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Publications of Interest

Pre-Clinical Resources

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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Publications of Interest

Total mechanical energy of a ventricle model and cardiac oxygen consumption

Suga, H.

 

Abstract

Mechanical energy (ENG) required by a time-varying elastance model of the ventricle was compared with oxygen consumption per beat (VO2) of the canine left ventricle contracting under a variety of loading conditions. ENG needed for this model to increase its elastance during systole is shown to be equal to the sum of the potential energy built in the elastance during systole plus the external mechanical stroke work. This ENG is equivalent to the area (PVA) bounded by the end-systolic and end-diastolic P-V curves and the systolic limb of the P-V loop trajectory in the P-V plane. There was a high correlation (r = 0.89) between VO2s documented in the literature and PVAs assessed by the author from the accompanying P-V data from both isovolumic and ejecting contractions in 11 hearts. A linear regression analysis yielded an empirical equation: VO2 (ml O2/beat) = a . PVA (mmHg . ml/beat) + b, where a = 1.37 X 10(-5) and b = 0.027, which can be used to predict VO2 from PVA. A preliminary experimental study in my laboratory confirmed the validity of this empirical equation.

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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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Clinical Resources

The science behind percutaneous hemodynamic support: a review and comparison of support strategies

Burkhoff, D., Naidu, S. S.

Abstract

Patients in a variety of cardiovascular disease states may benefit from temporary percutaneous cardiac support, including those in acute decompensated heart failure, fulminant myocarditis, acute myocardial infarction with or without cardiogenic shock and those undergoing high-risk percutaneous coronary intervention. The ideal percutaneous cardiac support device is safe, easy to use and versatile enough to meet the needs of various clinical situations and patient cohorts. In addition, it should provide maximal hemodynamic support and protection against myocardial ischemia. With these goals in mind, the scientific principles that govern hemodynamic effectiveness and myocardial protection as they pertain to acute support devices are reviewed.

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Clinical Resources

Declining In-Hospital Mortality and Increasing Heart Failure Incidence in Elderly Patients With First Myocardial Infarction

Ezekowitz, J. A., Kaul, P., Bakal, J. A., Armstrong, P. W., Welsh, R. C., McAlister, F. A.

Abstract

OBJECTIVES: The purpose of this study was to examine the long-term incidence of heart failure (HF) in elderly patients with myocardial infarction (MI). BACKGROUND: In-hospital HF is common after MI and is associated with poor short-term prognosis. Limited data exist concerning the long-term incidence or prognosis of HF after MI, particularly in the era of coronary revascularization. METHODS: A population-based cohort of 7,733 patients > or = 65 years of age hospitalized for a first MI (International Classification of Diseases-9th Revision-Clinical Modification code 410.x) and without a prior history of HF was established between 1994 and 2000 in Alberta, Canada, and followed up for 5 years. RESULTS: During the index MI hospitalization, 2,831 (37%) MI patients were diagnosed with new HF and 1,024 (13%) died. Among hospital survivors who did not have HF during their index hospitalization (n = 4,291), an additional 3,040 patients (71%) developed HF by 5 years, 64% of which occurred in the first year. In total, 5,871 (76%) elderly patients who survived their first MI developed HF over 5 years. Among those who survived the index hospitalization, the 5-year mortality rate was 39.1% for those with HF during the index MI hospitalization compared with 26.7% among those without HF (p < 0.0001) during the index MI hospitalization. Over the study period, the 5-year mortality rate after MI decreased by 28%, whereas the 5-year rate of HF increased by 25%. CONCLUSIONS: In this large cohort of elderly patients without a history of HF, HF developed in three-quarters in the 5 years after their first MI; this proportion increased over time as peri-MI mortality rates declined. New-onset HF significantly increases the mortality risk among these patients.

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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.

VIEW

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.

VIEW

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.

VIEW

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.

VIEW

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.

VIEW

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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Clinical Resources

Feasibility of Early Mechanical Support During Mechanical Reperfusion of Acute Myocardial Infarct Cardiogenic Shock

O’Neill, W., Basir, M., Dixon, S., Patel, K., Schreiber, T., Almany, S.

