Left ventricular midwall function improves with antihypertensive therapy and regression of left ventricular hypertrophy in patients with asymptomatic hypertension.

Recent evidence suggests that regression of left ventricular hypertrophy (LVH) with antihypertensive therapy improves prognosis. The mechanism for this benefit is unknown but may be related to effects on myocardial performance. Midwall fractional shortening (mFS) is often depressed in patients with asymptomatic hypertension, is associated with LVH, and is a potent, independent predictor of outcome. We therefore examined whether antihypertensive therapy may improve midwall performance. mFS as well as conventional echocardiographic parameters were measured serially among 29 hypertensive persons during 6 months of drug therapy. Stress-adjusted and absolute midwall function improved by 10% and 11%, respectively (p <0.05), whereas no significant changes were detected in other measures of chamber function. Improvement in function was more pronounced in patients with concentrically remodeled ventricular geometry and in those who achieved greater reductions in left ventricular (LV) mass. Antihypertensive therapy and LV mass regression is associated with demonstrable improvements in cardiac performance when assessed using mFS. Determinations of mFS may have a promising role in identifying patients with early hypertensive heart disease, tracking responses to therapy, and in elucidating the potential beneficial effects associated with LV mass regression.

Antibiotics for myocardial infarction? A possible role of infection in atherogenesis and acute coronary syndromes.

The role of inflammatory mechanisms in the initiation, progression and clinical expression of atherosclerosis is increasingly appreciated. With this awareness, the possibility that acute or chronic infection may initiate or modulate these processes in an active area of investigation. Infectious organisms may influence the atherosclerotic process through direct local effects on the coronary endothelium, on vascular smooth muscle cells and on macrophages in the atherosclerotic lesion. Infection may also exert systemic effects by inducing the elaboration of cytokines, the creation of a hypercoagulable state and by activating monocytes, causing possible transmission of infectious material to atherosclerotic lesions. Macrophages may then elaborate multiple mediators which destabilise plaque, promoting rupture and progression. Seroepidemiological data have identified associations between clinically active atherosclerosis and evidence of infection with Helicobacter pylori, Chlamydia pneumoniae and some herpesviridae. In addition, pathological examinations have demonstrated the presence of infectious organisms in coronary artery plaques. Cytomegalovirus, for example, has been identified pathologically to be associated with transplant vasculopathy and with an increased risk of restenosis following coronary intervention. Finally, recent pilot trials have demonstrated that macrolide antibacterial treatment directed against C. pneumoniae reduces the risk of recurrent coronary events. Infectious organisms may therefore influence atherogenesis through multiple pathways, and pathological and seroepidemiological investigations provide evidence of this association. Future large-scale clinical trials are needed to further evaluate the evidence of causality and the efficacy of antibacterial therapy for coronary artery disease.

Midwall fractional shortening is an independent predictor of left ventricular diastolic dysfunction in asymptomatic patients with systemic hypertension.

Conventional measures of left ventricular (LV) systolic performance suggest that diastolic dysfunction precedes the development of systolic dysfunction in hypertension. Midwall fractional shortening is a new measure of systolic function that identifies hypertensive patients who have evidence of target-organ damage, impaired contractile reserve, and increased mortality. We therefore sought to determine whether depressed midwall fiber shortening is associated with abnormal diastolic function. Echocardiograms were obtained in 102 otherwise healthy hypertensive patients without treatment with normal conventional measures of systolic function. Of these, 15 had depressed midwall shortening based on previously described normative relations. Patients with depressed midwall shortening had slightly higher blood pressure. Abnormal diastolic function, defined as late (A) LV inflow velocity greater than early (E) velocity, was observed in 33% of those with normal midwall shortening but in 60% of those with depressed shortening (p <0.05). Patients with A/E >1 had lower absolute midwall fiber shortening (15 +/- 3% vs 18 +/- 3%, p <0.0001) but similar endocardial shortening. Patients with abnormal midwall shortening had higher A/E and longer isovolumic relaxation times (both p <0.05). In multivariate analysis, midwall fractional shortening, age, and heart rate were independent predictors (p <0.01) of A/E in a model including blood pressure, LV mass, and endocardial shortening. We conclude that subnormal midwall shortening predicts LV diastolic abnormalities in this population of hypertensive patients with otherwise normal measures of LV systolic function. Contrary to our previous understanding, depressed LV systolic performance, when identified with this newer method, occurs coincidentally with impaired diastolic function.

Antithrombotic therapy and venous graft disease.

