The psychosocial and psychiatric side of cystic fibrosis in adolescents and adults.

Increasing numbers of cystic fibrosis (CF) patients are surviving into adulthood. An understanding of the psychiatric and psychosocial aspects of CF in adults and adolescents is therefore more important than ever. There is a large body of evidence indicating that the psychological and psychosocial functioning of people with CF is similar to that of well people, until the disease becomes severe. However, there is also evidence that patients do suffer an increased likelihood of psychiatric problems, such as depression, and of scoring poorly on physical functioning measures of quality of life. Studies have found conflicting evidence as to any association between degree of respiratory impairment and psychological functioning. Coping styles seem to have a large effect upon the quality of life of CF patients. People with cystic fibrosis can have problems with sexuality, platonic relationships and independence. Families of patients also suffer problems, which can affect the patients themselves. Non-compliance is a complicated problem with many patients. New treatments for people with CF are emerging, such as lobe transplants from live donors and gene therapy, with possible new psychosocial problems resulting. Furthermore, older studies are becoming increasingly inapplicable as treatment and prognosis changes. Therefore, more research is needed in this field.

Activation of cardiac c-Jun NH(2)-terminal kinases and p38-mitogen-activated protein kinases with abrupt changes in hemodynamic load.

The role of mitogen-activated protein kinase (MAPK) pathways as signal transduction intermediates of hemodynamic stress leading to cardiac hypertrophy in the adult heart is not fully established. In a rat model of pressure-overload hypertrophy, we examined whether activation of MAPK pathways, namely, the extracellular signal-regulated protein kinase (ERK), c-Jun NH(2)-terminal kinase (JNK), and the p38-MAPK pathways, occurs during rapid changes in hemodynamic load in vivo. A slight activation of ERK2 and marked increases in JNK1 and p38-MAPK activities were observed 30 minutes after aortic banding. The increase in p38-MAPK activity was accompanied by an increase in the phosphorylation of the p38 substrate MAPK-activated protein kinases 2 and 3. Activation of these kinases was coincident with an increase in phosphorylation of c-Jun and activating transcription factor-2 (ATF-2) and enhanced DNA binding of activator protein-1 factors. Thus, hemodynamic stress of the adult rat heart in vivo results in rapid activation of several parallel MAPK kinase cascades, particularly stress-activated MAPK and p38-MAPK and their target transcription factors c-Jun and ATF-2.

Endothelin-A receptor antagonism during acute myocardial infarction in rats.

Endothelin levels are increased in rats with experimentally induced myocardial infarction. The purpose of this study was to determine whether endothelin-A (ET(A)) receptor antagonism alters ventricular remodeling and the development of heart failure after myocardial infarction (MI). We administered 10 mg/kg/day of A-127722 to rats post-MI for 6 weeks. A hemodynamic study was performed and passive pressure-volume curves obtained. In rats without infarcts, ET(A) receptor antagonist (n = 8; vehicle, n = 5) had no effect. However, in rats with infarcts ET(A) antagonism (n=14, MI = 35%; vehicle: n = 19, MI = 32%) reduced systemic arterial and LV systolic (but not end-diastolic) pressures and shifted the pressure-volume relationship to the right. Because LV mass was not changed, the volume-to-mass ratio was increased and was correlated inversely with the ability of the LV to maximally develop pressure. This increase in volume at low distending pressures was also coupled with a tendency (P < 0.06) for reduced scar thickness, suggesting that early initiation of an ET(A) receptor antagonism increased infarct expansion. The reduction in blood pressure offset the increase in volume such that wall stresses were unchanged, as was LV mass. The early use of ET(A) receptor antagonism in the rat model of myocardial infarction did not beneficially alter LV remodeling.

Temporal dissociation of left ventricular function and remodeling following experimental myocardial infarction in rats.

