Caspase Inhibition Attenuates Contractile Dysfunction Following Cardioplegic Arrest and Rewarming in the Setting of Left Ventricular Failure
Abstract
Hyperkalemic cardioplegic arrest (HCA) and rewarming evokes postoperative myocyte contractile dysfunction, a phenomenon of particular importance in settings of preexisting left ventricular (LV) failure. Caspases are intracellular proteolytic enzymes recently demonstrated to degrade myocardial contractile proteins. This study tested the hypothesis that myocyte contractile dysfunction induced by HCA could be ameliorated with caspase inhibition in the setting of compromised myocardial function. LV myocytes were isolated from control pigs (n = 9, 30 kg) or pigs with LV failure induced by rapid pacing (n = 6, 240 bpm for 21 days) and were randomized to the following: (1) normothermia (2003 myocytes), incubation in cell culture medium for 2 hours at 37 degrees C; (2) HCA only (506 myocytes), incubation for 2 hours in hypothermic HCA solution (4 degrees C, 24 mEq K); or (3) HCA + z-VAD, incubation in hypothermic HCA solution supplemented with 10 microM of the caspase inhibitor z-VAD (z-Val-Ala-Asp-fluoromethyl-ketone, 415 myocytes). Inotropic responsiveness was examined using beta-adrenergic stimulation (25 nM isoproterenol). Ambient normothermic myocyte shortening velocity (microm/s) was reduced with LV failure compared with control values (54 +/- 2 versus 75 +/- 2, respectively, P < 0.05). Following HCA, shortening velocity decreased in the LV failure and control groups (27 +/- 5 and 45 +/- 3, P < 0.05). Institution of z-VAD increased myocyte shortening velocity following HCA in both the LV failure and control groups (49 +/- 5 and 65 +/- 5, P < 0.05). Moreover, HCA supplementation with z-VAD increased beta-adrenergic responsiveness in both groups compared with HCA-only values. This study provides proof of concept that caspase activity contributes to myocyte contractile dysfunction following simulated HCA. Pharmacologic caspase inhibition may hold particular relevance in the execution of cardiac surgical procedures requiring HCA in the context of preexisting LV failure.
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Inhibiting caspases can both reduce the occurrence of heart failure or slow its progression after MI as well as improve contractile function.
“Accordingly, inhibiting caspases can both reduce the occurrence of heart failure or slow its progression after MI (45, 131, 374, 383, 384) as well as improve contractile function (45).”
From Cardiac remodeling in obesity (2008) · cites this paper as [384]
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- Authors
- Yarbrough, W. M., Mukherjee, R., Squires, C. E., Reese, E. S., Leiser, J. S., Stroud, R. E., Sample, J. A., Hendrick, J. W., Mingoia, J. T., McLean, J. E., Hardin, A. E., Dowdy, K. B., & Spinale, F. G.
- Affiliations
- Medical University of South Carolina (US)
- Venue
- Journal of Cardiovascular Pharmacology
- Published
- 2004-12
- Volume
- 44
- Issue
- 6
- Pages
- 645-650
- ISSN
- 0160-2446 (ISSN-L)
- OpenAlex
- W2040554602
- Cited by
- 4
- References
- 21
- Citations by year
- 2020: 1 · 2014: 1 · 2013: 1
- FWCI
- 0.00
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Cardiovascular Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL 07260, HL-56603, R01HL056603, P01HL048788, HL-48788, T32HL007260)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Health Sciences › Medicine › Surgery › Cardiac and Coronary Surgery Techniques
- Health Sciences › Medicine › Surgery › Transplantation: Methods and Outcomes
- Keywords
- caspase inhibition, zVAD, left ventricular failure, beta-adrenergic responsiveness, isoproterenol, cardiac surgery
- MeSH terms
- Adrenergic beta-Agonists, Animals, Cardioplegic Solutions, Cardiotonic Agents, Cell Separation, Enzyme Inhibitors, Heart Arrest, Induced, Heart Failure, Hyperkalemia, Myocardial Contraction, Swine, Rewarming, Ventricular Dysfunction, Left, Myocytes, Cardiac, Caspase Inhibitors, In Vitro Techniques
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