Mechano-chronotropic Unloading During the Acute Phase of Myocardial Infarction Markedly Reduces Infarct Size via the Suppression of Myocardial Oxygen Consumption.

The oxygen supply-demand imbalance is the fundamental pathophysiology of myocardial infarction (MI). Reducing myocardial oxygen consumption (MVO2) in acute MI (AMI) reduces infarct size. Since left ventricular (LV) mechanical work and heart rate are major determinants of MVO2, we hypothesized that the combination of LV mechanical unloading and chronotropic unloading during AMI can reduce infarct size via synergistic suppression of MVO2. In a dog model of ischemia-reperfusion, as we predicted, the combination of mechanical unloading by Impella and bradycardic agent, ivabradine (IVA), synergistically reduced MVO2. This was translated into the striking reduction of infarct size with Impella + IVA administered 60 min after the onset of ischemia compared to no treatment (control) and Impella groups (control 56.3 ± 6.5, Impella 39.9 ± 7.4 and Impella + IVA 23.7 ± 10.6%, p < 0.001). In conclusion, Impella + IVA during AMI reduced infarct size via marked suppression of MVO2. The mechano-chronotropic unloading may serve as a powerful therapeutic option for AMI.

Left Ventricular Mechanical Unloading by Total Support of Impella in Myocardial Infarction Reduces Infarct Size, Preserves Left Ventricular Function, and Prevents Subsequent Heart Failure in Dogs.

BACKGROUND: Acute myocardial infarction remains a leading cause of chronic heart failure. Excessive myocardial oxygen demand relative to supply is the fundamental mechanism of myocardial infarction. We thus hypothesized that left ventricular (LV) mechanical unloading by the total support of transvascular LV assist device Impella could minimize oxygen demand, thereby reducing infarct size and preventing subsequent heart failure. METHODS AND RESULTS: In 20 dogs, we ligated the left anterior descending coronary artery for 180 minutes and then reperfused. We introduced Impella from 60 minutes after the onset of ischemia to 60 minutes after reperfusion. In the partial support group, Impella supported 50% of total cardiac output. In the total support group, systemic flow totally depends on Impella flow. Four weeks after ischemia/reperfusion (I/R), we compared LV function and infarct size among 4 groups: sham (no I/R), I/R (no Impella support), partial support, and total support. Compared with I/R, total support lowered LV end-diastolic pressure (15.0±3.5 versus 4.7±1.7 mm Hg; P<0.001), increased LV end-systolic elastance (4.3±0.8 versus 13.9±5.1 mm Hg/mL; P<0.001), and decreased NT-proBNP (N-terminal pro-B-type natriuretic peptide) level (4081±1123 versus 1773±390 pg/mL; P<0.05). Furthermore, total support markedly reduced infarct size relative to I/R, whereas partial support decreased infarct size to a lesser extent (I/R, 16.3±2.6; partial support, 8.5±4.3; and total support, 2.1±1.6%; P<0.001). CONCLUSIONS: LV mechanical unloading by the total support of Impella during the acute phase of myocardial infarction reduced infarct size and prevented subsequent heart failure in dogs.

Pulmonary arterial input impedance reflects the mechanical properties of pulmonary arterial remodeling in rats with pulmonary hypertension.

AIMS: Although pulmonary arterial remolding in pulmonary hypertension (PH) changes the mechanical properties of the pulmonary artery, most clinical studies have focused on static mechanical properties (resistance), and dynamic mechanical properties (compliance) have not attracted much attention. As arterial compliance plays a significant role in determining afterload of the right ventricle, we evaluated how PH changes the dynamic mechanical properties of the pulmonary artery using high-resolution, wideband input impedance (ZPA). We then examined how changes in ZPA account for arterial remodeling. Clarification of the relationship between arterial remodeling and ZPA could help evaluate arterial remodeling according to hemodynamics. MAIN METHODS: PH was induced in Sprague-Dawley rats with an injection of Sugen5416 (20 mg/kg) and 3-week exposure to hypoxia (10% oxygen) (SuHx). ZPA was evaluated from pulmonary artery pressure and flow under irregular pacing. Pulmonary histology was examined at baseline and 1, 3, and 8 weeks (n = 7, each) after Sugen5416 injection. KEY FINDINGS: SuHx progressively increased pulmonary arterial pressure. ZPA findings indicated that SuHx progressively increased resistance (baseline: 9.3 ±â€¯3.6, SuHx1W: 20.7 ±â€¯7.9, SuHx3W: 48.8 ±â€¯6.9, SuHx8W: 62.9 ±â€¯17.8 mm Hg/mL/s, p < 0.01) and decreased compliance (baseline: 11.9 ±â€¯2.1, SuHx1W: 5.3 ±â€¯1.7, SuHx3W: 2.1 ±â€¯0.7, SuHx8W: 1.9 ±â€¯0.6 × 10-3 mL/mm Hg, p < 0.01). The time constant did not significantly change. The progressive reduction in compliance was closely associated with wall thickening of small pulmonary arteries. SIGNIFICANCE: The finding that changes in resistance were reciprocally associated with those in compliance indicates that resistant and compliant vessels are anatomically inseparable. The analysis of ZPA might help evaluate arterial remodeling in PH according to hemodynamics.

