Levosimendan enhances left ventricular systolic and diastolic function in conscious dogs with pacing-induced cardiomyopathy.

We examined the left ventricular (LV) mechanical actions of levosimendan (LSM) before and after the development of pacing-induced cardiomyopathy in conscious dogs chronically instrumented for measurement of aortic and LV pressure, +dP/dt, subendocardial segment length, and cardiac output (CO). The slope (Mw) of the regional preload recruitable stroke work relation was used to assess myocardial contractility. Diastolic function was evaluated with a time constant of isovolumic relaxation (tau), the maximal rate of segment-lengthening velocity (dL/dt), and a regional chamber-stiffness constant (Kp). On different experimental days, dogs were assigned to receive LSM (12- or 24-microgram/kg loading dose and 0.2 or 0.4 microgram/kg/min infusion) before rapid ventricular pacing was initiated. Dogs were then paced at 240 beats/min for 22 +/- 2 days, and the low and high doses of LSM were repeated on separate days. LSM increased Mw and +dP/dt in dogs before the initiation of pacing, consistent with enhanced myocardial contractility. LSM also improved indices of LV diastolic function (decreases in tau and Kp and increases in dL/dt) in dogs before pacing. Rapid ventricular pacing over a 3-week period increased LV end-diastolic pressure and produced systolic (decreases in Mw and +dP/dt) and diastolic (increases in tau and Kp and decreases in dL/dt) dysfunction. LSM significantly (p < 0.05) increased Mw (54 +/- 3 to 98 +/- 6 mm Hg) +dP/dt and dL/dt (57 +/- 13 to 72 +/- 13 mm/s) and decreased tau (66 +/- 4 to 52 +/- 3 ms) and Kp (1.14 +/- 0.14 to 0.71 +/- 0.03 mm-1) in the presence of LV dysfunction. In contrast to the findings in normal dogs, however, LSM did not alter heart rate and calculated indices of myocardial oxygen consumption in dogs after pacing. The findings indicate that LSM produces favorable alterations in hemodynamics and positive inotropic and lusitropic effects in conscious dogs with left ventricular dysfunction.

Temporal dependence of coronary collateral development.

OBJECTIVE: Previous evidence suggests that episodes of myocardial ischemia of sufficient duration and intensity are required to produce coronary collateral development during repetitive coronary occlusion. This investigation tested the hypothesis that coronary collateral development is also temporal-dependent. METHODS: Chronically instrumented dogs (n = 16) were subjected to brief (2 min) left anterior descending coronary artery (LAD) occlusions, once every hour, 8 h a day, for 3 weeks or once every hour, 24 h a day for 1 week. Collateral perfusion (radioactive microspheres), LAD contractile function (ultrasonic crystals), and post-occlusive flow debt repayment (LAD flow probe) were measured during occlusions 1, 55, 105, and 155. RESULTS: Increases (P < 0.05 in subendocardial collateral blood flow to ischemic myocardium, progressive normalization of contractile function during LAD occlusion, and successive reduction in flow debt repayment were observed in dogs receiving occlusions over 3 weeks. In contrast, dogs receiving the same number of coronary occlusions over 1 week demonstrated minimal increases in collateral blood flow, persistent regional contractile dysfunction, and sustained flow debt repayment. CONCLUSIONS: The results demonstrate that LAD collateral development in response to repetitive coronary occlusion requires sufficient time for growth adaptation of the collateral circulation to occur.

Effects of levosimendan on left ventricular function: correlation with plasma concentrations in conscious dogs.

OBJECTIVES: To test the hypothesis that the hemodynamic and left ventricular functional actions of levosimendan (Orion Pharmaceutica, Espoo, Finland), a new myofilament calcium sensitizer with phosphodiesterase-inhibiting properties, in conscious dogs are correlated with plasma concentrations of the drug measured with reverse-phase, high-performance liquid chromatography. DESIGN: Prospective investigation. SETTING: Research laboratory. PARTICIPANTS: Fifteen chronically instrumented dogs. INTERVENTIONS: On different experimental days, dogs were assigned to receive intravenous levosimendan (12 or 24 micrograms/kg loading dose and 0.2 or 0.4 microgram/kg/min infusion, respectively). MEASUREMENTS AND MAIN RESULTS: Systemic and coronary hemodynamics, left ventricular function, and plasma concentrations were determined at scheduled intervals during and after levosimendan infusions. Levosimendan increased heart rate and cardiac output and decreased left ventricular end-diastolic pressure and systemic vascular resistance. Levosimendan caused dose-related enhancement of left ventricular systolic (increases in regional preload recruitable stroke work slope and +dP/dtmax) and diastolic functions (decreases in the time constant of isovolumic relaxation and regional chamber stiffness). The elimination half-life of levosimendan was 0.76 +/- 0.04 hours. CONCLUSIONS: The hemodynamic actions and left ventricular functional effects of levosimendan correlated closely with plasma concentrations and returned to baseline values within 3 hours after discontinuation of the drug.

Levosimendan potentiates the inotropic actions of dopamine in conscious dogs.