Abstract

Although only preliminary, initial experience suggests that rapid door-to-support times are feasible. This approach results in the rapid reversal of the shock state in most patients, allowing operators to obtain TIMI flow grade III rates comparable to those in patients with non-shock ST-segment elevation MI and may improve survival. Given these encouraging pilot data, a large formal quality initiative entitled the Detroit Cardiogenic Shock Initiative has been launched.

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Clinical Resources

Hemodynamic Support With a Microaxial Percutaneous Left Ventricular Assist Device (Impella) Protects Against Acute Kidney Injury in Patients Undergoing High-Risk Percutaneous Coronary Intervention

Flaherty, M. P., Pant, S., Patel, S. V., Kilgore, T., Dassanayaka, S., Loughran, J. H., Rawasia, W., Dawn, B., Cheng, A., Bartoli, C. R.

Abstract

RATIONALE:

Acute kidney injury (AKI) is common during high-risk percutaneous coronary intervention (PCI), particularly in those with severely reduced left ventricular ejection fraction. The impact of partial hemodynamic support with a microaxial percutaneous left ventricular assist device (pLVAD) on renal function after high-risk PCI remains unknown.

OBJECTIVE:

We tested the hypothesis that partial hemodynamic support with the Impella 2.5 microaxial pLVAD during high-risk PCI protected against AKI.

METHODS AND RESULTS:

In this retrospective, single-center study, we analyzed data from 230 patients (115 consecutive pLVAD-supported and 115 unsupported matched-controls) undergoing high-risk PCI with ejection fraction ≤35%. The primary outcome was incidence of in-hospital AKI according to AKI network criteria. Logistic regression analysis determined the predictors of AKI. Overall, 5.2% (6) of pLVAD-supported patients versus 27.8% (32) of unsupported control patients developed AKI (P<0.001). Similarly, 0.9% (1) versus 6.1% (7) required postprocedural hemodialysis (P<0.05). Microaxial pLVAD support during high-risk PCI was independently associated with a significant reduction in AKI (adjusted odds ratio, 0.13; 95% confidence intervals, 0.09-0.31; P<0.001). Despite preexisting CKD or a lower ejection fraction, pLVAD support protection against AKI persisted (adjusted odds ratio, 0.63; 95% confidence intervals, 0.25-0.83; P=0.04 and adjusted odds ratio, 0.16; 95% confidence intervals, 0.12-0.28; P<0.001, respectively).

CONCLUSIONS:

Impella 2.5 (pLVAD) support protected against AKI during high-risk PCI. This renal protective effect persisted despite the presence of underlying CKD and decreasing ejection fraction.

VIEW

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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Clinical Resources

The Current Use of Impella 2.5 in Acute Myocardial Infarction Complicated by Cardiogenic Shock: Results from the USpella Registry

WILLIAM W. O ’NEILL, THEODORE SCHREIBER, DAVID H. W. WOHNS, CHARANJIT RIHAL, SRIHARI S. NAIDU, ANDREW B. CIVITELLO, SIMON R. DIXON, JOSEPH M. MASSARO, BRIJESHWAR MAINI, E. MAGNUS OHMAN

Abstract

Prompt revascularization with percutaneous coronary intervention (PCI) has significantly reduced the incidence of cardiogenic shock (CS) and improved survival in the setting of acute myocardial infarction (AMI).1,2 However, when it occurs, CS remains a highly fatal complication following an AMI,3 despite aggressive revascularization and other adjunctive therapies.3,4 Percutaneous ventricular assist devices (pVADs) have been shown to provide superior hemodynamic support compared to intraaortic balloon pump (IABP) counterpulsation.4,5 In light of the recently reported studies that have failed to show a hemodynamicorsurvivalbenefitofIABPinthesetting ofpost‐AMICS,6–10physiciansmightadoptareflexive strategytousepVADsinthissettingmoreoften.While prospective randomized and adequately powered clinicaltrialsremainwarrantedtoevaluatethepotential benefits of these new devices, real‐world observational data can be useful to provide clinical insights on their use in daily routine practice. In the present study, we sought to evaluate the current use of Impella 2.5 in patients with confirmed CS complicating an AMI undergoing PCI. In particular, we were interested in evaluating the outcomes of patients who received hemodynamic support with Impella 2.5 (Abiomed, Inc., Danvers, MA, USA), prior to PCI versus those who received Impella 2.5 after PCI.

VIEW

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.

