Disturbance of peripheral microvascular function in congestive heart failure secondary to idiopathic dilated cardiomyopathy

OBJECTIVES: Previous studies of peripheral microvascular function in human heart failure have concentrated on changes in flow, and there is little information concerning the impact of heart failure on the principal determinants of transcapillary fluid exchange. This study investigated whether alterations in capillary pressure and microvascular fluid permeability can be detected in subjects with idiopathic dilated cardiomyopathy. METHODS: Finger nailfold capillary pressure and calf capillary filtration coefficient (CFC) were measured in parallel studies of two overlapping groups of 12 non-oedematous subjects with idiopathic dilated cardiomyopathy and mild to moderate heart failure and in age- and sex-matched healthy controls. Capillary pressure was measured by direct cannulation using an electronic resistance feedback servonulling technique, and CFC by mercury-in-silastic strain gauge plethysmography using a modification of the technique which avoids assumptions concerning isovolumetric venous pressure. RESULTS: Following correction for differences in skin temperature, capillary pressure was lower in the subjects with heart failure (P = 0.02). Both CFC and isovolumetric venous pressure were greater in the subjects with heart failure than in controls (3.4 +/- 0.9 vs. 2.6 +/- 0.7 ml.min-1.mmHg-1.100 ml-1, P = 0.03; 27.1 +/- 8.4 vs. 17.2 +/- 7.2 mmHg, P = 0.01). CONCLUSIONS: These data suggest that factors other than changes in arterial inflow and venous outflow pressures are likely to play an important role in the disruption of microvascular homeostasis which occurs in heart failure. Changes in capillary hydraulic conductance may contribute to the pathogenesis of oedema.     

Oxygen transport to muscle during exercise in chronic congestive heart failure secondary to idiopathic dilated cardiomyopathy

In chronic heart failure, oxygen delivery during exercise is impaired mainly because of failure of cardiac output to increase normally. Compensatory mechanisms are hemoglobin concentration increase, right-ward shift in the oxyhemoglobin dissociation curve, and blood flow redistribution from the nonexercising organs to the exercising muscles.     

Actin mutations in dilated cardiomyopathy, a heritable form of heart failure

To test the hypothesis that actin dysfunction leads to heart failure, patients with hereditary idiopathic dilated cardiomyopathy (IDC) were examined for mutations in the cardiac actin gene (ACTC). Missense mutations in ACTC that cosegregate with IDC were identified in two unrelated families. Both mutations affect universally conserved amino acids in domains of actin that attach to Z bands and intercalated discs. Coupled with previous data showing that dystrophin mutations also cause dilated cardiomyopathy, these results raise the possibility that defective transmission of force in cardiac myocytes is a mechanism underlying heart failure.     

Retardation of skeletal development and cervical abnormalities in transgenic mice expressing a dominant-negative retinoic acid receptor in chondrogenic cells

Skeletal formation is a fundamental element of body patterning and is strictly regulated both temporally and spatially by a variety of molecules. Among these, retinoic acid (RA) has been shown to be involved in normal skeletal development. However, its pleiotropic effects have caused difficulty in identifying its crucial target cells and molecular mechanisms for each effect. Development of cartilage primordia is an important process in defining the skeletal structures. To address the role of RA in skeletal formation, we have generated mice expressing a dominant-negative retinoic acid receptor (RAR) in chondrogenic cells by using the type II collagen alpha1 promoter, and we have analyzed their phenotypes. These mice exhibited small cartilage primordia during development and retarded skeletal formation in both embryonic and postnatal periods. They also showed selective degeneration in their cervical vertebrae combined with homeotic transformations, but not in their extremities. The cervical phenotypes are reminiscent of phenotypes involving homeobox genes. We found that the expression of Hoxa-4 was indeed reduced in the cartilage primordia of cervical vertebrae of embryonic day 12.5 embryos. These observations demonstrate that endogenous RA acts directly on chondrogenic cells to promote skeletal growth in both embryonic and growing periods, and it regulates the proper formation of cervical vertebrae. Furthermore, RA apparently specifies the identities of the cervical vertebrae through the regulation of homeobox genes in the chondrogenic cells. Great similarities of the phenotypes between our mice and reported RAR knockout mice revealed that chondrogenic cells are a principal RA target during complex cascades of skeletal development.     

