Effects of avertin versus xylazine-ketamine anesthesia on cardiac function in normal mice.

Anesthetic regimens commonly administered during studies that assess cardiac structure and function in mice are xylazine-ketamine (XK) and avertin (AV). While it is known that XK anesthesia produces more bradycardia in the mouse, the effects of XK and AV on cardiac function have not been compared. We anesthetized normal adult male Swiss Webster mice with XK or AV. Transthoracic echocardiography and closed-chest cardiac catheterization were performed to assess heart rate (HR), left ventricular (LV) dimensions at end diastole and end systole (LVDd and LVDs, respectively), fractional shortening (FS), LV end-diastolic pressure (LVEDP), the time constant of isovolumic relaxation (tau), and the first derivatives of LV pressure rise and fall (dP/dt(max) and dP/dt(min), respectively). During echocardiography, HR was lower in XK than AV mice (250 +/- 14 beats/min in XK vs. 453 +/- 24 beats/min in AV, P < 0.05). Preload was increased in XK mice (LVDd: 4.1 +/- 0.08 mm in XK vs. 3.8 +/- 0.09 mm in AV, P < 0.05). FS, a load-dependent index of systolic function, was increased in XK mice (45 +/- 1.2% in XK vs. 40 +/- 0.8% in AV, P < 0.05). At LV catheterization, the difference in HR with AV (453 +/- 24 beats/min) and XK (342 +/- 30 beats/min, P < 0.05) anesthesia was more variable, and no significant differences in systolic or diastolic function were seen in the group as a whole. However, in XK mice with HR <300 beats/min, LVEDP was increased (28 +/- 5 vs. 6.2 +/- 2 mmHg in mice with HR >300 beats/min, P < 0.05), whereas systolic (LV dP/dt(max): 4,402 +/- 798 vs. 8,250 +/- 415 mmHg/s in mice with HR >300 beats/min, P < 0.05) and diastolic (tau: 23 +/- 2 vs. 14 +/- 1 ms in mice with HR >300 beats/min, P < 0.05) function were impaired. Compared with AV, XK produces profound bradycardia with effects on loading conditions and ventricular function. The disparate findings at echocardiography and LV catheterization underscore the importance of comprehensive assessment of LV function in the mouse.

Load versus humoral activation in the genesis of early hypertensive heart disease.

BACKGROUND: The role of load versus angiotensin II (Ang II) and endothelin-1 (ET) in the pathogenesis of hypertensive heart disease is controversial. We sought to determine whether alterations in cardiac structure and function due to hypertension (HTN) were dependent on Ang II or ET activation. Methods and Results-- Bilateral renal wrapping to produce HTN (n=12) or sham surgery (n=6) was performed in adult dogs. Weekly blood pressure, plasma renin activity, Ang II, ET, and catecholamines were measured. Systolic (end-systolic elastance, Ees) and diastolic (tau) function were assessed in sham and HTN dogs at 5 (HTN-5wk) or 12 (HTN-12wk) weeks. Ang II and ET were assayed in the left ventricle (LV) and kidney. Mean arterial pressure was higher in renal wrap dogs at week 1 (*P<0.05 versus controls: 139+/-4* versus 123+/-4 mm Hg), week 5 (174+/-7* versus 124+/-4 mm Hg), and week 12 (181+/-12* versus 124+/-4 mm Hg). LV mass index was increased in HTN-5wk (22%*) and HTN-12wk (39%*). LV fibrosis was increased in HTN-12wk. Ees was preserved in HTN-5wk and HTN-12wk. tau was increased in HTN-5wk (50+/-3* ms) and HTN-12wk (62+/-10* ms) dogs compared with sham (41+/-2 ms). Plasma Ang II, ET, catecholamines, and plasma renin activity were unchanged during the progressive HTN. Ang II and ET in LV and kidney were not different from controls. CONCLUSIONS: Systemic HTN induces LV hypertrophy, myocardial fibrosis, and isolated diastolic dysfunction in the absence of local or systemic activation of Ang II or ET. These findings suggest that load is the prevailing stimulus for the structural and functional changes associated with early hypertensive heart disease.

