Irvin Krukenkamp - Academia.edu (original) (raw)

Papers by Irvin Krukenkamp

Research paper thumbnail of Tissue-Engineered Myocardial Patch Derived From Extracellular Matrix Provides Regional Mechanical Function

Circulation, Aug 30, 2005

Background-Extracellular matrix (ECM), a tissue-engineered scaffold, recently demonstrated cardio... more Background-Extracellular matrix (ECM), a tissue-engineered scaffold, recently demonstrated cardiomyocyte population after myocardial implantation. Surgical restoration of myocardium frequently uses Dacron as a myocardial patch. We hypothesized that an ECM-derived myocardial patch would provide a mechanical benefit not seen with Dacron. Methods and Results-Using a canine model, a full thickness defect in the right ventricle was repaired with either Dacron or ECM. A third group had no surgery and determined baseline RV function. Eight weeks later, global systolic function was assessed by the preload recruitable stroke work relationship. Regional systolic function was measured by systolic area contraction (SAC), calculated by high density mechanical mapping. Tau was used to assess global diastolic function. Recoil rate and diastolic shear were used as measures of regional diastolic function. After functional data acquisition, tissue was fixed for histological evaluation. Global systolic and diastolic functions were similar at baseline and after ECM and Dacron implantation. Regional systolic function was greater in the ECM group compared with the Dacron group (SAC: 4.1Ϯ0.9% versus Ϫ1.8Ϯ1.1, PϽ0.05). Regional diastolic function was also greater in the ECM group (recoil rate (°sec Ϫ1 ): Ϫ44Ϯ7 versus Ϫ17Ϯ2, ECM versus Dacron; PϽ0.05). Immunohistochemical analysis revealed cardiomyocytes in the ECM implant region, a finding not seen with Dacron. Conclusion-At 8 weeks, an ECM-derived tissue-engineered myocardial patch provides regional mechanical function, likely related to cardiomyocyte population. These results are in sharp contrast to Dacron, a commonly used myocardial patch. (Circulation. 2005;112[suppl I]:I-144-I-149.)

Research paper thumbnail of Myocardial protection and cardioplegia

Curr Opin Cardiol, 1993

Over the past year there has been a tremendous enthusiasm for the novel technique of warm heart s... more Over the past year there has been a tremendous enthusiasm for the novel technique of warm heart surgery. In contradistinction to hypothermic myocardial preservation, warm cardiac surgery provides for operative repair in a nonischemic heart. Warm cardioplegia can be administered in an antegrade or retrograde manner, continuously, and perhaps even intermittently. It may have beneficial effects on systemic perfusion and may be a useful adjunct in the setting of acute cardiac ischemia. There likewise has been a burgeoning enthusiasm for the retrograde cardioplegic delivery route. Many reviews of clinical work using both warm and cold retrograde cardioplegia have identified the advantage of this technique, particularly in the setting of valve replacement and reoperation for coronary revascularization. Finally, new avenues of investigation in ischemia and reperfusion including inquiry into the role of neutrophils in reperfusion injury and modification of the reduced thiol pool to modulate the postischemic burst of oxygen-free radical production.

Research paper thumbnail of Preconditioning With PKC and the ATP-Sensitive Potassium Channels: A Codependent Relationship

Both potassium channel openers and protein kinase C have been shown to independently elicit the m... more Both potassium channel openers and protein kinase C have been shown to independently elicit the myoprotective preconditioning response. However, the in vivo dependency between the two is unknown. Thirty-seven sheep were divided into seven groups; animals received no pretreatment, pinacidil, pinacidil and potassium channel opener blocker glibenclamide, protein kinase C activator 4beta-phorbol-12,13-dibutyrate (PDBu), or PDBu and protein kinase C blocker chelerythrine. The last two groups underwent opposite blockade, chelerythrine + pinacidil, or glibenclamide + PDBu. All groups underwent 60 minutes of regional ischemia followed by 180 minutes of reperfusion. Regional function was assessed throughout the experiment, and at the conclusion of the study the infarct size (as a percentage of the area at risk) was determined. Infarct size decreased in the groups receiving only pinacidil or PDBu (control: 54%+/-3%, pinacidil: 25% +/-2%, PDBu: 21%+/-3%; p<0.05 pinacidil or PDBu versus control). This preconditioning protection was lost when the direct blocker was given (58%+/-5%, glibenclamide + pinacidil; 70%+/-6%, chelerythrine + PDBu; p = not significant versus control). The preconditioning response was again attenuated when the opposite blockers were given (64%+/-5%, chelerythrine + pinacidil; 63%+/-1%, glibenclamide + PDBu; p = not significant versus control). There was no significant difference in regional function. This study shows that both protein kinase C and potassium channels are necessary and codependent for preconditioning in the in vivo heart.

Research paper thumbnail of Nitric oxide–generating β-adrenergic blocker nipradilol preserves postischemic cardiac function

The Annals of Thoracic Surgery, Sep 30, 1999

Background. Preconditioning protects the heart from ischemic injury, but some of its effects are ... more Background. Preconditioning protects the heart from ischemic injury, but some of its effects are reversed by β-adrenergic blockade. We hypothesize that because nitric oxide is known to precondition the heart, the nitric oxide–generating β-blocker nipradilol may simultaneously precondition and provide clinically relevant β-blockade.Methods. Isolated, crystalloid-perfused rabbit hearts underwent 1 hour of left anterior descending coronary artery ischemia followed by 1

Research paper thumbnail of Nitric Oxide-Generating b-Adrenergic Blocker Nipradilol Preserves Postischemic Cardiac Function