BACKGROUND: Left ventricular function early after myocardial infarction (MI) predicts subsequent clinical outcome. Nevertheless, the relationship between early changes in left ventricular function and subsequent left ventricular remodeling has not been well defined. METHODS AND RESULTS: To explore the temporal relationship between left ventricular function and remodeling after MI, rats (n = 63) underwent coronary artery ligation with and without reperfusion at 45 or 180 minutes or a sham operation. All animals were followed up by serial echocardiography preligation; 4, 24, and 48 hours; and 1, 2, 3, 4, 6, and 9 weeks after MI. Measures of global left ventricular size and function and regional wall motion were obtained at physiological heart rates. Histological infarct sizes (range, 0% to 52%) were determined in all animals. Within 4 hours of MI, fractional area change (FAC) decreased dramatically in association with an increase in left ventricular systolic cavity area, whereas diastolic area increased more gradually. Early FAC was related to infarct size (r = -0.82; P < .000), predicted the extent of left ventricular enlargement (P = .0001), and remained depressed throughout the duration of follow-up. Regional wall motion excursion and systolic wall thickness decreased in the infarcted and noninfarcted regions in animals with large infarctions. CONCLUSIONS: The rate of left ventricular dilatation after MI in rats is proportional to initial left ventricular function, although left ventricular function remains relatively constant as the ventricle progressively enlarges. Regional myocardial function after a large MI is abnormal in noninfarcted as well as infarcted regions.

Inducible nitric oxide synthase and tumor necrosis factor in animal models of myocardial necrosis induced by coronary artery ligation or isoproterenol injection.

BACKGROUND: Increased expression of inducible nitric oxide synthase (iNOS) has been described in humans with cardiomyopathies. Most animal models of ischemia-induced heart failure use the surgical ligation of coronary arteries. However, studies of iNOS expression in these models may be confounded by a robust immune response because of the surgical procedure itself leading to iNOS expression in the heart, as well as in other tissues. METHODS AND RESULTS: iNOS expression was studied in adult male rats injected subcutaneously with either 250 mg/kg of isoproterenol (ISO) or vehicle on 2 consecutive days. This approach induces diffuse myocardial necrosis and leads to the development of a dilated cardiomyopathy. Hearts from ISO-injected animals harvested at 6 weeks had evidence of apical and subendocardial scarring. These hearts showed a 9.6-fold (left ventricle [LV], P = .004) and an 11.9-fold (right ventricle, P = .002) increase in the expression of tumor necrosis factor (TNF), and a 6.8-fold increase (LV, P = .0183) in iNOS messenger RNA compared with vehicle-injected controls. iNOS protein also was detectable by immmunoprecipitation in left ventricular muscle from ISO-injected animals, as well as by immunohistochemical analysis. CONCLUSION: Expression of TNF and iNOS in the heart is increased in an experimental model of dilated cardiomyopathy that minimizes the confounding effects of surgery, supporting a role for the activation of innate immunity signaling pathways in the pathogenesis of heart failure.

Effects of reperfusion on arrhythmias and death after coronary artery occlusion in the rat: increased electrical stability independent of myocardial salvage.

OBJECTIVES: This study sought to delineate salvage-dependent from salvage-independent coronary reperfusion in acute myocardial infarction and the effects on spontaneously occurring arrhythmias and arrhythmic death in rats. BACKGROUND: Reperfusion of the infarct-related artery might increase electrical stability independently of salvage of ischemic myocardium. METHODS: In 98 conscious rats the electrocardiogram was monitored by telemetry for 48 h after MI, and all episodes of ventricular tachycardia (VT) and ventricular fibrillation (VF) were analyzed. Reperfusion at 45 min (RP45) (n = 15), 90 min (RP90) (n = 18) and 180 min (RP180) (n = 30) min was compared with permanent coronary artery occlusion (CAO) (n = 35) with respect to the post-reperfusion periods. RESULTS: RP45, RP90 and RP180 reduced the incidence of VT by 93%, 98% and 88% and VF by 89%, 97% and 92%, respectively (all p < 0.01 vs. CAO). The all-cause mortality rate was reduced from 47% (CAO) to 8% (RP45, p < 0.05) and 0% (RP90, p < 0.01); after RP180 it was 17% (CAO 42%, p = 0.08). All reperfusion regimens reduced arrhythmic deaths: 47% to 8% (RP45, p < 0.05), 47% to 0% (RP90, p < 0.01) and 42% to 8% (RP180, p < 0.05). Infarct size was identical to that during CAO (49 +/- 10% [mean +/- SD]) and RP180 (49 +/- 10%), whereas preferentially epicardial salvage occurred at RP45 (36 +/- 8%, p < 0.001) and RP90 (38 < 10%, p < 0.001). CONCLUSIONS: Early and late reperfusion reduce the incidence and duration of VT and VF in conscious rats with acute MI. Thereby, arrhythmia-related mortality is improved through the prevention of fatal VF episodes. Thus, reperfusion increases the electrical stability of the heart independently of myocyte salvage, as proposed by the open artery hypothesis.

