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Mechanical Pre-Conditioning With Acute Circulatory Support Before Reperfusion Limits Infarct Size in Acute Myocardial Infarction

Navin K. Kapur, Xiaoying Qiao, Vikram Paruchuri, Kevin J. Morine, Wajih Syed, Sam Dow, Nimish Shah, Natesa Pandian, Richard H. Karas.

Abstract

Objectives

This study tested the hypothesis that first reducing myocardial work by unloading the left ventricle (LV) with a novel intracorporeal axial flow catheter while delaying coronary reperfusion activates a myocardial protection program and reduces infarct size.

Background

Ischemic heart disease is a major cause of morbidity and mortality worldwide. Primary myocardial reperfusion remains the gold standard for the treatment of an acute myocardial infarction (AMI); however, ischemia–reperfusion injury contributes to residual myocardial damage and subsequent heart failure. Stromal cell-derived factor (SDF)-1α is a chemokine that activates cardioprotective signaling via Akt, extracellular regulated kinase, and glycogen synthase kinase-3β.

Methods

AMI was induced by occlusion of the left anterior descending artery (LAD) via angioplasty for 90 min in 50-kg male Yorkshire swine (n = 5/group). In the primary reperfusion (1° Reperfusion) group, the LAD was reperfused for 120 min. In the primary unloading (1° Unloading) group, after 90 min of ischemia the axial flow pump was activated and the LAD left occluded for an additional 60 min, followed by 120 min of reperfusion. Myocardial infarct size and kinase activity were quantified.

Results

Compared with 1° Reperfusion, 1° Unloading reduced LV wall stress and increased myocardial levels of SDF-1α, CXCR4, and phosphorylated Akt, extracellular regulated kinase, and glycogen synthase kinase-3β in the infarct zone. 1° Unloading increased antiapoptotic signaling and reduced myocardial infarct size by 43% compared with 1° Reperfusion (73 ± 13% vs. 42 ± 8%; p = 0.005). Myocardial levels of SDF-1 correlated inversely with infarct size (R = 0.89; p < 0.01).

Conclusions

Compared with the contemporary strategy of primary reperfusion, mechanically conditioning the myocardium using a novel axial flow catheter while delaying coronary reperfusion decreases LV wall stress and activates a myocardial protection program that up-regulates SDF-1α/CXCR4 expression, increases cardioprotective signaling, reduces apoptosis, and limits myocardial damage in AMI.

Key Words

myocardial infarction; reperfusion injury; ventricular assist devices

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Pre-Clinical Resources

Left ventricular support by catheter-mounted axial flow pump reduces infarct size

Meyns, B., Stolinski, J., Leunens, V., Verbeken, E., Flameng, W

Abstract

OBJECTIVES: We sought to investigate the effect of a catheter-mounted microaxial blood pump (Impella, Aachen, Germany) on myocardial infarct size. BACKGROUND: The small rotary blood pump Impella provides unloading of the left ventricle and is introducible via the femoral artery. METHODS: Myocardial infarction was induced by occlusion of major branches of the left anterior descending coronary artery for 60 min followed by 120 min of reperfusion in 26 sheep. The animals were allocated to four groups: group 1 had no support; group 2 was fully supported with the pump during ischemia and reperfusion; group 3 was supported during reperfusion only; and group 4 was partially supported during reperfusion. Infarct size, hemodynamics, myocardial oxygen consumption, lactate extraction, and myocardial flow were analyzed. RESULTS: Infarct size was significantly reduced in the pump-supported animals (percent area at risk in group 1: 67.2 +/- 4.6%; group 2: 18.1 +/- 10%; group 3: 41.6 +/- 5.8%; group 4: 54 +/- 8%; p = 0.00001). The pump produced 4.1 +/- 0.1 l/min at full support and 2.4 +/- 0.1 l/min at partial support. The pump significantly increased the diastolic and mean blood pressures (groups 2, 3, and 4) and significantly decreased the left ventricular end-diastolic pressure (groups 2 and 3). During ischemia, myocardial flow was not influenced by pump support. At reperfusion, the fully supported group had significantly higher myocardial flow. Pump support reduced myocardial oxygen consumption significantly, and this reduction correlates strongly with the reduction in infarct size (r = 0.9). CONCLUSIONS: Support by a microaxial blood pump reduces myocardial oxygen consumption during ischemia and reperfusion and leads to a reduction of infarct size. This reduction in infarct size correlates with the degree of unloading during reperfusion.

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Pre-Clinical Resources

Early Assistance With Left Ventricular Assist Device Limits Left Ventricular Remodeling After Acute Myocardial Infarction in a Swine Model

Sun, X., Li, J., Zhao, W., Lu, S., Guo, C., Lai, H., Wang, C.

