Perspective of healthcare providers on assessing the quality and accessibility of health services for chronic diseases in Jordan during Covid-19: a mixed method study.

BACKGROUND: Hospital services in all parts of the world were severely affected by the crisis caused by the Coronavirus pandemic. This was particularly concerning for patients who suffer from chronic diseases. AIM: This study aimed to: assess the level of quality and accessibility of chronic disease services from the perspectives of healthcare providers, assess the association between healthcare providers' socio-demographic factors and their perspectives on accessibility and quality level, and explore the providers' perspectives on the barriers and facilitators of quality and accessibility to chronic disease health services during the COVID -19 pandemic. METHOD: Design: An explanatory mixed method design was employed in this study using a questionnaire and focus group discussion approach. The questionnaire consisted of three sections including, demographic, accessibility, and quality. SAMPLE: A convenience sampling approach was used to collect the quantitative from 412 healthcare providers working at public, private, and teaching hospitals. A purposive sample of 12 healthcare providers were interviewed to collect the qualitative data. ANALYSIS: The quantitative data were analyzed using SPSS Statistics Version 25. The qualitative data was analyzed using the thematic analysis approach. RESULTS: This study found that the quality and accessibility of chronic disease services in northern Jordan were affected during COVID-19. Quantitative: The majority of the participants reported moderate level of accessibility and quality. Qualitative: Four main and six subthemes were identified: 1) Accessibility barriers including transportation and fear of infection; 2) Accessibility facilitators including availability of Personal Protective Equipment (PPE) and Covid-19 vaccination; 3) Quality barriers including staff shortage; 4) Quality facilitators including safety protocol. CONCLUSION: The quality and accessibility of chronic disease services were affected due to the healthcare system restating to address the Covid-19 pandemic. Different barriers and facilitators for chronic disease healthcare services accessibility and quality were identified. The findings of this study lay the ground for healthcare decision and policymakers to develop strategies and formulate polices to ensure these patients receive the needed healthcare services, and hence improve their health outcomes.

A multicenter, randomized trial of percutaneous coronary intervention versus bypass surgery in high-risk unstable angina patients. The AWESOME (Veterans Affairs Cooperative Study #385, angina with extremely serious operative mortality evaluation) investigators from the Cooperative Studies Program of the Department of Veterans Affairs.

This multicenter, prospective randomized trial was designed to test the hypotheses that percutaneous coronary intervention (PCI) is a safe and effective alternative to coronary artery bypass grafting (CABG) for patients with refractory ischemia and high risk of adverse outcomes. As a comparison of revascularization strategies, the trial specifically allows surgeons and interventionists to use new techniques as they become clinically available. After 42 months of this 72-month trial, 17,624 patients have been screened and 2022 met eligibility requirements: 341 have been randomized to either CABG or PCI, and the remaining 1681 are being prospectively followed in a registry. The 3-year overall survival of patients in the registry and randomized trial is comparable. To enhance accrual into the randomized trial, site visits were conducted, a few low-accruing hospitals were put on probation and/or replaced, eligibility criteria were reviewed at annual meetings of investigators, and the accrual period was extended by 1 year. These data demonstrate that a prospective randomized trial and registry of coronary revascularization for medically refractory high-risk patients is feasible.

Effects of endothelial and inducible nitric oxide synthases inhibition on circulatory function in rats after myocardial infarction.