Venous graft disease is a thromboproliferative process and places a serious limitation on the symptom-free survival of patients after coronary artery bypass grafting. The efficacy of antithrombotics, especially during the first year after surgery, is suggested by an understanding of the four described phases of disease development. Studies examining the usefulness of hemostatic factors, such as lipoprotein (a) and fibrinogen, in identifying patients at added risk for graft occlusion are reviewed. Aspirin begun within the first day after surgery remains the mainstay of current preventive therapy, but the potential for other antiplatelet agents alone or in combination is explored. In a two-by-two trial, the efficacy of low-dose oral anticoagulation with warfarin (Coumadin) was equivocal. Aggressive cholesterol reduction decreased progression and need for revascularization by 30%. Future examinations are needed to define the optimal intensity and timing of therapy and to explore the role of newer, more potent antithrombotic agents.

Regulation of cardiac myocyte contractile function by inducible nitric oxide synthase (iNOS): mechanisms of contractile depression by nitric oxide.

Inflammatory cytokines have been implicated in the reversible depression of cardiac contractile function accompanying local or systemic immune stimulation. Incubation of cardiac myocytes with soluble components in the supernatant from cultured rat lung macrophages activated with endotoxin decreases their contractile response to beta-adrenergic stimulation through the induction of iNOS and the subsequent production of nitric oxide by these cells. In the present study, we characterize the mechanisms underlying NO's attenuation of adrenergic responsiveness in cardiac myocytes. iNOS was induced in cultured ventricular myocytes from adult rats by incubation for 20 h with conditioned medium from lipopolysaccharide (LPS)-activated macrophages. iNOS induction did not induce any alteration in beta-adrenergic receptor density or affinity, Galphai protein abundance, or adenylyl cyclase activity in cultured myocytes. Myocyte exposure to activated macrophage-conditioned medium markedly attenuated the elevation of cAMP in response to isoproterenol (Iso, 2 nM). Induction of iNOS with the macrophage-conditioned medium also potentiated the Iso-induced increase in myocyte cGMP. This cGMP increase was totally abolished by NOS inhibitors. NOS inhibition also returned the attenuated cAMP response to 2 nM Iso to levels observed in control cells. Pre-incubation of the cells in isobutylmethylxanthine (IBMX), a phosphodiesterase inhibitor, also partly reversed the attenuation of cAMP increase with 2 nM Iso in cells expressing iNOS. Brief (15 min) exposure of myocytes to the NO donor, S-nitrosoacetylcysteine (SNAC, 100 micro M) which produced a three-fold increase in intracellular cGMP, also decreased by half the contractile response of cardiac myocytes to Iso (2 nM). We conclude that NO endogenously produced by iNOS decreases the intracellular levels of cAMP in response to beta-adrenergic stimulation in isolated cardiac myocytes, in part through a cGMP-mediated mechanism. This effect may participate in the NO-dependent depression of cardiac function following cytokine exposure.

Thrombosis, antithrombotic agents, and the antithrombotic approach in cardiac disease.

To develop a rational approach to antithrombotic therapy, in cardiac disease, a sound understanding is required (1) of the hemostatic processes leading to thrombosis, (2) of the various antithrombotic agents, and (3) of the relative risks of thrombosis and thromboembolism in the various cardiac disease entities. With the understanding of pathogenesis and risk of thrombus formation, a rational approach to the use of antiplatelet and anticoagulant agents can be formulated. Those at high risk of thrombus formation should generally receive a high degree of antithrombotics and, depending on the pathophysiology of the thrombus, may benefit from the concomitant use of antiplatelet and anticoagulant agents. Those with a medium risk of thrombus formation may benefit with the use of an antiplatelet agent alone or anticoagulants alone. Patients at low risk of thrombus formation should not receive antithrombotics. Such rational approach to antithrombotic therapy serves as the basis of this article.

Usefulness of subnormal midwall fractional shortening in predicting left ventricular exercise dysfunction in asymptomatic patients with systemic hypertension.

We have recently shown that a subgroup of asymptomatic hypertensive patients exhibit subnormal left ventricular (LV) midwall fiber shortening at rest and that this finding predicts morbidity and mortality independently of age, blood pressure (BP), or the presence of LV hypertrophy. However, it is unknown whether abnormal midwall fractional shortening predicts either subnormal LV functional reserve or extracardiac damage in asymptomatic hypertensive patients. Accordingly, we compared radionuclide cineangiographic LV ejection fraction at rest and maximum exercise as well as clinical findings between 89 patients with normal and 16 patients with subnormal midwall fractional shortening by echocardiogram. Patients with low midwall fractional shortening were similar in gender, age, and systolic BP to those with normal shortening but had higher mean diastolic BP and body mass indexes (both p < 0.05). The 2 groups also had similar resting ejection fraction (56 +/- 9% vs 55 +/- 15%, with normal or subnormal shortening, respectively, p = NS). Patients with subnormal midwall fractional shortening had higher LV mass and tended to have higher urinary protein excretion and serum creatinine levels. Subnormal LV ejection fraction with exercise (< 54%) was observed in 13 of 89 patients (15%) with normal midwall fractional shortening but in 7 of 16 patients (44%) with subnormal shortening (p < 0.05). Multiple linear regression analysis revealed that midwall fractional shortening independently predicted exercise performance (p < 0.001). Thus, subnormal midwall fractional shortening predicts depressed LV fractional reserve in asymptomatic hypertensive patients and may contribute to identification of patients with extracardiac target-organ damage.