Abstract

Although left ventricular assist devices (LVADs) have been commonly used for patients with cardiogenic shock after acute myocardial infarction (AMI), their effects on post-AMI prognosis remain to be elucidated. In this study, we aimed to explore the effects of an LVAD on left ventricular (LV) remodeling and function at the postinfarction stage in a swine model. AMI was induced by ligation of the circumflex artery or its branches for 120 min, followed by 120 min of reperfusion. In the assist group (n = 6), LVAD was initiated at 90 min after ischemia and was maintained for support until 120 min after reperfusion, whereas the control group (n = 6) received no support. LV pressure, volume, wall stress, and stroke work were all decreased by LVAD assistance at the ischemia and reperfusion stages, and blood pressure and cardiac output were maintained. All swine were studied 1 month after the procedure, and those in the assist group showed less increased end-diastolic volumes (assist vs. control: 57.9 ± 6.6 vs. 79.0 ± 6.7 mL, P = 0.032) and sphericity (assist vs. control: 1.33 ± 0.16 vs. 1.51 ± 0.12, P = 0.01), as well as improved ejection fractions (assist vs. control: 59.0 ± 7.8 vs. 42.3 ± 6.0%, P = 0.002). Furthermore, despite a presence of a similar initial ischemic area, the percent of infarcted myocardium was reduced by 49.9% in the assist group (assist vs. control: 18.1 ± 4.8 vs. 35.3 ± 6.2%, P < 0.001). These results suggested that early assistance with an LVAD in AMI limited LV remodeling, preserved postinfarction systolic function, and improved the prognosis.

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Pre-Clinical Resources

Relation between left ventricular oxygen consumption and pressure-volume area in conscious dogs

Nozawa, T., Cheng, C. P., Noda, T., Little, W. C.

Abstract

BACKGROUND: The relation between left ventricular (LV) oxygen consumption (MVO2) and pressure-volume area (PVA) developed in isolated hearts provides a powerful method to understand cardiac energetics. We investigated application of this relation to the intact circulation, determining its response to steady-state and transient load alterations and enhanced contractility in conscious animals. METHODS AND RESULTS: Eight dogs were instrumented to measure LV pressure (micromanometer), LV volume (three sonomicrometers), and left circumflex and anterior descending coronary artery flows (ultrasonic flowmeter). Data were acquired after recovery from the surgery with the animals awake and unsedated. After administration of hexamethonium and atropine, steady-state loading conditions were changed with phenylephrine or nitroprusside in four to five steps before and during the infusion of dobutamine (6 to 10 micrograms.-1kg.-1min). MVO2 and PVA obtained under steady-state conditions were linearly correlated both before and during dobutamine. The MVO2-PVA relation obtained on a beat-to-beat basis during transient caval occlusion was less linear and not coincident with the steady-state relation. Dobutamine shifted the steady-state MVO2-PVA relation upward in all hearts, increasing the MVO2 axis intercept of the MVO2-PVA relation (P < .01). This intercept correlated with ventricular contractility assessed by the slope (Ees) of the LV end-systolic pressure-volume relation determined by caval occlusion (r = .76, P < .05). The slope of the MVO2-PVA relation increased with dobutamine in seven of eight animals, with the inverse of the slope (representing contractile efficiency) being 31 +/- 6% during control and 24 +/- 6% after dobutamine (P = .06). CONCLUSIONS: MVO2 and PVA are linearly related during steady-state alterations in loading conditions in conscious dogs but not on a beat-by-beat basis during transient caval occlusion. Increase in contractility by dobutamine produces an upward shift of the MVO2-PVA relation.

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Pre-Clinical Resources

Effect of reduced aortic compliance on cardiac efficiency and contractile function of in situ canine left ventricle

Kelly, R. P., Tunin, R., Kass, D. A.

Abstract

This study tests the hypothesis that arterial vascular stiffening adversely influences in situ left ventricular contractile function and energetic efficiency. Ten reflex-blocked anesthetized dogs underwent a bypass operation in which a Dacron graft was sewn to the ascending aorta and connected to the infrarenal abdominal aorta via a plastic conduit. Flow was directed through either native aorta or plastic conduit by placement of vascular clamps. Arterial properties were measured from aortic pressure-flow data, and ventricular function was assessed by pressure-volume (PV) relations. Coronary sinus blood was drained via an extracorporeal circuit for direct measurement of myocardial O2 consumption (MVO2). Data at multiple steady-state preload volumes were combined to derive chamber function and energetics relations. Energetic efficiency was assessed by the inverse slope of the MVO2-PV area relation. Directing flow through plastic versus native aorta resulted in a 60-80% reduction in compliance but little change in mean resistance. Arterial pulse pressure rose from 34 to 99 mm Hg (p less than 0.001). Contractile function assessed by the end-systolic PV relation, stroke work-end-diastolic volume relation, and dP/dtmax at matched end-diastolic volume did not significantly change. However, MVO2 increased by 32% (p less than 0.01) and was matched by a rise in PV area, such that the MVO2-PV area relation and efficiency was unaltered. The MVO2 required to sustain a given stroke volume, however, increased from 20% to 40%, depending on the baseline level (p less than 0.001). Thus, whereas the contractile function and efficiency of normal hearts are not altered by ejection into a stiff vascular system, the energetic cost to the heart for maintaining adequate flow is increased. This suggests a mechanism whereby human vascular stiffening may yield little functional decrement at rest but limit reserve capacity under conditions of increased demand.

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Pre-Clinical Resources

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

Saku, K., Kakino, T., Arimura, T., Sakamoto, T., Nishikawa, T., Sakamoto, K., Ikeda, M., Kishi, T., Ide, T., Sunagawa, K.

Abstract

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.

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Pre-Clinical Resources

Mechanically unloading the left ventricle before coronary reperfusion reduces left ventricular wall stress and myocardial infarct size

Kapur, N. K., Paruchuri, V., Urbano-Morales, J. A., Mackey, E. E., Daly, G. H., Qiao, X., Pandian, N., Perides, G., Karas, R. H.

