The VCD Mouse Model of Menopause and Perimenopause for the Study of Sex Differences in Cardiovascular Disease and the Metabolic Syndrome.

In females, menopause, the cessation of menstrual cycling, is associated with an increase in risk for several diseases such as cardiovascular disease, osteoporosis, diabetes, the metabolic syndrome, and ovarian cancer. The majority of women enter menopause via a gradual reduction of ovarian function over several years (perimenopause) and retain residual ovarian tissue. The VCD mouse model of menopause (ovarian failure in rodents) is a follicle-deplete, ovary-intact animal that more closely approximates the natural human progression through perimenopause and into the postmenopausal stage of life. In this review, we present the physiological parameters of how to use the VCD model and explore the VCD model and its application into the study of postmenopausal disease mechanisms, focusing on recent murine studies of diabetic kidney disease, the metabolic syndrome, and hypertension.

The renal thiazide-sensitive Na-Cl cotransporter as mediator of the aldosterone-escape phenomenon.

The kidneys "escape" from the Na-retaining effects of aldosterone when circulating levels of aldosterone are inappropriately elevated in the setting of normal or expanded extracellular fluid volume, e.g., in primary aldosteronism. Using a targeted proteomics approach, we screened renal protein extracts with rabbit polyclonal antibodies directed to each of the major Na transporters expressed along the nephron to determine whether escape from aldosterone-mediated Na retention is associated with decreased abundance of one or more of renal Na transporters. The analysis revealed that the renal abundance of the thiazide-sensitive Na-Cl cotransporter (NCC) was profoundly and selectively decreased. None of the other apical solute-coupled Na transporters displayed decreases in abundance, nor were the total abundances of the three ENaC subunits significantly altered. Immunocytochemistry showed a strong decrease in NCC labeling in distal convoluted tubules of aldosterone-escape rats with no change in the cellular distribution of NCC. Ribonuclease protection assays (RPAs) revealed that the decrease in NCC protein abundance was not associated with altered NCC mRNA abundance. Thus, the thiazide-sensitive Na-Cl cotransporter of the distal convoluted tubule appears to be the chief molecular target for regulatory processes responsible for mineralocorticoid escape, decreasing in abundance via a posttranscriptional mechanism.

Aldose reductase-deficient mice develop nephrogenic diabetes insipidus.

Aldose reductase (ALR2) is thought to be involved in the pathogenesis of various diseases associated with diabetes mellitus, such as cataract, retinopathy, neuropathy, and nephropathy. However, its physiological functions are not well understood. We developed mice deficient in this enzyme and found that they had no apparent developmental or reproductive abnormality except that they drank and urinated significantly more than their wild-type littermates. These ALR2-deficient mice exhibited a partially defective urine-concentrating ability, having a phenotype resembling that of nephrogenic diabetes insipidus.

Localization of glucokinase gene expression in the rat brain.

The brain contains a subpopulation of glucosensing neurons that alter their firing rate in response to elevated glucose concentrations. In pancreatic beta-cells, glucokinase (GK), the rate-limiting enzyme in glycolysis, mediates glucose-induced insulin release by regulating intracellular ATP production. A similar role for GK is proposed to underlie neuronal glucosensing. Via in situ hybridization, GK mRNA was localized to hypothalamic areas that are thought to contain relatively large populations of glucosensing neurons (the arcuate, ventromedial, dorsomedial, and paraventricular nuclei and the lateral area). GK also was found in brain areas without known glucosensing neurons (the lateral habenula, the bed nucleus stria terminalis, the inferior olive, the retrochiasmatic and medial preoptic areas, and the thalamic posterior paraventricular, interpeduncular, oculomotor, and anterior olfactory nuclei). Conversely, GK message was not found in the nucleus tractus solitarius, which contains glucosensing neurons, or in ependymal cells lining the third ventricle, where others have described its presence. In the arcuate nucleus, >75% of neuropeptide Y-positive neurons also expressed GK, and most GK+ neurons also expressed KIR6.2 (the pore-forming subunit of the ATP-sensitive K+ channel). The anatomic distribution of GK mRNA was confirmed in micropunch samples of hypothalamus via reverse transcription-polymerase chain reaction (RT-PCR). Nucleotide sequencing of the recovered PCR product indicated identity with nucleotides 1092-1411 (within exon 9 and 10) of hepatic and beta-cell GK. The specific anatomic localization of GK mRNA in hypothalamic areas known to contain glucosensing neurons and the coexpression of KIR6.2 and NPY in GK+ neurons support a role for GK as a primary determinant of glucosensing in neuropeptide neurons that integrate multiple signals relating to peripheral energy metabolism.

