizing agent, significantly lowers blood pressure and modestly increases cardiac output in vivo, but its direct impact on cardiac function is unknown. To determine whether TRO could prevent high-glucose-induced dysfunction, normal myocytes were maintained in culture for 1-2 days in either normal medium containing 5 mmol/l glucose or high-glucose medium containing 25 mmol/l glucose. TRO (5 micromol/l) was added to both normal and high-glucose media. Mechanical properties were evaluated using a high-resolution video-edge detection system, and Ca2+ transients were recorded in fura-2-loaded myocytes. Relaxation from peak contraction was significantly longer in myocytes cultured in high glucose. Treating cells with TRO either attenuated or prevented the high-glucose effects, without changing the mechanical properties of myocytes cultured in normal medium. TRO also prevented the abnormally slow rates of Ca2+ transient decay induced by high glucose. Collectively, these data demonstrate that TRO can protect against the high-glucose-induced relaxation defects, perhaps through changes in intracellular Ca2+ handling. If TRO has both vasodilatory actions and beneficial cardiac properties (e.g., improvement of diastolic function) in the presence of hyperglycemia, this antidiabetic agent may prove to have significant salutary cardiovascular effects in type II diabetes.

Net costs from three perspectives of using low versus high osmolality contrast medium in diagnostic angiocardiography.

OBJECTIVES: We conducted an economic analysis to assess the extent to which a reduction in adverse drug reactions induced by low osmolality compared with high osmolality contrast media during diagnostic angiocardiography would result in savings to hospitals, society and third-party payers that would offset the substantially higher price of low osmolality contrast medium. BACKGROUND: Substitution of low osmolality for high osmolality contrast media in the approximately 1 million diagnostic angiocardiographic procedures performed each year in the United States could substantially increase health care costs. Cost-effectiveness estimates should include savings that might occur through reduced costs of managing adverse drug reactions. METHODS: In a randomized clinical trial of 505 persons under-going diagnostic angiography with either high osmolality or low osmolality contrast medium, we measured and compared 1) material costs of contrast media, and 2) costs from three perspectives of incremental resources used to manage contrast-related adverse drug reactions. We also performed sensitivity analyses to examine the effect of different assumptions with regard to relative risk, absolute risk and costs of adverse drug reactions on estimates of net cost of use of high osmolality and low osmolality contrast media. RESULTS: One-hundred thirty-seven (54.2%) of 253 patients receiving high osmolality contrast medium and 44 (17.5%) of 252 patients receiving low osmolality contrast medium experienced adverse drug reactions. The average cost (from society's perspective) of resources used to manage adverse drug reactions per patient undergoing angiography was significantly (p = 0.0001) greater for high osmolality (mean $249) versus low osmolality (mean $92) contrast medium. Differential costs (from the hospital's perspective) were $67 greater for high osmolality contrast medium. Charges and professional fees (from the payer's perspective) were $182 greater for high osmolality (mean $312) than for low osmolality (mean $130) contrast medium (p = 0.42, NS). The higher differential and average costs of managing adverse drug reactions with high osmolality contrast medium offset 33% and 75%, respectively, of the $207 difference in mean material costs, but these estimates are sensitive to infrequent high cost cases. CONCLUSIONS: Although low osmolality contrast medium is not cost-saving in diagnostic angiocardiography, its higher price is partially offset by lower management costs of adverse drug reactions. The cost offset for the hospital is lower than that for society and may not be realized by third-party payers. These methods and results may be useful in establishing clinical and payment guidelines for use of alternative contrast media in diagnostic angiocardiography.

Effects of metformin on tyrosine kinase activity, glucose transport, and intracellular calcium in rat vascular smooth muscle.

Metformin enhances peripheral insulin action and reduces blood pressure in hypertensive rats. Our group has previously reported that insulin and insulin-like growth factor I (IGF-1) attenuate both agonist-induced vascular smooth muscle cell (VSMC) contraction and associated increases in cytosolic free calcium ([Ca]i). Thus, changes in insulin actions may explain in part metformin's vascular effects. However, metformin's mechanism of action at the vasculature had not been elucidated. Therefore, the purpose of this study was to determine whether metformin evokes alterations in VSMC insulin and IGF-I receptors, glucose transport, and/or [Ca]i. We quantitated hormone binding and tyrosine kinase (TK) activity in partially purified insulin and IGF-I receptors prepared from metformin-treated (100 microM) and control rat aortic VSMC in culture. Glucose transport was assessed by 2-deoxyglucose uptake. Metformin exposure for 24 h 1) increased basal TK activity (metformin, 3.49 +/- 0.39; control, 1.77 +/- 0.39 pmol 32P incorporated/mg protein; P < 0.01) without changes in insulin-or IGF-I stimulated TK activity, 2) increased 2-deoxyglucose transport in a dose-dependent manner, 3) decreased thrombin-induced elevation in [Ca]i (metformin, 10.3%; control, 35.3% over basal; P < 0.05), These insulin/IGF-I-like effects of metformin may help explain some of its vascular actions.