Differential effects of natriuretic peptides and NO on LV function in heart failure and normal dogs.

beta-Adrenergic hyporesponsiveness in congestive heart failure (CHF) is mediated, in part, by nitric oxide (NO). NO and brain natriuretic peptide (BNP) share cGMP as a second messenger. Left ventricular (LV) function and inotropic response to intravenous dobutamine (Dob) were assessed during sequential intracoronary infusion of saline, HS-142-1 (a BNP receptor antagonist), and HS-142-1 + N(G)-monomethyl-L-arginine (L-NMMA) in anesthetized dogs with CHF due to rapid pacing and in normal dogs during intracoronary infusion of saline, exogenous BNP, and sodium nitroprusside (SNP). In CHF dogs, intracoronary HS-142-1 did not alter the inotropic response to Dob [percent change in first derivative of LV pressure (% Delta dP/dt) 47 +/- 4% saline vs. 54 +/- 7% HS-142-1, P = not significant]. Addition of intracoronary L-NMMA to HS-142-1 enhanced the response to Dob (% Delta dP/dt 73 +/- 8% L-NMMA + HS-142-1, P < 0.05 vs. H142-1). In normal dogs, intracoronary SNP blunted the inotropic response to Dob (% Delta dP/dt 93 +/- 6% saline vs. 71 +/- 5% SNP, P < 0.05), whereas intracoronary BNP had no effect. In CHF dogs, the time constant of LV pressure decay during isovolumic relaxation increased with intracoronary HS-142-1 (48 +/- 4 ms saline vs. 58 +/- 5 ms HS-142-1, P < 0.05) and further increased with intracoronary L-NMMA (56 +/- 6 ms HS-142-1 vs. 66 +/- 7 ms L-NMMA + HS-142-1, P < 0.05). Endogenous BNP and NO preserve diastolic function in CHF, whereas NO but not BNP inhibits beta-adrenergic responsiveness.

Specificity of the stress electrocardiogram during adenosine myocardial perfusion imaging in patients taking digoxin.

BACKGROUND: In patients taking digoxin, the exercise electrocardiogram has a lower specificity for detecting coronary artery disease. However, the effect of digoxin on adenosine-induced ST-segment depression is unknown. The purpose of this study was to evaluate the specificity of the electrocardiogram during adenosine myocardial perfusion imaging in patients taking digoxin. METHODS: Between May 1991 and September 1997, patients (n = 99) taking digoxin who underwent adenosine stress imaging with thallium-201 or technetium-99m sestamibi and coronary angiography within 3 months were retrospectively identified. Exclusion criteria included prior myocardial infarction, coronary artery angioplasty or bypass surgery, left bundle branch block, paced ventricular rhythm, or significant valvular disease. Twelve-lead electrocardiograms were visually interpreted at baseline, during adenosine infusion, and during the recovery period. The stress electrocardiogram was considered positive if there was > or =1 mm additional horizontal or downsloping ST-segment depression or elevation 0.08 seconds after the J-point compared with the baseline tracing. RESULTS: ST-segment depression and/or elevation occurred in 24 of 99 patients. There were only 2 false-positive stress electrocardiograms, yielding a specificity of 87% and positive predictive value of 92%. All 8 patients with > or =2 mm ST segment depression had multivessel disease by coronary angiography. CONCLUSIONS: ST-segment depression or elevation during adenosine myocardial perfusion imaging in patients taking digoxin is highly specific for coronary artery disease. Marked (> or =2 mm) ST-segment depression and/or ST-segment elevation is associated with a high likelihood of multivessel disease.

Diastolic heart failure in the community.

Although it is now widely recognized that isolated diastolic dysfunction can lead to the classic signs and symptoms of congestive heart failure (CHF), this disease process is poorly understood and remains of great interest and concern to cardiovascular disease specialists, as well as to primary care physicians. Recent epidemiologic data have suggested that diastolic heart failure is predominantly a disease of the elderly, the fastest growing segment of our population. Diagnosis is often difficult in this subgroup of patients due to the presence of confounding comorbidities. However, early identification in community-based practices and timely intervention is important due to the significant disability and death that results from this progressive disease process. The poor prognosis of CHF patients with systolic dysfunction is shared by those with isolated diastolic heart failure and preserved systolic function. Further studies of the prevalence, clinical characteristics, and natural history of patients with diastolic dysfunction are needed. This review focuses on the emerging data regarding the prevalence and natural history of diastolic heart failure in the community.