Background. Preconditioning protects the heart from ischemic injury, but some of its effects are ... more Background. Preconditioning protects the heart from ischemic injury, but some of its effects are reversed by b-adrenergic blockade. We hypothesize that because ni- tric oxide is known to precondition the heart, the nitric oxide- generating b-blocker nipradilol may simulta- neously precondition and provide clinically relevant b-blockade. Methods. Isolated, crystalloid-perfused rabbit hearts underwent 1 hour of left anterior descending coronary artery

Research paper thumbnail of Determination of the Regional Function of the Heart

Piping and Component Analysis and Diagnosis, 2002

Research paper thumbnail of Tissue-engineered myocardial patch derived from extracellular matrix provides regional mechanical function

Circulation, Jan 30, 2005

Extracellular matrix (ECM), a tissue-engineered scaffold, recently demonstrated cardiomyocyte pop... more Extracellular matrix (ECM), a tissue-engineered scaffold, recently demonstrated cardiomyocyte population after myocardial implantation. Surgical restoration of myocardium frequently uses Dacron as a myocardial patch. We hypothesized that an ECM-derived myocardial patch would provide a mechanical benefit not seen with Dacron. Using a canine model, a full thickness defect in the right ventricle was repaired with either Dacron or ECM. A third group had no surgery and determined baseline RV function. Eight weeks later, global systolic function was assessed by the preload recruitable stroke work relationship. Regional systolic function was measured by systolic area contraction (SAC), calculated by high density mechanical mapping. Tau was used to assess global diastolic function. Recoil rate and diastolic shear were used as measures of regional diastolic function. After functional data acquisition, tissue was fixed for histological evaluation. Global systolic and diastolic functions were ...

Research paper thumbnail of Reperfusion Injury" and Myocardial Protection by Cardioplegia: An Opinion

Journal of thrombosis and thrombolysis, 1997

Research paper thumbnail of Platelet Activation and Free Emboli Formation in Flow Past Mechanical Heart Valves

Advances in Bioengineering, 2002

Research paper thumbnail of Determination of myocardial function with high spatial resolution in the regionally ischemic beating rabbit heart

Myocardial ischemia is generally a regional phenomenon, necessitating the measurement of regional... more Myocardial ischemia is generally a regional phenomenon, necessitating the measurement of regional function with high spatial resolution. Herein, the technique of computer aided speckle interferometry (CASI) is developed to measure myocardial function with high spatial resolution in the beating rabbit heart exposed to regional ischemia. Silicon carbide particles were applied to the surface of isolated rabbit hearts and a pressure

Research paper thumbnail of Cytosolic Calcium Transport During Myocardial Protection

Developments in Cardiovascular Medicine, 1996

Research paper thumbnail of High volume perfusion

Developments in Cardiovascular Medicine, 1993

Research paper thumbnail of Combined coronary artery bypass and carotid endarterectomy: long-term results

Cardiovascular Surgery, 2002

Research paper thumbnail of Direct Effect of High-dose Insulin on the Depressed Heart after Beta-blockade or Ischemia

The Thoracic and Cardiovascular Surgeon, 1986

The direct cardiac effects of high-dose insulin (HDI) were assessed in 13 canine hearts supported... more The direct cardiac effects of high-dose insulin (HDI) were assessed in 13 canine hearts supported by cardiopulmonary bypass. Isovolumic peak developed pressure (PDP, mmHg), coronary blood flow (CBF, ml/beat/100 g LV) and myocardial oxygen consumption (MVO2, ml O2/beat/100 g LV) were determined during incremental left ventricular balloon inflation before and after functional depression by beta-blockade (0.2 mg/kg propranolol) or 2 hours cardioplegic ischemia at 28 degrees C. The 2 regimens gave an overall functional reduction of 46 +/- 3% and 42 +/- 2%, respectively. The hearts were then challenged with an aortic root bolus of 1000 IU insulin. A glucose clamp was maintained at physiological levels. Insulin reversed the negative inotropic effect of propranolol to 80% of control function and normalized heart rate. Despite the significant amelioration of systolic function by HDI, MVO2 indexed for cardiac effort did not change. Neither systolic function nor heart rate was changed in the ischemically depressed hearts. In conclusion, HDI reverses the negative inotropic effect of beta-adrenergic receptor blockade without augmenting oxygen utilization. Apart from effects ascribable to systemic vasodilation and metabolic shifts, no direct cardiac inotropic stimulation can be expected on the post-ischemically depressed, nondiabetic myocardium unless there is a persistent negative effect of beta-blockers.

Research paper thumbnail of Modeling Stroke Risk After Coronary Artery Bypass and Combined Coronary Artery Bypass and Carotid Endarterectomy