OBJECTIVES: To examine the relative roles of eNOS and iNOS (endothelial and inducible nitric oxide synthases) on basal and beta-adrenergic receptor (beta-AR)-stimulated arterial hemodynamic responses after myocardial infarction (MI). METHODS: Left ventricular (LV) pressures and steady-state and pulsatile arterial hemodynamics were measured at baseline, and after acute NOS inhibition with either NG-nitro-L-arginine methyl ester (L-NAME, 100 mg/kg) or iNOS inhibition with aminoguanidine (AG, 75 mg/kg) in sham-operated and MI Sprague-Dawley rats. RESULTS: In sham rats, L-NAME decreased (P < 0.05) peak positive LV dP/dt and aortic blood velocity by 19% and 53%, respectively, and increased (P < 0.05) mean arterial pressure (MAP); systemic vascular resistance, and LV end-diastolic pressure (EDP) by 20, 189 and 89%, respectively. The frequency-dependent components of hemodynamics including aortic input impedance modulus, characteristic impedance, and phase shift were increased (P < 0.05) with L-NAME, while pulsatile power was decreased (P < 0.05). AG increased (P < 0.05) aortic input impedance modulus and characteristic impedance but had no effect on any other hemodynamic variable. In MI rats, L-NAME decreased (P < 0.05) LV dP/dt and aortic blood velocity by 22 and 55%, respectively, and increased (P < 0.05) SVR by 108%. There was no effect of L-NAME on MAP or LV EDP in MI rats. After MI, AG increased (P < 0.05) heart rate and LV dP/dt but had no effect on other LV or pulsatile hemodynamic variables. Compared to sham rats, heart rate, LV dP/dt, and blood velocity-isoproterenol dose responses were shifted downward (P < 0.05), while SVR-isoproterenol dose response was shifted upward (P < 0.05) in MI rats. In sham rats, L-NAME potentiated (P < 0.05, at > 10(-2) micrograms/kg) the isoproterenol-induced increase in LV dP/dt and aortic blood velocity, and potentiated (P < 0.05) the isoproterenol-induced decline in SVR. As expected, AG had no effects on isoproterenol-stimulated hemodynamics in sham rats. After MI, there was no effect of L-NAME or AG on isoproterenol-stimulated hemodynamics. CONCLUSIONS: (1) Circulatory and cardiac responses to inhibition of NO by L-NAME suggest that eNOS, but not iNOS, is the principal regulator of integrated arterial hemodynamic function in rats. (2) Both basal and beta-AR-stimulated NO regulation of hemodynamic are attenuated after MI. (3) The attenuation of arterial hemodynamic effects after isoproterenol is mediated, in part, by alterations in the beta-AR-activation of eNOS system after MI.

Effects of AT1 receptor blockade after myocardial infarct on myocardial fibrosis, stiffness, and contractility.

Angiotensin II type 1 (AT1) receptor blockade attenuates myocardial fibrosis after myocardial infarction (MI). However, whether inhibition of fibrosis by AT1 receptor blockade influences myocardial stiffness and contractility is unknown. We measured left ventricular (LV) hemodynamics, papillary muscle function, and myocardial stiffness and fibrosis in rats randomized to losartan or placebo 1 day after MI and treated subsequently for 8 wk. Losartan decreased LV and right ventricular weights as well as mean aortic and LV systolic pressures in sham and MI rats. LV end-diastolic pressure increased after MI and was decreased with losartan. Maximal developed tension and peak rate of tension rise and decline were decreased in MI vs. sham rats. Interstitial fibrosis developed after MI and was prevented in losartan-treated MI rats. The development of abnormal myocardial stiffness after MI was prevented by losartan. After MI, AT1 receptor blockade prevents an abnormal increase in myocardial collagen content. This effect was associated with a normalization of passive myocardial stiffness.

Large artery remodeling during aging: biaxial passive and active stiffness.

To examine arterial mechanical changes during aging, pressure-radius and axial force-radius curves were measured in vivo in carotid arteries from 6- and 23-month-old Brown Norway X Fischer 344 rats. Incremental passive circumferential stiffness (measured at 50, 100, and 200 mm Hg) was higher (P<0.01) in the 23- compared with the 6-month-old rats (14.02+/-1.23 versus 6.58+/-1.51; 2.68+/-0.56 versus 0.99+/-0.34; 1.10+/-0.24 versus 0.69+/-0.15 dyne/mm2x10(3), respectively). Incremental passive axial stiffness was increased (P<0.01) in the 23- compared with the 6-month-old rats (7.95+/-0.70 versus 4.24+/-0.81; 1.91+/-0.10 versus 0.61+/-0.16; 0.58+/-0.09 versus 0.36+/-0.06 dyne/mm2x10(3), respectively). Active incremental circumferential arterial stiffness at 100 and 200 mm Hg was increased (P<0.01) in the older rats. In 6-month-old rats, activation of vascular smooth muscle enhanced (P<0.01) the incremental circumferential and axial stiffness measured at 200 mm Hg. In 23-month-old rats, only active incremental stiffness was increased (P<0.01) at 200 mm Hg. Aging increased (P<0.05) media thickness, collagen content, and the collagen/elastin ratio by 12%, 21%, and 38%, respectively. Elastin density and the number of smooth muscle cell nuclei were decreased by 20% and 31%, respectively, with aging. Thus, structural alterations that occur with aging are associated with changes in both active and passive stiffness. Vascular smooth muscle tone modulates arterial wall anisotropy differently during aging.