Alterations in intravascular volume affect the relation between right ventricular diastolic collapse and the hemodynamic severity of cardiac tamponade.

Right ventricular diastolic collapse has been demonstrated to be a sensitive and specific sign of cardiac tamponade. Because the shape and position of the right ventricular wall are related to the relative pressures within the pericardial space and the right ventricular chamber, the usefulness of right ventricular diastolic collapse as a marker of cardiac tamponade may be influenced by intravascular volume and right heart filling pressures. This study was undertaken to determine the effects of volume loading and hemorrhage on the point within the hemodynamic progression of cardiac tamponade at which right ventricular diastolic collapse first appears. Five unanesthetized, chronically instrumented dogs were studied with two-dimensional echocardiography during 41 episodes of cardiac tamponade induced by the intrapericardial infusion of warm saline solution. Intravascular volume was adjusted before cardiac tamponade to a hypovolemic, euvolemic or hypervolemic state using saline solution and dextran infusion or hemorrhaging to achieve the prescribed mean right atrial blood pressure. The measurements recorded during each episode of cardiac tamponade were right atrial blood pressure, aortic blood pressure, cardiac output (by electromagnetic flow meter), heart rate and intrapericardial pressure. When compared with the euvolemic state, the onset of right ventricular diastolic collapse in volume contraction occurred at a lower intrapericardial pressure (with a lower aortic blood pressure and cardiac output), whereas in volume expansion it occurred at a higher intrapericardial pressure (with a higher aortic blood pressure and cardiac output). Volume expansion delayed the decrease in hemodynamic variables during cardiac tamponade in this canine model.

Misdiagnosis of pericardial cyst by echocardiography and computed tomography scanning.

We saw a patient who had clinical features of right-sided heart failure. Echocardiography and computed tomography findings were incorrectly interpreted as demonstrating an intracardiac mass. At surgery, a pericardial cyst externally compressing the right ventricular cavity was found. We conclude that, although noninvasive tests may play a valuable role in evaluating intracardiac masses, interpretation may be difficult and misdiagnoses are possible.

Survivors of prehospitalization sudden death. Characteristic clinical and angiographic features.

Cardiac catheterization and angiography were performed in 57 survivors of prehospitalization sudden cardiac death (PSD). Fifty-two had coronary artery disease. In most, the disease was severe, with almost universal involvement of the anterior descending artery. Associated left ventricular dysfunction was common. Although the majority of survivors had severe coronary artery disease, only 16 had an acute myocardial infarction associated with the PSD event and the extent of their coronary artery disease generally was less severe than those who died suddenly of an arrhythmia and no myocardial infarction. Cardiovascular symptoms of long duration prior to sudden death were not uncommon, although sudden death was the initial cardiac symptom in some. Others had crescendo angina as the initial symptom, and a few had a clinical history compatible with Prinzmetal's angina. Although severe coronary artery disease was the most common underlying abnormality, PSD may be an expression of multiple causes.

Recovery of contractile function in post-ischaemic reperfused myocardium of conscious dogs: influence of nicorandil, a new antianginal agent.

The effects of intravenous administration of nicorandil, a new antianginal agent, on the recovery of regional myocardial contractile function after a 10 minute coronary artery occlusion were studied in chronically instrumented conscious dogs. Compared with the control group nicorandil administration resulted in an increase in heart rate and a decrease in blood pressure with an overall increase in the double product during the preocclusion period, no significant difference in double product during ischaemia, and a significant decrease in double product during reperfusion. After reperfusion the return of regional contractile function was appreciably enhanced in the nicorandil treated group. These effects were seen immediately after coronary reflow and persisted throughout the reperfusion period. These data suggest that nicorandil protects ischaemic cardiac tissue, and that the beneficial actions may be mediated through a reduction in left ventricular afterload.

Should the elderly be resuscitated following out-of-hospital cardiac arrest?