Effect of left ventricular sphericity on the evolution of ventricular dysfunction in rats with diffuse isoproterenol-induced myocardial necrosis.

BACKGROUND: Previous studies in heart failure have suggested that increased left ventricular (LV) sphericity is a precursor to hemodynamic deterioration, although these studies have predominantly used models with segmental damage due to coronary vessel occlusion and have only made baseline assessments of LV function. The purpose of this study was to examine the relationship between LV geometry and hemodynamic compromise through time in heart failure due to graded, diffuse myocardial injury with a patent coronary circulation. METHODS AND RESULTS: Rats received two injections of either 0, 85, 170, or 340 mg/kg isoproterenol. At 2, 6, and 16 weeks after injection, baseline hemodynamics, peak pressure-generating (aortic occlusion) and flow-generating (Tyrode's volume loading) capacities, and ventricular pressure-volume curves, dimensions, and histological scoring were measured. Increased LV sphericity preceded deterioration in baseline cardiac output, although it was the most powerful correlate of the dose-dependent decreases in peak cardiac output and ejection fraction. Time-dependent increases in pressure-generating capacity at a given volume were also due to compensatory increases in LV sphericity. The extent of right ventricular damage was also a strong correlate of peak flow-generating capacity. CONCLUSIONS: This study demonstrates that isoproterenol-induced myocardial necrosis resulted in progressive hemodynamic dysfunction of the left ventricle which most closely correlated with alterations in LV geometry. Although increases in LV sphericity preceded decrements in baseline function, techniques that assessed peak LV function demonstrated that increased LV sphericity was directly correlated with decreased peak flow-generating capacity, underscoring the clinical importance of these geometric alterations.

Cardiac myocyte membrane wounding in the abruptly pressure-overloaded rat heart under high wall stress.

The potential role of transient sarcolemmal membrane wounding as a signal transduction event for cardiomyocyte hypertrophy was evaluated in rats with short-term pressure overload caused by banding of the proximal aorta. This procedure resulted in significant increases in left ventricular systolic (1.5-fold) and end-diastolic (2.6-fold) pressures and wall stresses that were associated with significant wall thinning and cavitary enlargement. Quantitative image analysis of frozen sections of the stressed ventricles obtained 60 minutes after banding demonstrated a 6- to 10-fold increase in cytosolic staining with a horseradish peroxidase-labeled anti-albumin antibody compared with sham-operated controls, indicating that an increase in transient sarcolemmal membrane permeability (wounding) is an early response to an abrupt increase in hemodynamic load in vivo. We conclude that an intense hemodynamic stress in vivo can result in histologically detectable cardiomyocyte wounding.

The heart and conduit vessels in hypertension.

The heart and conduit vessels, integral components of a pulsatile pumping system, undergo complex adaptive and degenerative changes in response to the increased load of hypertension. Over the last two decades, great technological strides have been made with regards to further discovering the role of the heart and conduit vessels in hypertension. This article reviews the adaptation of the heart and vessels to hypertension, the clinical implications of these structural and functional changes, and the effects of therapy on cardiovascular function.

Comparison of techniques for measuring pulse-wave velocity in the rat.

We evaluated methods for measuring average and regional pulse-wave velocity along the full length of the aorta in 18-mo-old ether-anesthetized male spontaneously hypertensive rats. Catheter-tip manometers were placed in the ascending and descending thoracic aorta via the right carotid and left femoral arteries, respectively. As the distal catheter was withdrawn at 1-cm intervals, the relationship between the distal catheter insertion distance and distance between transducers was determined from the intercept of the insertion distance vs. transmission delay regression line. Methods that assessed the foot-to-foot time delay between pressures accurately predicted the separation between catheters (measured distance of 1.43 cm; intercept of 1.40 +/- 0.5 cm; P = not significant) were highly reproducible (coefficient of variation of 2.3% for repeated measurements) and showed minimal variability (range 509 +/- 30 to 600 +/- 29 cm/s) along the full length of the aorta. Methods that made use of the pressure-pressure transfer function were spatially (range of values along the aorta 367 +/- 17 to 722 +/- 39 cm/s) and temporally more variable, especially during vasoconstriction with methoxamine, due to the effects of reflected waves.

Equipotent antihypertensive agents variously affect pulsatile hemodynamics and regression of cardiac hypertrophy in spontaneously hypertensive rats.

