A minimally invasive approach for open surgical thoracoabdominal aortic replacement: experimental concept for a novel surgical procedure.

Objectives: We aimed to develop a simple, reliable, and timesaving technique for the therapy of thoracoabdominal aortic (TAA) aneurysms that are not suitable for endovascular repair. Methods: In this pilot study, we sought to combine the advantages of classic open vascular procedure with the use of endoscopic surgical tools and small skin incisions to develop a minimally invasive approach for TAA replacement. The following procedures were used: endoscopic exposure and closure of the lower intercostal arteries; small posterolateral thoracotomy and left retroperitoneal incisions to expose the anastomotic regions of the aorta; partial anticoagulation; passive bypass and sequential aortic clamping; tunnelling of the graft through the native aortic lumen (endoaneurysmorrhaphy) and open performance of vascular anastomosis. Results: Five mixed-breed dogs (25-35 kg) underwent minimally invasive TAA replacement. All animals survived the operation without blood transfusion (lowest Hb = 5.5 mg/dl). Total operation time was 364 ± 46.3 min. Clamping times were 17.6 ± 3.2 min for proximal anastomosis, 33.2 ± 2.48 min for visceral patch and 11 ± 2.3 min for distal anastomosis. The pull-through procedure of graft through the native aorta was performed during the visceral clamp time. Conclusions: Surgical replacement of the TAA through small transverse incisions of the thoracic and abdominal wall is feasible and allows open performance of all vascular anastomosis with no leakage at any anastomotic site. Further experimental studies and clinical implementation are needed to establish the safety and long-term outcome of minimally invasive TAA replacement as a possible primary therapeutic tool for complex aneurysms that are not suitable for endovascular treatment and require open surgical repair.

Characterization of pericardial and plasma ghrelin levels in patients with ischemic and non-ischemic heart disease.

Ghrelin is an endocrine regulatory peptide with multiple functions including cardioprotective effects. It is produced in various tissues among others in the myocardium. Pericardial fluid has been proven to be a biologically active compartment of the heart that communicates with the myocardial interstitium. Thus, pericardial level of certain agents may reflect their concentration in the myocardium well. In our study we measured acylated (active) and total (acylated and non-acylated) pericardial and plasma ghrelin levels of patients with ischemic and non-ischemic heart disease. Pericardial fluid and plasma samples were obtained from patients with coronary artery disease (ISCH, n=54) or valvular heart disease (VHD, n=41) undergoing cardiac surgery. Acylated pericardial ghrelin concentrations were found to be significantly higher in patients with ischemic heart disease (ISCH vs. VHD, 32±3 vs. 16±2pg/ml, p<0.01), whereas plasma levels of the peptide showed no difference between patient groups. Pericardial-to-plasma ratio, an index abolishing systemic effects on local ghrelin level was also significantly higher in ISCH group for both acylated and total ghrelin. Plasma total ghrelin showed negative correlation to BMI, plasma insulin and insulin resistance index HOMA-A. Pericardial acylated and total ghrelin concentrations were negatively correlated with posterior wall thickness (R=-0.31, p<0.05 and R=-0.35, p<0.01, respectively). Plasma insulin concentration and HOMA-A showed significant negative correlation with pericardial ghrelin levels. In conclusion, increased pericardial active ghrelin content and higher pericardial-to-plasma ghrelin ratio were found in ischemic heart disease as compared to non-ischemic patients suggesting an increased ghrelin production of the chronically ischemic myocardium. According to our results, pericardial ghrelin content is negatively influenced by left ventricular hypertrophy and insulin resistance.

Comparison of elimination and cardiovascular effects of adenine nucleosides administered intrapericardially or intravenously in anesthetized dog.