Abnormal regulation of retinoic acid receptor beta2 expression and compromised allograft rejection in transgenic mice expressing antisense sequences to retinoic acid receptor beta1 and beta3

Transgenic mice carrying antisense sequences common to the retinoic acid receptors (RAR) beta1 and beta3 were produced to examine roles of RARbeta1 and beta3 in the immune system. There were no significant changes of endogenous RARbeta1/beta3 expression at the mRNA level in T cells, B cells, and macrophages of the transgenic mice (AS-RARbeta1/beta3 mice). However, there was a decrease of RARbeta1/beta3 protein in the T cells, as expected. Interestingly, a drastic up-regulation (7-10 fold) of RARbeta2 messages and a significant decrease of RARbeta4 messages in AS-RARbeta1/beta3 macrophages were observed compared with that of nontransgenic macrophages. RARbeta2 protein in the transgenic macrophages was also up-regulated. This suggests that there is a dual feedback control for the RARbeta expression. A repressed RARbeta1 and beta3 expression, presumably at the protein level, likely leads to a compensatory up-regulation of RARbeta2 and repression of RARbeta4, which is less active than RARbeta2. The AS-RARbeta1/beta3 mice had no gross abnormality. However, they had compromised rejection response to cardiac allografts. The alloantigen-specific T cell cytotoxicity was reduced, and the macrophage population in the spleen was decreased in these mice. These defects likely contribute to the slower rejection response in the AS-RARbeta1/beta3 mice, the existence of other defects not being excluded. Our study has suggested that RARbeta1 and RARbeta3 are necessary to optimize immune responses.     

Compromised allograft rejection response in transgenic mice expressing antisense sequences to retinoic acid receptor beta2

Our aim was to identify new genes involved in the cellular aspects of defense mechanism of Drosophila, as well as in melanotic tumor formation processes that are linked to blood cell disregulation. We have screened 1341 enhancer detector fly lines for expression of the lacZ reporter gene in larval hemocytes at the end of the third instar. We have selected 21 lines in which we observed a reproducible lacZ expression in blood cells. These lines were classified according to the subsets of hemocytes in which lacZ was expressed, and we identified five lines that can be used as lamellocyte markers. Three lines were selected for further analysis. The first exhibited strong lacZ expression in all lamellocytes. The second expressed lacZ in plasmatocytes and lamellocytes, and exhibited a melanotic tumor phenotype in larvae homozygous for the insertion. A third line showed a striking insertion-linked phenotype of melanized lymph glands (the hematopoietic organ), which resulted in the total absence of circulating hemocytes in the mutant larvae. We anticipate that this mutation, which we named domino, will prove a useful tool in the analysis of the role of hemocytes during the various aspects of immune response and melanotic tumor formation.     

Effects of maximally tolerated oral therapy on the six-minute walking test in patients with chronic congestive heart failure secondary to either ischemic or idiopathic dilated cardiomyopathy

In patients with heart failure, therapy with "maximally tolerated" oral doses of diuretics, vasodilators, and digitalis results in a significant increase in the distance walked during the 6-minute walking test, compared with conventional therapy at "standard" doses, indicating an improvement in exercise tolerance. The 6-minute walk test is a simple, inexpensive, and well-tolerated test to measure changes in exercise tolerance induced by pharmacologic interventions, even on a short-term basis.     

Depressed heart rate variability and arterial baroreflex in conscious transgenic mice with overexpression of cardiac Gsalpha

Using a continuous recognition memory procedure for spatial location information, rats were given sequential presentation of individual arms on a 12-arm maze. Each arm contained a Froot Loop reinforcement the first time it was presented, and latency to traverse the arm was measured. A subset of the arms were repeated, but did not contain reinforcement. Repeated arms were presented with lags ranging from zero to six (from zero to six different arm presentations occurred between the first and repeated presentation). After completion of acquisition training (significantly longer latencies for repeated arms in comparison with the first presentation of an arm), rats received lesions of the medial or lateral entorhinal cortex, pre- and parasubiculum, or served as sham-operated controls. Based on continued postsurgery training and additional tests, the results indicated that rats with pre- and parasubiculum or pre- and parasubiculum plus medial entorhinal cortex produced sustained impairment in performing the task. Medial or lateral entorhinal cortex and control lesions did not display any sustained deficits. The data suggest that working memory for spatial location information is mediated primarily by the pre- and parasubiculum, but not medial entorhinal and lateral entorhinal cortex.     

