Steven J. Lavine

Importance of the left ventricular filling pressure on diastolic filling in idiopathic dilated cardiomyopathy

Both mitral regurgitation and elevated left ventricular (LV) filling pressures may normalize or enhance rapid filling in patients with idiopathic dilated cardiomyopathy. To assess the individual effects of the LV filling pressure and mitral regurgitation, 33 normal subjects, 14 patients with cardiomyopathy and normal LV filling pressures (measured as mean pulmonary capillary pressure) and 26 patients with elevated LV filling pressures (greater than 15 mm Hg) were studied with transmitral spectral tracings derived from pulsed Doppler echocardiography. Both cardiomyopathy groups demonstrated similarly dilated left ventricles with reduced systolic dysfunction. Patients with cardiomyopathy and normal LV filling pressures had prolonged isovolumic relaxation periods and a reduced ratio of the rapid filling to atrial filling integrals. Patients with cardiomyopathy and elevated LV pressures demonstrated an increased peak rapid filling velocity (97 +/- 21 cm/s) and rapid filling fraction (74.8 +/- 16.2%) compared with normal subjects (80 +/- 16 cm/s, p less than 0.01; 62.4 +/- 12.5%, p less than 0.05) and patients with cardiomyopathy and normal LV filling pressures (81 +/- 27 cm/s, p less than 0.05; 59.3 +/- 8.8%, p less than 0.05). Conversely, the atrial filling fraction was decreased in the cardiomyopathy group with elevated LV filling pressures compared with normal subjects and patients with cardiomyopathy and normal LV filling pressures. Mitral regurgitation increased the peak rapid filling velocity in both cardiomyopathy groups without altering the distribution of diastolic filling. In conclusion, elevated LV filling pressures appear to affect the distribution of diastolic filling, whereas mitral regurgitation affects the peak rate of rapid filling.

Effect of mitral regurgitation on diastolic filling with left ventricular hypertrophy

Earlier studies have suggested that mitral regurgitation (MR) augments early left ventricular (LV) diastolic filling. To determine whether MR affects early diastolic filling in patients with abnormal diastolic filling, transmitral pulsed-wave Doppler recordings were used to study 32 normal subjects, 21 patients with LV hypertrophy, 23 with LV hypertrophy and MR and 15 patients with MR. Patients with MR had increased peak early filling velocities (MR 108 +/- 27 cm/s, normal 80 +/- 16 cm/s, p less than 0.01), peak atrial filling velocities (MR 72 +/- 18 cm/s, normal 55 +/- 12 cm/s, p less than 0.05) and increased deceleration rates (MR 5.0 +/- 1.9 m/s2, normal 3.5 +/- 1.2 m/s2, p less than 0.05). Patients with LV hypertrophy had reduced peak early filling velocities (69 +/- 14 cm/s, p less than 0.05) and increased peak atrial filling velocities (83 +/- 16 cm/s, p less than 0.001). There was also an increase in the atrial filling fraction and reduction in the rapid filling fraction as compared with normal patients. Patients with LV hypertrophy and MR had increased peak early filling velocities (98 +/- 26 cm/s, p less than 0.01 vs normal, p less than 0.001 vs LV hypertrophy patients), increased atrial filling velocities (84 +/- 27 cm/s, p less than 0.001 vs normal), increased deceleration rates (4.4 +/- 2.4 m/s2, p less than 0.05 vs normal) and a normal distribution of diastolic filling. Within the LV hypertrophy and MR group, diastolic filling parameters were similar when patients were subgrouped on the basis of auscultability of MR. MR augments early diastolic filling and may tend to normalize diastolic filling patterns in LV hypertrophy patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Diastolic filling in acute left ventricular dysfunction: Role of the pericardium☆

