Progression from hypertrophic to dilated cardiomyopathy in mice that express a mutant myosin transgene.

A mouse model of hypertrophic cardiomyopathy (HCM) was created by expression of a cardiac alpha-myosin transgene including the R(403)Q mutation and a deletion of a segment of the actin-binding domain. HCM mice show early histopathology and hypertrophy, with progressive hypertrophy in females and ventricular dilation in older males. To test the hypothesis that dilated cardiomyopathy (DCM) is part of the pathological spectrum of HCM, we studied chamber morphology, exercise tolerance, hemodynamics, isolated heart function, adrenergic sensitivity, and embryonic gene expression in 8- to 11-mo-old male transgenic animals. Significantly impaired exercise tolerance and both systolic and diastolic dysfunction were seen in vivo. Contraction and relaxation parameters of isolated hearts were also decreased, and lusitropic responsiveness to the beta-adrenergic agonist isoproterenol was modestly reduced. Myocardial levels of the G protein-coupled beta-adrenergic receptor kinase 1 (beta-ARK1) were increased by more than twofold over controls, and total beta-ARK1 activity was also significantly elevated. Induction of fetal gene expression was also observed in transgenic hearts. We conclude that transgenic male animals have undergone cardiac decompensation resulting in a DCM phenotype. This supports the idea that HCM and DCM may be part of a pathological continuum rather than independent diseases.

Pathophysiology of sodium and water retention in heart failure.

Heart failure is a leading cause of morbidity and mortality. In the United States, there are more than 5 million patients with heart failure and over 500,000 newly diagnosed cases each year. Numerous advances have been made in our understanding of the pathophysiologic mechanisms contributing to sodium and water retention in this condition. Important alterations in the sympathetic nervous system and the renin-angiotensin-aldosterone system have been described in heart failure, allowing the use of mechanism-specific treatments such as beta-adrenergic receptor antagonism and angiotensin-converting enzyme inhibition. As our understanding of the roles of the natriuretic peptides and the arginine vasopressin-aquaporin-2 system in the pathophysiology of heart failure evolves, treatments directed toward the alterations in these systems in heart failure can be further developed.

Myocardial-directed overexpression of the human beta(1)-adrenergic receptor in transgenic mice.

The beta(1)-adrenergic receptor (AR) is the dominant subtype in non-failing and failing myocardium. beta(1)-AR signaling, by the endogenous neurotransmitter norepinephrine, is central to the regulation of myocardial contractility. In heart failure, the beta(1)-AR undergoes subtype-selective downregulation which may protect against the increased cardiac adrenergic drive associated with this pathophysiological state. To examine the hypothesis that chronically increased beta(1)-AR mediated signaling has adverse myocardial effects, transgenic mice overexpressing the human beta(1)-AR in a cardiac-selective context were produced, utilizing an alpha-myosin heavy chain (MHC) promoter. In these mice, beta(1)-AR protein abundance was approximately 24-46-fold (1-2 pmol/mg protein) that of wild-type mice. Histopathological examination of young (4 months old) and old (approximately 9 months old) transgenic mouse hearts consistently demonstrated large areas of interstitial replacement fibrosis, marked myocyte hypertrophy and myofibrilar disarray. In addition, increased expression of the pre-apoptotic marker, Bax, was observed coincident with regions of fibrosis accompanied by an increased apoptotic index, as measured by TUNEL assay. Older non-transgenic mice exhibited a slight tendency towards a decreased fractional shortening, whereas older beta(1)-AR transgenic mice had a marked reduction in fractional shortening (%FS approximately 30) as determined by echocardiography. Additionally, older beta(1)-AR transgenic mice had an increased left ventricular chamber size. In summary, cardiac-directed overexpression of the human beta(1)-AR in transgenic mice leads to a significant histopathological phenotype with no apparent functional consequence in younger mice and a variable degree of cardiac dysfunction in older animals. This model system may ultimately prove useful for investigating the biological basis of adrenergically-mediated myocardial damage in humans.

Therapy of heart failure.

