Increased myocardial gene expression of tumor necrosis factor-alpha and nitric oxide synthase-2: a potential mechanism for depressed myocardial function in hibernating myocardium in humans.

BACKGROUND: Whether cardioinhibitory cytokines are elevated in regions of hibernating myocardium and account in part for the depression in resting function is currently not known. Methods and Results- Thirteen patients with stable ischemic ventricular dysfunction scheduled for bypass surgery underwent preoperative dobutamine echocardiography (DE) and intraoperative myocardial biopsies. The numbers of copies of mRNA for the negatively inotropic cytokines tumor necrosis factor-alpha (TNF-alpha) and inducible nitric oxide synthase (NOS2) were quantified by reverse transcription-polymerase chain reaction. In normal segments, myocardial TNF-alpha was barely detectable (1.2+/-0.4 copies per 10(6) copies of beta-actin). A 13.7-fold increase in myocardial TNF-alpha was observed in dysfunctional segments with a biphasic response to DE (contractile reserve and ischemia) and was highest (45.5-fold) in segments with ischemia and without contractile reserve (P<0.001). A similar graded increase was seen for NOS2. Cytokine results were also similar if analysis was performed using recovery of function at 3 months as the index of viability. The change in serum TNF-alpha and nitrite levels from baseline to 3 months after surgery correlated inversely with both the change in ejection fraction and the number of DE viable segments (r=-0.92 to -0.93; P<0.001). CONCLUSIONS: TNF-alpha and NOS2 gene expression is regionally upregulated in hibernating myocardium to a level intermediate between that of normal regions and ischemic regions without contractile reserve. This, along with a decline in serum cytokine levels after revascularization proportional to the extent of myocardial viability, suggests a contributing role for cardioinhibitory cytokines in the observed depression of function seen in hibernating myocardium.

Identification of hibernating myocardium with quantitative intravenous myocardial contrast echocardiography: comparison with dobutamine echocardiography and thallium-201 scintigraphy.

BACKGROUND: There are currently no data on the accuracy of intravenous myocardial contrast echocardiography (MCE) in detecting myocardial hibernation in man and its comparative accuracy to dobutamine echocardiography (DE) or thallium 201 (Tl(201)) scintigraphy. METHODS AND RESULTS: Twenty patients with coronary artery disease and ventricular dysfunction underwent MCE 1 to 5 days before bypass surgery and repeat echocardiography at 3 to 4 months. Patients also underwent DE (n=18) and rest-redistribution Tl(201) tomography (n=16) before revascularization. MCE was performed using continuous Optison infusion (12 to 16 cc/h) with intermittent pulse inversion harmonics and incremental triggering (1:1 to 1:8). Myocardial contrast intensity (MCI) replenishment curves were constructed to derive quantitative MCE indices of blood velocity and flow. Recovery of function occurred in 38% of dysfunctional segments. MCE parameters of perfusion in hibernating myocardium were similar to segments with normal function and higher than dysfunctional myocardium without recovery of function (P<0.001). The best MCE parameter for predicting functional recovery was Peak MCIxbeta, an index of myocardial blood flow (area under the curve, 0.83). MCE parameters were higher in segments with contractile reserve and Tl(201) uptake > or =60% (P<0.05) and identified viable segments without contractile reserve by DE. The sensitivity of Peak MCIxbeta >1.5 dB/s for recovery of function was 90% and was similar to Tl(201) scintigraphy (92%) and any contractile reserve (80%); specificity was higher than for Tl(201) and DE (63%, 45%, and 54%, respectively; P<0.05). CONCLUSIONS: MCE with intravenous contrast identifies myocardial hibernation in humans. Prediction of viable myocardium with MCE is best using quantification of myocardial blood flow and provides improved accuracy compared with DE and Tl(201) scintigraphy.

Microvascular structural correlates of myocardial contrast echocardiography in patients with coronary artery disease and left ventricular dysfunction: implications for the assessment of myocardial hibernation.

BACKGROUND: Myocardial contrast echocardiography (MCE) has been used to evaluate myocardial viability. There are no data, however, on the pathological determinants of myocardial perfusion by MCE in humans and the implications of such determinants. METHODS AND RESULTS: MCE was performed in 20 patients with coronary artery disease and ventricular dysfunction within 24 hours before myocardial biopsy at surgery using a continuous Optison infusion (12 to 16 cc/h), with intermittent pulse inversion harmonics and incremental triggering. Peak myocardial contrast intensity (MCI) and the rate of increase in MCI (beta) were quantitated. Thirty-six transmural myocardial biopsies (2 per patient) were obtained by transesophageal echocardiography. Total microvascular (<100 microm) density, capillary density and area, arteriolar and venular density, and percent collagen content were quantitated with immunohistochemistry. Peak MCI correlated with microvascular density (r=0.59, P<0.001) and capillary area (r=0.64, P<0.001) and inversely correlated with percent collagen content (r=-0.45, P=<0.01). The best relation was observed when the ratio of peak MCI in the 2 biopsied segments in each patient was compared with the ratio of microvascular density and capillary area (r=0.84 and 0.87, respectively; P<0.001). A significant overlap in microvascular density was seen between segments with and without recovery of function. The new MCE indices of blood velocity (beta) and flow (peak MCIxbeta) better identified recovery of function compared with microvascular density and the sole use of peak MCI. CONCLUSIONS: Microvascular integrity is a significant determinant of maximal MCI in humans. MCE indices of blood velocity and flow are important parameters that predict recovery of function after revascularization.