Abstract

BACKGROUND: Ischemia/reperfusion injury worsens infarct size, a major determinant of morbidity and mortality after acute myocardial infarction (MI). We tested the hypothesis that reducing left ventricular wall stress with a percutaneous left atrial-to-femoral artery centrifugal bypass system while delaying coronary reperfusion limits myocardial injury in a model of acute MI. METHODS AND RESULTS: MI was induced by balloon occlusion of the left anterior descending artery in adult male swine. In the MI group (n=4), 120 minutes of left anterior descending artery occlusion was followed by 120 minutes of reperfusion without mechanical support. In the mechanically supported group (MI+unload; n=4), percutaneous left atrial-to-femoral artery bypass was initiated after 120 minutes of ischemia, and left anterior descending artery occlusion was prolonged for an additional 30 minutes, followed by 120 minutes of reperfusion with device support. All animals were euthanized after reperfusion, and infarct size was quantified by triphenyltetrazolium chloride staining. Compared with baseline, mean left ventricular wall stress and stroke work were not changed at any point in the MI group but were decreased after reperfusion in the MI+unload group (mean left ventricular wall stress, 44 658 versus 22 963 dynes/cm(2); stroke work, 2823 versus 655 mm Hg.mL, MI versus MI+unload). Phosphorylation of reperfusion injury salvage kinase pathway proteins from noninfarcted left ventricular tissue was unchanged in the MI group but was increased in the MI+unload group. Compared with the MI group, total infarct size was reduced in the MI+unload group (49% versus 28%, MI versus MI+unload). CONCLUSIONS: These data support that first unloading the left ventricle despite delaying coronary reperfusion during an acute MI reduces myocardial injury.

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What Is Acute Unloading?

International Cardiology Review on A-CURE 2016

A summary of the talks given at the 1st Annual A-CURE Symposium in Rome, Italy, in August of 2016.

Abstract

This supplement to the International Cardiology Review is devoted to the proceedings of the first annual A-CURE Symposium that was held in Rome, Italy, in August of 2016. The 1-day meeting brought together experts from a number of disciplines – including interventional cardiologists, heart failure specialists, cardiac surgeons, molecular biologists, and biomedical engineers – to discus the science behind and clinical applications of acute cardiac unloading.  Over 100 physicians, clinical and pre-clinical researchers, basic researchers, medical students, post-doctoral scientists, and graduate students from 21 different countries were in attendance. The ICR Supplement features a number of the presentations from the Symposium describing the basic science underlying acute cardiac unloading, its clinical applications, and the opportunities in and challenges of performing clinical trials.

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Pre-Clinical Resources

Percutaneous cardiac support during myocardial infarction drastically reduces mortality: perspectives from a swine model

Maria Giovanna Trivella, Alessandra Piersgilli, Fabio Bernini, Gualtiero Pelosi, Silvia Burchielli, Stefano Puzzuoli, Claudia Kusmic, Antonio L’Abbate

Abstract

Background/aims

Acute myocardial infarction (AMI) with cardiogenic shock (CS) remains the leading cause of in-hospital death in acute coronary syndromes. In the AMI-CS pig model we tested the efficacy of temporary percutaneous cardiorespiratory assist device (PCRA) in rescuing the failing heart and reducing early mortality.

Methods

In open-chest pigs we induced AMI by proximal left anterior descending coronary artery (LAD) ligation. Eight animals without PCRA (C group) were compared with 12 animals otherwise treated with PCRA (T group), starting approximately at 60 minutes post-occlusion and lasting 120-180 minutes. In 3 animals of the T group, regional myocardial oxygen content was also imaged by two-dimensional near infrared spectroscopy (2D-NIRS) with and without PCRA, before and after LAD reperfusion.

Results

All animals without PCRA died despite unrelenting resuscitation maneuvers (120 minutes average survival time). Conversely, animals treated with PCRA showed a reduction in life-threatening arrhythmia and maintenance of aortic pressure, allowing interruption of PCRA in all cases early in the experiments, with sound hemodynamics at the end of the observation period. During LAD occlusion, NIRS showed severe de-oxygenation of the LAD territory that improved with PCRA. After PCRA suspension and LAD reperfusion, the residual de-oxygenated area proved to be smaller than the initial risk area.

Conclusions

In AMI, PCRA initiated during advanced CS drastically reduced early mortality from 100% to 0% in a 4-5 hour observation period. PCRA promoted oxygenation of the ischemic area during LAD occlusion. Results support the use of PCRA as first line of treatment in AMI-CS, improving myocardial rescue and short-term survival.

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Videos

Derek Hausenloy, MD, PhD, Duke National University Singapore Reducing Myocardial Infarct Size: Translational Challenges and Opportunities

Dr. Hausenloy provides insights into translational opportunities in the field of ischemia reperfusion injury at the 2016 A-CURE Symposium.

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Videos

Roger Hajjar, MD, PhD, Mt. Sinai

Dr. Hajjar speaks on the potential use of Impella support to enhance the efficacy of cardiac gene therapy approaches to heart failure.

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Pre-Clinical Resources

Left Ventricular Unloading Using an Impella CP Improves Coronary Flow and Infarct Zone Perfusion in Ischemic Heart Failure

Abstract

Background-—Delivering therapeutic materials, like stem cells or gene vectors, to the myocardium is difficult in the setting of
ischemic heart failure because of decreased coronary flow and impaired microvascular perfusion (MP). The aim of this study was to
determine if mechanical left ventricular (LV) unloading with the Impella increases coronary flow and MP in a subacute myocardial
infarction.