The incidence and prevalence of heart failure is on the rise. It has become the single most expensive health care item in the United States and the number one discharge diagnosis in the elderly. The goals of therapy include both prevention and treatment of heart failure. In recent years research studies and randomized clinical trials have revolutionized the understanding of the pathophysiology and treatment of this disease. This article focuses on the medical management of chronic systolic heart failure based on the pathophysiology of the disease. Systolic heart failure is characterized by a decrease in left ventricular function and cardiac output, which results in activation of several neurohormonal compensatory systems. The long term effects of this neurohormonal activation leads to further deterioration of cardiac function. The use of hydralazine and nitrates to reduce the systemic vascular resistance was the first to show an improvement in mortality and morbidity. Then angiotensin converting enzyme inhibitors, by inhibiting the renin angiotensin system, demonstrated a greater improvement in mortality and morbidity. More recently the inhibition of the sympathetic stimulation with beta-blockers has been shown to have an additive effect on morbidity and mortality in combination with angiotensin-converting enzyme inhibitors. Digoxin and diuretics remain important for improving symptoms and decreasing hospitalizations but have not been shown to decrease mortality. The most recent advance in the treatment of cardiac failure is the demonstration that the aldosterone antagonists, spironolactone decreases morbidity and mortality.

Cardiac myosin heavy chains lacking the light chain binding domain cause hypertrophic cardiomyopathy in mice.

Myosin is a chemomechanical motor that converts chemical energy into the mechanical work of muscle contraction. More than 40 missense mutations in the cardiac myosin heavy chain (MHC) gene and several mutations in the two myosin light chains cause a dominantly inherited heart disease called familial hypertrophic cardiomyopathy. Very little is known about the biochemical defects in these alleles and how the mutations lead to disease. Because removal of the light chain binding domain in the lever arm of MHC should alter myosin's force transmission but not its catalytic function, we tested the hypothesis that such a mutant MHC would act as a dominant mutation in cardiac muscle. Hearts from transgenic mice expressing this mutant myosin are asymmetrically hypertrophied, with increases in mass primarily restricted to the cardiac anterior wall. Histological examination demonstrates marked cellular hypertrophy, myocyte disorganization, small vessel coronary disease, and severe valvular pathology that included thickening and plaque formation. Skinned myocytes and multicellular preparations from transgenic hearts exhibited decreased Ca2+ sensitivity of tension and decreased relaxation rates after flash photolysis of diazo 2. These experiments demonstrate that alterations in myosin force transmission are sufficient to trigger the development of hypertrophic cardiomyopathy.

Sudden infant death syndrome, child sexual abuse, and child development.

Since the introduction of the Back to Sleep Campaigns, there has been a dramatic reduction in sudden infant death syndrome in this country. Steven Blatt and Victoria Meguid review the literature surrounding sleep position. Investigators have continued efforts to find other modifiable risk factors of sudden infant death syndrome. A prospective study of more than 33,000 neonates found a link between a prolonged QT electrocardiogram interval and sudden infant death syndrome. Also discussed are investigations seeking to explain the relationship between smoking and sudden infant death syndrome. Ann Botash, Florence Jean-Louis and Mongkae Ploy Siripornsawan review the latest thinking on genital warts and their relation to specific viral etiologies and child sexual abuse. Other symptoms and signs of sexual abuse are the focus of a number of articles that can help the practitioner care for these unfortunate children. Catherine Church reviews medication options for children diagnosed with pervasive developmental disorders or autism spectrum disorders. Finally, in this article, risperidone, fluoxetine and naltrexone are reviewed.

Diagnosis and treatment of diastolic heart failure.

Up to 40% of patients with heart failure have isolated diastolic dysfunction. With proper management, the prognosis is generally more favorable than in systolic dysfunction. Distinguishing diastolic from systolic dysfunction is essential since the optimal therapy for one condition may aggravate the other. New echocardiographic methods enable accurate diagnoses.

The pulmonary circulation of homozygous or heterozygous eNOS-null mice is hyperresponsive to mild hypoxia.

Acute hypoxic vasoconstriction and development of hypoxic pulmonary hypertension (PHTN) are unique properties of the pulmonary circulation. The pulmonary endothelium produces vasoactive factors, including nitric oxide (NO), that modify these phenomena. We tested the hypothesis that NO produced by endothelial nitric oxide synthase (eNOS) modulates pulmonary vascular responses to hypoxia using mice with targeted disruption of the eNOS gene (eNOS-/-). Marked PHTN was found in eNOS-/- mice raised in mild hypoxia when compared with either controls or eNOS-/- mice raised in conditions simulating sea level. We found an approximate twofold increase in partially and fully muscularized distal pulmonary arteries in eNOS-/- mice compared with controls. Consistent with vasoconstriction being the primary mechanism of PHTN, however, acute inhalation of 25 ppm NO resulted in normalization of RV pressure in eNOS-/- mice. In addition to studies of eNOS-/- mice, the dose-effect of eNOS was tested using heterozygous eNOS+/- mice. Although the lungs of eNOS+/- mice had 50% of normal eNOS protein, the response to hypoxia was indistinguishable from that of eNOS-/- mice. We conclude that eNOS-derived NO is an important modulator of the pulmonary vascular response to chronic hypoxia and that more than 50% of eNOS expression is required to maintain normal pulmonary vascular tone.