VIEW

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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Clinical Resources

Abiomed Receives FDA IDE Approval for Initiation of Door to Unloading (DTU) Prospective Feasibility Study

Abstract

DANVERS, Mass., Oct. 27, 2016 (GLOBE NEWSWIRE) — Abiomed, Inc. (NASDAQ:ABMD), a leading provider of breakthrough heart support and recovery technologies, announced today the U.S. Food and Drug Administration (FDA) approval of a prospective feasibility study to evaluate the use of the Impella CP heart pump for unloading of the left ventricle prior to primary percutaneous coronary intervention (PCI) in patients presenting with ST segment elevation myocardial infarction (STEMI), without cardiogenic shock. This trial will focus on feasibility and safety, and lay the groundwork for a future trial, designed to measure the impact that unloading may have on infarct size related to reperfusion injury, an acceleration of myocardial damage at the time of revascularization, in STEMI patients.

Impella® heart pumps are not currently approved for use in STEMI patients without cardiogenic shock. The STEMI patient segment is contributing to the growing heart failure population and represents a potential new patient indication that may benefit from Impella pump unloading the left ventricle.

STEMI is a type of heart attack caused by a blockage in one of the main heart arteries, preventing the flow of oxygen to the heart. It is estimated that 965,000 people a year have heart attacks 1 , of which approximately 200,000 are classified as STEMI2. The current standard of care is called Door to Balloon “DTB”, for the angioplasty balloon. The recommended treatment in guidelines for STEMI is revascularization (opening the blocked artery) to restore oxygen supply to the heart muscle through primary PCI within 90 minutes or less from the time of first medical contact. Despite current guidelines, 76% of patients experiencing their first acute myocardial infarction (AMI), will develop heart failure within five years 3 . Additionally, within five years of a patient surviving their first heart attack, 36% of men and 47% of women will die due to heart failure1. It is estimated that the number of heart failure patients will grow to 8 million people by 2030 with enormous associated costs 4 . Survival from heart attacks has been improved by the successful DTB protocol; however, this treatment is speculated to be contributing to the growing epidemic of heart failure.

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Publications of Interest

Hemodynamics of Mechanical Circulatory Support

Daniel Burkhoff, Gabriel Sayer, Darshan Doshi, Nir Uriel

Abstract

An increasing number of devices can provide mechanical circulatory support (MCS) to patients with acute hemodynamic compromise and chronic end-stage heart failure. These devices work by different pumping mechanisms, have various flow capacities,are inserted by different techniques,and have different sites from which blood is with drawn and returned to the body. These factors result in different primary hemodynamic effects and secondary responses of the body. However, these are not generally taken into account when choosing a device for a particular patient or while managing a patient undergoing MCS. In this review, we discuss fundamental principles of cardiac, vascular, and pump mechanics and illustrate how they provide a broad foundation for understanding the complex interactions between the heart, vasculature, and device, and how they may help guide future research to improve patient outcomes. (J Am Coll Cardiol 2015;66:2663–74) © 2015 by the American College of Cardiology Foundation.

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Pre-Clinical Resources

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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Publications of Interest

FDA approves the Door To Unloading clinical study investigating the feasibility of primary ventricular unloading in the clinical setting

A-CURE Working Group faculty members Navin Kapur, William O’Neill, and Jeff Moses have been selected as steering committee members for upcoming DTU trial.

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Clinical Resources

Relationship Between Therapeutic Effects on Infarct Size in Acute MI and One-year Outcomes: Patient-Level Analysis of Randomized Clinical Trials

James Udelson, Harry P. Selker, Robin Ruthazer, Holger Thiele, Manesh R Patel, E. Magnus Ohman, Akiko Maehara, Paul L. Jenkins, Melissa Nichols, Ori Ben-Yehuda, Gregg W. Stone