Stroke, 2003

Background and Purpose-The goals of this study were to compare the ability of statewide and insti... more Background and Purpose-The goals of this study were to compare the ability of statewide and institutional models of stroke risk after coronary artery bypass (CAB) to predict institution-specific results and to examine the potential additive stroke risk of combined CAB and carotid endarterectomy (CEA) with these predictive models. Methods-An institution-specific model of stroke risk after CAB was developed from 1975 consecutive patients who underwent nonemergent CAB from 1994 to 1999 in whom severe carotid stenosis was excluded by preoperative duplex screening. Variables recorded in the New York State Cardiac Surgery Program database were analyzed. This model (model I) was compared with a published model (model II) derived from analysis of the same variables using New York statewide data from 1995. Predicted and observed stroke risks were compared. These formulas were applied to 154 consecutive combined CAB/CEA patients operated on between 1994 and 1999 to determine the predicted stroke risk from CAB alone and thereby deduce the maximal added risk imputed to CEA. Results-Risk factors common to both models included age, peripheral vascular disease, cardiopulmonary bypass time, and calcified aorta. Additional risk factors in model I also included left ventricular hypertrophy and hypertension. Risk factors exclusive to model II included diabetes, renal failure, smoking, and prior cerebrovascular disease. Our observed stroke rate for isolated CAB was 1.7% compared with a rate predicted with model II (statewide data) of 1.56%. The observed stroke rate for combined CEA/CAB was 3.9%. When the Stony Brook model (model I) based on patients without carotid stenosis was used, the predicted stroke rate was 2.8%. When the statewide model (model II), which included some patients with extracranial vascular disease, was used, the predicted stroke rate was 3.4%. The differences between observed and predicted stroke rates were not statistically significant. Conclusions-Estimation of stroke risk after CAB was similar whether statewide data or institution-specific data were used. The statewide model was applicable to institution-specific data collected over several years. Common risk factors included age, aortic calcification, and peripheral vascular disease. The observed differences in the predicted stroke rates between models I and II may be due to the fact that carotid stenosis was specifically excluded by duplex ultrasound from the patient population used to develop model I. Modeling stroke risk after CAB is possible. When these models were applied to patients undergoing combined CAB/CEA, no additional stroke risk could be ascribed to the addition of CEA. Such models may be used to identify groups at increased risk for stroke after both CAB and combined CAB/CEA. The ultimate place for CEA in patients undergoing CAB will be defined by prospective randomized trials. (Stroke. 2003; 34:1212-1217.)

Research paper thumbnail of Myocardial recovery from ischemia is impaired in CD36-null mice and restored by myocyte CD36 expression or medium-chain fatty acids

Proceedings of the National Academy of Sciences, 2003

Long-chain fatty acid uptake, which provides a large part of myocardial energy, is impaired in hu... more Long-chain fatty acid uptake, which provides a large part of myocardial energy, is impaired in human and murine hearts deficient in the membrane fatty acid translocase, FAT͞CD36. We examined myocardial function in CD36-null mice using the working heart. Fatty acid oxidation and stores of glycogen, triglycerides, and ATP were reduced in CD36-deficient hearts and were restored to WT levels by rescue of myocyte CD36. Under normal perfusion conditions, CD36-null hearts had similar cardiac outputs and end-diastolic pressures as WT or transgenic hearts. After 6 min of ischemia, cardiac output decreased by 41% and end diastolic pressure tripled for CD36-null hearts, with no significant changes in WT or transgenic hearts. Null hearts also failed more frequently after ischemia as compared with WT or transgenics. To dissect out contribution of fatty acid uptake, a perfusate-lacking fatty acids was used. This decreased cardiac output after ischemia by 30% in WT hearts as compared with 50% for CD36-deficient hearts. End diastolic pressure, a negative index of myocardial performance, increased after ischemia in all heart types. Addition to the perfusate of a medium-chain fatty acid (caprylic acid) that does not require CD36 for uptake alleviated poor ischemic tolerance of CD36-null hearts. In summary, recovery from ischemia is compromised in CD36-deficient hearts and can be restored by CD36 rescue or by supplying medium-chain fatty acids. It would be important to determine whether the findings apply to the human situation where polymorphisms of the CD36 gene are relatively common.

Research paper thumbnail of Developmental differences in cytosolic calcium accumulation associated with surgically induced global ischemia: Optimization of cardioplegic protection and mechanism of action

The Journal of Thoracic and Cardiovascular Surgery, 1996

Objective: The effect of cardioplegic solutions with high concentrations of potassium or magnesiu... more Objective: The effect of cardioplegic solutions with high concentrations of potassium or magnesium (or both) on cytosolic calcium accumulation was investigated with fura-2 in isolated perfused mature (n = 24) and aged (n = 24) rabbit hearts. Methods: We compared cytosolic calcium accumulation before ischemia (control), during 30 minutes of ischemia and 30 minutes of reperfusion under global ischemia, or after treatment with potassium (20 mmol/L), magnesium (20 retool/L), or both. Results: Cytosolic calcium accumulation was increased during global ischemia in the mature heart (from 178.7 +-. 24.2 in the control group to 393.6 +-25.5 nmol/L; p < 0.005) and in the aged heart (from 187.4 + 18.7 in the control group to 501.0 +-46.1 nmol/L; p < 0.005). Potassium reduced cytosolic calcium accumulation during ischemia in both the mature and aged hearts (300.9 _ 23.2 and 365.2 -27.7 nmol/L, respectively; p < 0.05 vs global ischemia). Magnesium and potassium/magnesium completely controlled cytosolic calcium accumulation in the mature heart (198.7 +-27.5 nmol/L; p < 0.01 vs global ischemia andp < 0.05 vs potassium: 182.3 _+ 22.7 nmol/L;p < 0.05 vs global ischemia and potassium, respectively). Magnesium and potassium/magnesium attenuated cytosolic calcium accumulation in the aged heart (261.3 -+ 26.7, 262.3 +-. 25.2 nmol/L, respectively; p < 0.01 vs global ischemia). These changes in cytosolic calcium accumulation correlated with improved postischemic ventricular function. To investigate the mechanism(s) of magnesium-supplemented cardioplegic inhibition of cytosolic calcium accumulation, we performed parallel studies (n = 43) using nifedipine, ryanodine, and dimethylthiourea. Nifedipine with or without ryanodine reduced eytosolic calcium accumulation. Dimethylthiourea did not alter cytosolic calcium accumulation during global ischemia. Our results suggest that eytosolic calcium accumulation during global ischemia was mainly increased via the sarcolemmal 1-type calcium channel and the sarcoplasmic reticulum calcium-release channel. The modulating action of potassium/ magnesium cardioplegia on cytosolic calcium accumulation during ischemia would appear to act through the inhibition of the myocardial 1-type calcium channel and the sarcoplasmic reticulum calcium-release channel. Conclusion: Senescent cardiac dysfunction correlates with increased ischemia-induced cytosolic calcium accumulation. Magnesium-supplemented potassium cardioplegia ameliorates this age-related phenomenon at normothermia and may have important implications in myocardial protection in the elderly population. (J Thorac Cardiovasc Surg 1996;112:175-84) From the Division