Intrapericardial (IP) administration of certain cardioactive agents allows investigation of local pharmacological actions on the heart and may carry potential benefit to influence myocardial function. The cardioprotective adenosine (ADO) and inosine (INO) may be the most representative candidates. Elimination and cardiovascular effects of IP and intravenously (IV) applied ADO and INO were compared on anesthetized dogs. Their pericardial and systemic concentrations were measured after consecutive administration of increasing ADO and INO doses. In the case of IP administration at the end of the incubation period, pericardial concentrations of adenine nucleosides significantly exceeded the control values. However, the IV applied ADO and INO were rapidly metabolized in the systemic plasma. As characteristic hemodynamic effects, small but sustained decrease in heart rate (IP ADO) and increase in myocardial contractility (IP INO) were observed. During IV administration, ADO and INO exerted remarkable effects on all hemodynamic variables, which then gradually disappeared in 15 minutes. In summary, the elimination of ADO and INO was significantly slower in the pericardial fluid than in the plasma. Considering the balanced cardiac actions and lack of strong systemic hemodynamic effects, IP administration of adenine nucleosides may suggest a promising approach in the local treatment of the diseased heart.

Adaptation of the right ventricle to an increased afterload in the chronically volume overloaded heart.

BACKGROUND: Increased right ventricular afterload is a common problem after correction of various heart diseases with chronic volume overload. We determined the effects of an acute increase of right ventricular afterload in normal and chronically volume overloaded hearts. METHODS: In 6 dogs, volume overload was induced by chronic arteriovenous shunts for 3 months. Six sham-operated animals served as controls. After closing the shunts, right ventricular systolic and end-diastolic pressure as well as end-diastolic volume were measured by conductance catheter. In addition, pressure-volume loops were recorded. Myocardial contractility was described by the slope of the end-systolic pressure-volume relationship. Afterload was increased to right ventricular systolic pressure to 35 mm Hg and to 50 mm Hg by pulmonary banding. RESULTS: Chronic volume overload resulted in a significant increase of right ventricular systolic pressure (34 +/- 2 versus 25 +/- 2 mm Hg, p < 0.05), end-diastolic pressure (10.4 +/- 1.7 versus 6.8 +/- 0.4 mm Hg, p < 0.05), and end-diastolic volume (39 +/- 2 versus 33 +/- 3 mL, p < 0.05). Baseline contractility (1.47 +/- 0.24 versus 1.53 +/- 0.32 mm Hg/mL) did not differ. While afterload increase to 35 and 50 mm Hg led to stepwise increase in contractility (2.73 +/- 0.30 mm Hg/mL and 4.15 +/- 0.30 mm Hg/mL, p < 0.05 versus baseline, respectively) at unchanged end-diastolic pressure and volume in controls, it showed only a slight increase (2.11 +/- 0.38 mm Hg/mL and 2.99 +/- 0.29 mm Hg/mL, p < 0.05 versus sham) with concomitant increase in end-diastolic pressure (12.4 +/- 2.2 mm Hg/mL and 16.3 +/- 1.9 mm Hg, p < 0.05) and volume (42 +/- 4 mL and 48 +/- 8 mL, p < 0.05) in the chronically volume overloaded group. CONCLUSIONS: Chronic volume overload per se does not impair right ventricular contractility. However, the inotropic adaptation (homeometric autoregulation) to an increased afterload is limited, which is partly compensated by the Frank-Starling mechanism (heterometric autoregulation).

The coronary effects of parathyroid hormone.

OBJECTIVE: The aim of the present study was to characterize the role of the ATP-sensitive potassium channels (K(+)(ATP)) in the coronary dilator action of parathyroid hormone (PTH). METHODS: Dose-response curves of intracoronary administrated PTH (0.15-1.33 nmol) were obtained in control phases and during continuous intracoronary administration of the K(+)(ATP) channel-selective antagonist glibenclamide (0.1-1.0 micromol/min) in dogs (n = 13). RESULTS: Increments of integrated coronary conductance (excess coronary conductance) at PTH doses of 0.15 and 1.33 nmol were 1.17 versus 0.03 ml/mm Hg (p < 0.05) and 4.03 versus 0.94 ml/mm Hg (p < 0.05) in the control versus during maximal blockade, respectively. CONCLUSION: The results indicate that the activation of K(+)(ATP) channels significantly contributes to the PTH-induced coronary vasodilation.

Intrapericardial adenine nucleosides induce elevation of endothelin-1 concentration in the pericardial space of the dog heart.