BACKGROUND: Converting enzyme inhibitors are more effective than arteriolar vasodilators at regressing left ventricular hypertrophy in spontaneously hypertensive rats (SHR), possibly because of nonhemodynamic factors. However, the pulsatile component of hemodynamic load has not been evaluated in this model. METHODS AND RESULTS: We measured pulsatile hemodynamics in 18-month-old male SHR after 6 months of therapy with either zofenopril (Z), hydralazine (H), or water (W). Hydralazine and zofenopril reduced mean arterial pressure comparably (W, 106 +/- 23 versus H, 81 +/- 12 versus Z, 84 +/- 18 mm Hg, P = .002) yet had a differential effect on the ratio of left ventricular weight to body weight (W, 3.9 +/- 0.5 versus H, 3.3 +/- 0.4 versus Z, 2.4 +/- 0.2 g/kg, P < .005). Hydralazine-treated SHR had increased characteristic impedance (P = .0011) and a persistently low ratio of the reflected-wave transit time to left ventricular ejection time (P < .001), which contributed to early and late systolic loading, respectively, of the left ventricle. Consequently, only zofenopril-treated SHR had a significant reduction in left ventricular systolic force-time integral (P = .02), a measure of total ventricular load. There were no differences in systolic stress-time integral, suggesting that mass was appropriate to load when all elements of steady-flow and pulsatile load were considered. CONCLUSIONS: A blunted reduction in total left ventricular load, due to increased pulsatile load in SHR treated with hydralazine, provided a hemodynamic basis for the differential regression of hypertrophy in this model of genetic hypertension.

Arrhythmias and death after coronary artery occlusion in the rat. Continuous telemetric ECG monitoring in conscious, untethered rats.

BACKGROUND: The onset of acute myocardial infarction (MI) is accompanied by a rapid increase in electrical instability and often fatal ventricular arrhythmias. The aim of this study was to assess the continuous arrhythmia profile during the initial 48 hours after coronary artery ligation in the rat in relation to time course, mortality, and infarct size. METHODS AND RESULTS: Continuous ECG recording were obtained in 26 conscious, untethered rats for 24 hours before and 48 hours after coronary ligation by use of an implantable telemetry system. All episodes of ventricular tachycardia and fibrillation were counted and their durations summed. Infarct size was measured at 48 hours after MI or after spontaneous death. After ligation, two distinctly active arrhythmogenic periods developed (A1, 0 to 0.5 hours; A2, 1.5 to 9 hours), each followed by a quiescent phase of low ectopy (Q1, 0.5 to 1.5 hours; Q2, 10 to 48 hours). The total mortality rate of 65% was found within the two active periods, with 13 of 15 deaths occurring in A2. Rats with larger infarcts (> or = 50%) and nonsurvivors tended to have increased arrhythmia frequency and duration compared with both animals with smaller MIs (< 50%) and survivors. CONCLUSIONS: Two distinct arrhythmogenic periods occur in rats with acute MI that may be caused by different mechanisms and correspond to the bimodal arrhythmia time course seen in dogs and humans after acute MI. Telemetric monitoring of the ECG in the conscious rat after infarction will be useful in assessment of the differential effects of therapeutic interventions on these two arrhythmogenic periods and in the study of potential mechanisms for the spontaneous resolution of ventricular ectopy and risk of sudden death.

Characteristics of a model of myocardial infarction produced by coronary artery ligation in the rat.

The rat model of coronary artery ligation is widely used to study myocardial infarction, ventricular remodeling, and congestive heart failure. Total infarct size and the relationship between endocardial and epicardial infarction were characterized in 691 animals that survived permanent ligation of the left coronary artery. Infarct size was determined from serial histologic sections of the left ventricle (LV), followed by planimetry of muscle and scar circumferences. Mean infarct size was 34.5% ± 13.3% of total left ventricular circumference. Rats surviving longer durations to terminal study had a smaller mean infarct size. Infarct transmurality, as described by the ratio of epicardial-to-endocardial infarct sizes, was 0.78 ± 0.01. The transmurality ratio increased and its variability decreased as infarct size increased. Subendocardial infarcts were more frequent among small infarcts and had smaller areas of endocardial infarction. Although infarct size was highly variable, infarct size indexed to endocardial infarct size was less variable. Infarct size indexed to endocardial infarct size may therefore represent a significantly more powerful method for assessing the effects of treatments to reduce infarct size.

Measurement of aortic input impedance in rats.