Patients with congestive heart failure and elevated left ventricular filling pressures demonstrate an abnormal pattern of diastolic filling that is characterized by a redistribution of diastolic filling to early diastole with reduced reliance on late diastolic filling. The diastolic filling pattern superficially resembles that which is seen with constrictive pericarditis. To examine potential mechanisms for these clinical findings, a model of ischemic left ventricular dysfunction was produced in seven dogs by repeated coronary microsphere embolization, producing a dilated left ventricle with reduced systolic function. Measurements of left ventricular systolic and end-diastolic pressures, rate of rise of left ventricular pressure (dP/dt) and echocardiographic end-diastolic and end-systolic areas were obtained at baseline, during intermediate embolization (moderate left ventricular systolic dysfunction, dilation and mild increases in left ventricular end-diastolic pressure), postembolization (further embolization resulting in severe left ventricular systolic dysfunction, dilation and marked increases in left ventricular end-diastolic pressure), after thoracotomy and after pericardiectomy. The filling fraction at 1/3 and 1/2 of diastole and the time constant of left ventricular pressure decline were also determined. Repetitive coronary microembolization caused progressive left ventricular dilation and decreasing systolic function, which did not change after opening the chest or pericardium. The filling fraction at 1/3 and 1/2 of diastole declined with intermediate embolization (12.0 +/- 5.6% and 23.1 +/- 10.8%, respectively) as compared with baseline values (29.0 +/- 11.9%, 42.9 +/- 15.6%, p less than 0.05). After embolization, there was an increase in the 1/3 and the 1/2 filling fraction (47.5 +/- 8.9%, 72.0 +/- 6.0%, respectively, p less than 0.01) as compared with baseline values.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of Ibutilide, a New Class III Agent, On Sustained Atrial Fibrillation in a Canine Model of Acute Ischemia and Myocardial Dysfunction Induced By Microembolization

The effect of ibutiJide, a new Class III antiarrhythmic agent, upon acute onset atriai fibriJIation was investigated in a closed‐chest canine model of acute left ventricular fLVj dysfunction. Twenty‐four anesthetized mongrel dogs, mean weight 24.9 ± 4 kg were subjected to coronary artery microsphere emboiization and volume Joading, followed by attempted induction of atrial fihrillation (AF) by rapid atrial pacing. Acute ischemic LV dysfunction was successfully induced by emboiization in aii dogs, and caused significant (P < 0.02) decreases in LV systolic pressure, peak + dp/dt (and − dp/dtj, stroke volume, and RR interval; whereas LV end diastolic pressure and QTc significantiy increased. Sustained AF (≥ 30 min) was successfully induced in 15 of 24 dogs (62%) and unsustained AF (< 30 min) was induced in the remainder (38%). At 30 minutes after induction of sustained AF, 15 dogs were randomized to intravenous ibutiiide (0.15 mg/kg, given as a 0.075 mg/kg bolus, followed by 0.075 mg/kg infusion over 1 hour; n = 7) or placebo (saline; n = 8). There were no statistically significant differences between the ibutilide and the placebo groups with respect to mean LV systolic pressure, LV end diastoJic pressure, LV dp/dt, RR intervaJ, or QTc intervaJ during AF prior to infusion. All seven dogs receiving ibutiJide converted to sinus rhythm after a median of 3 minutes (range 0.5–26 min), whiJe onJy three of eight pJacebo dogs (P < 0.03J converted to sinus rhythm after a median duration of 30 minutes (range 15–60 min) (P < 0.04 for difference in time to conversionj. QTc prolonged by 27 ± 17%, 1 hour after ibutiJide, but was unaJtered after pJacebo (P ≥ 0.02). There were no significant hemodynamic changes after either ibutiJide or pJacebo. We concJude that: (1) sustained AF (> 30 min) can be readily induced in this closed‐chest animal model and used t o test antiarrhythmic agents acutely; and (2) intravenous ibutiJide is effective in rapidJy terminating acute onset AF; the drug prolongs the QTc intervaJ but does not exacerbate preexisting hemodynamic compromise in the acutely ischemic LV.

Pattern of left ventricular diastolic filling associated with right ventricular enlargement