Methods and Results-—Anterior transmural myocardial infarction (infarct size, 26.03.4%) was induced in Yorkshire pigs. At 2
weeks after myocardial infarction, 6 animals underwent mechanical LV unloading by Impella, whereas 4 animals underwent
pharmacological LV unloading using sodium nitroprusside for 2 hours. LV unloading with Impella significantly reduced end-diastolic
volume (1611mL, P=0.02) and end-diastolic pressure (EDP; 3223 mm Hg, P=0.03), resulting in a significant decrease in LV
end-diastolic wall stress (EDWS) (infarct: 71.614.7 to 43.310.8 kdynes/cm2 [P=0.02]; remote: 66.620.9 to 40.613.3 kdynes/
cm2 [P=0.02]). Coronary flow increased immediately and remained elevated after 2 hours in Impella-treated pigs. Compared
with the baseline, MP measured by fluorescent microspheres significantly increased within the infarct zone (10981%, P=0.003),
but not in the remote zone. Although sodium nitroprusside effectively reduced LV-EDWS, 2 (50%) of sodium nitroprusside–treated
pigs developed profound systemic hypotension. A significant correlation was observed between the infarct MP and EDWS (r2=0.43,
P=0.03), suggesting an important role of EDWS in regulating MP during LV unloading in the infarcted myocardium.

Conclusions-—LV unloading using an Impella decreased EDWS and increased infarct MP without hemodynamic decompensation.
Mechanical LV unloading is a novel and efficient approach to increase infarct MP in patients with subacute myocardial infarction.

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Pre-Clinical Resources

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 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

Keita Saku, Takamori Kakino, Takahiro Arimura, Genya Sunagawa, Takuya Nishikawa, Takafumi Sakamoto, Takuya Kishi, Hiroyuki Tsutsui, Kenji Sunagawa

Abstract

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.

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Pre-Clinical Resources

Left Ventricular Unloading Using an Impella CP Improves Coronary Flow and Infarct Zone Perfusion in Ischemic Heart Failure Journal of the American Heart Association

Shin Watanabe, MD; Kenneth Fish, PhD; Jason C. Kovacic, MD, PhD; Olympia Bikou, MD; Lauren Leonardson, LVT; Koichi Nomoto, MD;
Jaume Aguero, MD; Navin K. Kapur, MD; Roger J. Hajjar, MD; Kiyotake Ishikawa, MD

Abstract

Background-—Delivering therapeutic materials, like stem cells or gene vectors, to the myocardium is difficult in the setting of ischemic heart failure because of decreased coronary flow and impaired microvascular perfusion (MP). The aim of this study was to determine if mechanical left ventricular (LV) unloading with the Impella increases coronary flow and MP in a subacute myocardial infarction.

Methods and Results-—Anterior transmural myocardial infarction (infarct size, 26.03.4%) was induced in Yorkshire pigs. At 2 weeks after myocardial infarction, 6 animals underwent mechanical LV unloading by Impella, whereas 4 animals underwent pharmacological LV unloading using sodium nitroprusside for 2 hours. LV unloading with Impella significantly reduced end-diastolic volume (1611%, P=0.02) and end-diastolic pressure (EDP; 3223%, P=0.03), resulting in a significant decrease in LV enddiastolic wall stress (EDWS) (infarct: 71.614.7 to 43.310.8 kdynes/cm2 [P=0.02]; remote: 66.620.9 to 40.613.3 kdynes/cm2 [P=0.02]). Coronary flow increased immediately and remained elevated after 2 hours in Impella-treated pigs. Compared with the baseline, MP measured by fluorescent microspheres significantly increased within the infarct zone (10981%, P=0.003), but not in the remote zone. Although sodium nitroprusside effectively reduced LV-EDWS, 2 (50%) of sodium nitroprusside–treated pigs developed profound systemic hypotension. A significant correlation was observed between the infarct MP and EDWS (r2=0.43, P=0.03), suggesting an important role of EDWS in regulating MP during LV unloading in the infarcted myocardium.

Conclusions-—LV unloading using an Impella decreased EDWS and increased infarct MP without hemodynamic decompensation. Mechanical LV unloading is a novel and efficient approach to increase infarct MP in patients with subacute myocardial infarction.

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Pre-Clinical Resources

JAHA, 2018 Journal of the American Heart Association

Left Ventricular Unloading Using an Impella CP Improves Coronary Flow and Infarct Zone Perfusion in Ischemic Heart Failure

Abstract

Background-—Delivering therapeutic materials, like stem cells or gene vectors, to the myocardium is difficult in the setting of ischemic heart failure because of decreased coronary flow and impaired microvascular perfusion (MP). The aim of this study was to determine if mechanical left ventricular (LV) unloading with the Impella increases coronary flow and MP in a subacute myocardial infarction.

Methods and Results-—Anterior transmural myocardial infarction (infarct size, 26.03.4%) was induced in Yorkshire pigs. At 2 weeks after myocardial infarction, 6 animals underwent mechanical LV unloading by Impella, whereas 4 animals underwent pharmacological LV unloading using sodium nitroprusside for 2 hours. LV unloading with Impella significantly reduced end-diastolic volume (1611%, P=0.02) and end-diastolic pressure (EDP; 3223%, P=0.03), resulting in a significant decrease in LV enddiastolic wall stress (EDWS) (infarct: 71.614.7 to 43.310.8 kdynes/cm2 [P=0.02]; remote: 66.620.9 to 40.613.3 kdynes/cm2 [P=0.02]). Coronary flow increased immediately and remained elevated after 2 hours in Impella-treated pigs. Compared with the baseline, MP measured by fluorescent microspheres significantly increased within the infarct zone (10981%, P=0.003), but not in the remote zone. Although sodium nitroprusside effectively reduced LV-EDWS, 2 (50%) of sodium nitroprusside–treated pigs developed profound systemic hypotension. A significant correlation was observed between the infarct MP and EDWS (r2=0.43, P=0.03), suggesting an important role of EDWS in regulating MP during LV unloading in the infarcted myocardium.

