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Biomedical subjects

D Burkhoff

Publications and source records attributed to D Burkhoff.

At least 37 records · Page 2Linked to original sources
PubMed2000

Percutaneous transmyocardial laser revascularisation for severe angina: the PACIFIC randomised trial. Potential Class Improvement From Intramyocardial Channels.

BACKGROUND: Percutaneous transmyocardial laser revascularisation (PTMR) is a proposed catheter-based therapy for refractory angina pectoris when bypass surgery or angioplasty is not possible. We undertook a randomised trial to assess the safety and efficacy of this technique. METHODS: 221 patients with reversible ischaemia of Canadian Cardiovascular Society angina class III (61%) or IV (39%) and incomplete response to other therapies were recruited from 13 centres. Patients were randomly assigned PTMR with a holmium:YAG laser plus continued medical treatment (n=110) or continued medical treatment only (n=111). The primary endpoint was the exercise tolerance at 12 months. Analyses were by intention to treat. FINDINGS: 11 patients died and 19 withdrew; 92 PTMR-group and 99 medical-treatment-group patients completed the study. Exercise tolerance at 12 months had increased by a median of 89.0 s (IQR -15 to 183) with PTMR compared with 12.5 s (-67 to 125) with medical treatment only (p=0.008). On masked assessment, angina class was II or lower in 34.1% of PTMR patients compared with 13.0% of those medically treated. All indices of the Seattle angina questionnaire improved more with PTMR than with medical care only. By 12 months there had been eight deaths in the PTMR group and three in the medical treatment group, with similar survival in the two groups. INTERPRETATION: PTMR was associated with increased exercise tolerance time, low morbidity, lower angina scores assessed by masked reviewers, and improved quality of life. Although there is controversy about the mechanism of action, and the contribution of the placebo effect cannot be quantified, this unmasked study suggests that this palliative procedure provides some clinical benefits in the defined population of patients.

Adult↗
PubMed2000

PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts.

The ryanodine receptor (RyR)/calcium release channel on the sarcoplasmic reticulum (SR) is the major source of calcium (Ca2+) required for cardiac muscle excitation-contraction (EC) coupling. The channel is a tetramer comprised of four type 2 RyR polypeptides (RyR2) and four FK506 binding proteins (FKBP12.6). We show that protein kinase A (PKA) phosphorylation of RyR2 dissociates FKBP12.6 and regulates the channel open probability (Po). Using cosedimentation and coimmunoprecipitation we have defined a macromolecular complex comprised of RyR2, FKBP12.6, PKA, the protein phosphatases PP1 and PP2A, and an anchoring protein, mAKAP. In failing human hearts, RyR2 is PKA hyperphosphorylated, resulting in defective channel function due to increased sensitivity to Ca2+-induced activation.

Animals↗
PubMed2000

Radio frequency transmyocardial revascularization enhances angiogenesis and causes myocardial denervation in canine model.

BACKGROUND AND OBJECTIVE: Transmyocardial revascularization (TMR) relieves angina and improves exercise tolerance in patients. Angiogenesis and myocardial denervation have been proposed as factors contributing to these benefits. To test whether radio frequency transmyocardial revascularization (RF-TMR) enhances angiogenesis and causes myocardial denervation. STUDY DESIGN/MATERIALS AND METHODS: RF-TMR channels were created in 12 dogs which survived up to 4 weeks. Bromodeoxyuridine was administered subcutaneously to mark proliferating cells as an assay of angiogenesis. Western blot analysis of tyrosine hydroxylase and blood pressure response to topical bradykinin were used as indices of myocardial denervation. RESULTS: RF-TMR increased local vascularity by an average of 50%, whereas the rate of vascular cell proliferation was tripled over that of the untreated region. Changes in mean arterial pressure with bradykinin and tyrosine hydroxylase content were significantly decreased in RF-TMR regions as compared with normal myocardium in the same hearts. CONCLUSION: RF-TMR enhances angiogenesis and causes myocardial denervation in canine myocardium as with laser TMR.

Animals↗
PubMed2000

Histologic evidence that basic fibroblast growth factor enhances the angiogenic effects of transmyocardial laser revascularization.