Right ventricular (RV) dilatation associated with pressure overload may alter left ventricular (LV) geometry resulting in abnormal diastolic function as demonstrated by a smaller LV diastolic volume for a given LV diastolic pressure. To determine whether abnormalities in LV geometry due to RV dilatation result in abnormalities in the LV diastolic filling pattern, we obtained pulsed Doppler transmitral recordings from 23 patients with RV dilatation with RV systolic pressure estimated to be less than 40 mm Hg (group 1), 18 patients with RV dilatation and RV systolic pressures greater than or equal to 40 mm Hg (group 2) and 33 normal patients. RV systolic pressures were estimated from continuous wave Doppler peak tricuspid regurgitation velocities using the modified Bernoulli equation. Diastolic filling parameters in group 1 patients were similar to normals. In group 2 patient, increased peak atrial filling velocity (76 +/- 14 vs 57 +/- 12 cm/s, p less than 0.001), decreased peak rapid filling velocity/peak atrial filling velocity (1.1 +/- 0.4 vs 1.5 +/- 0.4, p less than 0.01), increased atrial filling fraction (41 +/- 14 vs 30 +/- 10%, p less than 0.01) and prolongation of the atrial filling period (171 +/- 47 vs 152 +/- 39 ms, p less than 0.05) were noted compared with the normal group. RV end-diastolic size and LV end-systolic shape were significantly correlated with the atrial filling fraction in group 2 patients. In patients with RV dilatation and RV systolic pressures greater than or equal to 40 mm Hg, there is increased reliance on atrial systolic contribution to the LV filling volume.

Effect of nitroglycerin-induced reduction of left ventricular filling pressure on diastolic filling in acute dilated heart failure.

Recent information has suggested that early diastolic filling may be influenced by the left ventricular filling pressure, especially in the failing left ventricle. Acute severe left ventricular dysfunction was induced in 14 dogs by severe left ventricular global ischemia produced by left main coronary artery microsphere embolization until the left ventricular end-diastolic pressure was greater than or equal to 20 mm Hg. To assess the importance of left ventricular filling pressure on left ventricular diastolic filling, nitroglycerin was infused and titrated to reduce left ventricular end-diastolic pressure to less than 15 mm Hg in seven dogs, whereas the remaining seven dogs were observed for 1 h after acute severe left ventricular dysfunction. In both groups of dogs, severe left ventricular dysfunction resulted in left ventricular dilation and elevation of end-diastolic pressure, reduction in area ejection fraction (echocardiographically determined) and an early redistribution of diastolic filling (increased filling fractions at one-third and one-half diastole) despite prolongation of the time constant of left ventricular pressure decline. Pressure-area plots shifted upward and rightward with severe left ventricular dysfunction and were unchanged at 1 h as were all other variables. Nitroglycerin infusion reduced left ventricular size and filling pressure, redistributed diastolic filling to later in diastole as characterized by reduced filling fraction at one-third diastole (left ventricular dysfunction 48.8 +/- 9.7%, nitroglycerin 17.9 +/- 7.9%, p less than 0.001) and shifted downward left ventricular pressure-area plots. Nitroglycerin also improved the time constant of relaxation (left ventricular dysfunction 83 +/- 15 ms, nitroglycerin 52 +/- 15 ms, p less than 0.001) and lengthened the diastolic filling period.(ABSTRACT TRUNCATED AT 250 WORDS)

Reversible cardiomyopathy after high-dose interleukin-2 therapy

We observed two patients who developed moderate global myocardial dysfunction during therapy with high-dose interleukin-2 (IL-2). Although cardiac enzymes became markedly elevated at the completion of a full course of IL-2, patients exhibited no ischemic symptoms. Serial echocardiography documented global myocardial dysfunction, which resolved in 5 days in one patient but persisted beyond 4 weeks in another. Asymptomatic reversible myocardial injury can occur with high-dose IL-2 and can persist beyond 4 weeks after stopping therapy. Review of the literature suggests an IL-2-associated myocarditis as an etiology.

Aqueous Oxygen Attenuation of Reperfusion Microvascular Ischemia in a Canine Model of Myocardial Infarction