Insulin, thyroid hormone, and heart function of diabetic spontaneously hypertensive rat.

Diabetes impairs cardiac performance more extensively in hypertensive rats than it does in nonhypertensive strains. A "low thyroid state" may contribute to the adverse cardiovascular effects of diabetes in spontaneously hypertensive rats (SHR). We tested this hypothesis by comparing the effects of thyroid hormone with those of insulin treatment on cardiac performance of diabetic SHR. Diabetes was induced with streptozotocin (45 mg/kg). Subsets of diabetic rats were treated with either insulin (10-20 units/kg/day) or triiodothyronine (8-10 micrograms/kg/day). Heart rate and systolic arterial pressure were obtained at weekly intervals. After 8 weeks, cardiac function was assessed using an isolated working heart preparation. Diabetes reduced arterial pressure and heart rate in vivo and markedly depressed cardiac performance under volume and pressure loading conditions ex vivo, confirming previous observations. As expected, insulin treatment prevented the bradycardia and depressor effect in vivo and the impairment of cardiac performance ex vivo caused by diabetes. The triiodothyronine treatment duplicated the effects of insulin on the hemodynamic measurements in vivo, and corrected nearly all depressed indexes of performance of diabetic SHR hearts ex vivo. Both treatment regimens successfully reduced 8-week mortality when compared with the untreated diabetic group. The results support the hypothesis that a low thyroid state may contribute to the cardiovascular dysfunction in diabetic SHR. Left ventricular hypertrophy may be an important factor in this phenomenon.

Ventricular relaxation of diabetic spontaneously hypertensive rat.

Diabetes, and possibly the hypothyroidism that attends diabetes, impairs mechanical relaxation of ventricular muscle, in part by depressing the rate of Ca2+ uptake by sarcoplasmic reticulum. Left ventricular hypertrophy exacerbates the adverse effects of diabetes on cardiac performance, but its effects on relaxation variables have not been well characterized. We examined the impact of streptozotocin-induced diabetes (8 weeks) on ventricular pressure load-dependent relaxation and sarcoplasmic reticular calcium uptake of hearts from spontaneously hypertensive rats and Wistar-Kyoto rats. Subsets of diabetic hypertensive rats were treated with either insulin (10 units/kg/day) or triiodothyronine (8-10 micrograms/kg/day). Diabetes impaired load-dependent relaxation and depressed sarcoplasmic reticular calcium uptake only in spontaneously hypertensive rat hearts. Either insulin or triiodothyronine treatment prevented the diabetes-induced depressions of both mechanical and biochemical indexes of relaxation. The results suggest that 1) hypertrophic ventricles of spontaneously hypertensive rats are more susceptible to the detrimental effects of diabetes on relaxation indexes than are the nonhypertrophic Wistar-Kyoto rat ventricles, and 2) the hypothyroidism that attends diabetes may contribute to the impaired relaxation of diabetic spontaneously hypertensive rat left ventricle.

The effect of changing state health policy on hospital uncompensated care.

This paper examines the effect of changing state policy, such as Medicaid eligibility, payment generosity, and HMO enrollment on provision of hospital uncompensated care. Using national data from the American Hospital Association for the period 1990 through 1995, we find that not-for-profit and public hospitals' uncompensated care levels respond positively to Medicaid payment generosity, although the magnitude of the effect is small. Not-for-profit hospitals respond negatively to Medicaid HMO penetration. Public and for-profit hospitals respond negatively to increases in Medicaid eligibility. Results suggest that public insurance payment generosity is an effective but inefficient policy instrument for influencing uncompensated care among not-for-profit hospitals. Further, in localities with high HMO penetration or high penetration of for-profit hospitals, it may be necessary to establish explicit payments for care of the uninsured.

Medicaid-eligible children who don't enroll: health status, access to care, and implications for Medicaid enrollment.

We estimate that 17% of Medicaid-eligible children in the United States are uninsured, with 27% covered by private insurance. Uninsured children have become a target for state outreach and enrollment efforts. However, the effort may not be a worthwhile use of resources if these children have sufficient access to primary care and are able to enroll in Medicaid should serious health problems arise. This analysis of health status, access to care, and use of preventive and other services suggests otherwise. Although the uninsured Medicaid-eligible children are slightly healthier than their enrolled counterparts, they face reduced access to care and lower rates of service use. After controlling for health status and other characteristics, we find that being uninsured increases the likelihood of being without a usual source of care by eight percentage points, and increases reporting of unmet needs by seven percentage points. Being uninsured also decreases by nine percentage points the proportion of children with any health provider visits, and increases by 12 percentage points the proportion with family out-of-pocket expenses exceeding $500. These findings lend support to the hypothesis that the enrollment process is onerous for some families. Targeted efforts to enroll uninsured Medicaid-eligible children could help in reducing the effect of barriers and reducing differences in access to care.