Left ventricular function and remodeling after myocardial infarction in aging rats.

Adaptations of the aging left ventricle (LV) to hemodynamic overload are functionally and structurally distinct from those of the young organism. This study describes the influence of aging on LV hemodynamics and remodeling late after myocardial infarction (MI) in Fischer 344 Brown Norway rats. In sham rats at 23 mo, LV weight, myocyte cross-sectional area (CSA), and myocardial fibrosis were increased, whereas LV dP/dt, LV relaxation, and maximal LV systolic function declined with respect to younger rats (7, 12, and 18 mo of age). Isometric myocardial function was evaluated in papillary muscles of 12- and 23-mo-old sham rats. Myocardial systolic function was decreased in older rats. To determine how aging affects LV function and remodeling after MI, rats were infarcted at 7 and 18 mo of age and were studied 5 mo later. Infarct size was similar in each group. Right ventricular weight, LV end-diastolic pressure, and volume index were increased, whereas LV dP/dt, peak cardiac index, and peak developed LV pressure declined after MI. However, there were no significant differences between young and older rats in any variable of LV systolic function or remodeling after MI. Myocyte CSA increased in younger rats after MI but was unchanged in 23-mo-old rats. After MI, myocardial fibrosis was significantly increased from baseline only in younger rats. The negative interaction of aging and MI on myocyte hypertrophy and fibrosis was highly significant. The findings indicate that baseline LV and myocradial function decline with age. In the aging rat after MI, despite limited compensatory hypertrophy and more advanced baseline myocardial fibrosis, the long-term functional and structural adaptations to MI are similar to those of the mature adult heart.

Development of a thyroid hormone analogue for the treatment of congestive heart failure.

The possibility that thyroid hormone or a thyroid hormone analogue that improves cardiac performance might be useful in the treatment of heart failure has-been examined. In the rat postinfarction model of heart failure, treatment with low doses (1.5 micrograms/100 g) of thyroxine (T4) for 3 days produced a positive inotropic response, including an increase in left ventricular (LV) dP/dt and a decrease in LV end-diastolic pressure (LVEDP). When treatment with T4 was continued at the same or higher doses (3 to 15 micrograms/100 g) for 10-12 days, heart rate was increased and improvement in LVEDP was not sustained. To identify an analogue with a more favorable hemodynamic profile, single- and double-ring compounds related to T4 were screened for thyromimetic activity in heart cell cultures and for their ability to bind thyroid hormone receptors. One of the analogues selected, 3,5-diiodothyropropionic acid (DITPA), was found to have inotropic selectivity in hypothyroid rats. When administered (375 micrograms/100 g) to rats with ventricular dysfunction after myocardial infarction in combination with captopril, there was improvement of the resting and stressed cardiac index and LV filling pressure. Similar improvement in cardiac performance was obtained when DITPA was administered to rabbits after infarction. Thus a thyroid hormone analogue with inotropic selectivity may be a useful adjunct to other measures in the treatment of heart failure.

Relative contribution of angiotensin II, bradykinin, and prostaglandins to the renal effects of converting enzyme inhibition in rats after chronic myocardial infarction.

We wished to determine whether enhanced bioavailability of bradykinin (BK) and vasodilatory prostaglandins contribute to renovascular and sodium-handling effects of angiotensin-converting enzyme (ACE) inhibition after myocardial infarction (MI). We studied rats after coronary artery ligation treated for 3 weeks with captopril or losartan (2 g/L drinking water for each agent). Hemodynamic and renal function studies were performed in conscious rats before and after sequential infusion BK inhibitor (BKI, 0.02 ng/kg/min) and indomethacin (1 mg/kg). Myocardial infarction increased filtration fraction (FF) 20% (p < .004) but did not change glomerular filtration rate (GFR), urine flow (UF), renal blood flow (RBF), renal vascular resistance (RVR), urine sodium (UNa), or fractional excretion of sodium (FENa). Captopril decreased (p < 0.001) mean arterial pressure (MAP) 25%, UF 61%, RVR 65%, and FENa 75% and increased (p < 0.05) GFR 22%, and RBF 34%. Losartan decreased (p < 0.05) MAP 27%, UF 52%, RVR 21%, and FENa 44%. In captopril-treated MI rats, BKI decreased (p < 0.05) GFR 22% and RBF 25% and increased (p < 0.05) RVR 32%, UNa 43%, and FENa 28%, whereas indomethacin decreased (p < 0.05) GFR 24% and increased (p < 0.05) UNa 86% and FENa 112%. In losartan-treated MI rats, BKI increased (p < 0.05) UNa 42% and FENa 60%, whereas indomethacin increased (p < 0.05) UNa 79% and FENa 85%. Activation of the BK and prostaglandin systems may play an important role in regulating renal function during chronic ACE inhibition, primarily by enhancing the renal vasodilatory effects of angiotensin II (AII) blockade.