Abstract

Infarct size (IS) after MI is related to long-term outcomes. Whether a change in IS from an intervention is related to the intervention’s effect on outcomes is unknown. A therapy-induced change in IS is related in direction and/or magnitude to the outcome effect of that therapy. We combined patient-level data from 10 randomized clinical trials of therapies for STEMI. IS was assessed by sestamibi imaging or cardiac MR with analysis in core labs. Each patient within a trial was assigned a variable to represent a treatment’s mean effect on IS. Cox proportional hazards models estimated the association of treatment-related IS to one-year adjudicated clinical outcomes of hospitalization for HF and all-cause mortality. The 10 trials included 2,458 patients, 24% women. IS was measured at median 5 days post-MI. Mean trial IS in the control groups in the 10 trials ranged from 12% – 35% of the LV, and from 12% – 40% among treatment groups. There was a significant relation of treatment effect on IS to treatment effect on one-year HF hospitalization (HR 0.83, 95% CI 0.75 to 0.93, p<0.001). There was no significant relation between treatment effect on IS to treatment effect on one-year mortality (HR 1.04, 95% CI 0.94 to 1.15). The relation to HF hospitalization was stable in sensitivity analyses adjusting for time from MI to IS assessment, and for considering HF as the main outcome and death as a competing risk. This patient-level analysis of randomized placebo-controlled trials of multiple therapeutics for STEMI suggests that a treatment-induced effect on IS is related in direction and quantifiable magnitude to a treatment effect on HF hospitalizations. The data enable the consideration of incorporating infarct size assessment into novel trial analytic approaches as a surrogate endpoint to assess new therapeutics.

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Pre-Clinical Resources

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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Pre-Clinical Resources

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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Pre-Clinical Resources

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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Clinical Resources

To Have Clinical Value, Future Cardioprotective Interventions Must Provide Additive Protection To That From a P2Y12 Receptor Antagonist

Michael Cohen, James M. Downey

Abstract

Patients with AMI are treated with P2Y12 receptor antagonists to suppress platelet aggregation. Although P2Y12 antagonists are used for their anticoagulant effect, our studies reveal that they are also potent postconditioning-mimetics. The latter properties are influencing pre-clinical and clinical searches for adjunctive cardioprotective interventions in unexpected ways. In situ monkey, rabbit, and rat hearts were subjected to ischemia/reperfusion after which hearts were removed, areas at risk determined, and infarct size measured by triphenyltetrazolium chloride staining. Animals were given cangrelor, an intravenous P2Y12 antagonist, starting 10 min before reperfusion to simulate treatment of patients with AMI prior to angioplasty. Infarction was approximately half that seen in untreated animals. This cardioprotection was abrogated by inhibitors of signaling used by postconditioning including wortmannin, LY294002, PD98059, 5-hydroxydecanoate, 8-sulfophenyltheophylline, MRS1754, and 2-mercaptopropionylglycine suggesting that cangrelor protects by a similar mechanism. None restored platelet reactivity indicating that protection was independent of anti-coagulation. Our hypothesis was further strengthened by failure of ischemic pre- or postconditioning to potentiate cangrelor’s cardioprotection. Similar results were seen with clopidogrel and ticagrelor, other P2Y12 antagonists, indicating a class effect. We propose that much of the ability of P2Y12 inhibitors to improve outcomes in AMI can be attributed to direct infarct size reduction from conditioning rather than prevention of stent thrombosis. Because patients treated with P2Y12 antagonists prior to revascularization are already postconditioned, adding another conditioning intervention will be futile. This would explain why recent large trials of ischemic postconditioning or the postconditioning-mimetic cyclosporine in AMI patients were unsuccessful in spite of strong preclinical results. Additional protection in today’s patients will require an intervention not dependent on the conditioning mechanism. Any such intervention must first demonstrate additive protection in animals that have additionally been treated with a P2Y12 antagonist before clinical trials are considered.

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Pre-Clinical Resources

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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Pre-Clinical Resources

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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Clinical Resources

Feasibility and Effectiveness of a Multidisciplinary Team Approach in Refractory Cardiogenic Shock Requiring Mechanical Circulatory Support: A Pilot Prospective Study

Byung-Soo Ko, Iosif Taleb, Ryan Larsen, Anwar Tandar, Tae Soo Kang, Stephen McKellar, Josef Stehlik, Greg Stoddard, Antigone Koliopoulou, Edward M. Gilbert, Jose Nativi-Nicolau, James Fang, Craig Selzman, Frederick Welt, Stavros G. Drakos