Research paper thumbnail of Blood cardioplegia in the senescent heart☆, ☆☆, ★, ★★

The Journal of Thoracic and Cardiovascular Surgery, 1995

As an increasingly aged population undergoes cardiac surgery, myocardial protective strategies mu... more As an increasingly aged population undergoes cardiac surgery, myocardial protective strategies must address the fundamental differences between adult and senescent myocardium. In a test of the hypothesis that senescent myocardium is less tolerant of cardioplegic arrest, adult (0.5 to 1.0 years) and senescent (6 to 9 years) sheep underwent 55 minutes of hypothermic blood cardioplegic arrest. A 5-minute dose of terminal warm blood cardioplegic solution was administered followed by 30 minutes of vented reperfusion. Left ventricular volume was monitored by means of sonomicrometric crystals in three orthogonal planes. Myocardial function was assessed with the preload recruitable stroke work relationship. Diastolic function was assessed with two techniques: the "stiffness" coefficient (i~), derived from the exponential end-diastolic pressure-volume relationship, and the time constant of isovolumic left ventricular pressure decay (tau). Data were acquired before arrest and after the reperfusion period. Contractility in the adult hearts was well preserved (preload recruitable stroke work: 63.7 -+ 6.1 versus 56.8 -+ 4.1 m J/beat per milliliter per 100 gm, prearrest versus postarrest, p = not significant). In contrast, senescent heart contractility was poorly preserved (56.8 -4.1 versus 35.4 -4.2 m J/beat per milliliter per 100 gm, p < 0.025). Early diastolic relaxation (tau) was prolonged in the adult hearts (42.5 -+ 3.3 versus 48.8 -3.5 msec prearrest versus postarrest, p < 0.05), whereas the senescent hearts were essentially unchanged (49.3 -3.1 versus 52.3 -+ 4.5 msec, p = 0.35). Myocardial stiffness (/3) was unchanged in both groups. When compared with adult hearts, contractility in senescent hearts is poorly preserved after cold blood cardioplegic arrest. Active diastolic relaxation, however, is more prolonged in adult hearts. Passive diastolic properties are unchanged in both groups. Because there are specific age-related differences in tolerance to cardioplegic arrest, extrapolation of myocardial protective strategies from studies in adult hearts to elderly patients may not be appropriate. (J THORAC CARDIOVASC SURG 1995;109: 269-74)

Research paper thumbnail of Gap junction uncoupling protects the heart against ischemia

The Journal of Thoracic and Cardiovascular Surgery, 2002

Many stimuli can successfully protect the heart against ischemia. We investigated whether gap jun... more Many stimuli can successfully protect the heart against ischemia. We investigated whether gap junction uncoupling before ischemia was myoprotective. We also studied the function of the adenosine triphosphate-dependent potassium channel, which has been implicated in the mechanism of pharmacologic preconditioning, with respect to gap junction physiology. Twenty-eight rabbit hearts were placed on a Langendorff perfusion apparatus. Five were given a 5-minute infusion of 1 mmol/L heptanol (a gap junction uncoupler), 5 were given 10 micromol/L 2,3-butanedione monoxime (an electromechanical uncoupler), and 6 were given no drug. The left anterior descending coronary artery was then occluded for 1 hour and reperfused for 2 hours. Six hearts received 10 micromol/L glybenclamide before heptanol to evaluate the role of the adenosine triphosphate-dependent potassium channel. Six hearts underwent ischemic preconditioning with 2 cycles of 5 minutes of global ischemia and reperfusion. Action-potential duration of the ischemic zone, left ventricular developed pressure, and coronary flow were measured continuously. Infarct size was determined at the end of reperfusion. Heptanol significantly reduced infarct size (from 46% +/- 2% to 22% +/- 5%, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;.01), an effect that was not prevented by glybenclamide. Butanedione monoxime decreased developed pressure but did not significantly reduce infarct size (46% +/- 5% vs 46% +/- 2%, P = not significant). There were no differences among groups with regard to developed pressure or action-potential duration. Directly blocking gap junctions preconditions the heart. This protection is not a direct result of a decrease in developed pressure before a prolonged ischemic period nor is it achieved through a mechanism involving the adenosine triphosphate-dependent potassium channel.

Research paper thumbnail of The topical application of anti-inflammatory drugs prevents postoperative atrial fibrillation in a canine model

Journal of the American College of Surgeons, 2000

The ex-vivo storage of human saphenous vein (HSV) during coronary artery bypass surgery is limite... more The ex-vivo storage of human saphenous vein (HSV) during coronary artery bypass surgery is limited by endothelial cell preservation. However, preservation of endothelial function, as evidenced by nitric oxide (NO) production, is of prime importance in maintaining the vasomotor function of the graft and vein graft patency. The objectives of this study were to elucidate the 1) regulation of endothelial nitric oxide synthase (eNOS), and its interaction with the plasmalemmal caveolae at the molecular level, and 2) the ability of the endothelium to respond to agonist-mediated calcium signaling and the generation of nitric oxide in HSV.