Sleep apnoea: a therapeutic target in congestive heart failure

Most arteriovenous malformations usually arise from pre-existing named vessels. We report an unusual variant of an arteriovenous malformation. An 18-year-old man presented with a painful swelling of the right forearm. Arteriograms suggested branches of the anterior interosseous artery were feeding the malformation. Operative findings however, revealed the presence of a persistent median artery, which was contributing branches to the swelling.     

Unusual cause of pulmonary hypertension and congestive heart failure in a newborn

Anomalous systemic arterial supply to a lobe of the lung is a rare cause of pulmonary hypertension and congestive heart failure in the newborn period. We report the presentation and successful treatment of a neonate with this unusual anatomy. Proper diagnosis required both echocardiography and aortography, and surgical resection of the involved lobe was curative.     

Therapy of congestive heart failure in elderly persons

LVEF should be measured in all elderly persons with CHF Underlying causes and precipitating causes of CHF should be treated. Persons with CHF associated with abnormal LVEF should be treated with a low sodium diet, diuretics, and ACE inhibitors. If CHF persists, digoxin should be added. If CHF still persists, isosorbide dinitrate plus hydralazine should be added. If CHF still persists, a beta blocker should also be added. However, calcium channel blockers should not be used. Persons with CHF associated with normal LVEF should be treated with a low sodium diet, diuretics, and ACE inhibitors. If CHF persists, a beta blocker, isosorbide dinitrate plus hydralazine, or a calcium channel blocker should be added to the therapeutic regimen. If sinus rhythm is present, digoxin should not be used. Persons with CHF and abnormal or normal LVEF unable to tolerate ACE inhibitors should be treated with losartan.     

Decrease of cardiac chaos in congestive heart failure

The electrical properties of the mammalian heart undergo many complex transitions in normal and diseased states. It has been proposed that the normal heartbeat may display complex nonlinear dynamics, including deterministic chaos, and that such cardiac chaos may be a useful physiological marker for the diagnosis and management of certain heart trouble. However, it is not clear whether the heartbeat series of healthy and diseased hearts are chaotic or stochastic, or whether cardiac chaos represents normal or abnormal behaviour. Here we have used a highly sensitive technique, which is robust to random noise, to detect chaos. We analysed the electrocardiograms from a group of healthy subjects and those with severe congestive heart failure (CHF), a clinical condition associated with a high risk of sudden death. The short-term variations of beat-to-beat interval exhibited strongly and consistently chaotic behaviour in all healthy subjects, but were frequently interrupted by periods of seemingly non-chaotic fluctuations in patients with CHF. Chaotic dynamics in the CHF data, even when discernible, exhibited a high degree of random variability over time, suggesting a weaker form of chaos. These findings suggest that cardiac chaos is prevalent in healthy heart, and a decrease in such chaos may be indicative of CHF.     

Calcium antagonists and sympathetic activity in congestive heart failure

OBJECTIVE: To review the sympathetic abnormalities occurring in heart failure, their pathophysiological importance and clinical relevance, and the effects of drug treatment, with particular reference to calcium antagonists. SYMPATHETIC ACTIVATION IN HEART FAILURE: Indirect and direct approaches to study sympathetic function in humans have documented conclusively that sympathetic activation represents a hallmark of cardiac failure syndrome. Evidence indicates that sympathetic overactivity is associated with, and probably caused by, a baroreflex impairment and that it has adverse effects on patients' prognosis and survival. GOALS OF DRUG TREATMENT IN CONGESTIVE HEART FAILURE: In the past, drug treatment in heart failure was aimed at improving patients' survival by ameliorating cardiac hemodynamics. It is now established that a major goal of therapeutic intervention is also to reduce sympathetic activation characterizing heart failure. CALCIUM ANTAGONISTS IN HEART FAILURE: Studies with short-acting calcium antagonists show that they enhance sympathetic activation and that this has an adverse effect on patients' survival. In contrast, third generation calcium antagonists such as amlodipine, which have a slow onset and long duration of action, do not adversely affect sympathetic function and reflex cardiovascular control. Indeed, evidence suggests calcium antagonists with this profile may exert favorable clinical effects.     