PURPOSE: Elderly and younger patients who were successfully resuscitated and hospitalized following out-of-hospital cardiac arrest were studied to determine if there was a significant difference in hospital course and long-term survival between the two groups. PATIENTS AND METHODS: The study consisted of 214 consecutive patients, divided into two age groups: elderly (more than 70 years, n = 112) and younger (less than 70 years, n = 102). Hospital charts and paramedic run data were retrospectively reviewed for each patient and findings were compared between the two age groups. RESULTS: Prior to cardiac arrest, 47 of 112 (42 percent) elderly patients had a history of heart failure, compared with 19 of 102 (18 percent) younger patients, and were more commonly taking digitalis (51 percent versus 29 percent) and diuretics (47 percent versus 26 percent). Younger patients, however, more often had an acute myocardial infarction at the time of the cardiac arrest (33 percent versus 16 percent). At the time of cardiac arrest, 83 percent of younger patients demonstrated ventricular fibrillation, compared with 71 percent of the elderly. In contrast, electromechanical dissociation was five times more common in the elderly patients. Although hospital deaths were more common in the elderly (71 percent versus 53 percent), the length of hospitalization and stay in intensive care units were not significantly different between the age groups. The number of neurologic deaths was similar in both age groups, as were residual neurologic impairments. Only five elderly patients and six younger patients required placement in extended-care facilities. Calculated long-term survival curves demonstrated similar survival in both age groups, with approximately 65 percent of hospital survivors alive at 24 months after hospital discharge. CONCLUSION: Resuscitation of elderly patients in whom out-of-hospital cardiac arrest occurs is reasonable and appropriate, according to the findings of this study. Even though elderly patients are more likely than younger patients to die during hospitalization, the hospital stay of the elderly is not longer, the elderly do not have more residual neurologic impairments, and survival after hospital discharge is similar to that in younger patients.

Mitral valve prolapse requiring surgery. Clinical and pathologic study.

The clinical, hemodynamic, surgical, and pathologic findings in 30 patients who required mitral valvular surgery and who had a preoperative diagnosis of mitral valve prolapse were reviewed. The mean age of the patients was 59.5 years; 28 patients were over 45 years of age and 10 were over 60 years. Surprisingly, 20 were males. A long history of systolic murmur was common, whereas symptoms of heart failure were of abrupt onset. At the time of surgery, a local holosystolic murmur typical of mitral regurgitation was present, although a mid- to late systolic click was not heard in any of the patients. Electrocardiographic abnormalities were present in all patients, with 13 patients demonstrating atrial fibrillation. Only four patients had a normal heart size radiographically. Echocardiography confirmed the radiographic findings, in that 27 patients demonstrated left atrial and ventricular enlargement. All 29 patients undergoing cardiac catheterization and angiography demonstrated a prolapsing mitral valve with severe regurgitation. Surgical and pathologic examination revealed findings characteristic of a myxomatous valve in all patients, with 19 also demonstrating ruptured chordae tendineae. This study demonstrates that heart failure requiring valvular surgery occurs in a subset of patients with mitral valve prolapse. In this subset, males predominate and most are over 50 years of age. These patients may be asymptomatic for many years, demonstrating mild to moderate mitral valvular regurgitation, before heart failure develops.

Coronary steal-induced increase in myocardial infarct size after pharmacologic coronary vasodilation.

This study was performed to determine if maximal coronary arterial vasodilation of nonischemic areas would produce an increase in myocardial infarct size through a "steal" of collateral flow from an ischemic region. Myocardial infarction was produced by a 2 hour occlusion and reperfusion of the distal left anterior descending coronary artery in anesthetized dogs. Five minutes after occlusion, 7 dogs were given saline solution, and in 12 dogs the coronary vasodilator chromonar (8 mg/kg, intravenously) was administered. Chromonar produced a significant increase (p less than 0.05) in blood flow to nonischemic regions and a concomitant decrease in flow to ischemic areas. Associated with these changes in flow was an elevation in total release and peak plasma creatine kinase compared with values in saline-treated control dogs. Myocardial infarct size determined with nitroblue tetrazolium stanining was significantly increased (p less than 0.05). These demonstarte that maximal coronary vasodilation of nonischemic areas can result in an extension of myocardial infarction by a steal of collateral flow away from the ischemic region.

Redistribution of myocardial blood flow distal to a dynamic coronary arterial stenosis by sympathomimetic amines: comparison of dopamine, dobutamine and isoproterenol.