Microtubules modulate cardiomyocyte beta-adrenergic response in cardiac hypertrophy.

The role of microtubules in modulating cardiomyocyte beta-adrenergic response was investigated in rats with cardiac hypertrophy. Male Sprague-Dawley rats underwent stenosis of the abdominal aorta (hypertensive, HT) or sham operation (normotensive, NT). Echocardiography and isolated left ventricular cardiomyocyte dimensions demonstrated cardiac hypertrophy in the HT rats after 30 wk. Cardiomyocyte microtubule fraction was assayed by high-speed centrifugation and Western blot. In contrast to previous reports of increased microtubules after acute pressure overload, microtubule fraction for HT was significantly lower than that for NT. Cardiomyocytes were exposed to either 1 microM colchicine, 10 microM taxol, or equivalent volume of vehicle. Colchicine decreased microtubules, and taxol increased microtubules in both groups. Cardiomyocyte cytosolic calcium ([Ca2+]c) and shortening/relaxation dynamics were assessed during exposure to increasing isoproterenol concentrations. The beta-adrenergic response for these variables in the HT group was blunted compared with NT. However, increased microtubule assembly by taxol partially recovered the normal beta-adrenergic response for time to peak [Ca2+]c, time to peak shortening, and mechanical relaxation variables. Microtubule assembly may play a significant role in determining cardiomyocyte beta-adrenergic response in chronic cardiac hypertrophy.

Congenital duplication of the tricuspid valve presenting as a circumscribed obstructive mass in the right ventricular outflow tract.

Congenital duplication of the tricuspid valve is a rare condition. We present a case of a 32-year-old man with an increase in intensity of a long-standing heart murmur and intermittent palpitations. The murmur was evaluated by transthoracic and transesophageal echocardiography that identified a mass in the right ventricle and right ventricular outflow tract resulting in partial obstruction of the right ventricular outflow tract. This mass was determined to be congenital duplication of the tricuspid valve by histologic examination after surgical excision.

Comparison of amlodipine and long-acting diltiazem in the treatment of mild or moderate hypertension.

The comparative effects of the once a day calcium channel antagonists amlodipine and long-acting diltiazem were assessed in a parallel design, investigator-blinded, multicenter trial in 123 patients with diastolic blood pressures ranging from 95 to 114 mm Hg before treatment. Patients were randomized to one of the two drugs and titrated at 2-week intervals to 5 or 10 mg of amlodipine or 180, 240, or 360 mg of long-acting diltiazem during a 10-week treatment period. Both drugs significantly reduced resting, sitting, standing, and 24-h ambulatory systolic and diastolic pressures. Amlodipine caused significantly greater reductions in sitting and standing systolic pressures, standing diastolic pressures, and 24-h ambulatory systolic and diastolic pressures versus diltiazem. Sitting systolic pressures were reduced from 151.9 +/- 2.0 (SE) at baseline to 137.9 +/- 1.8 mm Hg with amlodipine treatment and from 149.0 +/- 2.1 to 145.1 +/- 2.5 mm Hg with diltiazem. Sitting diastolic pressures were reduced from 100.2 +/- 0.6 to 87.8 +/- 1.0 mm Hg with amlodipine and from 101.1 +/- 1.0 to 91.9 +/- 1.1 mm Hg with diltiazem. Reductions in standing systolic pressures after treatment were -12.1 +/- 1.5 mm Hg amlodipine v -4.6 +/- 1.5 mm Hg diltiazem (P < .01), and reductions in standing diastolic pressures were -11.8 +/- 0.9 mm Hg amlodipine v -8.6 +/- 0.9 mm Hg diltiazem (P < .02). Heart rates did not change significantly with either drug during the study. Two subjects in each group dropped out because of adverse experiences. Although both agents were well tolerated and reduced blood pressures consistently over the 10-week test period, amlodipine was more effective than diltiazem in reducing systolic and diastolic blood pressures to the target pressures of < 140 mm Hg systolic and < 90 mm Hg diastolic over a range of doses widely used in clinical practice.