Uncorrected microvascular ischemia may contribute to left ventricular impairment during reperfusion after prolonged coronary artery occlusion. Attenuation of such ischemia in microvessels with impaired erythrocyte flow may require delivery of oxygen at high levels in plasma. Intraarterial infusion of aqueous oxygen (AO) can be used in a site specific manner to achieve hyperoxemic levels of oxygenation in the perfusate. With this new approach, the hypothesis was tested that reperfusion microvascular ischemia can be attenuated.After a 90 min coronary balloon occlusion in a canine model, AO hyperoxemic intracoronary perfusion was performed for 90 min after a 30 min period of autoreperfusion. Control groups consisted of normoxemic reperfusion, both passive (autoreperfusion) and active (roller pump). A significant improvement in left ventricular ejection fraction (p < 0.05) at 2 hr of reperfusion was noted only in the AO hyperoxemia group (17 ± 6% by two dimensional echo), without a significant reduction in the improvement 1 hr after termination of treatment. During AO hyperoxemic perfusion, ECG ST segment isoelectric deviation normalized, and frequency of ventricular premature contractions was significantly reduced, in contrast to the autoreperfusion control group (p < 0.05). Microvascular blood flow, measured as the ischemic/normal left ventricular segment ratio by radiolabeled microspheres immediately after AO hyperoxemic perfusion, was double the value of the autoreperfusion control group at 2 hr of reperfusion (p < 0.05).We conclude that reperfusion microvascular ischemia is attenuated by intracoronary AO hyperoxemic perfusion and acutely improves left ventricular function in this model.

Effect of changes in contractility on the index of myocardial performance in the dysfunctional left ventricle

BackgroundThe index of myocardial performance has prognostic power in patients with cardiomyopathy and following myocardial infarction. As the index of myocardial performance has been shown to be preload and afterload dependent, the effect of altering contractility on IMP and its components with left ventricular dysfunction has been incompletely delineated.MethodsChronic left ventricular dysfunction was induced in 10 canines using coronary microsphere embolization. Each dog was instrumented and imaged with 2D echo and Doppler. At the same atrially paced rate, contractility was increased with a dobutamine infusion and then following 4 weeks of oral digoxin.ResultsWith chronic left ventricular dysfunction, a reduced left ventricular ejection fraction (42 ± 3%, p < 0.001) and increased index of myocardial performance (0.58 ± 0.17, p < 0.01) due to isovolumic contraction time lengthening and shortened left ventricular ejection time were noted. Dobutamine increased ejection fraction (p < 0.001), reduced left ventricular end diastolic pressure (p < 0.01), and reduced the index of myocardial performance (0.33 ± 0.17, p < 0.001) due to isovolumic contraction time, isovolumic relaxation time, and left ventricular ejection time shortening. Digoxin increased ejection fraction (p < 0.05), reduced left ventricular end diastolic pressure (p < 0.05), and reduced the index of myocardial performance (0.42 ± 0.13, p < 0.01) due to isovolumic contraction time shortening (p < 0.001). Both dobutamine and digoxin lengthened the diastolic filling period (p < 0.01).ConclusionIncreased inotropy with digoxin and dobutamine reduced the index of myocardial performance in dogs with left ventricular dysfunction. Shortened isovolumic contraction time, increased diastolic filling period, and reduced left ventricular end diastolic pressure with digoxin may provide insight into its efficacy in heart failure.

Effect of inotropic and vasodilator therapy on left ventricular diastolic filling in dogs with severe left ventricular dysfunction

Inotropic and vasodilator therapy for congestive heart failure improve left ventricular systolic performance by different mechanisms. However, the nature and extent to which diastolic filling is altered have not been well described. Acute severe left ventricular dysfunction was induced in 21 dogs by severe left ventricular global ischemia produced by left main coronary artery microsphere embolization until left ventricular end-diastolic pressure was greater than or equal to 18 mm Hg. Dobutamine was infused in seven dogs until the peak positive first derivative of left ventricular pressure (dP/dt) increased by greater than or equal to 33%. Nitroprusside was infused in seven dogs until left ventricular end-diastolic pressure was less than 15 mm Hg. Seven dogs were observed for 1 h after the induction of acute severe left ventricular dysfunction and served as the control group. In all groups of dogs, severe left ventricular dysfunction resulted in left ventricular dilation, reduction in area ejection fraction, elevation of left ventricular end-diastolic pressure and an early redistribution of diastolic filling (increased 1/3 and 1/2 filling fractions) despite a markedly abnormal time constant of relaxation. No changes were noted in any variable after 1 h of observation in the seven control dogs. Nitroprusside reduced left ventricular size and filling pressure, increased cardiac output, improved relaxation and redistributed diastolic filling to later in diastole as characterized by a reduced 1/3 filling fraction (19.4 +/- 7.4% versus 51.4 +/- 10%, p less than 0.001). The pressure-area curve was shifted downward and leftward.(ABSTRACT TRUNCATED AT 250 WORDS)