Survival after myocardial infarction in rats: captopril versus losartan.

OBJECTIVES: This study sought to compare the effects of angiotensin-converting enzyme inhibition versus angiotensin II receptor blockade on survival in rats with myocardial infarction. BACKGROUND: The effects of specific nonpeptide angiotensin receptor blocking agents on survival after myocardial infarction are unknown. METHODS: Rats with a moderate to large myocardial infarction were treated with captopril (2 g/liter drinking water, n = 87) or losartan (2 g/liter drinking water, n = 96). Therapy was initiated immediately after coronary artery ligation and continued for 1 year. RESULTS: Uncensored median survival in captopril-treated rats that survived at least 48 h was 201.5 days versus 236.0 days for losartan-treated rats (p = 0.066). Median survival censored for rats with lung infections was 201.5 days in captopril-treated rats versus 243.0 days for losartan-treated rats (p = 0.028). Conscious hemodynamic measurements and remodeling data obtained at 1 year in the surviving rats (n = 5 for captopril; n = 9 for losarton) revealed no differences in heart weight, left ventricular pressure, dP/dt, cardiac index, time constant of relaxation or any variable of left ventricular remodeling. The only differences (mean +/- SD) were an increase in heart rate (293 +/- 19 vs. 266 +/- 15 beats/min, p < 0.05) and a decrease in peak developed pressure (153 +/- 21 vs. 180 +/- 16 mm Hg, p < 0.05) in the losartan-treated rats. CONCLUSIONS: We conclude that in this experimental model of heart failure, there was no significant difference between survival after angiotensin II receptor blockade with losartan and with angiotensin-converting enzyme inhibition with captopril.

Large artery remodeling after myocardial infarction.

Rats with myocardial infarction (MI) after coronary artery ligation (n = 75) and sham operated rats (n = 40) were treated with captopril (2 g/l drinking water), hydralazine (80 mg/l drinking water), or untreated water for 3 wk. Arterial hemodynamics, carotid artery mechanical properties, and water permeability were measured. Arterial wall stress and interstitial fluid velocity were calculated. In infarcted rats, the characteristic impedance at matched pressure was increased by 135% (P < 0.02); captopril and hydralazine decreased characteristic impedance (P < 0.015). MI altered the material constants; captopril but not hydralazine normalized these constants. Water permeability was increased by 221% (P < 0.001) in infarcted rats; captopril but not hydralazine reversed water permeability (P < 0.05). MI resulted in a 59% increase (P < 0.05) in the arterial collagen area and a 22% decrease (P < 0.05) in the media thickness. Captopril but not hydralazine decreased (P < 0.03) collagen area. In conclusion, 1) arterial remodeling defined by alterations in the passive mechanical properties, water permeability, and structure occurs in rats after MI; and 2) captopril but not hydralazine reverses the arterial remodeling.

Rat infarct model of myocardial infarction and heart failure.

This review outlines the development and current use of the rat coronary artery ligation model of heart failure. The techniques to ligate the left coronary artery and to obtain morphologic/hemodynamic measurements are described. The authors show how the pathology seen in this model relates to clinical ischemic heart disease. An effort is made throughout the review to relate the changes that occur in this model to clinically relevant observations. For example, the progression to heart failure in these rats is similar to what happens when a patient sustains a large myocardial infarction, survives, but goes on to develop heart failure without another ischemic insult. In both rats and people with large infarctions, the noninfarcted myocardium, even though not damaged at the time of the infarct, cannot compensate sufficiently to prevent the eventual development of heart failure. In addition to being a good approximation of human disease, the responses to pharmacologic interventions, like angiotensin converting enzyme inhibitors, in rats has proved useful in predicting what will happen in humans given the same treatment. More recent data on the molecular control of ventricular remodeling emphasizes how this model will provide important information in the study of integrated physiology by examining biochemical, pharmacologic, and physiologic changes in the same tissue.