OBJECTIVES: To determine whether addition of basic fibroblast growth factor (bFGF), an angiogenic growth factor, enhances the angiogenic effects of transmyocardial laser revascularization (TMR). BACKGROUND: TMR is an investigational therapy for treating patients with medically refractory angina not amenable to traditional therapies. Histologic and blood flow studies in animals have suggested that TMR enhances angiogenesis above that normally seen in ischemic myocardium. We tested the hypothesis that bFGF administered into TMR channels further enhance the angiogenic effects of TMR. METHODS: Chronic ischemia was created in 3 groups of dogs using an ameroid constrictor on the proximal LAD. In the bFGF group (n = 5) non-transmyocardial channels were created in the LAD territory and bFGF, (100 ng/ml) dissolved in pluronic gel was injected into the each channel. In the TMR group (n = 7), transmyocardial channels were created without bFGF. A control group (n = 7) had ischemia without TMR of bFGF. 5-bromo-2'-deoxyuridine (BrdU) was administered to mark proliferating cells. After 8 weeks survival, colored microspheres were injected to assess the regional myocardial blood flow. RESULTS: TMR and TMR+bFGF increased total vascular density by approximately 40% over that observed in the control group. However, the number of large vessels (internal diameter > or = 50 microm) was doubled by the addition of bFGF, and this correlated with a 50% increase in the density of proliferating vascular cells and a tripling of the total estimated vascular cross sectional area. Blood flow to the LAD territory was increased by TMR compared to controls, with no further benefit observed in the bFGF group. CONCLUSIONS: On a histologic basis, basic fibroblast growth factor further enhances angiogenesis following TMR in ischemic myocardium mainly by increasing the size but not the total number of vessels.

Animals↗
PubMed2000

Maximizing hemodynamic effectiveness of biventricular assistance by direct cardiac compression studied in ex vivo and in vivo canine models of acute heart failure.

OBJECTIVE: Direct cardiac compression improves effective ventricular contractility. However, associated reductions in filling volumes and increases in arterial pressure occurring at the onset of direct cardiac compression limit the degree to which cardiac output is augmented. We tested the hypothesis that active preload and afterload control maximizes the hemodynamic effectiveness of direct cardiac compression. METHODS AND RESULTS: Studies in isolated canine hearts loaded with a computer-controlled volume servo system that mimicked heart failure were used to clearly define the hemodynamic effects of direct cardiac compression. Immediately on initiation of direct cardiac compression, ventricular end-diastolic pressure and volume decreased substantially, arterial pressure increased, but stroke volume did not change significantly. When end-diastolic pressure was restored to about 20 mm Hg, stroke volume doubled; decreasing afterload resistance further increased stroke volume by about 30%. Such load adjustments were then tested in vivo in a canine model of acute heart failure induced by coronary artery microembolizations titrated to decrease cardiac output to 33% +/- 9% of control as end-diastolic pressure rose to 20.6 +/- 2.2 mm Hg. Direct cardiac compression decreased end-diastolic pressure to 11.4 +/- 2.6 mm Hg while increasing cardiac output from 0.8 +/- 0.2 to 1. 4 +/- 0.5 L/min (to only approximately 55% of normal). Restoring end-diastolic pressure to 19.6 +/- 2.2 mm Hg by infusions of saline solution increased cardiac output to 1.9 +/- 0.5 L/min. Afterload reduction (nitroprusside), while maintaining end-diastolic pressure at 19.8 +/- 1.3 mm Hg, increased cardiac output to its baseline, 2.8 +/- 1.1 L/min. CONCLUSIONS: Direct cardiac compression significantly improves ventricular pumping capacity and can restore cardiac output to about 60% of normal in the setting of acute heart failure. When combined with active preload and afterload manipulations, direct cardiac compression can restore cardiac output to normal.

Analysis of Variance↗
PubMed1999

Physiological and hemodynamic evaluation of nonuniform direct cardiac compression.