Research paper thumbnail of Tissue-Engineered Myocardial Patch Derived From Extracellular Matrix Provides Regional Mechanical Function

Circulation, Aug 30, 2005

Background-Extracellular matrix (ECM), a tissue-engineered scaffold, recently demonstrated cardio... more Background-Extracellular matrix (ECM), a tissue-engineered scaffold, recently demonstrated cardiomyocyte population after myocardial implantation. Surgical restoration of myocardium frequently uses Dacron as a myocardial patch. We hypothesized that an ECM-derived myocardial patch would provide a mechanical benefit not seen with Dacron. Methods and Results-Using a canine model, a full thickness defect in the right ventricle was repaired with either Dacron or ECM. A third group had no surgery and determined baseline RV function. Eight weeks later, global systolic function was assessed by the preload recruitable stroke work relationship. Regional systolic function was measured by systolic area contraction (SAC), calculated by high density mechanical mapping. Tau was used to assess global diastolic function. Recoil rate and diastolic shear were used as measures of regional diastolic function. After functional data acquisition, tissue was fixed for histological evaluation. Global systolic and diastolic functions were similar at baseline and after ECM and Dacron implantation. Regional systolic function was greater in the ECM group compared with the Dacron group (SAC: 4.1Ϯ0.9% versus Ϫ1.8Ϯ1.1, PϽ0.05). Regional diastolic function was also greater in the ECM group (recoil rate (°sec Ϫ1 ): Ϫ44Ϯ7 versus Ϫ17Ϯ2, ECM versus Dacron; PϽ0.05). Immunohistochemical analysis revealed cardiomyocytes in the ECM implant region, a finding not seen with Dacron. Conclusion-At 8 weeks, an ECM-derived tissue-engineered myocardial patch provides regional mechanical function, likely related to cardiomyocyte population. These results are in sharp contrast to Dacron, a commonly used myocardial patch. (Circulation. 2005;112[suppl I]:I-144-I-149.)

Research paper thumbnail of Myocardial protection and cardioplegia

Curr Opin Cardiol, 1993

Over the past year there has been a tremendous enthusiasm for the novel technique of warm heart s... more Over the past year there has been a tremendous enthusiasm for the novel technique of warm heart surgery. In contradistinction to hypothermic myocardial preservation, warm cardiac surgery provides for operative repair in a nonischemic heart. Warm cardioplegia can be administered in an antegrade or retrograde manner, continuously, and perhaps even intermittently. It may have beneficial effects on systemic perfusion and may be a useful adjunct in the setting of acute cardiac ischemia. There likewise has been a burgeoning enthusiasm for the retrograde cardioplegic delivery route. Many reviews of clinical work using both warm and cold retrograde cardioplegia have identified the advantage of this technique, particularly in the setting of valve replacement and reoperation for coronary revascularization. Finally, new avenues of investigation in ischemia and reperfusion including inquiry into the role of neutrophils in reperfusion injury and modification of the reduced thiol pool to modulate the postischemic burst of oxygen-free radical production.

Research paper thumbnail of Preconditioning With PKC and the ATP-Sensitive Potassium Channels: A Codependent Relationship

Both potassium channel openers and protein kinase C have been shown to independently elicit the m... more Both potassium channel openers and protein kinase C have been shown to independently elicit the myoprotective preconditioning response. However, the in vivo dependency between the two is unknown. Thirty-seven sheep were divided into seven groups; animals received no pretreatment, pinacidil, pinacidil and potassium channel opener blocker glibenclamide, protein kinase C activator 4beta-phorbol-12,13-dibutyrate (PDBu), or PDBu and protein kinase C blocker chelerythrine. The last two groups underwent opposite blockade, chelerythrine + pinacidil, or glibenclamide + PDBu. All groups underwent 60 minutes of regional ischemia followed by 180 minutes of reperfusion. Regional function was assessed throughout the experiment, and at the conclusion of the study the infarct size (as a percentage of the area at risk) was determined. Infarct size decreased in the groups receiving only pinacidil or PDBu (control: 54%+/-3%, pinacidil: 25% +/-2%, PDBu: 21%+/-3%; p&lt;0.05 pinacidil or PDBu versus control). This preconditioning protection was lost when the direct blocker was given (58%+/-5%, glibenclamide + pinacidil; 70%+/-6%, chelerythrine + PDBu; p = not significant versus control). The preconditioning response was again attenuated when the opposite blockers were given (64%+/-5%, chelerythrine + pinacidil; 63%+/-1%, glibenclamide + PDBu; p = not significant versus control). There was no significant difference in regional function. This study shows that both protein kinase C and potassium channels are necessary and codependent for preconditioning in the in vivo heart.

Research paper thumbnail of Nitric oxide–generating β-adrenergic blocker nipradilol preserves postischemic cardiac function

The Annals of Thoracic Surgery, Sep 30, 1999

Background. Preconditioning protects the heart from ischemic injury, but some of its effects are ... more Background. Preconditioning protects the heart from ischemic injury, but some of its effects are reversed by β-adrenergic blockade. We hypothesize that because nitric oxide is known to precondition the heart, the nitric oxide–generating β-blocker nipradilol may simultaneously precondition and provide clinically relevant β-blockade.Methods. Isolated, crystalloid-perfused rabbit hearts underwent 1 hour of left anterior descending coronary artery ischemia followed by 1

Research paper thumbnail of Nitric Oxide-Generating b-Adrenergic Blocker Nipradilol Preserves Postischemic Cardiac Function