The adenine nucleosides, adenosine (ADO) and inosine (INO), and the endothelin-1 (ET-1) play an important role in the regulation of coronary and myocardial functions. The pericardial fluid accumulates these regulatory agents and reflects well their levels in the myocardial interstitium. This offers a possibility to examine the local adenine nucleoside-endothelin interactions in heart tissue. We have previously demonstrated that increased levels of intrapericardial (i.p.) ET-1 enhanced significantly the adenine nucleoside concentrations of the pericardial fluid samples. In this study the effects of i.p.-administered ADO and INO were investigated on the pericardial concentrations of ET-1 in the in situ dog heart. The ET-1 concentrations were determined (enzymelinked immunosorbent assay) in the samples obtained from the pericardial fluid and from the arterial plasma before and after i.p. administration of increasing doses of ADO (10, 100 and 1000 muM, n = 8) and INO (1, 10 and 100 mM, n = 8). Standard hemodynamic variables were recorded continuously. We found that i.p. ADO and INO induced dose-dependent increases of pericardial ET-1 levels after a 15-minute incubation period in pericardial (ET-1max,ADO, +121 +/- 26%, P < 0.02; and ET-1max,INO, +84 +/- 27%, P < 0.05) but not in the plasma samples. The i.p. nucleosides elicited slight but characteristic alterations in the heart rate and ventricular contractility (dP/dt). The results suggest that the pericardial adenine nucleosides interact with the myocardial ET-1 and this effect may be provoked from, and can also be detected in, the pericardium.

Cardiovascular responses to catecholamines and interactions with endothelin-1 and adenine nucleosides in the pericardium of the dog heart.

The pericardial fluid may accumulate endogenous regulatory agents, such as catecholamines, endothelin or adenine nucleosides. However, very little information is available on the cardiovascular effects of intrapericardial (i.p.) catecholamines and their interaction with the endogenous endothelins and adenine nucleosides. The cardiovascular effects of increasing doses of i.p.- administered dopamine boluses (0.06-8 micromol/kg, n = 8) were studied in the in situ canine heart: systemic blood pressure, heart rate and left ventricular dP/dt were recorded, and pericardial infusate samples were obtained to measure the changes in endothelin-1 (ET-1), adenosine and inosine levels (enzyme-linked immunosorbent assay and high-performance liquid chromatography methods, respectively). The responses to i.p. dopamine were compared with the effects of i.p. norepinephrine boluses (0.004-0.5 micromol/kg, n = 8). Dopamine elicited dose-dependent increases of heart rate (P < 0.01), and the highest dose of dopamine resulted in significant elevation in dP/dt and blood pressure (P < 0.01) with a nearly twofold increase of i.p. ET-1 (from 14.3 +/- 0.1 pg/mL to 26.1 +/- 0.1 pg/mL, P < 0.02) and a more than threefold augmentation of i.p. adenosine (from 2.9 +/- 0.5 microM to 11.1 +/- 3.0 microM, P < 0.05), but not of inosine levels. Similar responses were obtained with i.p. norepinephrine. The results confirm that i.p. catecholamines exert significant hemodynamic effects and modulate ET-1 and adenosine release from the heart. However, the pattern of catecholamine actions initiated from the pericardium may characteristically differ from that of intravascular ones.

Nitrogen oxide blockade does not aggravate the endothelin-1-induced myocardial ischemia and release of purine metabolites from the dog heart.

Increased intrapericardial levels of endothelin-1 (ET-1) induce myocardial ischemia and concomitant release of the purine metabolites adenosine (ADO), inosine (INO) and hypoxanthine (HXA) into the pericardial fluid. However, the potential modulatory role of nitrogen monoxide in compensating the ET-1-induced ischemic stress is not fully elucidated. The pericardial elevations of purine metabolite concentrations in the pericardial fluid after ET-1 administration (150 pmol/kg intrapericardially) were measured in the in situ dog heart with (n = 6) or without (n = 5) systemic nitrogen monoxide synthase blockade (30 mg/kg (G)-nitro-L-arginine methyl ester, followed by 6 mg/min intravenously). After control sampling, three consecutive pericardial infusate samples (ET1, ET2, ET3) were obtained for purine metabolite determinations (high-performance liquid chromatography-ultraviolet). It was found that intrapericardial ET-1 elevated the pericardial purine metabolite concentrations significantly in both groups. No significant differences were detected between the control and (G)-nitro-L-arginine methyl ester-treated groups in ischemic changes of pericardial ADOmax (+3.27 +/- 1.13 microM versus +1.84 +/- 0.56 microM), INOmax (+15.21 +/- 2.3 microM versus +12.09 +/- 4.04 microM) and HXAmax (+16.34 +/- 2.98 microM versus +17.09 +/- 5.22 microM) levels and in the maximal ST elevations (0.43 +/- 0.05 mV versus 0.61 +/- 0.08 mV). The hemodynamic variables did not change with ET-1 administration. In conclusion, systemic nitrogen monoxide synthase blockade does not aggravate the ET-1-induced acute myocardial ischemia and the release of purine metabolites, suggesting that endogenous nitrogen monoxide is not a supplementary factor to purine metabolites in this type of coronary adaptive responses.