BACKGROUND: Biventricular direct cardiac compression (DCC) has the potential to support the failing heart without the complications associated with a blood/device interface encountered with the use of current ventricular assist devices. A clinically designed DCC device that provides compression pressure around the base of the heart in synchrony with native ventricular contractions was evaluated with the use of an ex vivo and in vivo canine model of heart failure. METHODS AND RESULTS: The device was tested over a series of ventricular preloads with the use of an ex vivo canine heart preparation and computerized afterload system that mimicked the conditions of heart failure. The end-systolic pressure-volume relation of the left and right ventricles was shifted upward in parallel by DCC, with the magnitude of the shift averaging 40% of the device compression pressure. The device was tested in vivo with the use of a canine model of acute ischemic heart failure in which graded reductions in ventricular function were created through serial coronary artery embolizations. Under the most severe condition of heart failure, DCC improved cardiac output (CO) by 104% (0.80+/-0.33 to 1.63+/-0.40 L/min) and mean arterial pressure by 95% (45.6+/-11 to 89.0+/-18.2 mm Hg). The CO was typically restored to approximately 60% of the normal baseline value, despite attempts to further increase CO by increasing the amount or duration of compression pressure. CONCLUSIONS: Nonuniform DCC significantly improves the left and right ventricular pressure-generating capability and, in the setting of acute heart failure, can increase CO and mean arterial pressure. Such DCC devices can potentially avoid the complications associated with currently available ventricular support devices that involve a blood/device interface.

Animals↗
PubMed1999

Transmyocardial laser revascularisation compared with continued medical therapy for treatment of refractory angina pectoris: a prospective randomised trial. ATLANTIC Investigators. Angina Treatments-Lasers and Normal Therapies in Comparison.

BACKGROUND: Transmyocardial revascularisation (TMR) is an operative treatment for refractory angina pectoris when bypass surgery or percutaneous transluminal angioplasty is not indicated. We did a prospective randomised trial to compare TMR with continued medication. METHODS: We recruited 182 patients from 16 US centres with Canadian Cardiovascular Society Angina (CCSA) score III (38%) or IV (62%), reversible ischaemia, and incomplete response to other therapies. Patients were randomly assigned TMR and continued medication (n=92) or continued medication alone (n=90). Baseline assessments were angina class, exercise tolerance, Seattle angina questionnaire for quality of life, and dipyridamole thallium stress test. We reassessed patients at 3 months, 6 months, and 12 months, with independent masked angina assessment at 12 months. FINDINGS: At 12 months, total exercise tolerance increased by a median of 65 s in the TMR group compared with a 46 s decrease in the medication-only group (p<0.0001, median difference 111 s). Independent CCSA score was II or lower in 47.8% in the TMR group compared with 14.3% in the medication-only group (p<0.001). Each Seattle angina questionnaire index increased in the TMR group significantly more than in the medication-only group (p<0.001). INTERPRETATION: TMR lowered angina scores, increased exercise tolerance time, and improved patients' perceptions of quality of life. This operative treatment provided clinical benefits in patients with no other therapeutic options.

Aged↗
PubMed1999

Hemodynamic effects of direct biventricular compression studied in isovolumic and ejecting isolated canine hearts.

BACKGROUND: Biventricular direct cardiac compression (DCC) can potentially support the failing heart without the complications associated with a blood/device interface. The effect of uniform DCC on left and right ventricular performance was evaluated in 7 isolated canine heart preparations. METHODS AND RESULTS: A computer-controlled afterload system either constrained the isolated heart to contract isovolumically or simulated hemodynamic properties of physiological ejection. Biventricular DCC was provided by a chamber surrounding the heart that allowed adjustment of the compression pressure, onset time, and duration. Through a series of ventricular preloads, the effect of DCC on the end-systolic pressure-volume relationship (ESPVR) was evaluated under isovolumic and ejecting conditions. Under both conditions, DCC shifted the ESPVR of the left and right ventricles upward by an amount approximately equal to the compression pressure. The augmentation of end-systolic pressure for each initial preload tested, however, was less under ejecting conditions, because reductions in end-systolic and end-diastolic volumes occurred with ejection. Nevertheless, the net effect was to increase stroke volume. Measurement of M&f1;O2 demonstrated that at a given ventricular volume, M&f1;O2 did not change with DCC; however, peak ventricular pressure increased substantially, so that the effective pressure-volume area increased. CONCLUSIONS: Biventricular DCC can augment end-systolic pressure with no added costs of M&f1;O2. Under ejecting conditions, this augmentation of ventricular contracting ability manifests as increases in stroke volume. Thus, DCC represents a feasible alternative form of ventricular assist, and devices that support the heart in this manner should be further explored.