The effects of dopamine, dobutamine and isoproterenol on coronary hemodynamics, severity of stenosis, distal bed resistance and transmural myocardial perfusion gradients with radioactive microspheres were studied in dogs with a mild obstruction of the left circumflex coronary artery anesthetized with morphine-chloralose. Changes in transmural blood flow were related to the ratio of the diastolic aortic pressure-time index to tension-time index (DPTI/TTI) and the ratio of the distal diastolic coronary pressure-time index to tension-time index (DDPTI/TTI). At doses of 5 microgram/kg per min, dopamine had no significant effect on DPTI/TTI, DDPTI/TTI or endocardial/epicardial flow ratio; however, dobutamine produced a slight decrease in this flow ratio and in DDPTI/TTI. At doses of 10 microgram/kg per min, both drugs produced a significant (p less than 0.05) reduction in diastolic coronary pressure distal to the stenosis. DDPTI/TTI and endocardial/epicardial flow ratio without change in DPTI/TTI. In comparison, isoproterenol (0.01 and 0.05 microgram/kg per min) produced dose-related decreases in endocardial/epicardial flow ratio, DDPTI/TTI and DPTI/TTI. During infusion of each sympathomimetic agent, there was a corresponding reduction in distal bed vascular resistance but a concomitant increase in stenosis resistance. The results also show that dopamine and dobutamine, as well as isoproterenol, area capable of producing a maldistribution of coronary blood flow distal to a mild coronary arterial stenosis and that such a redistribution of glow is dependent on dose, reduction of the distal diastolic coronary pressure-time index and decrease in DDPTI/TTI. It is further concluded that hemodynamic changes distal to a coronary arterial stenosis seriously jeopardize the usefulness of DPTI/TTI; however, DDPTI/TTI can be used to predict drug effects on the endocardial/epicardial flow ratio in an ischemic area. This study demonstrates that "fixed" stenoses can undergo dynamic processes and sympathomimetic amines increase the resistance to flow through a stenotic coronary artery in the nonfailing heart.

Comparison of outcome of paramedic-witnessed cardiac arrest in patients younger and older than 70 years.

To obtain further information concerning differences in the mechanism of out-of-hospital cardiac arrest between elderly and younger patients, 381 consecutive patients who experienced out-of-hospital cardiac arrest, and whose arrest was witnessed by paramedics, were studied. In 91% of cases the arrest occurred at the time the patient's cardiac rhythm was monitored. Patients were divided into 2 age groups: elderly patients were greater than 70 years (187) and younger patients were less than 70 years (194). Elderly patients more commonly had a past history of heart failure (25 vs 10%, p less than 0.003) and were more commonly taking digoxin (40 vs 20%, p less than 0.005) and diuretics (35 vs 25%, p less than 0.004). Before the cardiac arrest, elderly patients were more likely to be complaining of dyspnea (53 vs 40%, p less than 0.009), whereas younger patients were more likely to complain of chest pain (27 vs 13%, p less than 0.001). Forty-two percent of younger patients demonstrated ventricular fibrillation as the initial out-of-hospital rhythm associated with the arrest, compared to only 22% of elderly patients (p less than 0.001). Besides patient age, initial cardiac rhythm varied according to the patient's complaint preceding the arrest. Sixty-eight percent of patients with chest pain demonstrated ventricular fibrillation, whereas only 21% of patients with dyspnea demonstrated ventricular fibrillation. Elderly patients could be as successfully resuscitated as younger patients; however, 24% of younger patients survived, compared to only 10% of elderly patients (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Usefulness of right ventricular diastolic collapse in diagnosing cardiac tamponade and comparison to pulsus paradoxus.

To compare the sensitivity, specificity and predictive value of right ventricular (RV) diastolic collapse and pulsus paradoxus as signs of cardiac tamponade, 21 consecutive patients with pericardial effusion and suspected cardiac tamponade underwent prospective hemodynamic and echocardiographic evaluation. Simultaneous hemodynamic and echocardiographic data were obtained in all patients before and after pericardiocentesis. Cardiac tamponade was considered present when there was diastolic equilibration of the intrapericardial, right atrial and pulmonary capillary wedge pressures and elevation of these pressures to more than 10 mm Hg. RV diastolic collapse was 93% sensitive and 100% specific in diagnosing cardiac tamponade, whereas pulsus paradoxus was only 79% sensitive and 40% specific. The positive and negative predictive values of RV diastolic collapse (100% and 83%) were considerably better than pulsus paradoxus (81% and 40%) and demonstrate that RV diastolic collapse is more sensitive, specific and predictive of cardiac tamponade than is pulsus paradoxus. Serial simultaneous hemodynamic and echocardiographic observations at multiple points during pericardiocentesis in a smaller subgroup (5 patients) also suggest that the hemodynamic effects of RV diastolic collapse in cardiac tamponade are mediated by an increase in intrapericardial pressure.

A prospective study of mitral valvular prolapse in young men.