Left ventricular performance and remodeling in rabbits after myocardial infarction. Effects of a thyroid hormone analogue.

BACKGROUND: Because the rat postinfarction model differs from human heart failure with respect to the composition of myosin heavy chain (MHC) isoforms and other contractile proteins, alternative animal models are needed for the development of new treatments for human heart failure. The purpose of this study was threefold: (1) to test the feasibility of using the V3(beta,beta) rabbit postinfarction model for the study of heart failure by characterizing the effects of chronic coronary artery occlusion on the left ventricle; (2) to determine whether the thyroid hormone analogue 3,5-diiodothyropropionic acid (DITPA) produces improvements in left ventricular function; and (3) to determine the effects of myocardial infarction and treatment with DITPA on MHC protein isoforms. METHODS AND RESULTS: Male New Zealand White rabbits underwent proximal circumflex coronary artery ligation. After infarction, rabbits were treated with DITPA (3.75 mg/kg body wt) or placebo for 21 days and then underwent conscious and open-chest hemodynamic studies. In separate groups of rabbits, beta- and alpha-MHC isoforms were separated, and relative proportions were measured using gradient sodium dodecyl sulfate-polyacrylamide gel electrophoresis and laser densitometry. Infarction resulted in increased left ventricular end-diastolic pressure and prolonged left ventricular relaxation (tau) (P = .001 for both variables). Postinfarction treatment with DITPA decreased left ventricular end-diastolic pressure and tau (P = .002 and P = .001, respectively) and increased maximum positive and negative dP/dt (P = .002 and P = .016, respectively). Infarcted rabbits treated with DITPA had no significant changes in heart rate or left ventricular systolic pressure compared with untreated rabbits with infarction. There were no significant differences in heart rate, positive dP/dt, peak systolic pressure, or tau between sham-operated rabbits and sham-operated rabbits treated with DITPA. Although infarction resulted in increased left ventricular diameter, there were no effects of DITPA on left ventricular remodeling. Neither myocardial infarction nor treatment with DITPA altered the ratio of MHC isoforms. CONCLUSIONS: Rabbits that survive occlusion of the circumflex artery will develop myocardial dysfunction and left ventricular remodeling. Therapy with DITPA, a thyroid hormone analogue, produces improvement in ventricular performance and reduces end-diastolic pressure. The hemodynamic effects of DITPA were not associated with alterations of MHC isoforms. Whether DITPA represents the prototype of a previously undescribed class of agents for the treatment of heart failure will need to be determined by clinical trials.

Identification of simple substituted phenols with thyromimetic activity: cardiac effects of 3,5-diiodo-4-hydroxyphenylpropionic acid.

To define the minimal structural requirements for cardiac activity of thyroid hormone analogs, a series of substituted phenols were screened for their ability to bind bacterially expressed thyroid hormone receptors. Compounds with binding activity then were tested for their ability to induce expression of alpha-myosin heavy chain mRNA in primary cultures of fetal rat cardiomyocytes, a sensitive marker for potential inotropic activity. 3,5-Diiodo-4-hydroxyphenylpropionic acid (DIHPA) was found to bind specifically to bacterially expressed alpha-1 and beta-1 thyroid hormone receptors (Kaff approximately 1 to 2 x 10(5) M-1) and to induce alpha-myosin heavy chain (EC50 approximately 5 x 10(-7)). To assess the effects of DIHPA on cardiac performance in vivo, hemodynamic measurements were made in three groups of hypothyroid rats treated for 5 days with s.c. doses of DIHPA (15 mg/100 g), L-thyroxine (T4, 1.5 micrograms/100 g) or saline. Compared to controls, DIHPA and T4 produced increases in heart rate, left ventricular +dP/dtmax, -dP/dtmax, and isovolumic relaxation. In isometric papillary muscles preparations, DIHPA and T4 shortened time-to-peak tension and time-from-peak tension to 50% decline as compared with saline-treated controls. Muscles from both drug-treatment groups showed similar responses to graded doses of isoproterenol (10(-8) to 10(-3) M) and to variations in Ca++ concentration of the muscle bath (0.3125 to 3.75 x 10(-3) M). Thus, DIHPA is a novel thyromimetic compound with effects on myocardial function similar to those observed with T4.