Conclusions-—LV unloading using an Impella decreased EDWS and increased infarct MP without hemodynamic decompensation. Mechanical LV unloading is a novel and efficient approach to increase infarct MP in patients with subacute myocardial infarction.

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Pre-Clinical Resources

Circulation Heart Failure, May 2018

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

Abstract

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.

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Videos

Dr. Kiyotake Ishikawa, Icahn School of Medicine at Mount Sinai

Left ventricular unloading leading to unloading of the left atria, and subsequent inhibition of atrial arrhythmia due to decrease atrial wall stress.

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Videos

Dr. Elazer Edelman, MIT & Harvard University

Dr. Edelman at the the 2017 A-CURE Symposium speaking on device-based approaches to monitor cardiac function of patients on Impella support.

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What Is Acute Unloading?

Dr. Carlos del Rio, MyoKardia and QTest Labs

The Paradoxical Energetic Energetic Costs of Acute Mechanical Unloading

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What Is Acute Unloading?

Dr. Jacob Moller, University of Odense Denmark

Comparative hemodynamics of ECMO and Impella support in a model of cardiogenic shock

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Pre-Clinical Resources

Improved Regional Myocardial Blood Flow, Left Ventricular Unloading, and Infarct Salvage Using an Axial-Flow, Transvalvular Left Ventricular Assist Device

Richard W. Smalling, David B. Cassidy, Robert Barrett,Bruce Lachterman, Patty Felli, James Amirian

Abstract

The concept of salvage of ischemic myocardial tissue by reperfusion therapy has been suggested by animal1 and human2 studies. Some investigators have reported that the level of collateral flow to the bed at risk determines ultimate infarct size3 others have suggested that the amount of collateral flow and degree of functional recovery are not correlated.4

An additional possible benefit of reperfusion therapy is the concept that late reperfusion may not salvage left ventricular (LV) tissue or function but may limit infarct expansion.5 Additionally, reperfusion may induce further myocardial damage; however, there is no clear consensus regarding the extent or possible modification of this problem.6 Recent interest has focused on the actions of free radicals and use of free radical scavengers at the time of reperfusion. Unfortunately, at the present time, these studies have yielded conflicting results possibly because of differences in models and agents used.7,8

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Pre-Clinical Resources

Left Ventricular Support by Catheter-Mounted Axial Flow Pump Reduces Infarct Size

Bart Meyns, Jarek Stolinski, Veerle Leunens, Erik Verbeken, Willem Flameng

Abstract

The transvalvular assist device Impella (Aachen, Germany) is a potent, miniaturized pump that offers the possibility of unloading the left ventricle (LV) via the femoral placement (1). In vivo and clinical use of this device has indicated that the pump produces a mean flow of 4.2 l/min at maximal rotational speed (2). Mechanical unloading of the myocardium during ischemiaandreperfusionhasbeenshowntoreduceLVpressure work and myocardial oxygen consumption (3–5). However, the installation of a left heart bypass during myocardial infarction (MI) is a cumbersome clinical procedure, with important comorbidity. Pharmacologic approaches, such as the early use of beta-blockers,nitroglycerin,andangiotensin-convertingenzyme inhibitors, have achieved infarct size reduction in experimental models (6–10). The use of beta-blockers and angiotensin-converting enzyme inhibitors has rapidly advanced from experimental studies to the clinical recommendation as standard therapy in most patients experiencing an MI. However, clinical trials on the early use (first day of
infarction) showed an increased incidence of hypotension (9–12). Mechanical support combines the beneficial effects of myocardial unloading and an increase in perfusion pressure. It can therefore be used early, even during ischemia and in myocardial failure. This new pump allows unloading of the LV via a peripheral approach in the setting of acute MI. We wanted to investigate the effect of this microaxial blood pump on MI size.

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Pre-Clinical Resources

Adjunctive Left Venticular Unloading During Myocardial Reperfusion Plays a Major Role in Minimizing Myocardial Infarct Size

Laschinger JC, Grossi EA, Cunningham JN Jr, Krieger KH, Baumann FG, Colvin SB, Spencer FC.

Abstract

Although prompt institution of reperfusion following coronary artery occlusion has been shown to limit myocardial infarct size, significant “reperfusion injury” may result. We investigated in a canine model whether maintenance of the left ventricle in an unloaded state during the initial reperfusion period following acute myocardial ischemia would result in greater limitation of infarct size or modify the development of reperfusion injury. Group I (control, n = 6) underwent 6 hours of occlusion of the left anterior descending coronary artery without further intervention. In both Group II (n = 6) and Group III (n = 6), the snare was released after 2 hours and hearts were reperfused for 4 hours. In Group III only, the left ventricle was maintained in an unloaded state throughout the entire reperfusion interval via pulsatile left atrial-femoral artery bypass. The results showed that reperfusion of the left ventricle in an unloaded state resulted in significantly improved limitation of both infarct size (area of infarct/area at risk = 16.6% for Group III versus 72.0% for Group I and 55.4% for Group II, p less than 0.001) and area of microvascular damage (area of microvascular damage/area at risk = 4.8% for Group III versus 30.6% for Group II, p less than 0.001). These results indicate that although myocardial reperfusion of the type provided by thrombolysis and/or angioplasty techniques does result in limitation of infarct size when compared to no reperfusion, this limitation is not optimal unless the left ventricle is unloaded during the initial reperfusion period.