Left ventricular external subannular plication: an indirect off-pump mitral annuloplasty method in a canine model.

OBJECTIVE: Mitral annular dilatation in cardiomyopathy is due to left ventricular chamber enlargement. We hypothesized that the size of the mitral annulus could be "indirectly" reduced if the plicating sutures were placed externally into subannular myocardium. METHODS: In healthy mongrel dogs, an off-pump technique to create external subannular plication was designed and implemented. The sutures were placed directly into the myocardium below the atrioventricular groove. In 14 dogs, the sutures were tightened with tourniquets, and after a 30-minute observation period the hearts were arrested. Subsequently the mitral annular size was measured with the tourniquets still tight and then released. In 6 dogs, circumflex coronary blood flow, coronary blood flow reserve, and left ventricular systolic function were also measured during experiments. RESULTS: Subannular plication had no significant effect on the animals' hemodynamic stability, and it did not generate any arrhythmias. Suture tightening effectively reduced postmortem mitral annular diameter and circumference by 17% (30.8 +/- 0.4 mm and 96.8 +/- 1.1 mm vs 25.6 +/- 0.4 mm and 80.4 +/- 1.1 mm, respectively, P <.001) and mitral annular area by 31% (747 +/- 17 mm(2) vs 517 +/- 14 mm(2), P <.001). Circumflex coronary blood flow (39.0 +/- 7.9 mL/min vs 37.2 +/- 7.2 mL/min, P not significant) and left ventricular systolic function (dP/dt(max) 1705 +/- 237 mm Hg/s vs 1928 +/- 330 mm Hg/s, P not significant) remained unchanged (n = 6). CONCLUSION: In healthy hearts, subannular ventricular plication resulted in a significant indirect mitral annular size reduction without compromising circumflex coronary blood flow or left ventricular systolic performance.

Poly-ADP-ribose polymerase inhibition protects against myocardial and endothelial reperfusion injury after hypothermic cardiac arrest.

OBJECTIVE: Free radical production and related cytotoxicity during ischemia and reperfusion might lead to DNA strand breakage, which activates the nuclear enzyme poly-ADP-ribose synthetase and initiates an energy-consuming and inefficient cellular metabolic cycle with transfer of the adenosine diphosphate-ribosyl moiety of nicotinamide adenine dinucleotide (NAD(+)) to protein acceptors. We investigated the effects of poly-ADP-ribose synthetase inhibition on myocardial and endothelial function during reperfusion in an experimental model of cardiopulmonary bypass. METHODS: Twelve anesthetized dogs underwent hypothermic cardiopulmonary bypass. After 60 minutes of hypothermic cardiac arrest, reperfusion was started after application of either saline vehicle (control, n = 6) or PJ34 (10 mg/kg), a potent poly-ADP-ribose synthetase inhibitor (n = 6). Biventricular hemodynamic variables were measured by means of a combined pressure-volume conductance catheter, and the slope of the end-systolic pressure-volume relationships was calculated at baseline and after 60 minutes of reperfusion. Left anterior descending coronary blood flow, endothelium-dependent vasodilatation to acetylcholine, and endothelium-independent vasodilatation to sodium nitroprusside were also determined. RESULTS: The administration of PJ34 led to a significantly better recovery of left and right ventricular systolic function (P <.05) after 60 minutes of reperfusion. In addition, the inotropic adaptation potential of the right ventricle to an increased afterload was better preserved in the PJ34 group. Coronary blood flow was also significantly higher in the PJ34 group (P <.05). Although the vasodilatory response to sodium nitroprusside was similar in both groups, acetylcholine resulted in a significantly higher increase in coronary blood flow in the PJ34 group (P <.05). CONCLUSIONS: Poly-ADP-ribose synthetase inhibition improves the recovery of myocardial and endothelial function after cardiopulmonary bypass with hypothermic cardiac arrest.