We examined the hemodynamic and left ventricular (LV) functional actions of dopamine with and without levosimendan in dogs chronically instrumented for measurement of aortic and LV pressure, +dP/dtmax, subendocardial segment length, and cardiac output (CO). On different experimental days, dogs were randomly assigned to receive dopamine (2.5, 5.0, and 10.0 micrograms kg-1 min-1) in the absence and presence of levosimendan (0.125, 0.25, and 0.5 microgram kg-1 min-1) or levosimendan alone. Dopamine increased heart rate (HR), CO, stroke volume (SV), and pressure-work index (PWI) and decreased systemic vascular resistance (SVR). Dopamine also increased LV systolic and end-diastolic pressures (LVSP and LVEDP) and mean arterial pressure (MAP). Dopamine caused dose-related positive inotropic [increases in preload recruitable stroke work (Mw) and + dP/ dtmax] and lusitropic effects [decreases in the time constant of isovolumic relaxation (tau) and increases in maximum segment-lengthening velocity (dL/dtmax)]. Dopamine also increased the regional chamber thickness constant (Kp) concomitant with increases in LVEDP. In the presence of levosimendan, dopamine-induced increases in HR, PWI, CO, and SV and decreases in SVR were enhanced. Increases in MAP, LVSP, and LVEDP observed with dopamine alone were attenuated by the addition of levosimendan. Dopamine-induced increases in Mw and +dP/dtmax were enhanced by levosimendan. Reductions in tau and increases in dL/dtmax produced by dopamine were similar with and without levosimendan. However, levosimendan abolished increases in Kp caused by dopamine alone. Levosimendan alone caused dose-related improvements in indices of LV systolic and diastolic function. The results indicate that levosimendan potentiates the positive inotropic effects of dopamine in conscious, unsedated dogs, while attenuating the deleterious action of dopamine on chamber compliance.

Comparison of the cardiovascular effects of two novel superoxide dismutase mimetics, SC-55858 and SC-54417, in conscious dogs.

The hemodynamic actions and left ventricular mechanical effects of two new superoxide dismutase mimetics, SC-55858 [Manganese (II) dichloro (2R,3R,8R,9R-bis-cyclohexano-1,4,7,10,13-pentaazacyclopentadeca ne)] (n = 10) and SC-55417 [Manganese (II) dichloro (trans-2,3-cyclohexano-1,4,7,10,13-pentaazacyclopentadecane) ] (n = 8), were studied in chronically instrumented dogs in the conscious state and after 30 min equilibration at 0.033, 0.067, 0.233, and 0.667 microM.kg-1.min-1 SC-55858 or SC-54417 (total doses of 1, 2, 7, and 20 microM.kg-1). SC-55858 and SC-54417 increased heart rate and decreased mean arterial pressure and left ventricular systolic and end-diastolic pressures. SC-55858 decreased preload recruitable stroke work slope and +dP/dtmax and increased the time constant of isovolumic relaxation, consistent with a direct negative inotropic and lusitropic effect. In contrast, SC-54417 did not depress left ventricular systolic and diastolic function. Decreases in mean arterial pressure caused by SC-55858 may be secondary to negative inotropic effects and reduction in cardiac preload. In contrast, SC-54417 does not depress myocardial contractility but also reduces arterial pressure via venodilation.

Heart failure with normal systolic function: a common disorder in older people.

OBJECTIVE: To review the incidence, pathophysiology, significance, diagnosis, and treatment of heart failure with normal systolic function in older patients. DATA SOURCE: Scientific reports of diastolic ventricular dysfunction in both the general population and the geriatric population were identified from repeated searches of the MEDLINE database and citations from appropriate articles. STUDY SELECTION: Studies were included only if they demonstrated proper methodology, were from a reputable source, and were published in a peer-reviewed journal. DATA EXTRACTION AND SYNTHESIS: Relevant data were obtained from the articles, with special importance placed on studies designed to examine older patients exclusively or as part of a subgroup in a larger study. Emphasis was placed on data pertaining to the pathophysiology, prognosis, and diagnosis of patients with diastolic dysfunction compared with normals and patients with systolic dysfunction as an etiology of heart failure. Therapeutic interventions were selected for the presence of prospective data with concrete end points such as mortality, functional class, exercise capacity, and regression of left ventricular hypertrophy. CONCLUSION: Diastolic ventricular dysfunction is a significant problem in older people, with at least 40% of older heart failure patients having diastolic dysfunction as the etiology of their heart failure. The pathophysiology of diastolic dysfunction is varied but usually involves impaired left ventricular relaxation and/or increased ventricular stiffness, each partially related to normal aging changes, as well as underlying cardiovascular diseases. The significance of heart failure caused by diastolic dysfunction is great, with increased morbidity and mortality compared with other cardiac diseases that have the same preserved systolic function. Diagnosis of diastolic dysfunction can be clinically difficult and often requires further testing to determine if diastolic dysfunction is present. At this time, no therapy specifically treats diastolic dysfunction, but several medications, such as diuretics, calcium channel blockers, beta blockers, and angiotension-converting enzyme inhibitors, offer symptomatic relief and may prevent progression of the disorder.

CT or US-guided fine needle aspiration biopsy in gastric neoplasms.

Gastric carcinoma of the linitis plastica type is occasionally difficult to diagnose endoscopically because of the large inflammatory response and the sparsity of tumor cells. Five patients who presented with signs and symptoms of gastric carcinoma underwent upper gastrointestinal endoscopy to confirm the diagnosis of carcinoma. In each case the gross appearance of the stomach was felt to represent gastric carcinoma but the biopsy and/or brushing specimens were unable to make the diagnosis. Ultrasound or CT in each of these five patients demonstrated thickening of the gastric wall and, in one instance, evidence of extensive metastatic disease. Fine needle aspiration biopsy was performed and a diagnosis of adenocarcinoma was made cytologically. Four were primary gastric adenocarcinoma of the linitis plastica type and one was metastatic adenocarcinoma from the breast. It is suggested that guided aspiration biopsy be performed when the diagnosis of gastric carcinoma cannot be confirmed endoscopically.