Douglas F. Larson

The mitral valve orifice method for noninvasive two-dimensional echo Doppler determinations of cardiac output.

We developed and validated a mitral valve orifice method for Doppler cardiac output determination. In 15 open-chest dogs, cardiac output was controlled and measured by a roller pump interposed between the right atrium and pulmonary artery as a right-heart bypass. Left heart flows were measured in the open-chest dog model by Doppler measurements at the mitral valve orifice and compared not only to volume flow measured by the roller pump, but to electromagnetic flow meters as well. The maximum mitral valve orifice area was measured off short-axis two-dimensional echocardiographic views by planimetry. The maximal orifice was then adjusted for its diastolic variation in size by calculating a ratio of mean-to-maximal mitral valve separation on a derived M-mode echocardiogram. Flow was sampled parallel to mitral valve inflow in a four-chamber plane. The multiplication of mean flow throughout the cardiac cycle by the mean mitral valve area after correction for diastolic size variation yielded a cardiac output determination that could be compared to the roller pump measurement. Fifty-two cardiac output determinations over roller pump values of 1–5 1/min yielded a high correlation between roller pump flows and Doppler (r = 0.97 + 0.23 1/min). Our study shows that the mitral valve orifice provides an accurate site for Doppler cardiac output measurements.

Prolactin receptors on human lymphocytes and their modulation by cyclosporine

Prolactin receptors have been identified for the first time on human peripheral blood lymphocytes. These receptors are present on T- and B-cells as well as monocytes. The specific binding of [125I]prolactin to these cells can be selectively enhanced at certain concentrations and blocked by higher concentrations of cyclosporine , a known immunosuppressive agent which inhibits the mitogenesis of T-cells. Prolactin also induces ornithine decarboxylase, a key growth regulatory enzyme, in lymphocytes. Therefore, we suggest that the lymphocyte prolactin receptor may be involved in regulating lymphocyte function, and that one of the actions of cyclosporine is to block this rather ubiquitously occurring receptor.

Inflammatory cytokine inhibition of erythropoiesis in patients implanted with a mechanical circulatory assist device.

Mechanical circulatory assist devices (MCADs) are increasingly utilized independently of cardiac transplantation in the management of heart failure. Though MCAD use incorporates inherent mechanical risks, the inevitable onset of chronic anemia, with its associated morbidity and mortality, is also a significant concern. MCAD support has been correlated with elevated plasma levels of inflammatory cytokines TNF-α, IL-1b, and IL-6, which have separately been found to inhibit erythropoietin (Epo)-induced erythrocyte (RBC) maturation. Previous analysis of hematological parameters for MCAD-sup-ported patients concluded that an amplified inflammatory response impedes RBC proliferation and recovery from hemolytic anemia. Additional analysis may bolster this assertion. Hemoglobin concentration (HC), RBC distribution width (RDW), mean cell volume (MCV), and cardiac index were retrospectively analysed for 78 MCAD-supported patients implanted for greater than 30 days at the University of Arizona Health Sciences Center from 1996 to 2002. Analysis confirms that the HC, a conventional marker for anemia, declines with MCAD placement and remains below the clinically defined, minimum normal value. Inversely, the RDW rises above maximum normal measure, signifying an increased fraction of juvenile RBCs. The MCV remains unchanged and within normal limits, demonstrating adequate substrate for RBC formation. MCAD performance also stabilizes as adequate perfusion returns. These results further support our previously published conclusion that a sufficient response of erythropoiesis occurs in reaction to the onset of anemia by an increased production of immature RBCs. However, the cells never fully mature and join circulation. The patient’s inflammatory cytokine response to the implanted device most likely mediates the chronic MCAD-induced anemia by inhibition of Epo effects.

Cerebral blood flow in the diabetic patient

Diabetes is a major risk factor for cardiovascular disease. Coronary revascularization utilizing cardiopulmonary bypass (CPB) is frequently required for the diabetic patient. Nondiabetic individuals can autoregulate cerebral blood flow (CBF) through metabolic and perfusion pressure mechanisms during CPB. However, it has been reported that diabetic patients have impaired CBF autoregulation during CPB. It is possible, therefore, that impaired CBF autoregulation may contribute to postoperative neuropsychologic dysfunction. The mechanisms for this defect may reside in impaired endothelial-dependent responses in the diabetic that are related to morphological and functional changes linking the vascular endothelium and the vascular smooth muscle. The morphological changes occurring in the diabetic include microangiopathy and macroangiopathy which are characterized by endothelial cell (EC) hyperplasia and basement membrane thickening. Also, significant functional changes in local control of vascular tone, such as an imbalance in the synthesis and secretion of vasoactive factors by the EC and abnormal reactivity of the vascular smooth muscle, are seen in the diabetic when compared to the nondiabetic. More specifically, vascular responses to both calcium-dependent pathways of vasoconstriction and nitric oxide pathways of vasorelaxation have been shown to significantly differ between the diabetic and nondiabetic. The emphasis of this discussion is to examine the molecular mechanisms by which diabetes alters vascular function, with emphasis placed on regulation of cerebral artery blood flow during CPB.