Altered Na(+)- H(+)- exchange activity in the spontaneously hypertensive perfused rat heart.

Intracellular pH (pHi) and developed pressure during hypercapnic acidosis were studied in the spontaneously hypertensive rat (SHR) heart and Wistar-Kyoto controls. Developed pressure was determined using a modified Langendorff isovolumic perfusion technique and 31P magnetic resonance spectroscopy was used to determine pHi. In response to acidosis, both developed pressure and pHi first decreased and then partially recovered. In the SHR group, pHi during the early periods of acidosis was significantly higher than in the control group while there was no significant difference in the steady-state pHi. The addition of 5-(N,N)-hexamethylene-amiloride (HMA), a specific inhibitor of Na(+)-H+ exchange, abolished these difference. Furthermore, HMA was found to inhibit recovery in pHi and developed pressure during acidosis in both groups. These results demonstrate that Na(+)-H(+)-exchange in the rat heart plays a major role in pHi regulation and contributes to functional recovery during acidosis. In addition, Na(+)-H(+)-exchange activity, as previously found in other tissues in hypertension, is increased in the SHR heart.

Study of ischemic myocardial buffering capacity in perfused rat heart through rapidly interleaved 1H and 31P MRS measurements.

We present a method for the direct correlation of quantitative changes in lactate concentration and intracellular pH during global ischemia in the perfused rat heart using rapidly interleaved 31P MRS and water-suppressed 1H MRS acquisitions. The ischemic myocardial buffering capacity was determined and found to be consistent with previous experimentation.

Gallbladder disease in children and adolescents.

A 20-year experience with gallbladder disease in 85 children and adolescents was reviewed. Sixty-five patients had idiopathic cholelithiasis and cholecystitis (group I); 20 patients had cholelithiasis and cholecystitis secondary to a predisposing disease or other pathologic diagnoses (group II). For group I patients, 100% were greater than age 12, 92.3% were female, 60% were overweight, 20% had a positive family history, and 27.7% had had a previous pregnancy. For group II patients, 60% were less than age 13, 45% were female, 15% were overweight, 5% had a positive family history, and none had previously been pregnant. Symptomatology in group I, but not group II, patients matched that seen in adults. Group I, but not group II, patients experienced delays in diagnosis. These data indicate that children and adolescents with gallbladder disease constitute two distinct populations and that idiopathic cholelithiasis and cholecystitis must be considered as a potential cause of chronic abdominal pain in otherwise healthy adolescents.

Antibiotic-associated pseudomembranous colitis in siblings.

Pseudomembranous colitis induced by antibiotics is not commonly diagnosed in children. Recent developments have clarified the pathogenesis and suggested that agents such as cholestyramine are therapeutically useful. Two siblings with pseudomembranous colitis were carefully studied and may serve to alert pediatricians to an approach to this entity.

Lipoprotein-X and other tests in the diagnosis of obstructive jaundice in the infant.

The infant with elevated direct-reacting bilirubin levels requires an early specific diagnosis to identify those who would require early surgical intervention and those in whom the bilirubin levels will eventually return to normal. This study compares the accuracy of three tests: the serum lipoprotein-X (LP-X), the I131 rose bengal (IRB) excretion and the serum alpha-fetoprotein (AFP) in making a specific diagnosis in 15 patients. When used individually the accuracy of the tests varies from 56-100%. The LP-X and IRB excretion are more specific and when in agreement are 100% acurate in the diagnosis of the neonatal hepatitis syndrome (NHS) or extrahepatic biliary obstruction (EHBO). This study suggests that both the LP-X and IRB excretion should be used in the investigation of the infant with conjugated hyperbilirubinemia.

Radionuclide diagnosis of bleeding Meckel's diverticulum in children.

The preoperative diagnosis of rectal bleeding due to Meckel's diverticulum in children has major difficulties when only standard clinical and radiographic technics are utilized. During the past three years we have done 70 studies with Tc99m pertechnetate for this suspected diagnosis using scintillation camera imaging and computer analysis. Five positive cases were identified and all verified at surgery. No false positives were noted. We believe this to be a safe and available procedure that should be considered a primary diagnostic modality in the investigation of young children with suspected bleeding Meckel's diverticulum.