Background. Preconditioning protects the heart from ischemic injury, but some of its effects are ... more Background. Preconditioning protects the heart from ischemic injury, but some of its effects are reversed by b-adrenergic blockade. We hypothesize that because ni- tric oxide is known to precondition the heart, the nitric oxide- generating b-blocker nipradilol may simulta- neously precondition and provide clinically relevant b-blockade. Methods. Isolated, crystalloid-perfused rabbit hearts underwent 1 hour of left anterior descending coronary artery

Research paper thumbnail of Determination of the Regional Function of the Heart

Piping and Component Analysis and Diagnosis, 2002

Research paper thumbnail of Tissue-engineered myocardial patch derived from extracellular matrix provides regional mechanical function

Circulation, Jan 30, 2005

Extracellular matrix (ECM), a tissue-engineered scaffold, recently demonstrated cardiomyocyte pop... more Extracellular matrix (ECM), a tissue-engineered scaffold, recently demonstrated cardiomyocyte population after myocardial implantation. Surgical restoration of myocardium frequently uses Dacron as a myocardial patch. We hypothesized that an ECM-derived myocardial patch would provide a mechanical benefit not seen with Dacron. Using a canine model, a full thickness defect in the right ventricle was repaired with either Dacron or ECM. A third group had no surgery and determined baseline RV function. Eight weeks later, global systolic function was assessed by the preload recruitable stroke work relationship. Regional systolic function was measured by systolic area contraction (SAC), calculated by high density mechanical mapping. Tau was used to assess global diastolic function. Recoil rate and diastolic shear were used as measures of regional diastolic function. After functional data acquisition, tissue was fixed for histological evaluation. Global systolic and diastolic functions were ...

Research paper thumbnail of Reperfusion Injury" and Myocardial Protection by Cardioplegia: An Opinion

Journal of thrombosis and thrombolysis, 1997

Research paper thumbnail of Platelet Activation and Free Emboli Formation in Flow Past Mechanical Heart Valves

Advances in Bioengineering, 2002

Research paper thumbnail of Determination of myocardial function with high spatial resolution in the regionally ischemic beating rabbit heart

Myocardial ischemia is generally a regional phenomenon, necessitating the measurement of regional... more Myocardial ischemia is generally a regional phenomenon, necessitating the measurement of regional function with high spatial resolution. Herein, the technique of computer aided speckle interferometry (CASI) is developed to measure myocardial function with high spatial resolution in the beating rabbit heart exposed to regional ischemia. Silicon carbide particles were applied to the surface of isolated rabbit hearts and a pressure

Research paper thumbnail of Cytosolic Calcium Transport During Myocardial Protection

Developments in Cardiovascular Medicine, 1996

Research paper thumbnail of High volume perfusion

Developments in Cardiovascular Medicine, 1993

Research paper thumbnail of Combined coronary artery bypass and carotid endarterectomy: long-term results

Cardiovascular Surgery, 2002

Research paper thumbnail of Direct Effect of High-dose Insulin on the Depressed Heart after Beta-blockade or Ischemia

The Thoracic and Cardiovascular Surgeon, 1986

The direct cardiac effects of high-dose insulin (HDI) were assessed in 13 canine hearts supported... more The direct cardiac effects of high-dose insulin (HDI) were assessed in 13 canine hearts supported by cardiopulmonary bypass. Isovolumic peak developed pressure (PDP, mmHg), coronary blood flow (CBF, ml/beat/100 g LV) and myocardial oxygen consumption (MVO2, ml O2/beat/100 g LV) were determined during incremental left ventricular balloon inflation before and after functional depression by beta-blockade (0.2 mg/kg propranolol) or 2 hours cardioplegic ischemia at 28 degrees C. The 2 regimens gave an overall functional reduction of 46 +/- 3% and 42 +/- 2%, respectively. The hearts were then challenged with an aortic root bolus of 1000 IU insulin. A glucose clamp was maintained at physiological levels. Insulin reversed the negative inotropic effect of propranolol to 80% of control function and normalized heart rate. Despite the significant amelioration of systolic function by HDI, MVO2 indexed for cardiac effort did not change. Neither systolic function nor heart rate was changed in the ischemically depressed hearts. In conclusion, HDI reverses the negative inotropic effect of beta-adrenergic receptor blockade without augmenting oxygen utilization. Apart from effects ascribable to systemic vasodilation and metabolic shifts, no direct cardiac inotropic stimulation can be expected on the post-ischemically depressed, nondiabetic myocardium unless there is a persistent negative effect of beta-blockers.

Research paper thumbnail of Modeling Stroke Risk After Coronary Artery Bypass and Combined Coronary Artery Bypass and Carotid Endarterectomy