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Improving left ventricular unloading following prolonged cardiac arrest using a minimally invasive left ventricular assist device: a prospective animal study in pigs

Andreas Ebeling, Richard Zayat, Michael Fries, Mattias Derwall

Abstract

Cardiopulmonary resuscitation (CPR) is an emergency procedure deployed when a patient suffers cardiac arrest (CA). Compared to conventional CPR, improved survival is observed after CA when CPR is conducted in the presence of a minimally invasive left ventricular assist device, Impella 2.5 (iCPR). However, data on myocardial function during and following iCPR are lacking. To assess cardiac functional parameters during and following iCPR. Five 55.2±2.4 kg pigs were anesthetized, intubated, and implanted with an Impella 2.5. Ventricular fibrillation (VF) was electrically induced and left untreated for 9 minutes before defibrillation was attempted following six minutes of iCPR. During iCPR, the Impella device was set to the maximally achievable flow. 1hr following return of spontaneous circulation (ROSC), mild therapeutic hypothermia was induced for 16 h using a total of 4 liters of 6° C cold saline infusions and ice bags. To assess myocardial recovery, we used 2-D echocardiography, tissue Doppler (TDI), and Speckle-tracking. All animals received transesophageal echocardiography at baseline, during untreated cardiac arrest, at the initiation of iCPR, 30 minutes, and 5 hours following ROSC. Left ventricular (LV) systolic parameters returned to baseline values 5 h after ROSC (global longitudinal strain: -25±4.3% vs. -20±2.7%; p=0.388; EF(%): 64±8.8 vs. 61.32±10.3, p=0.971; stroke volume index (mL/m2): 28.32±8.9 vs. 24.71±12.86, p=0.545). LV volume unloading was also observed over the same time period. LV end-diastolic volume was 55.38±2.8 mL at baseline, peaked after CA at 64.7±9.9 mL, fell to 45.69±7.4 mL 30 min after initiation of iPCR, and was maintained at 49.46±13.9 mL 5 h after ROSC. Recovery of the RV systolic parameters was not observed during the first 5 h following ROSC (baseline vs. 5hr after ROSC: TDI derived TASV (cm/s): 11.6±1 vs. 8.5±1, p=0.005, RV- FAC (%): 42±6.2 vs. 33±6.9, p=0.006). iCPR is able to achieve a full recovery of LV systolic parameters and provides sufficient LV volume unloading. The observed RV distension is likely attributable to extensive volume loading. Further studies are needed to analyze long term LV and RV function following CA and iCPR support

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LV Unloading using an Impella CP Reduces Wall Stress and Improves Coronary Flow and Perfusion in Infarcted Myocardium

Kiyotake Ishikawa, Shin Watanabe, Lauren Leonardson, Kenneth Fish, Roger J Hajjar

Abstract

LV unloading may improve coronary perfusion by increasing cardiac output and reducing LV wall stress. Whether sustained LV unloading improves myocardial perfusion in a post-MI setting remains uncertain. Unloading a post-MI LV with an Impella CP increases coronary flow and myocardial perfusion by reducing LV wall stress and increasing cardiac output. To mimic patients who need LV support, large anterior transmural MI was induced by occluding the proximal LAD for 90 minutes in Yorkshire pigs (n=5, 40-50 Kg) followed by a thrombus injection through the balloon lumen to induce total occlusion of the LAD. Two-weeks after the MI, animals underwent LV unloading with an Impella CP for 120 minutes. Epicardial coronary flow was assessed by coronary flow wire before, 5 minutes and 120 minutes after LV unloading. Myocardial perfusion was assessed using fluorescent microspheres before and 120 minutes after LV unloading. Coronary angiograms revealed TIMI 2 flow in 4 animals, and TIMI 3 flow in one animal. LV unloading with maximal pump support (P8) for two hours resulted in an increase in total cardiac output (3.08 to 3.93 l/min, P=0.07). Impella support significantly reduced end-diastolic volume (109±17 to 85±12 mL, P=0.02) and end-diastolic pressure (29.3±5.6 to 19.2±6.9 mmHg) resulting in a significant decrease in LV end-diastolic wall stress (infarct: 34.4±5.5 to 20.2±5.2 kdynes/cm2, P=0.03; remote: 32.4±8.6 to 19.3±6.0 kdynes/cm2, P=0.03). Coronary flow increased acutely (LAD: 6.7±1.8 to 10.2±1.5 cm/s, P=0.03, LCx: 8.4±2.7 to 10.4±3.6 cm/s, P=0.31) and remained elevated at 120 minutes (LAD: 9.8±1.3 cm/s, P=0.058, LCx: 12.4±4.2 cm/s, P=0.058). Compared to baseline, myocardial perfusion as measured by fluorescent microspheres within the infarct zone was significantly increased (87±67%, P=0.02), while perfusion of the remote non-ischemic myocardium was similar compared to the baseline (-2±15%, P=0.89), likely due to auto-regulation in the non-injured myocardium. Sustained LV unloading using an Impella CP increases coronary flow and perfusion of infarcted myocardium for at least 2-hours.