The effects of endothelin-A receptor blockade during the progression of pacing-induced congestive heart failure

OBJECTIVES: We sought to identify the effects of endothelin (ET) subtype-A (ET(A))) receptor blockade during the development of congestive heart failure (CHF) on left ventricle (LV) function and contractility. BACKGROUND: Congested heart failure causes increased plasma levels of ET and ET(A) receptor activation. METHODS: Yorkshire pigs were assigned to four groups: 1) CHF: 240 beats/min for 3 weeks; n=7; 2) CHF/ET(A)-High Dose: paced for 2 weeks then ET(A) receptor blockade (BMS 193884, 50 mg/kg, b.i.d.) for the last week of pacing; n=6; 3) CHF/ET(A)-Low Dose: pacing for 2 weeks then ET(A) receptor blockade (BMS 193884, 12.5 mg/kg, b.i.d.) for the last week, n=6; and 4) Control: n=8. RESULTS: Left ventricle fractional shortening decreased with CHF compared with control (12+/-1 vs. 39+/-1%, p < 0.05) and increased in the CHF/ET(A) High and Low Dose groups (23+/-3 and 25+/-1%, p < 0.05). The LV peak wall stress and wall force increased approximately twofold with CHF and remained increased with ET(A) receptor blockade. With CHF, systemic vascular resistance increased by 120%, was normalized in the CHF/ET(A) High Dose group, and fell by 43% from CHF values in the Low Dose group (p < 0.05). Plasma catecholamines increased fourfold in the CHF group and were reduced by 48% in both CHF/ET(A) blockade groups. The LV myocyte velocity of shortening was reduced with CHF (32+/-3 vs. 54+/-3 microm/s, p < 0.05), was higher in the CHF/ET(A) High Dose group (39+/-1 microm/s, p < 0.05), and was similar to CHF values in the Low Dose group. CONCLUSIONS: ET(A) receptor activation may contribute to the progression of LV dysfunction with CHF.     

Exercise-related ventilatory abnormalities and survival in congestive heart failure

This retrospective study of 104 New York Heart Association class 1 to 4 heart failure patients undergoing exercise stress testing with gas exchange analysis demonstrated that the ventilatory equivalent for carbon dioxide at anaerobic threshold is useful in determining prognosis in patients with severe congestive heart failure, particularly when used in combination with peak exercise oxygen consumption. A ventilatory equivalent for carbon dioxide >50 and peak oxygen consumption < or =15.0 ml/kg/min defines a very high-risk patient group who should be prioritized for transplantation.     

Reversed ventilation-perfusion mismatch involving a pediatric patient in congestive heart failure

Over the past 13 yr, at least 11 specific etiologies of reversed ventilation-perfusion mismatch have been reported in the literature. In this article, a case of reversed ventilation-perfusion mismatch involving a patient in congestive heart failure receiving dobutamine and milrinone therapy is presented. A brief review of the topic of reversed ventilation-perfusion mismatch is presented.     

Chronic congestive heart failure. Description and survival of 190 consecutive patients with a diagnosis of chronic congestive heart failure based on clinical signs and symptoms

The malaria parasite life cycle presents several targets for attack, but these different parts of the life cycle are susceptible to different types of host immune response. For example, the sporozoite is most sensitive to immune antibody, while liver stage parasites can be eliminated by cytotoxic T lymphocytes. Attachment of merozoites to erythrocytes, on the other hand, can be blocked by antibody. Convincing experimental evidence shows that completely protective immunity to malaria can be induced. The challenge now is to design recombinant or synthetic vaccines that induce the right types of immune responses to specific life cycle stages. This requires the identification and characterization of B- and T-lymphocyte epitopes expressed by the parasite or by parasitized host cells. These epitopes must be incorporated into a delivery system that maximizes the interaction between the vaccine epitopes and the host immune system. Many epitopes from several parts of the life cycle are already characterized; development of multivalent vaccines, that is, vaccines which contain immunogens from more than one part of the life cycle, is a promising area for research efforts.