Stroke, 2003

Background and Purpose-The goals of this study were to compare the ability of statewide and insti... more Background and Purpose-The goals of this study were to compare the ability of statewide and institutional models of stroke risk after coronary artery bypass (CAB) to predict institution-specific results and to examine the potential additive stroke risk of combined CAB and carotid endarterectomy (CEA) with these predictive models. Methods-An institution-specific model of stroke risk after CAB was developed from 1975 consecutive patients who underwent nonemergent CAB from 1994 to 1999 in whom severe carotid stenosis was excluded by preoperative duplex screening. Variables recorded in the New York State Cardiac Surgery Program database were analyzed. This model (model I) was compared with a published model (model II) derived from analysis of the same variables using New York statewide data from 1995. Predicted and observed stroke risks were compared. These formulas were applied to 154 consecutive combined CAB/CEA patients operated on between 1994 and 1999 to determine the predicted stroke risk from CAB alone and thereby deduce the maximal added risk imputed to CEA. Results-Risk factors common to both models included age, peripheral vascular disease, cardiopulmonary bypass time, and calcified aorta. Additional risk factors in model I also included left ventricular hypertrophy and hypertension. Risk factors exclusive to model II included diabetes, renal failure, smoking, and prior cerebrovascular disease. Our observed stroke rate for isolated CAB was 1.7% compared with a rate predicted with model II (statewide data) of 1.56%. The observed stroke rate for combined CEA/CAB was 3.9%. When the Stony Brook model (model I) based on patients without carotid stenosis was used, the predicted stroke rate was 2.8%. When the statewide model (model II), which included some patients with extracranial vascular disease, was used, the predicted stroke rate was 3.4%. The differences between observed and predicted stroke rates were not statistically significant. Conclusions-Estimation of stroke risk after CAB was similar whether statewide data or institution-specific data were used. The statewide model was applicable to institution-specific data collected over several years. Common risk factors included age, aortic calcification, and peripheral vascular disease. The observed differences in the predicted stroke rates between models I and II may be due to the fact that carotid stenosis was specifically excluded by duplex ultrasound from the patient population used to develop model I. Modeling stroke risk after CAB is possible. When these models were applied to patients undergoing combined CAB/CEA, no additional stroke risk could be ascribed to the addition of CEA. Such models may be used to identify groups at increased risk for stroke after both CAB and combined CAB/CEA. The ultimate place for CEA in patients undergoing CAB will be defined by prospective randomized trials. (Stroke. 2003; 34:1212-1217.)

Research paper thumbnail of Myocardial recovery from ischemia is impaired in CD36-null mice and restored by myocyte CD36 expression or medium-chain fatty acids

Proceedings of the National Academy of Sciences, 2003

Long-chain fatty acid uptake, which provides a large part of myocardial energy, is impaired in hu... more Long-chain fatty acid uptake, which provides a large part of myocardial energy, is impaired in human and murine hearts deficient in the membrane fatty acid translocase, FAT͞CD36. We examined myocardial function in CD36-null mice using the working heart. Fatty acid oxidation and stores of glycogen, triglycerides, and ATP were reduced in CD36-deficient hearts and were restored to WT levels by rescue of myocyte CD36. Under normal perfusion conditions, CD36-null hearts had similar cardiac outputs and end-diastolic pressures as WT or transgenic hearts. After 6 min of ischemia, cardiac output decreased by 41% and end diastolic pressure tripled for CD36-null hearts, with no significant changes in WT or transgenic hearts. Null hearts also failed more frequently after ischemia as compared with WT or transgenics. To dissect out contribution of fatty acid uptake, a perfusate-lacking fatty acids was used. This decreased cardiac output after ischemia by 30% in WT hearts as compared with 50% for CD36-deficient hearts. End diastolic pressure, a negative index of myocardial performance, increased after ischemia in all heart types. Addition to the perfusate of a medium-chain fatty acid (caprylic acid) that does not require CD36 for uptake alleviated poor ischemic tolerance of CD36-null hearts. In summary, recovery from ischemia is compromised in CD36-deficient hearts and can be restored by CD36 rescue or by supplying medium-chain fatty acids. It would be important to determine whether the findings apply to the human situation where polymorphisms of the CD36 gene are relatively common.

Research paper thumbnail of Developmental differences in cytosolic calcium accumulation associated with surgically induced global ischemia: Optimization of cardioplegic protection and mechanism of action

The Journal of Thoracic and Cardiovascular Surgery, 1996

Objective: The effect of cardioplegic solutions with high concentrations of potassium or magnesiu... more Objective: The effect of cardioplegic solutions with high concentrations of potassium or magnesium (or both) on cytosolic calcium accumulation was investigated with fura-2 in isolated perfused mature (n = 24) and aged (n = 24) rabbit hearts. Methods: We compared cytosolic calcium accumulation before ischemia (control), during 30 minutes of ischemia and 30 minutes of reperfusion under global ischemia, or after treatment with potassium (20 mmol/L), magnesium (20 retool/L), or both. Results: Cytosolic calcium accumulation was increased during global ischemia in the mature heart (from 178.7 +-. 24.2 in the control group to 393.6 +-25.5 nmol/L; p < 0.005) and in the aged heart (from 187.4 + 18.7 in the control group to 501.0 +-46.1 nmol/L; p < 0.005). Potassium reduced cytosolic calcium accumulation during ischemia in both the mature and aged hearts (300.9 _ 23.2 and 365.2 -27.7 nmol/L, respectively; p < 0.05 vs global ischemia). Magnesium and potassium/magnesium completely controlled cytosolic calcium accumulation in the mature heart (198.7 +-27.5 nmol/L; p < 0.01 vs global ischemia andp < 0.05 vs potassium: 182.3 _+ 22.7 nmol/L;p < 0.05 vs global ischemia and potassium, respectively). Magnesium and potassium/magnesium attenuated cytosolic calcium accumulation in the aged heart (261.3 -+ 26.7, 262.3 +-. 25.2 nmol/L, respectively; p < 0.01 vs global ischemia). These changes in cytosolic calcium accumulation correlated with improved postischemic ventricular function. To investigate the mechanism(s) of magnesium-supplemented cardioplegic inhibition of cytosolic calcium accumulation, we performed parallel studies (n = 43) using nifedipine, ryanodine, and dimethylthiourea. Nifedipine with or without ryanodine reduced eytosolic calcium accumulation. Dimethylthiourea did not alter cytosolic calcium accumulation during global ischemia. Our results suggest that eytosolic calcium accumulation during global ischemia was mainly increased via the sarcolemmal 1-type calcium channel and the sarcoplasmic reticulum calcium-release channel. The modulating action of potassium/ magnesium cardioplegia on cytosolic calcium accumulation during ischemia would appear to act through the inhibition of the myocardial 1-type calcium channel and the sarcoplasmic reticulum calcium-release channel. Conclusion: Senescent cardiac dysfunction correlates with increased ischemia-induced cytosolic calcium accumulation. Magnesium-supplemented potassium cardioplegia ameliorates this age-related phenomenon at normothermia and may have important implications in myocardial protection in the elderly population. (J Thorac Cardiovasc Surg 1996;112:175-84) From the Division