Abstract

The diversity in both the etiology and the clinical course of refractory cardiogenic shock makes the management of this critical condition challenging. Although a multidisciplinary team based approach has been recommended, it has not been widely adopted. We sought to investigate the feasibility and effectiveness of a multidisciplinary team approach in patients with RCS. A multidisciplinary “SHOCK TEAM”, comprised of a heart failure cardiologist, an interventional cardiologist, an intensivist, and a cardiothoracic surgeon, was established in April 2015 as a part of the Utah Cardiac Recovery-SHOCK program. The program prospectively investigates the management and outcomes of consecutive RCS patients who (i) require temporary percutaneous mechanical circulatory support (MCS) based on predefined criteria and clinical protocol, and (ii) are being managed by the SHOCK TEAM. Nineteen patients who have been enrolled since the launch of the program were compared with the immediately preceding 40 consecutive patients who presented with RCS requiring percutaneous MCS (control group). Baseline characteristics including age (56 vs. 55 in control), comorbidities, presenting hemodynamics, duration of shock before reaching the tertiary care center were comparable between the two groups. We found a marginally significant lower 30-day mortality in the SHOCK TEAM group in a Cox regression model (38.9% vs. 60% in control group; HR, 0.65, p=0.07). ICU stay and hospital stay also tended to be shorter in the SHOCK TEAM group (mean ± SD, 13 ± 13 vs. 27 ± 59 days in control, p=0.33 and 16 ± 15 vs. 31 ± 59 days in control, p=0.30). Furthermore, “Door-to-MCS implementation” time was compared between the groups to evaluate whether the team approach would lead to delays in management, and there was no significant difference. A multidisciplinary shock team approach seems to be feasible, practical, and may improve outcomes of patients with RCS.

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Clinical Resources

Prognostic relevance of intra-aortic balloon pump in patients with acute myocardial infarction complicated by cardiogenic shock: Nationwide population study in Taiwan

Surenjav Chimed, Batmyagmar Khuyag

Abstract

Intra‐aortic balloon pump (IABP) is the most widely used form of mechanical circulatory support in patients with cardiogenic shock. However, usefulness of IABP in this high risk patient population is conflicting. We examined whether the patient prognosis in Taiwan treated with IABP has improved when IABP was actively used for mechanical circulatory support. We used Taiwan’s National Health Insurance Research Database to retrospectively review 3145 (2358 men [75%]) cardiogenic shock patients who treated primary PCI due to acute myocardial infarction (AMI) between 2000 and 2012. Primary outcome was all cause mortality and secondary outcome was heart failure. A total of 1417 patients who received IABP therapy and 1728 patients who not received non-IABP were selected in this study. The mean age of IABP group and non-IABP group was 68.1±13.1 years and 67±13.3 years, respectively (p=0.02). Median follow-up time for death was 1.51 years in non-IABP group and 1.07 years in IABP group (p<0.0001). Median follow-up time for heart failure was 0.28 years in non-IABP group and 0.09 years in IABP group (p<0.0001). During follow-up period, the adjusted hazard ratio for overall mortality was 1.22 (CI 95% 1.10-1.35, p<0.0001) and for overall heart failure was 1.24 (CI 95% 1.08-1.41, p<0.001). Risk factors for all-cause mortality were previous heart failure, diabetes, chronic kidney disease and hypertension. In this nationwide, population-based, retrospective cohort study, we found that mortality rate and heart failure rate not declined in cardiogenic shock patients who underwent primary PCI plus IABP therapy. Therefore, new type of mechanical circulatory support such as Impella should be considered for high risk, cardiogenic shock patients with AMI.

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Clinical Resources

Association between left ventricular global longitudinal strain and acute pulmonary edema caused by increased left ventricular afterload in patients with STEMI

Surenjav Chimed, Batmyagmar Khuyag, Amarjargal Baldandorj, Lkhagvasuren Zundui, Narantuya Davaakhuu