Age-related left ventricular function in the mouse: analysis based on in vivo pressure-volume relationships

Our study compared left ventricular (LV) function between senescent and young adult mice through in situ pressure-volume loop analysis. Two groups of mice ( n = 9 each), 6-mo-old and 16-mo-old (senescent) mice, were anesthetized with urethan and α-chloralose, and their LV were instrumented with a Millar 1.4-Fr conductance micromanometer catheter for the acquisition of the pressure-volume loops. The senescent mice had a significantly decreased contractile function related to load-dependent parameters, including stroke volume index, ejection fraction, cardiac output index, stroke work index, and maximum derivative of change in systolic pressure over time. The load-independent parameters, preload recruitable stroke work and the slope (end-systolic volume elastance) of the end-systolic pressure-volume relationship, were significantly decreased in the senescent mice. Heart rate and arterial elastance were not different between the two groups; however, the ventricular-to-vascular coupling ratio (ratio of elastance of artery to end-systolic volume elastance) was increased by threefold in the senescent mice ( P < 0.001). Thus there were significant decreases in contractile function in the senescent mouse heart that appeared to be related to reduced mechanical efficiency but not related to arterial elastance.Our study compared left ventricular (LV) function between senescent and young adult mice through in situ pressure-volume loop analysis. Two groups of mice (n = 9 each), 6-mo-old and 16-mo-old (senescent) mice, were anesthetized with urethan and alpha-chloralose, and their LV were instrumented with a Millar 1.4-Fr conductance micromanometer catheter for the acquisition of the pressure-volume loops. The senescent mice had a significantly decreased contractile function related to load-dependent parameters, including stroke volume index, ejection fraction, cardiac output index, stroke work index, and maximum derivative of change in systolic pressure over time. The load-independent parameters, preload recruitable stroke work and the slope (end-systolic volume elastance) of the end-systolic pressure-volume relationship, were significantly decreased in the senescent mice. Heart rate and arterial elastance were not different between the two groups; however, the ventricular-to-vascular coupling ratio (ratio of elastance of artery to end-systolic volume elastance) was increased by threefold in the senescent mice (P < 0. 001). Thus there were significant decreases in contractile function in the senescent mouse heart that appeared to be related to reduced mechanical efficiency but not related to arterial elastance.

The effect of variations of pulsed Doppler sampling site on calculation of cardiac output: an experimental study in open-chest dogs.

We measured aortic flow by two-dimensional Doppler echocardiography in an open-chest dog model to examine how variations in Doppler sample volume length and position influence aortic hemodynamic flow calculations. Fourteen dogs underwent right-heart bypass, in which venous return from the venae cavae drained by gravity to a reservoir. A variable-speed roller pump returned the blood to the pulmonary artery, fixing left-sided cardiac input and output. Echo Doppler measurements were performed using a 3.5-MHz transducer placed directly on the aortic arch to determine internal aortic cross-sectional area. The transducer was then directed to image the aortic arch for Doppler velocity measurements and the various sampling sites were investigated. Doppler cardiac output could then be determined for each of the various sample volumes over a range of known roller pump settings. Doppler velocity was analyzed using fast Fourier transform spectral analysis. Mean velocity over the cardiac cycle was obtained by planimetry of the area under the Doppler velocity curve with a minicomputer. Doppler-derived determinations of cardiac output achieved a correlation of r = 0.98–0.99 to values obtained by the roller pump over a range of cardiac outputs from 0.75–5 1/min. The standard error of the estimate was 0.2 I/min. In this laminar flow model, there was no difference between the predictive accuracy of any of the sampling sites over the range of roller pump flows. Our study shows that Doppler velocity measurements can be used to quantify aortic flow over a clinically useful range and that variations of sample length and position did not produce significant differences in calculated flows.

Role of T Lymphocytes in Hypertension-Induced Cardiac Extracellular Matrix Remodeling