Pericardial concentrations of adenosine, inosine and hypoxanthine in an experimental canine model of spastic ischaemia.

It has been shown that the adenosine concentration in the pericardial fluid of the normal heart is higher by one order of magnitude than that of the venous plasma. A further increase in the pericardial adenosine concentration was also demonstrated in myocardial ischaemia or hypoxia. It was proposed that pericardial nucleoside levels may represent the interstitial concentrations of the adenine nucleosides. An experimental model was designed to determine the intrapericardial concentrations of adenosine, inosine and hypoxanthine during coronary spasm provoked by intracoronary administration of endothelin-1 (ET-1; 0.08+/-0.02 nmol/g of myocardial tissue). In the in situ dog heart (n=10), adenosine, inosine and hypoxanthine concentrations were determined by HPLC in fluid samples collected from the closed pericardial sac before and after ET-1 administration, and from the systemic arterial blood. Systemic blood pressure, heart rate and standard ECG were registered continuously. We found that the nucleoside concentrations in the infusate samples increased significantly during coronary spasm [adenosine, 1.49+/-0.44 compared with 0.37+/-0.07 microM (P<0.05); inosine, 27.43+/-11.51 compared with 0.47+/-0.11 microM (P<0.05); hypoxanthine, 21.17+/-6.49 compared with 4.91+/-1.24 microM (P<0.05)], while a significant decrease in blood pressure and an elevation in ECG ST segments were observed. The levels of the purine metabolites did not change in the systemic blood. The data indicate that changes in adenine nucleoside levels measured in pericardial infusate samples reflect activation of coronary metabolic adaptation in this model of spastic ischaemia, and that pericardial nucleoside levels may characterize alterations in interstitial adenine nucleoside concentrations.

Endothelin-1-induced elevations in purine metabolite concentrations -- autoregulatory protection in the canine pericardium?

Pericardial fluid accumulates the cardioprotective purine metabolites, as well as the endogenous vasoconstrictor agent endothelin-1 (ET-1). The aim of the present study was to characterize the pericardial concentrations of the purine metabolites adenosine, inosine and hypoxanthine before and after intrapericardial administration of ET-1 to the in situ heart. The closed pericardial sac of anaesthetized dogs (n=9) was cannulated for ET-1 administration and for obtaining native pericardial fluid and control pericardial infusate samples (C1 and C2), as well as consecutive pericardial infusate samples (samples I, II and III) obtained 15 min after intrapericardial administration of 150 pmol/kg ET-1. In an additional five dogs, using the same protocol, ventricular epicardial and endocardial monophasic action potential recordings were performed to assess local ischaemic electrophysiological changes. Significant elevations of pericardial purine metabolite concentrations (measured by HPLC) were found in sample II compared with sample C2: adenosine, 4.5+/-1.7 compared with 0.5+/-0.1 microM (P<0.05); inosine, 18.3+/-2.8 compared with 0.9+/-0.2 microM (P<0.001); hypoxanthine, 38.1+/-8.0 compared with 13.4+/-2.6 microM (P<0.01). Systemic blood pressure, left ventricular pressure and contractility, and systemic plasma levels of the purine metabolites remained unchanged during the ET-1 effect, while significant ECG ST elevations (ST(max) 0.68+/-0.01 mV; P<0.001) were observed. In the five dogs analysed electrophysiologically, the left ventricular epicardial monophasic action potential duration and upstroke velocity decreased significantly at time point II compared with C2, while the endocardial monophasic action potential duration and upstroke velocity did not show ischaemia-related changes. The results suggest that intrapericardial administration of ET-1 induces subepicardial ischaemia, with parallel activation of coronary metabolic adaptive and cardiac self-protective mechanisms in the epimyocardial layer of the heart.