Measurement of aortic input impedance in the rat is complicated by a high basal heart rate but is possible if appropriate compensation is made for frequency-dependent errors in modulus and phase resulting from analog filters in the equipment and from nonalignment of pressure and flow sensors. Because input impedance is a complex quantity, accurate values for both phase and modulus are required before meaningful interpretation of the data can be made. We measured aortic pressure and electromagnetic ascending aortic blood flow in mature, ether-anesthetized, open-chest male Wistar rats. Pressure and flow waveforms were averaged in the time domain and converted to Fourier series. Flow moduli were corrected for the measured frequency response of the flowmeter. Phase spectra were corrected by the classic frequency-domain and two new time-domain methods. Compensation for instrumentation errors was assessed at two different flowmeter filter settings in five animals. Reproducibility, variability, and the effects of vasoconstriction were assessed in 43 animals. Three methods of estimating characteristic impedance from the impedance spectra were evaluated and found to produce comparable results at baseline and following pharmacological elevation of blood pressure with graded methoxamine infusion. Physiologically equivalent values for phase, as assessed by comparing oscillatory power calculated from the impedance spectra, were obtained with each of the phase-correction techniques. The new time-domain methods facilitate the assessment of aortic input impedance in this small animal model because they do not require measurement of the spatial separation between pressure and flow transducers and pulse wave velocity in the proximal aorta.

Regression of left ventricular hypertrophy as viewed from the periphery.

Despite the advances in antihypertensive therapy, the majority of patients who develop heart failure have antecedent hypertension, left ventricular hypertrophy, and a poor prognosis. Studies in animals and humans have shown that equipotent antihypertensive agents variously effect the regression of cardiac hypertrophy, one of the reasons for which may be the differences in their effects on vascular load and structure. Recent advances in instrumentation (micromanometers, applanation tonometers, ultrasonic probes, and so forth) have permitted the noninvasive measurement of pressure contours, vessel diameters, and pulse-wave velocity. This new technology has allowed the evaluation of the effects of antihypertensive agents on arterial compliance and structure in relation to the agent's ability to regress left ventricular hypertrophy.

Progressive ventricular remodeling in response to diffuse isoproterenol-induced myocardial necrosis in rats.

The purpose of the present study was to gain a better understanding of the relation between ventricular remodeling and heart failure by assessing the adaptation of the heart through time to graded myocardial injury in the presence of a patent coronary circulation. Left ventricular (LV) remodeling is a dynamic response of the heart to injury and a critical component in the development of heart failure. However, most previous studies have been in the presence of an occluded coronary vessel, which may in itself effect remodeling. Male Wistar rats received two subcutaneous injections of either 0, 85, 170, or 340 mg isoproterenol per kilogram of body weight. At 2, 6, and 16 weeks after injection, LV pressure, the pressure-volume relation, and histology were assessed. The graded myocardial necrosis produced in isoproterenol-treated rats was associated with dose-dependent increases in LV end-diastolic pressure, volume indexes, and global diastolic wall stress. In the higher dose groups, the LV continued to enlarge after 2 weeks, resulting in a further reduction in the ratio of LV mass to volume and a persistent rise in diastolic wall stress. These progressive changes in LV structure were associated with an increase in long-term mortality in rats from the intermediate- and high-isoproterenol dose groups. The present study in rats demonstrates that diffuse isoproterenol-induced myocardial necrosis results in a progressive enlargement of the LV cavity that is out of proportion to mass, a finding similar to that observed in discrete myocardial infarction.

Development and prevention of congestive heart failure following myocardial infarction.

Ischemic heart disease is the major etiology for the development of congestive heart failure. Patients with acute myocardial infarction have a greatly increased risk for mortality and for manifesting symptomatic heart failure. This risk is not a uniform one but is greatly augmented in patients with a more extensive infarction and, consequently, a more depressed global ventricular function. An important concept that was derived from studies in rats with myocardial infarction and has been confirmed in patients is that ventricular enlargement, which has been shown to be a marker for an adverse outcome, can be a progressive process that leads to further deterioration of ventricular performance. Both experimental and early clinical studies have indicated that chronic therapy with an angiotensin converting enzyme inhibitor may attenuate this progressive ventricular enlargement. More definitive clinical trials are currently under way to determine whether this form of therapy, which may diminish the extent of ventricular enlargement over time, will result in an improvement in survival and in the prevention of the development of congestive heart failure. The addition of this pharmacological therapy to that of the primary prevention of atherosclerosis and that of the limitation of infarct size should make a substantial impact on the reduction of the incidence of congestive heart failure.