Animals↗
PubMed1999

Holmium:YAG laser transmyocardial revascularization relieves angina and improves functional status.

BACKGROUND: Transmyocardial revascularization (TMR) surgery uses laser channeling of diseased myocardium to treat ischemia and angina. Rigorous prospective randomized studies have been previously unavailable. METHODS: Forty-three patients were randomized to a medication group and 43 to a group scheduled for TMR surgery and medication. All had advanced cardiac ischemia with CCSA class 3 or 4 angina, took at least 2 cardiac medications at maximum doses, and were ineligible for angioplasty or bypass. RESULTS: Forty-two of 43 TMR group patients received surgery and were discharged after hospitalizations averaging 3.2 days. Two suffered perioperative MIs, with one death. Four others died within 12 months of surgery, 3 from cardiac events and 1 from pneumonia. Five medical group patients died from cardiac events within 12 months. Three, 6, and 12 month exams showed angina class improvement in TMR patients compared to preoperative values (3.86 +/- 0.05 vs 1.71 +/- 0.2, P < 0.0001), and to controls at 12 months (3.77 +/- 0.07 vs 1.71 +/- 0.2, P < 0.0001). Exercise tolerance improved in TMR patients over preoperative values, and was better than medication group scores after 12 months (490 +/- 17 sec. vs 294 +/- 12 sec., p = 0.0002). CONCLUSIONS: Holmium:YAG laser channeling of the myocardium improves function and reduces angina in advanced cardiac patients who lack alternative therapeutic options.

Angina Pectoris↗
PubMed1999

Factors correlating with risk of mortality after transmyocardial revascularization.

OBJECTIVES: The purpose of this study was to determine factors correlating with the risk of postoperative mortality after transmyocardial laser revascularization (TMR). BACKGROUND: Clinical studies have indicated that TMR reduces angina by an average of two classes in patients with medically refractory symptoms not treatable by coronary artery bypass graft (CABG) or percutaneous transluminal coronary angioplasty. Factors which correlate with mortality after TMR, however, have not been extensively investigated. METHODS: One hundred thirty-two patients with severe angina underwent TMR as sole therapy with a CO2 laser. Age, gender, ejection fraction, prior CABG, unstable angina and the severity of coronary artery disease (graded on the basis of a newly proposed Anatomic Myocardial Perfusion index, AMP) were each determined. Each vascular territory (left anterior descending artery [LAD] left circumflex artery and posterior descending artery [PDA]) was graded as either having (AMP = 1) or not having (AMP = 0) blood flow through an unobstructed major vessel in the territory. Univariate and multivariate analysis determined which factors correlated with mortality. RESULTS: Patients with at least one AMP = 1 vascular territory (overall AMP = 1) had a 5% (4/82) postoperative mortality rate (POM), compared with 25% (12/49) with overall AMP 0 (p = 0.002). Left anterior descending artery AMP (p = 0.03) and previous CABG (p = 0.04) each correlated with the risk of POM. However, multivariate analysis indicated that no factor improved the correlation obtained with overall AMP by itself. With regard to overall mortality (Kaplan-Meier curves), univariate analysis also revealed correlations with overall AMP (p < 0.001), LAD AMP (p = 0.005), previous CABG (p = 0.003) and PDA AMP (p = 0.05) each individually correlated with mortality. Multivariate analysis indicated that overall AMP = 1, female gender and previous CABG together correlated best with lower postoperative mortality. CONCLUSIONS: Patients with good blood flow to at least one region of the heart through a native artery or a patent vascular graft have a markedly reduced risk of perioperative and longer term mortality.