Cardiomyocyte dysfunction in insulin-resistant rats: a female advantage.

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.

The role of perspective in defining economic measures for the evaluation of medical technology.

Perspectives in an economic analysis of medical technology reflect who makes decisions about the use of or payment for medical resources. Commonly used perspectives include those of providers, insurers, the individual, and society. Perspective is a critical determinant of study design, affecting the time horizon, types of resources considered, and economic cost measures assigned to those resources. Individuals involved in technology assessment for either research or policy-making purposes should be aware of the complexities of defining costs from different perspectives.

Determinants of public and private insurance enrollment among Medicaid-eligible children.

BACKGROUND: Many Medicaid-eligible children are not enrolled in Medicaid and are not covered by private insurance. Reducing persistent lack of insurance for children requires a better understanding of why Medicaid-eligible children do not participate. RESEARCH QUESTIONS: Does the availability of free or low-cost medical services substitute for Medicaid or private insurance enrollment among Medicaid-eligible children? Does the availability and affordability of insurance coverage, particularly the offer of employer-sponsored insurance (ESI) and the presence of managed care, affect child insurance coverage? RESEARCH DESIGN: We use data from the National Health Interview Survey for 1994 and 1995, supplemented with county level measures of insurance and provider supply, to estimate a multinomial choice model of insurance coverage among children identified as Medicaid-eligible. We focus on county supply of public hospitals and community/migrant health centers (C/MHC); and the availability and cost of ESI. We control for child and parent characteristics. RESULTS: A positive effect of C/MHC supply is found on Medicaid enrollment, but no evidence is found of substitution between low-cost providers and Medicaid or private coverage. Local availability of ESI and private HMO penetration increased private insurance enrollment. CONCLUSIONS: Local community providers can play an important role in outreach and enrollment for Medicaid. Availability and cost of ESI constrain private coverage for Medicaid-eligible children. Policies that encourage offers of insurance coverage by employers, decrease premiums, and encourage adoption of managed care could have important positive effects on coverage for this population.

Diabetes rapidly induces contractile dysfunctions in isolated ventricular myocytes.

To determine whether diabetes-induced cardiac dysfunction is due to contractile dysfunction at the single-cell level, mechanical properties and Ca2+ transients were evaluated in ventricular myocytes isolated from diabetic rats. Rats were made diabetic by injection with streptozotocin and killed either 4-6 days or 8 wk after treatment. Shortening and relengthening (twitch) properties were evaluated in isolated myocytes with a high-resolution (120-Hz) video-based edge-detection system during electrical stimulation between 0.1 and 5 Hz. A separate cohort of myocytes was loaded with fura 2 to assess intracellular Ga2+ transients. Long-term (8-wk) but not short-term (4- to 6-day) diabetes depressed peak twitch amplitude. Diabetes markedly prolonged both the contraction and relaxation phases from both diabetic models. Additionally, 35% of the long-term diabetic myocytes could not pace at 5 Hz, and 48% of the short-term diabetic myocytes developed a hypercontracture at that frequency. Intracellular Ca2+ measurements showed slower Ca(2+)-transient decays in myocytes from short-term diabetic rats. These data demonstrate that contractile dysfunction seen in the diabetic heart is due, in part, to abnormalities of the myocyte. Furthermore, these abnormalities are present after only 4-6 days of diabetes, suggesting a rapid alteration in the processes regulating myocyte shortening and relengthening, which likely include impaired Ca2+ sequestration or extrusion.

Low insulin and high glucose induce abnormal relaxation in cultured adult rat ventricular myocytes.

One of the most prominent myocardial defects associated with diabetes is abnormal diastole. We have recently reported that this dysfunction involves prolonged relaxation (relengthening) in isolated ventricular myocytes that occurs within days after the induction of diabetes. The present study was designed to evaluate the role of insulin and glucose int he etiology of this dysfunction with a serum-free myocyte culture system. Adult rat ventricular myocytes were cultured for 1-4 days in a "diabetic-like" medium containing five times less insulin and approximately five times more glucose than in our normal medium. Mechanical properties and Ca2+ transients (fura 2) were evaluated with a high-resolution (120-Hz) video-based edge-detection/spectro-fluormetric system. The cells were field stimulated to contract at slow and physiologically relevant rates, and indexes of contraction and relaxation were evaluated. Relengthening was markedly longer in myocytes cultured in low-insulin-high-glucose (LIHG) medium compared with those in normal medium, whereas contraction was unaffected. Intracellular Ca2+ transients showed slower rates of decay in myocytes cultured in LIHG medium. These data demonstrate that maintaining normal ventricular myocytes in an LIHG environment prolongs relaxation in a manner similar to the effects of in vivo diabetes. Furthermore, the abnormal relaxation is inducible in 1 day, suggesting rapid alterations in processes regulating relaxation, which likely include impaired Ca2+ sequestration and/or extrusion.