Combination treatment with captopril and the thyroid hormone analogue 3,5-diiodothyropropionic acid. A new approach to improving left ventricular performance in heart failure.

BACKGROUND: An agent that improves left ventricular (LV) performance by non-cAMP-mediated mechanisms would be valuable in the treatment of chronic heart failure. We have shown earlier that the thyroid hormone analogue 3,5-diiodothyropropionic acid (DITPA) binds to nuclear receptors, alters transcription of T3-responsive genes, and increases +dP/dtmax in hypothyroid rats with substantially less effect on heart rate and metabolism than thyroid hormone, which makes it a selective cardiotonic agent. METHODS AND RESULTS: To determine whether DITPA might be useful in treating heart failure, we compared chronic treatment with normal saline, captopril (2 g/L), or the combination of DITPA (375 micrograms/100 g) and captopril (2 g/L) in Sprague-Dawley rats beginning 3 weeks after coronary artery ligation. Both DITPA/captopril and captopril treatment decreased LV end-diastolic pressure compared with controls (21 +/- 2 and 26 +/- 2 mm Hg, respectively, vs 34 +/- 3 mm Hg, P < .05 for each). The addition of DITPA to captopril produced a 36% increase in resting cardiac index (P < .05) and shifted the cardiac function curve upward and to the left, indicative of enhanced myocardial performance. Also, DITPA/captopril compared with captopril treatment or control produced an increase in the rate of LV relaxation, as manifested by a decrease in tau, the time constant of LV pressure decline (17.5 +/- 1.0 vs 22.2 +/- 1.7 milliseconds, P < .05) and a larger absolute value for -dP/dtmax (-4561 +/- 361 vs -3346 +/- 232 mm Hg/s, P < .05). These changes occurred without changes in heart rate, LV mass, LV systolic pressure, or peripheral resistance relative to captopril treatment (P > .05). CONCLUSIONS: The combination of DITPA and captopril improved cardiac output, increased -dP/dtmax, and increased the rate of LV relaxation to a greater extent than captopril treatment in the rat postinfarction model of heart failure. Use of a cardiotonic analogue of thyroid hormone represents a new approach to improving LV performance and may be a useful adjunct to afterload reduction for the treatment of heart failure.

Studies on the use of thyroid hormone and a thyroid hormone analogue in the treatment of congestive heart failure.

In heart failure, cardiac output is insufficient to meet the needs of the body for oxygen delivery. Available data suggest that alterations in thyroid hormone metabolism may contribute to defective myocardial performance. Accordingly, thyroid hormone or a thyroid hormone analogue that improves cardiac performance might be useful in the treatment of heart failure and has been studied. Experimental and theoretical results of these studies are reviewed and indicate that thyroid hormone increases cardiac output by a combination of effects on the heart and peripheral circulation, specifically by increasing myocardial contractile performance and decreasing venous compliance. In the rat postinfarction model of heart failure, treatment with low doses of thyroxine (1.5 micrograms/100 g) for 3 days produced a positive inotropic response, including an increase in rate of change of left ventricular pressure and a decrease in left ventricular end-diastolic pressure. These changes could be attributed to conversion to triiodothyronine, the active intracellular form of thyroid hormone. When treatment with thyroxine was continued at the same or higher doses (3 to 15 micrograms/100 g) for 10 to 12 days, heart rate increased and improvement in left ventricular end-diastolic pressure was not sustained. More favorable results were obtained with 3,5-diiodothyropropionic acid, a cardiotonic thyroid hormone analogue administered at doses of 375 microgram/100 g, given in combination with captopril. Thus, triiodothyronine or a thyroid hormone analogue may be a useful adjunct to other measures in the treatment of heart failure.

Baroreflex control of heart rate in rats with heart failure after myocardial infarction: effects of captopril.