Abstract

Acute pulmonary edema (APE) is common complication after ST elevation myocardial infarction (STEMI) and often associated with poor prognosis. It is usually caused by decreases of left ventricular contractility and subsequent increase of left ventricular afterload. In this study we aimed to determine association between left ventricular global longitudinal strain (GLS) parameter and APE caused by increased left ventricular afterload. We chose patients with STEMI and who were treated by primary PCI in this study. Two dimensional speckle tracking echocardiography was used to assess left ventricular GLS. Study endpoint was APE caused by increased left ventricular afterload. Univariable and multivariable logistic regression analysis was used to determine association between GLS and APE. A total of 524 patients were enrolled. Mean age was 60 ± 13 years old and majority of patients were male 444 (84.7%). During admission, APE was occurred in 15 (2.9%) patients. Univariable logistic regression analysis showed GLS is significantly associated with APE and every 1 unit change of GLS is associated with 1.34 times increased probability of having APE (OR 1.34, 95% CI 1.17-1.53, p<0.001). After adjustment of clinical, angiographic and conventional echocardiographic indices, left ventricular GLS was independently associated with APE (OR 1.25, 95% CI 1.06-1.46, p<0.01). Predictive capacity of left ventricular GLS was better than LVEF (c-statistic 0.824, 95% CI 0.719-0.929, p<0.001). Speckle tracking derived GLS is strong and independent predictor of APE caused by increased left ventricular afterload in patients with STEMI after primary PCI. Prognostic capacity of GLS is better than LVEF.

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Pre-Clinical Resources

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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Clinical Resources

Potential of Regenerative Therapy with Medical Assist Devices

Timothy Henry

Abstract

Heart failure continues to be the leading cause of morbidity and mortality not only in the United States but throughout the world. Despite advances in medical and device therapy, many patients continue to have significant symptoms leaving heart transplantation, left ventricular assist devices (LVAD), or palliative care as the only options. This has stimulated interest in regenerative therapies including stem cell therapy. Based on positive preclinical results, the initial clinical trials used predominantly autologous bone marrow mononuclear stem cells (BMC). Trials with BMC demonstrated excellent safety but only modest efficacy most likely due to the significant variability with autologous BMC which is related to the decline in the number and potency of stem cells with age and cardiac risk factors. This has stimulated the next generation of cell therapies which include allogeneic cells, cardiac derived cells, and enhanced cultured autologous cells. A recent large double-blind, placebo controlled Phase 2 trial using enhanced BMC cells (IxCell-DCM) demonstrated a significant reduction in mortality and cardiovascular hospitalizations in cell-treated patients. A second large Phase 2 trial using enhanced mesenchymal stem cells (MSCs) will be presented at ESC and a large Phase 3 trial with allogeneic MSCs is underway. An even more attractive idea is to combine the benefits of novel, mechanical left ventricular support devices with regenerative therapy. To date, there have been a total of 67 patients randomized in 11 published clinical trials with the combination of cell therapy and LVAD trials. The largest of these (N=30) was an NIH-sponsored trial using allogeneic MSCs which demonstrated a potential benefit in LVAD weaning and a suggestion of mortality benefit. In summary, despite optimal medical and device therapy the number of patients with advanced HF continues to grow. Both novel mechanical assist devices and regenerative therapy represent potential solutions. The combination of these two unique therapies may be a particularly attractive solution.

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Clinical Resources

Assessment of Impella position on supine chest X-ray in the intensive care unit. Introduction and applicability of the Aortic Valve Location Ratio

Dagmar M. Ouweneel, Krischan D. Sjauw, Esther M.A. Wiegerinck, Alexander Hirsh, Jan Baan Jr, Bas A.J.M. de Mol, Wim K. Lagrand, R. Nils Planken, José P.S. Henriques

Abstract

Maintaining correct Impella position is a key factor for optimal functioning of the Impella device. The aortic valve is an important landmark for correct positioning. It would be of great value if the device position could be determined accurately by plain supine chest X-ray in the intensive care unit. The aim was to develop a ratio-based tool for determination of the aortic valve location on plain supine X-ray which can be used to monitor Impella position in the intensive care unit. Supine anterior-posterior chest X-ray of patients with an aortic valve prosthesis (n=473) were analyzed to determine the location of the aortic valve. We calculated several ratios with the potential to determine the position of the aortic valve. The Aortic Valve Location (AVL) ratio, defined as the distance between the carina and the aortic valve, divided by the thoracic width, was found to be the best performing ratio. The AVL ratio determines the location of the aortic valve caudal to the carina, at a distance of 0.25±0.05 times the thoracic width for male patients and 0.28±0.05 times the thoracic width for female patients. The AVL ratio was validated using computed tomography images of patients with angina pectoris without known valvular disease (n=95). There was a good correlation between the Impella position assessed with the AVL ratio and with echocardiography (n=53). The Aortic Valve Location Ratio enables accurate and reproducible localization of the aortic valve on supine chest X-ray. This tool is easily applicable and can be used for assessment of cardiac device position in patients on the ICU.

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