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LV Unloading using Impella CP Improves LA Pressure, Function, and Stiffness

Shin Watanabe, Kenneth Fish, Lauren Leonardson, Roger J Hajjar, Kiyotake Ishikawa

Abstract

The impact of pLVAD on LA function and stiffness in HF remains unclear.
Hypothesis: Unloading the LV with an Impella CP improves trans-mitral pressure gradient, leading to a reduction of LA pressure and improved LA function and stiffness. HF is induced by percutaneously occluding the proximal LAD for 90 minutes in Yorkshire pigs (n=4, 40-50 Kg). Two-weeks after the MI, animals underwent LV unloading with an Impella CP for 150 minutes. LA pressure was directly measured by a trans-septal approach and LA volumes were assessed by 3-dimensional echocardiography. LA stiffness was approximated as the slope of minimal and maximal LA pressure–volume coordinates as described previously (Circ Heart Fail. 2015;8:295-303.). Two-weeks after the MI, the animals presented with impaired LVEF (69.7±10.5 to 38.6±7.0 %, P=0.03) and a dilated LV (LV end-systolic volume: 24.55±10.7 to 65.3±16.3 mL, P=0.04) without significant mitral regurgitation. LV unloading with maximal pump support (P8) resulted in an increase in total cardiac output (2.80±0.18 to 3.27±0.22 l/min, P=0.03) and reduced LV end-diastolic pressure (27.5±10.1 to 17.9±4.5 mmHg, P=0.06). These changes were accompanied by a significant reduction in mean LA pressure (17.3±2.6 to 10.8±2.1 mmHg, P=0.001). LA volumes assessed by 3-dimensional echocardiography were also reduced (LA Maximal volume: 40.3±4.6 to 29.0±2.3 ml, P=0.006, LA Minimal volume: 20.3±2.7 to 15.0±2.3 ml, P=0.002). While the total LAEF was not altered from the baseline (49.3±6.4 to 48.5±6.5%, P=0.85), passive LAEF was significantly increased (17.7±1.9 to 39.4±5.6 %, P=0.008), suggesting an improved trans-mitral suction effect. Additionally, LA stiffness assessed by pressure-volume coordinates was improved with Impella support (1.41±0.52 to 0.30±0.16 mmHg/ml, P=0.03). LV unloading using an Impella CP improves passive LA function and reduces mean LA pressure in a recent MI setting. Along with improved LA stiffness, these data implicate a beneficial impact of LV unloading on relieving HF symptoms.

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Inhibition of the inflammatory injury following myocardial ischemia-reperfusion in the mouse

Antonio Abbate, Stephano Toldo

Abstract

Reperfusion is effective in reducing ischemic injury in acute myocardial infarction (AMI). Ischemia, however, triggers a secondary injury, known as reperfusion injury, contributing to the overall infarct size. Multiple mechanisms are being explored to favorably modify the effects of reperfusion injury. We hypothesize that inhibition of the Nod-like Receptor Protein-3 (NLRP3) inflammasome limits infarct size following myocardial ischemia/reperfusion (I/R), by inhibiting the inflammatory component of the reperfusion injury. We induced AMI in adult mice by transient ligation of the left anterior descending coronary artery for 30 or 75 minutes. We tested 3 different strategies to inhibit the NLRP3 inflammasome: a newly designed small molecule specifically inhibiting the inflammasome (NLPR3inh), plasma derived alpha-1 antitrypsin (AAT) shown to inhibit the NLRP3 inflammasome, and a synthetic oligopeptide (SP16) designed to reproduce the C-terminal peptide of AAT. Infarct size was measured at 1, 3 and 24 hours and expressed as % of area at risk. Infarct size increased with duration of ischemia from 43±4% with 30 minutes to 65±3% with 75 minutes if ischemia (P<0.001) showing a wavefront of ischemic injury. After 30 minutes of ischemia, however, infarct size progressively increased from 1 to 24 hours after reperfusion (11±2% at 1 hour, 30±5% at 3 hours and 43±4% at 24 hours) showing a wavefront of reperfusion injury. Administration of the NLRP3inh, AAT or SP16 given immediately at reperfusion or within 30 minutes after reperfusion following 30 or 75 minutes of ischemia significantly reduced infarct size at 24 hours (-56%, -44%, -55%, respectively, vs vehicle, all P<0.01). Pharmacological inhibition of the NLRP3 inflammasome within 1 hour of reperfusion limits the secondary inflammatory injury and infarct size following myocardial ischemia-reperfusion in the mouse. Pharmacological interventions alone or in conjunction with other interventions show promise to significantly further improve outcome post myocardial infarction.