Aged↗
PubMed1999

An examination of potential mechanisms underlying transmyocardial laser revascularization induced increases in myocardial blood flow.

Within the past few years, transmyocardial laser revascularization (TMR) has attracted the attention of cardiologists and cardiac surgeons as a therapy for patients suffering from otherwise treatable coronary artery disease. Clinical studies have consistently shown symptomatic improvement that lasts at least 1 year in a majority of patients. The original hypothesis that prompted development of the technique was that direct myocardial perfusion from the chamber could be achieved through chronically patent channels, as is the case in reptilian hearts. Results of our early studies failed to support this hypothesis and we turned to investigations aimed at testing other possible explanations. The experiments, which are reviewed in this article, showed that TMR enhances vascular growth in ischemic myocardium.

Alligators and Crocodiles↗
PubMed1999

The role of angiotensin II AT1 receptor in the maintenance of hemodynamics in a canine model of coronary microembolization-induced heart failure.

The purpose of this study was to determine whether Angiotensin II (Ang II) contributes to the regulation of resting hemodynamics via Ang II type 1 (AT1) receptors in awake dogs with coronary microembolization-induced heart failure. Six dogs were surgically instrumented for measurement of systemic hemodynamics and for coronary microembolization. The acute hemodynamic effects of a selective AT1-receptor antagonist, GR138950 (1 mg/kg, i.v.), were determined before and after congestive heart failure (CHF). GR138950 had no effects on hemodynamics before CHF Daily coronary microembolizations (through the previously implanted coronary catheter) resulted in CHF, as documented by hemodynamic measurements, a slight but significant increased Ang II plasma level (17.4 +/- 1.6 vs. 23 +/- 1.0 pg/ml; p < 0.05), and characteristic clinical signs of CHF. After CHF, GR138950 significantly increased left ventricular dP/dt(max) (LVdP/dt(max)) from 1,754 +/- 68 to 2,347 +/- 114 mm Hg/s and decreased LV systolic pressure (LVSP) from 118 +/- 5 to 101 +/- 7 mm Hg; meanwhile, heart rate (from 132 +/- 4 to 102 +/- 6 beats/min) and LV end-diastolic pressure (LVEDP; from 17 +/- 3 to 9 +/- 1.5 mm Hg) were significantly decreased. Mean arterial pressure (MAP) was not affected. The peak effects occurred 90 min after administration. Thus Ang II contributes significantly to resting hemodynamics via AT1 receptors in this CHF model; that is, the specific AT1 blocker inhibits the negative inotropic actions of Ang II in the CHF state.

Angiotensin II↗
PubMed1999

A role for the renin-angiotensin system in the evolution of cardiac memory.

INTRODUCTION: We studied the role of the cardiac renin-angiotensin II system in the genesis of cardiac memory, in which T wave changes induced by ventricular pacing (VP) accumulate and persist during subsequent sinus rhythm. METHODS AND RESULTS: Anesthetized dogs were instrumented via a thoracotomy and three 20-minute runs of VP were interspersed with periods of normal sinus rhythm sufficient to permit T wave recovery to 90% of control. Memory was quantified as the change (delta) in T wave vector angle showing accumulation over the three monitoring periods. In five control dogs T wave vector = -27 +/- 49 degrees, and this shifted by 104 degrees (P < 0.05) over the three postpacing recovery periods. In seven dogs infused with the receptor blocker saralasin, five infused with the angiotensin-converting enzyme inhibitor captopril, and four infused with the tissue protease inhibitor chymostatin, there were significant reductions in the incidence and the accumulation of memory. In four other experiments, we used isolated, blood-perfused canine hearts to demonstrate that VP used to induce memory alters the contractile pattern of the left ventricle. CONCLUSIONS: We propose that the alteration in myocardial stretch induced by pacing activates angiotensin II synthesis by cardiac cells. We propose, further that the endogenous cardiac renin-angiotensin II system (blocked by saralasin, captopril and by chymostatin) is an important contributor to the induction of memory.

Angiotensin II↗
PubMed1999

Factors contributing to pressure overload-induced immediate early gene expression in adult rat hearts in vivo.