Small peptide libraries: combinatorial split-mix synthesis followed by combinatorial amino acid analysis of selected variants.

Peptides from small combinatorial libraries, covalently attached to polymeric TentaGel beads, can be directly sequenced using amino acid analysis. For libraries with restricted diversity, generated by the split-mix synthesis method, the amino acids on a selected single bead identified by pre-column derivatization with o-phthaldialdehyde (OPA) correlate directly with the sequence of a given peptide. This is shown on a tripeptide (343 different compounds) and a tetrapeptide (4096 different compounds) library. This method allows for rapid peptide sequence determination without relying on complex encoding strategies.

Autism, child abuse, and sudden infant death syndrome.

The current literature regarding the standard and nonstandard therapies for children with autism is reviewed. A long term, comprehensive, individualized, multidisciplinary approach remains the best treatment. Physicians caring for the victims of child abuse are frequently asked to render an opinion regarding soft-tissue bruising. A review of the literature suggests that estimation of the age of a bruise should not rely solely on color, but rather should be the result of careful history, a through physical examination, and possibly laboratory testing. The need for a standardized and systematic approach to sudden infant death syndrome is also reviewed. The psychological effects on the parents following sudden infant death is discussed and reveals maternal anxiety and depression and, to a lesser degree, paternal anxiety and depression following the loss of a child. Currently, sleep position continues to be a risk factor for sudden infant death syndrome, although immunizations may not be.

Child abuse, sudden infant death syndrome, and psychosocial development.

A review of the literature on child abuse continues to emphasize the importance of careful attention to physical findings. Children who are allegedly sexually abused very often have no abnormal physical findings, yet they may be subjected to repeat examinations in an attempt to document possible physical effects of the abuse. Information is reviewed about the potential psychologic impact of these repeated assessments on young children. Controversy regarding the etiology of sudden infant death syndrome persists, and risk factors are reviewed. Changes in recommendations for infant sleep position by the American Academy of Pediatrics are not universally implemented. The importance of death scene investigations in cases of sudden unexplained infant death is emphasized. A review of the current research on infant colic does not provide many new insights, and the etiology remains controversial. The primary care pediatrician has an important role in providing advice and counseling, albeit on an empiric basis.

HIV and family living. Preventing the spread of HIV and other diseases.

AIDS: HIV is spread through direct contact with body fluids, such as blood, semen, vaginal fluids, and breast milk. HIV is not spread through everyday contact. People with HIV are not dangerous to the people they live with at home or in the community and with whom they have ordinary, non-sexual contact. Certain precautions should be taken, however, to minimize risk. First, personal items such as razors, toothbrushes or earrings, should not be shared. Latex gloves should be worn by uninfected family members when they may come into contact with bodily fluids, and the family members should always wash their hands with soap and water after touching blood and other fluids, even if gloves have been worn. The person with HIV can be protected by minimizing exposure to food-borne illnesses carried by raw or undercooked meat, eggs or unpasteurized milk; limiting contact with people who have colds, the flu or diarrhea; and avoiding contact with cages or litter boxes of pets. To help clarify sanitary measures, some frequently asked questions are answered. These questions address the safety of sharing food with HIV-infected people; chickenpox infection and emergence of shingles; prevention of CMV infection; toxoplasmosis and cats; spread of M. avium complex (MAC); and the safety of contact between HIV-infected people and infants.^ieng

Child abuse, sudden infant death syndrome, and attention-deficit hyperactivity disorder.

A review of recent literature helps to clarify normal variations in the physical examination of children who are thought to have been sexually abused. In many instances, no abnormal physical findings are discovered. Clinicians must continue to pay careful attention to the history and work with other professionals to implement appropriate management, despite the lack of physical findings. Guidelines for evaluating sudden and unexpected infant deaths are reviewed. The current recommendations of the American Academy of Pediatrics for infant sleep positions are discussed in light of epidemiologic studies in the United States and other countries. Attention-deficit hyperactivity disorder appears to respond best to a combination of stimulant medication, parent training in coping with behavior of affected children, and social skill training for the affected children themselves. A review of recent research failed to reach consistent correlations between resistance to thyroid hormone and attention-deficit hyperactivity disorder.