A cardiac history, a physical examination, an electrocardiogram, phonocardiograms in the supine and standing positions, and an M-mode echocardiogram were obtained in 100 randomly selected, presumably healthy, male medical students (mean age, 26 years). Four percent met standard echocardiographic criteria for mitral valvular prolapse. No midsystolic clicks or late systolic murmurs were appreciated in this group, and none complained of chest pain or palpitations. To elucidate further the clinical implication of the echocardiographic pattern of mitral valvular prolapse, 24-hour ambulatory ECGs, multistage exercise tests, and scintiscans of myocardial perfusion at rest and after exercise (using radioactive 13nitrogen-labelled ammonium) were obtained, with normal results. The absence of life-threatening arrhythmias and exercise-induced abnormalities in these four asymptomatic subjects without abnormal physical findings suggests that the echocardiographic pattern of mitral valvular prolapse in such individuals may represent a variant of normal which does not require extensive evaluation.

Mitral valve prolapse in the elderly.

This study included 40 patients over 60 years of age with echocardiographic findings of mitral valve prolapse (MVP). Most of these patients were unaware of any cardiac disorder until the time of echocardiography. In the majority, the clinical manifestations were benign, and the duration of symptoms variable. Congestive heart failure (CHF) was noted in 10 patients (25 percent) who were unaware of having any cardiac disorders until the onset of their symptoms. In 5 patients (4 with CHF and 1 with endocarditis), surgical replacement of the prolapsed mitral valve was necessary. Endocarditis was present in 4 patients (10 percent), none of whom had been instructed in the prophylactic use of antibiotics. The physician's awareness of mitral valve prolapse in the elderly patient is important, since the disorder may not be as benign in aged patients as in younger ones, and life-threatening complications may occur.

Orbital Burkitt's lymphoma in a homosexual man with acquired immune deficiency.

A 22-year-old homosexual man had persistent systemic lymphadenopathy and a three-week history of rapid swelling and induration of his right upper eyelid. Acquired immune deficiency leading to the development of lymphoma was suspected. A biopsy specimen of the mass revealed Burkitt's lymphoma and treatment with systemic chemotherapy and radiation therapy resulted in remission. A significant number of patients with acquired immune deficiency are developing Burkitt's lymphoma. The three separate syndromes of acquired immune deficiency and their associated ophthalmic manifestations are discussed.

Xerophthalmia and cystic fibrosis.

We treated two infants with failure to thrive who presented with clinical evidence of conjunctival and corneal xerosis. One patient was referred with possible infectious corneal ulcer thought to exist because there were deep peripheral ulcerations of the cornea and associated hypopyon. The other patient was initially thought to have a nasolacrimal duct obstruction because of excessive tearing. Xerophthalmia secondary to vitamin A deficiency was suspected and led to the diagnosis and treatment of cystic fibrosis in each case. Therapy with vitamin A promptly resolved the xerosis, but it also caused a transient rise in intracerebral pressure. Xerophthalmia can still be a problem in developed countries when underlying disorders, such as cystic fibrosis, lead to vitamin A malabsorption.

Removal of radiation-induced cataracts in patients treated for retinoblastoma.

Experience with removal of radiation-induced cataract in patients treated for retinoblastoma is limited. We retrospectively reviewed the records of 38 patients with retinoblastoma (42 eyes) who underwent removal of radiation-induced cataract from 1973 to 1989. Nineteen eyes (45%) without macular tumors or severe radiation complications had final visual acuities in the range of 20/20 to 20/50. One eye (2.4%) developed a rhegmatogenous retinal detachment and four eyes (9.5%) were noted to have amblyopia after cataract removal. Three eyes (7%) developed retinoblastoma recurrence, one with extension of retinoblastoma into the subconjunctival space through the previous sclerotomy. Exenteration was performed and the patient was alive after 8 years. Cataract removal can be visually beneficial in selected patients with radiation-induced cataracts.

Activity of FL 1060, a new beta-lactam antibiotic, against urinary tract pathogens.

The effect of the new beta-lactam antibiotic FL 1060 on urinary tract pathogens, of which 71 were sensitive to and 100 resistant to ampicillin, is presented here. When tested by conventional methods FL 1060 was found to be highly active against ampicillin-sensitive strains of E. coli but phenotypically resistant variants readily emerged, particularly when a large inoculum was used. Thirty-one per cent of ampicillin-resistant strains were found to be sensitive to less than 500 mug FL 1060 per ml, and in general this antibiotic was more active than ampicillin against resistant strains. In a system simulating the mechanical features of the urinary bladder the activity of FL 1060 against three sensitive strains of E. coli was found to be greater than ampicillin in conditions of low, but not high, osmolality.