We determined the contributions of angiotensin II type 1 receptor (AT(1)) stimulation, adrenergic stimulation, and autonomic activation to pressure overload-induced c-fos expression in the adult rat heart in vivo. c-fos expression was increased in pressure-overloaded hearts created by aortic banding compared with sham-operated rats (458 +/- 100% vs. sham, P < 0.05). GR-138950, a selective AT(1) antagonist, did not blunt this expression (banding vs. banding + GR-138950: 458 +/- 100% vs. 500 +/- 125%, not significant). Atropine and hexamethonium partially decreased c-fos expression (banding vs. banding + atropine/hexamethonium: 700 +/- 67% vs. 400 +/- 67%, P < 0.05). Phentolamine had no significant effect on c-fos expression; however, propranolol inhibited the expression (banding vs. banding + propranolol: 492 +/- 108% vs. 154 +/- 15%, P < 0.05). The inhibition by propranolol was independent of the decreases in heart rate. Thus factors contributing to pressure overload-induced c-fos expression in adult rat hearts in vivo are different from those in neonatal myocytes in vitro undergoing stretch.

Animals↗
PubMed1998

Evolution and resolution of long-term cardiac memory.

BACKGROUND: Cardiac memory (CM) refers to T-wave changes induced by ventricular pacing or arrhythmia that accumulate in magnitude and duration with repeated episodes of abnormal activation. We report herein the kinetics of long-term CM and its association with the ventricular action potential. METHODS AND RESULTS: Dogs were paced from the ventricles at rates of 110 to 120 bpm for approximately 3 weeks. CM characterized by gradual sinus rhythm T vector rotation toward the paced QRS vector evolved in all dogs regardless of pacing site (left ventricular [LV] anterior apex or base, posterior LV, or right ventricular free wall). Cardiac hemodynamics and myocardial flow (microsphere studies) were unaltered by the pacing. Recovery time for the memory T wave to return to control increased with duration of the previous pacing. The protein synthesis inhibitor cycloheximide markedly (P<.05) and reproducibly attenuated evolution of CM. When pacing was performed from the atrium, CM did not occur. Standard microelectrode techniques were used to study action potential from the LV free wall of control and CM dogs. CM was associated with increased action potential duration in epicardial and endocardial but not midmyocardial cells, significantly altering the transmyocardial gradient for repolarization. CONCLUSIONS: CM is a dynamic process for which the final T vector is predicted by the paced QRS vector and which is associated with significant changes in epicardial and endocardial but not midmyocardial cell action potential duration, such that the transmural gradient of repolarization is altered. It is unaccompanied by evidence of altered hemodynamics or flow, requires a change in pathway of activation, and appears to require new protein synthesis.

Action Potentials↗
PubMed1998

Inflow valve regurgitation during left ventricular assist device support may interfere with reverse ventricular remodeling.

BACKGROUND: Left ventricular assist devices have been reported previously to reverse ventricular remodeling in patients with dilated cardiomyopathy. In patients with prolonged mechanical support, structural failure of the left ventricular assist device inflow valve can cause regurgitation into the left ventricle, which may affect adversely this process. METHODS: Left ventricular end-diastolic pressure-volume relation of hearts explanted from 8 patients with left ventricular assist device and 8 control subjects with idiopathic cardiomyopathy was determined ex vivo at the time of transplantation. RESULTS: Duration of mechanical support ranged from 210 to 276 days (mean +/- standard deviation = 283 +/- 76 days) in 3 patients with inflow valve regurgitation versus 100 to 155 days (132 +/- 22 days) in 5 patients without (p = 0.005). The end-diastolic pressure-volume relation of all hearts supported mechanically was shifted to the left toward normal controls. This effect was markedly attenuated in patients with inflow valve regurgitation. CONCLUSIONS: Mechanical assistance can cause reverse remodeling in patients with dilated cardiomyopathy as evidenced by the shift in the end-diastolic pressure-volume relation curve to the left. Inflow valve failure, associated with prolonged support, can attenuate changes in left ventricular structure and dimension. Ineffective pressure and volume unloading may explain these observations.

Cardiomyopathy, Dilated↗