Intravenous electrical vagal nerve stimulation prior to coronary reperfusion in a canine ischemia-reperfusion model markedly reduces infarct size and prevents subsequent heart failure.

BACKGROUND: Reducing myocardial damage is a prerequisite to prevent chronic heart failure after acute myocardial infarction (AMI). Although vagal nerve stimulation (VNS) has been repeatedly demonstrated to have potent anti-infarct effect, technical difficulties have precluded its clinical application. We developed a novel therapeutic strategy of intravenous VNS (iVNS) and examined whether iVNS administered prior to coronary reperfusion in a canine AMI model reduces infarct size and prevents heart failure. METHODS AND RESULTS: In 35 mongrel dogs, we induced ischemia by ligating the left anterior descending coronary artery and then reperfused 3h later (I/R). We transvenously placed a catheter electrode in the superior vena cava and adjusted the stimulation intensity to a level that induced bradycardia but maintained stable hemodynamics (continuous, 5.1±2.1V, 10Hz). We administered iVNS from onset (iVNS-0, n=7) or 90min after onset (iVNS-90, n=7) of ischemia until one hour after reperfusion. Four weeks after ischemia-reperfusion, iVNS markedly reduced infarct size (iVNS-0: 2.4±2.1%, p<0.05 and iVNS-90: 4.5±4.5%, p<0.05) compared with I/R control (I/R: 13.3±2.5%), and improved cardiac performance and hemodynamics. Atrial pacing (n=7) to abolish iVNS-induced bradycardia significantly attenuated the beneficial effects of iVNS. CONCLUSIONS: Short-term iVNS delivered prior to coronary reperfusion markedly reduced infarct size and preserved cardiac function one month after AMI. The bradycardic effect plays an important role in the beneficial effect of iVNS. How other mechanisms contribute to the reduction of infarct size remains to be studied.

Total Mechanical Unloading Minimizes Metabolic Demand of Left Ventricle and Dramatically Reduces Infarct Size in Myocardial Infarction.

BACKGROUND: Left ventricular assist device (LVAD) mechanically unloads the left ventricle (LV). Theoretical analysis indicates that partial LVAD support (p-LVAD), where LV remains ejecting, reduces LV preload while increases afterload resulting from the elevation of total cardiac output and mean aortic pressure, and consequently does not markedly decrease myocardial oxygen consumption (MVO2). In contrast, total LVAD support (t-LVAD), where LV no longer ejects, markedly decreases LV preload volume and afterload pressure, thereby strikingly reduces MVO2. Since an imbalance in oxygen supply and demand is the fundamental pathophysiology of myocardial infarction (MI), we hypothesized that t-LVAD minimizes MVO2 and reduces infarct size in MI. The purpose of this study was to evaluate the differential impact of the support level of LVAD on MVO2 and infarct size in a canine model of ischemia-reperfusion. METHODS: In 5 normal mongrel dogs, we examined the impact of LVAD on MVO2 at 3 support levels: Control (no LVAD support), p-LVAD and t-LVAD. In another 16 dogs, ischemia was induced by occluding major branches of the left anterior descending coronary artery (90 min) followed by reperfusion (300 min). We activated LVAD from the beginning of ischemia until 300 min of reperfusion, and compared the infarct size among 3 different levels of LVAD support. RESULTS: t-LVAD markedly reduced MVO2 (% reduction against CONTROL: -56 ± 9%, p<0.01) whereas p-LVAD did less (-21 ± 14%, p<0.05). t-LVAD markedly reduced infarct size compared to p-LVAD (infarct area/area at risk: CONTROL; 41.8 ± 6.4, p-LVAD; 29.1 ± 5.6 and t-LVAD; 5.0 ± 3.1%, p<0.01). Changes in creatine kinase-MB paralleled those in infarct size. CONCLUSIONS: Total LVAD support that minimizes metabolic demand maximizes the benefit of LVAD in the treatment of acute myocardial infarction.