Cardiac remodeling in response to pressure overload involves reorganization of the myocytes and extracellular matrix (ECM). Neurohormonal pathways have been described as effector pathways in left ventricular ECM reorganization in response to pressure overload; we now are assessing the role of the T lymphocyte in this process. Mice with defined differences in T-lymphocyte function (C57BL/6 SCID, C57BL/6 WT, and BALB/c) were treated with 50 mg/L of NG-nitro-l-arginine methyl ester in their drinking water for 30 days. The immune function of C57BL/6 WT mice was T-helper type 1 (TH1), BALB/c was TH2, and C57BL/6 SCID was null. The arterial blood pressure increased by 30% in all of the strains of mice. However, ventricular stiffness significantly decreased in the C57 SCID, significantly increased in the BALB/c, and did not change in the C57 WT. The characterization of matrix metalloproteinase induction and activation on day 30 was associated with T-lymphocyte function. The total cardiac fibrillar collagen, percentage of fibrillar collagen cross-linking, and the activity of the cross-linking enzyme lysyl oxidase-like–3 (LOXL-3) significantly decreased in the C57 SCID, significantly increased in the BALB/c, and did not change in the C57 WT. This study revealed that the LOXL-3 pathway, namely, gene expression, enzymatic activities, and LOXL-3–mediated collagen cross-linking, was associated with ventricular stiffness and incongruence with lymphocyte function. These data support the concept that the T lymphocytes may play a fundamental regulatory role in cardiac ECM composition through modulation of collagen synthesis, degradation, and cross-linking.

Heart disease, methamphetamine and AIDS.

Methamphetamine (MA) not only affects the nervous system but also has cardiac toxicity and immunosuppressive properties. This manuscript will provide support that there is a relationship between MA use and heart disease as well as immune dysfunction. The cardiovascular manifestations of acute MA use include tachycardia, atrioventricular arrhythmias, myocardial ischemia, myocardial ischemia and hypertension, resulting in cardiac lesions. Chronic use of MA causes cardiomyopathy including cellular infiltration, myocardial hypertrophy, myocardium rupture and fibrosis. The increased catecholamine levels are responsible for the cardiac lesions induced by MA. The additional problem with MA use is its potential to disrupt the immune system function leading to suppression of mitogen-stimulated lymphocyte, a reduction in circulating lymphocyte numbers and alternation T-lymphocyte cytokine secretion as well as B cell proinflammatory cytokine secretion. Concomitant MA use and Human Immunodeficiency Virus (HIV) infection not only enhances immunosuppression associated with HIV but also increases the heart disease occurrence with a coincidentally complication of AIDS or AIDS medications.

Side-Stream Cigarette Smoke Induces Dose-Response in Systemic Inflammatory Cytokine Production and Oxidative Stress

Side-stream cigarette smoke (SSCS), a major component of secondhand smoke, induces reactive oxygen species, which promote oxidative damage in tissues and organs. Inflammatory cytokines play an important role in the pathogenesis of atherosclerosis and heart failure. The present 4-month study examined the effect of various chronic SSCS exposure levels on splenic inflammatory cytokine secretion, heart contractile function, and pathology at 60- and 120-min per day, 5 days per week, for a total of 16 weeks. Tissue vitamin E level and lipid peroxide production also were tested to estimate the oxidative stress. The study found that the pro-inflammatory cytokines, interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-1β, significantly increased in 120-min SSCS-exposed mice. Decreased stroke volume and increased peripheral arterial resistance were observed in mice exposed to 120-min SSCS per day. Heart pathology was only found in 120-min SSCS-exposed mice. Cardiac and hepatic antioxidant vitamin E levels were decreased as a result of oxidative stress. Hepatic lipid peroxides were Increased upon 60-min SSCS exposure. The data also demonstrated that the cardiac α-tocopherol level has a strong correlation with stroke volume; splenic IL-1β has a strong negative correlation with stroke volume; splenic TNF-α has a very strong negative correlation with stroke volume. In conclusion, SSCS exposure induced systemic inflammatory responses. SSCS exposure also accentuated systemic lipid peroxidation with depletion of cardiac and hepatic antioxidant vitamin E level. Finally, SSCS exposure at 120 min per day decreased stroke volume and increased vascular resistance. Systemic IL-1 β and TNF-α production are responsible for heart contractile dysfunction. Free radicals may be responsible for the progression to heart contractile dysfunction induced, in part, by SSCS. Oxidized lipoprotein could contribute to the vascular functional changes. Exploring the mechanism of vascular dysfunction in mice is warranted. A more precise quantification of the smoking exposure dose in mice needs to be determined as well.

DIURESIS WITH CONTINUOUS INFUSION OF FUROSEMIDE AFTER CARDIAC SURGERY

We prospectively evaluated the diuretic effect of furosemide administered by bolus injection and by continuous infusion in 18 cardiac surgery patients. Nine patients were randomly assigned to receive 0.3 mg/kg of furosemide as a bolus injection at time 0 and again 6 hours later (nine patients) or 0.05 mg/kg per hour of furosemide as a constant infusion for 12 hours (nine patients). There were no significant differences between groups with respect to age, weight, creatinine clearance, changes in serum sodium and potassium levels, total urinary concentrations of sodium and potassium, or total urine volume for 12 hours. Diuresis during continuous infusion of furosemide was less variable from hour to hour than after bolus injection of furosemide and was sustained throughout the infusion period. Although the continuous infusion of furosemide will not provide the rapid and vigorous diuresis that is necessary in some clinical situations, it may be useful whenever a gentle, sustained diuresis is desired.