Pathophysiology of cardiomyopathies: Part I. Animal models and humans.

With the growing incidence of heart disease there is a need for new and better animal models that mimic human pathology. Investigators are encouraged to employ an interactive and collaborative approach to the study of heart failure; doing so may clarify many of the discrepancies found in the literature. It is clear from recent studies in animals that the pathophysiology may differ significantly between models, even though the endpoint, heart failure, has been attained. These observations indicate that etiologic factors as well as species and/or strain play a significant role in the cardiomyopathy. Investigators must now look beyond simply attaining the clinical syndrome of heart failure and ascertain which aspects of heart failure they are attempting to define and investigate.

Pathophysiology of cardiomyopathies: Part II. Drug-induced and other interventions.

Drug-induced cardiomyopathies are becoming widely used as models of heart failure. These models offer the advantage of precise control of the onset time and can often be studied in a longitudinal fashion. Toxin- and tachycardia-induced models, as well as nutritional deficiency models, possess certain clinically relevant features, thereby enhancing their appeal. By studying these types of models, key components of heart disease can be elucidated, and may provide important new insights into the pathophysiology of the clinical and functional end-point: heart failure.

Cardiac function of the diabetic renovascular hypertensive rat: effects of insulin and thyroid hormone treatment.

The influences of hypertension and hypothyroidism on diabetic cardiomyopathy are not clear. We studied this problem further by characterizing the effects of chronic triiodothyronine (T3) treatment on cardiac performance of diabetic renovascular hypertensive (RVH) rats. Hypertension was effected by clipping the left renal artery of Wistar-Kyoto (WKY) rats, and diabetes was induced 2 weeks later by streptozotocin (STZ; 55 mg/kg i.v.). The WKY strain was selected because it is relatively resistant to the cardiodepressant effects of diabetes, so that the influence of superimposed hypertension would be more apparent. Performance of working Krebs-Henseleit buffer perfused hearts was quantified by measuring left ventricular pressure and flow characteristics. The results showed that renovascular clipping caused a marked hypertension and left ventricular hypertrophy (LVH) but had no effect on perfused heart performance after 10 weeks. They also showed that diabetes during the final 8 weeks (i) caused a marked impairment in the performance of perfused hearts ex vivo of hypertensive rats but had no measurable effect in the normotensive WKY, (ii) had no effect on arterial pressure of either the normotensive or the hypertensive rats but reduced heart rate of hypertensive animals in vivo, and (iii) caused equivalent hyperglycemia, hypoinsulinemia, and hypothyroidism (depressed serum T3 and T4 levels) of hypertensive and normotensive rats. Treatment of diabetic RVH rats with T3 (10 micrograms.kg-1.day-1) in vivo was nearly as effective as insulin therapy (10 U.kg-1.day-1) in preventing the cardiac dysfunction ex vivo and was as effective as insulin therapy in preventing the bradycardia in vivo and the decline loss.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaldehyde depresses shortening and intracellular Ca2+ transients in adult rat ventricular myocytes.

Acetaldehyde (ACA), an ethanol metabolite, exerts both stimulatory and depressive effects on isolated myocardial tissue, but its impact on individual cardiac myocytes is unknown. The purpose of this study was to determine whether ACA-induced myocardial depression is due to an intrinsic alteration of the contractile properties of heart at the cellular level. Mechanical properties of adult rat ventricular myocytes were evaluated using a video edge-detection system. Myocytes were electrically stimulated to contract at 0.5 Hz under isotonic conditions in a physiological buffer containing 1 mM CaCl2. Contractile properties analyzed include: peak twitch amplitude (PTA), time-to-PTA (TPT), time-to-relengthening (TR90) and maximal velocities of shortening and relengthening (+/-dL/dt). Ca2+ transients were measured as fura-2 fluorescence intensity (FFI) changes. ACA (1-30 mM) disproportionately depressed PTA and FFI in a dose-dependent manner, with maximal inhibitions of 57 and 19%, respectively. Neither the durations nor maximal velocities of shortening and relengthening were affected by ACA. The depression of cell shortening by ACA was either attenuated or blocked by BayK 8644 or elevated extracellular Ca2+ (2.7 mM). In addition, ACA also reduced caffeine-induced FFI changes. These results suggest that ACA-induced myocardial depression in multicellular preparations is due to an intrinsic action on individual myocytes. The mechanism underlying ACA-induced myocardial depression may be due, in part, to either reduced Ca2+ entry through voltage-dependent Ca2+ channels and/or depression of sarcoplasmic reticular Ca2+ release.