Activation of the renin-angiotensin and sympathetic nervous systems in heart failure may result in altered baroreflex control of heart rate. To determine the specific effects of treatment with captopril on baroreceptor dysfunction in heart failure, baroreflex control of heart rate was measured in conscious rats with heart failure 6 weeks after ligation of the left coronary artery. Plasma norepinephrine was measured as a reflection of sympathetic nervous system activity. After bolus injections of phenylephrine (2-50 micrograms/kg) and nitroprusside (2-50 micrograms/kg), the arterial baroreflex was analyzed by fitting percentage of mean arterial pressure changes and heart rate changes to a logistic regression function. There were no differences in baroreflex function between normal and sham-operated rats. Plasma norepinephrine was increased (P < .05) in the heart-failure rats and did not change with captopril treatment. In untreated rats, heart failure increased (P < .05) the centering point by 900%, threshold by 243% and saturation by 89%, whereas decreasing (P < .05) the operational point by 73%. There was a decrease (P < .05) in the nitroprusside-related gain and an increase (P < .05) in phenylephrine-related gain, but the overall baroreflex gain was not changed. In heart-failure rats, captopril increased (P < .05) threshold, saturation and centering point and decreased (P < .05) operational point and nitroprusside- and phenylephrine-related gain abnormalities. The increase in operational point and decreases in threshold, saturation, centering point and phenylephrine-related gain were the results of a specific interactive effect of captopril in heart failure (P = .0033, .0176, .0509, .0217 and .0567, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of beta-adrenergic blockade on papillary muscle function and the beta-adrenergic receptor system in noninfarcted myocardium in compensated ischemic left ventricular dysfunction.

BACKGROUND: beta-Adrenergic receptor blockade has been reported to improve hemodynamics and beta-adrenergic receptor-adenylate cyclase function in idiopathic dilated cardiomyopathy. The purpose of this study was to determine the effects of beta-adrenergic receptor blockade on the beta-adrenergic receptor system and myocardial function in a model of compensated ischemic heart failure. METHODS AND RESULTS: We examined the effects of propranolol treatment on the beta-adrenergic receptor-adenylate cyclase system and isolated papillary muscle isometric function in noninfarcted left ventricular myocardium in rats after coronary artery ligation. In untreated rats with large myocardial infarction (MI), developed tension (DT) (3.0 +/- 0.7 versus 5.1 +/- 1.1 g/mm2), peak rate of tension rise (+dT/dt) (40.3 +/- 9.5 versus 71.2 +/- 12.0 g/mm2/sec), and peak rate of tension fall (-dT/dt) (24.4 +/- 5.0 versus 38.2 +/- 6.0 g/mm2/sec) were decreased (p < 0.05). In addition, DT, +dT/dt, and -dT/dt of untreated MI rats demonstrated an impaired response to isoproterenol stimulation compared with controls. beta-Adrenergic receptor density (Bmax) measured by [125I]iodocyanopindolol (ICYP) binding was decreased 23% after infarction (9.3 +/- 0.6 versus 12.0 +/- 1.8 fmol/mg protein [prot]) (p < 0.05); however, the dissociation constant (Kd) for ICYP was not changed (24.1 +/- 5.7 versus 33.2 +/- 12.1 pM). Adenylate cyclase activity in the presence of 10(-2) M MgCl2 was reduced (p < 0.05) in MI rats (30.3 +/- 10.8 versus 45.9 +/- 12.5 pmol cAMP/min/mg prot). Maximal isoproterenol (52.5 +/- 7.3 versus 79.9 +/- 10.0 pmol cAMP/min/mg prot), guanyl-5'-imidodiphosphate (GppNHp) (95 +/- 8 versus 141 +/- 25 pmol cAMP/min/mg prot) and forskolin (503 +/- 76 versus 753 +/- 157 pmol cAMP/min/mg prot) stimulation of adenylate cyclase was also decreased (p < 0.05). In addition, manganese-stimulated adenylate cyclase activity was depressed (p < 0.05) in MI rats compared with controls (23.5 +/- 2.8 versus 52.1 +/- 9.0 pmol cAMP/min/mg prot). Chronic propranolol treatment in MI rats improved DT (4.1 +/- 0.9 versus 3.0 +/- 0.7 g/mm2) and +dT/dt (54.4 +/- 11.3 versus 40.5 +/- 9.5 g/mm2/sec) (p < 0.05); however, isoproterenol-stimulated isometric function remained impaired. Propranolol treatment normalized Bmax (11.9 +/- 1.7 versus 9.3 +/- 0.6 fmol/mg prot) (p < 0.05), whereas adenylate cyclase activity remained depressed. CONCLUSIONS: After large MI in rats, there is impaired papillary muscle function with decreased beta-adrenergic receptors and adenylate cyclase activity in the noninfarcted myocardium. Propranolol treatment improved basal isometric muscle function and beta-adrenergic receptor density in rats after myocardial infarction but did not improve adenylate cyclase activity or isoproterenol-stimulated muscle function. These data suggest that there is a primary defect in adenylate cyclase function that persists despite upregulation of receptors with propranolol treatment.