Research paper thumbnail of Blood cardioplegia in the senescent heart☆, ☆☆, ★, ★★

The Journal of Thoracic and Cardiovascular Surgery, 1995

As an increasingly aged population undergoes cardiac surgery, myocardial protective strategies mu... more As an increasingly aged population undergoes cardiac surgery, myocardial protective strategies must address the fundamental differences between adult and senescent myocardium. In a test of the hypothesis that senescent myocardium is less tolerant of cardioplegic arrest, adult (0.5 to 1.0 years) and senescent (6 to 9 years) sheep underwent 55 minutes of hypothermic blood cardioplegic arrest. A 5-minute dose of terminal warm blood cardioplegic solution was administered followed by 30 minutes of vented reperfusion. Left ventricular volume was monitored by means of sonomicrometric crystals in three orthogonal planes. Myocardial function was assessed with the preload recruitable stroke work relationship. Diastolic function was assessed with two techniques: the "stiffness" coefficient (i~), derived from the exponential end-diastolic pressure-volume relationship, and the time constant of isovolumic left ventricular pressure decay (tau). Data were acquired before arrest and after the reperfusion period. Contractility in the adult hearts was well preserved (preload recruitable stroke work: 63.7 -+ 6.1 versus 56.8 -+ 4.1 m J/beat per milliliter per 100 gm, prearrest versus postarrest, p = not significant). In contrast, senescent heart contractility was poorly preserved (56.8 -4.1 versus 35.4 -4.2 m J/beat per milliliter per 100 gm, p < 0.025). Early diastolic relaxation (tau) was prolonged in the adult hearts (42.5 -+ 3.3 versus 48.8 -3.5 msec prearrest versus postarrest, p < 0.05), whereas the senescent hearts were essentially unchanged (49.3 -3.1 versus 52.3 -+ 4.5 msec, p = 0.35). Myocardial stiffness (/3) was unchanged in both groups. When compared with adult hearts, contractility in senescent hearts is poorly preserved after cold blood cardioplegic arrest. Active diastolic relaxation, however, is more prolonged in adult hearts. Passive diastolic properties are unchanged in both groups. Because there are specific age-related differences in tolerance to cardioplegic arrest, extrapolation of myocardial protective strategies from studies in adult hearts to elderly patients may not be appropriate. (J THORAC CARDIOVASC SURG 1995;109: 269-74)

Research paper thumbnail of Gap junction uncoupling protects the heart against ischemia

The Journal of Thoracic and Cardiovascular Surgery, 2002

Many stimuli can successfully protect the heart against ischemia. We investigated whether gap jun... more Many stimuli can successfully protect the heart against ischemia. We investigated whether gap junction uncoupling before ischemia was myoprotective. We also studied the function of the adenosine triphosphate-dependent potassium channel, which has been implicated in the mechanism of pharmacologic preconditioning, with respect to gap junction physiology. Twenty-eight rabbit hearts were placed on a Langendorff perfusion apparatus. Five were given a 5-minute infusion of 1 mmol/L heptanol (a gap junction uncoupler), 5 were given 10 micromol/L 2,3-butanedione monoxime (an electromechanical uncoupler), and 6 were given no drug. The left anterior descending coronary artery was then occluded for 1 hour and reperfused for 2 hours. Six hearts received 10 micromol/L glybenclamide before heptanol to evaluate the role of the adenosine triphosphate-dependent potassium channel. Six hearts underwent ischemic preconditioning with 2 cycles of 5 minutes of global ischemia and reperfusion. Action-potential duration of the ischemic zone, left ventricular developed pressure, and coronary flow were measured continuously. Infarct size was determined at the end of reperfusion. Heptanol significantly reduced infarct size (from 46% +/- 2% to 22% +/- 5%, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;.01), an effect that was not prevented by glybenclamide. Butanedione monoxime decreased developed pressure but did not significantly reduce infarct size (46% +/- 5% vs 46% +/- 2%, P = not significant). There were no differences among groups with regard to developed pressure or action-potential duration. Directly blocking gap junctions preconditions the heart. This protection is not a direct result of a decrease in developed pressure before a prolonged ischemic period nor is it achieved through a mechanism involving the adenosine triphosphate-dependent potassium channel.

Research paper thumbnail of The topical application of anti-inflammatory drugs prevents postoperative atrial fibrillation in a canine model

Journal of the American College of Surgeons, 2000

The ex-vivo storage of human saphenous vein (HSV) during coronary artery bypass surgery is limite... more The ex-vivo storage of human saphenous vein (HSV) during coronary artery bypass surgery is limited by endothelial cell preservation. However, preservation of endothelial function, as evidenced by nitric oxide (NO) production, is of prime importance in maintaining the vasomotor function of the graft and vein graft patency. The objectives of this study were to elucidate the 1) regulation of endothelial nitric oxide synthase (eNOS), and its interaction with the plasmalemmal caveolae at the molecular level, and 2) the ability of the endothelium to respond to agonist-mediated calcium signaling and the generation of nitric oxide in HSV.