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LV Unloading using Imepella Reduces LA Pressure and Volume Overload in Chronic Mitral Regurgitation

Kiyotake Ishikawa, Shin Watanabe, Lauren Leonardson, Kenneth Fish, Roger J Hajjar

Abstract

Mitral regurgitation is a common presentation in patients administered due to the decompensated chronic heart failure. Whether an LV-to-aorta pLVAD can be effective in relieving LA overload remains unclear. LV unloading using an Impella CP reduces LA pressure and volume by actively pumping the blood towards forward direction. Chronic heart failure with mitral regurgitation was induced in Yorkshire pigs (n=3, 20 Kg) by percutaneously severing chordae tendinae of the mitral apparatus with a biopsy catheter. Three months later (body weight 43.5 ± 5.0 Kg), the animals underwent LV unloading with an Impella CP with a maximal flow support (p8). Hemodynamics before and during the LV unloading were assessed by Swan-Ganz catheter and pressure volume loop catheter (Millar catheter) in both LA and LV. Additionally, LA volumes were assessed by 3-dimensional echocardiography before and during the Impella support. At 3 months, animals presented with moderate mitral regurgitation (regurgitant fraction 38±10%) with dilated LV (LV end-diastolic volume: 45.5±1.7 mL to 89.7±18.0, P=0.04, LV end-systolic volume: 12.5±1.6 mL to 31.2±10.9, P=0.10, Day0 to 3 month, respectively). LV unloading resulted in a significant reduction of LV end-diastolic pressure (13.6±2.6 to 4.0±4.0 mmHg, P=0.029). Although the visual assessment of MR degree by color-Doppler echocardiography did not change by LV unloading, mean LA pressure decreased significantly (12.3±7.1 to 9.3±6.1 mmHg, P=0.035). LA v-wave, which is accentuated in the mitral regurgitation due to the regurgitant flow, also reduced significantly, indicating a reduction of quantitative MR (17.3±11.2 to 12.3±9.5 mmHg, P=0.038). Furthermore, maximum LA volume assessed by three-dimensional echocardiography was significantly decreased (46.6±13.4 to 29.7±15.9 ml, P=0.043). LV-to-aorta pLVAD can alleviate LA pressure and volume overload in a heart failure due to mitral regurgitation.

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Hydrostatic pressure gradient ultrafiltration device: A novel approach for extracellular fluids removal

Yair Feld, Nitai Hanani, Giorgi Shtenberg

Abstract

This study explored the concept of a novel intra peritoneal absorption chamber for fluids removal through the peritoneal membranes. Fluid overload is a common & challenging clinical problem in acutely decompensated heart failure patients (ADHF). Normalization of fluid status in ADHF is associated with improved long term prognosis. Diuretic therapy is limited by kidney function and perfusion pressure, while dialysis and ultrafiltration are associated with significant hemodynamic and electrolyte imbalances when performed in the acute settings. We suggest a novel approach, in which a permeable absorption chamber is implanted in the peritoneum. A negative hydrostatic pressure in the absorption chamber is induced by a pump, prompting fluids ultrafiltration through the peritoneal membranes into the chamber. The accumulated extracellular fluids are drained to an ex vivo collection system or into the urinary system. To examine the feasibility of this concept, we implanted an absorption chamber in the peritoneum of rats and drained fluids through the transplanted chamber. An absorption chamber was prepared from a stainless steel coil with a diameter of 0.4 cm and a length of 3-6 cm covered by a collagen membrane (Permacol, Medtronic). The absorption chamber was implanted in the peritoneum cavity of four Sprague-Dawley rats. Two weeks post implantation the rats were anaesthetized and a peritoneal needle was inserted to the chamber. Extracellular fluid were drained from the chamber at an average rate of 16 ± 6 cc/kg/day during 3 hours of negative hydrostatic pressure induction. The fluids electrolytes and proteins were comparable to the serum content. Implantable absorption chamber enables extracellular fluids removal through the peritoneal membranes. This study suggests that an implantable absorption chamber may be used in fluid-overload clinical conditions, and serve as a possible novel heart failure therapy in acute and potentially chronic settings.

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A new animal model for investigation of mechanical unloading in hypertrophic and failing hearts: combination of transverse aortic constriction and heterotopic heart transplantation

Andreas Schaefer, Yvonne Schneeberger, Justus Stenzig, Daniel Biermann, Marisa Jelinek, Hermann Reichenspurner, Thomas Eschenhagen, Heimo Ehmke, Alexander P Schwoerer

Abstract

Previous small animal models for simulation of mechanical unloading are solely performed in healthy or infarcted hearts, not representing the pathophysiology of hypertrophic and dilated hearts emerging in heart failure patients. In this article, we present a new and economic small animal model to investigate mechanical unloading in hypertrophic and failing hearts: the combination of transverse aortic constriction (TAC) and heterotopic heart transplantation (hHTx) in rats. To induce cardiac hypertrophy and failure in rat hearts, three-week old rats underwent TAC procedure. Three and six weeks after TAC, hHTx with hypertrophic and failing hearts in Lewis rats was performed to induce mechanical unloading. After 14 days of mechanical unloading animals were euthanatized and grafts were explanted for further investigations. 50 TAC procedures were performed with a survival of 92% (46/50). When compared to healthy rats left ventricular surface decreased to 5.8±1.0 mm² (vs. 9.6± 2.4 mm²) (p= 0.001) after three weeks with a fractional shortening (FS) of 23.7± 4.3% vs. 28.2± 1.5% (p=0.01). Six weeks later, systolic function decreased to 17.1± 3.2% vs. 28.2± 1.5% (p=0.0001) and left ventricular inner surface increased to 19.9±1.1 mm² (p=0.0001). Intraoperative graft survival during hHTx was 80% with 46 performed procedures (37/46). All transplanted organs survived two weeks of mechanical unloading. Combination of TAC and hHTx in rats offers an economic and reproducible small animal model enabling serial examination of mechanical unloading in a truly hypertrophic and failing heart, representing the typical pressure overloaded and dilated LV, occurring in patients with moderate to severe heart failure.

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