Cardiac effects of 3,5-diiodothyropropionic acid, a thyroid hormone analog with inotropic selectivity.

Thyroid hormone exerts a strong positive inotropic action on the heart and induces alpha-myosin heavy chain (MHC) gene expression. 3,5-Diiodothyropropionic acid (DITPA), a carboxylic acid analog with low metabolic activity, was observed to induce alpha-MHC mRNA in heart cell culture with EC50 approximately 5 x 10(-7) M. To determine if the compound has positive inotropic actions, the effects of DITPA and L-thyroxine on heart rate, left ventricular pressures, left ventricular dP/dt, myosin isoenzymes and hepatic alpha-glycerolphosphate dehydrogenase activity were compared in hypothyroid rats. Binding affinities of DITPA and triiodothyronine for bacterially expressed alpha-1 and beta-1 thyroid hormone receptors (TRs) also were determined. Over the dosage range of 150 to 1500 micrograms/100 g, DITPA produced increases in left ventricular dP/dt comparable to those obtained with L-thyroxine at dosages of 1.5 to 15 micrograms/100 g, but with significantly less tachycardia. The increase in alpha-MHC mRNA was about the same with both compounds whereas alpha-MHC protein content and GPDH activity increased less with DITPA. These differences could not be explained by preferential binding of DITPA to TR subtypes. Because heart rate is a major determinant of myocardial oxygen consumption, DITPA is able to achieve increased cardiac performance at lower myocardial oxygen costs.

Arterial mechanics in spontaneously hypertensive rats. Mechanical properties, hydraulic conductivity, and two-phase (solid/fluid) finite element models.

To characterize the interaction between mechanical and fluid transport properties in hypertension, we measured in vivo elastic material constants and hydraulic conductivity in intact segments of carotid arteries in normal and spontaneously hypertensive rats (SHR). With the use of a finite element model, the arterial wall was modeled as a large-deformation, two-phase (solid/fluid) medium, which accounts for the existence and motion of the tissue fluid. Measurements of internal diameter and transmural pressures were obtained during continuous increases in pressure from 0 to 200 mm Hg. Strain and stress components were calculated based on a pseudostrain exponential energy density function. To measure the hydraulic conductivity, segments of the carotid artery were isolated, filled with a 4% oxygenated albumin-Tyrode's solution, and connected to a capillary tube. The movement of the meniscus of the capillary tube represented the fluid filtration across the artery. To study the influence of transmural pressure on hydraulic conductivity, measurement of fluid filtration across the arterial wall was obtained at transmural pressures of 50 and 100 mm Hg. The material constants in the SHR (n = 9) were higher (p less than 0.05 for all variables) than in normal rats (n = 10): c = 1,343 +/- 96 versus 1,158 +/- 65 mm Hg, b1 = 1.84 +/- 0.24 versus 1.22 +/- 0.22, b2 = 0.769 +/- 0.114 versus 0.616 +/- 0.11, b3 = 0.017 +/- 0.005 versus 0.0065 +/- 0.002, b4 = 0.206 +/- 0.04 versus 0.083 +/- 0.03, b5 = 0.0594 +/- 0.007 versus 0.0217 +/- 0.006, and b6 = 0.22 +/- 0.09 versus 0.123 +/- 0.02, respectively. The hydraulic conductivity of the total wall, calculated from the filtration data, was lower (p less than 0.05) at both 50 and 100 mm Hg in the SHR (n = 6) compared with normal rats (n = 7): 1.12 +/- 0.31 x 10(-8) and 0.72 +/- 0.23 x 10(-8) versus 1.95 +/- 0.53 x 10(-8) and 1.35 +/- 0.47 x 10(-8) cm/(sec.mm Hg), respectively. The intergroup comparisons between 50 and 100 mm Hg in both SHR and normal rats were also different (p less than 0.05). The finite element model was used to predict tissue fluid pressure distribution, tissue fluid velocity distribution, and total Cauchy stress gradients developed in the arterial wall during fluid pressurization in both species.(ABSTRACT TRUNCATED AT 400 WORDS)