Intracellular diglycerides in relation to glycaemic control in the myocardium: A pilot study in humans.

AIM: Intramyocellular diglycerides have been implicated in the development of insulin resistance in skeletal muscle. In the myocardium, excess lipid storage may also contribute to the appearance of diabetic cardiomyopathy, while diglycerides may have certain cardio-protective functions. However, little is known on intracellular diglyceride accumulation in the human heart. We aimed to determine diglyceride accumulation in the human myocardium in relation to diabetes status. METHODS: Six diabetic and six non-diabetic aged human subjects undergoing by-pass surgery participated in the study. Subjects were matched for age and body mass index. Intracellular diglyceride levels were measured in heart biopsy samples. Additional samples were taken from pectoralis major muscle that served as control. Whole body glycaemic control was assessed as the percent glycated haemoglobin. RESULTS: Intracellular diglycerides were significantly higher in the myocardium compared to pectoralis major (P<0.05). Although not statistically significant, diabetic subjects tended to accumulate smaller amounts of diglycerides compared to non-diabetic subjects in the myocardium. A linear negative correlation was observed between myocardial diglycerides and glycaemic control (r=0.632, P<0.05). CONCLUSIONS: Our data suggest that poor glycaemic control and diabetes may be associated with a defective accumulation of myocardial diglycerides, possibly blunting intracellular processes and contributing to the development of cardiomyopathy.

Ventricular assist devices: pharmacological aspects of a mechanical therapy.

Heart failure (HF) is a global epidemic that continues to cause significant morbidity and mortality despite advances in medical therapy. Ventricular assist device technology has emerged as a therapeutic option to bridge patients with end-stage HF to heart transplantation or as an alternative to transplantation in selected patients. In some patients, mechanical unloading induced by ventricular assist devices leads to improvement of myocardial function and a possibility of device removal. The implementation of this advanced technology requires multiple pharmacological interventions, both in the perioperative and long-term periods, in order to minimize potential complications and improve patient outcomes. We herein review the latest available evidence supporting the use of specific pharmacological interventions and current practices in the care of these patients: anticoagulation, bleeding management, pump thrombosis, infections, arrhythmias, right ventricular failure, hypertension, desensitization protocols, among others. Areas of uncertainty and ground for future research are also highlighted.

Limitation of infarct size by fixed coronary arterial stenosis maintained during reperfusion.

BACKGROUND: The effect on infarct size of a pre-infarction high-grade, fixed coronary arterial stenosis maintained during reperfusion, was evaluated. METHODS: This experimental study was carried out in the research laboratory of a University Hospital. A canine occlusion-reperfusion model was used. Twenty-eight dogs underwent proximal left anterior descending (LAD) coronary artery occlusion (O). In Group 1 (n=6) the O lasted for 6 hours. In Group 2 (n=6) the O lasted for 2 hours followed by 4 hours of reperfusion (R). In Group 3 (n=3), LAD was stenosed for 30 minutes followed by O for 6 hours. In Group 4 (n=7) LAD was stenosed for 30 minutes followed by O for 2 hours and then 4 hours of R during which the artery was kept stenosed at the same degree (fixed) as the initial one. In Group 5 (n=6) the protocol was identical to Group 4 with the additional use of the intra-aortic balloon pump during R. RESULTS: The infarcted myocardium was almost the same in Groups 1 and 3 (80.0+/-10.6% vs 77.3+/-3.8%, respectively, p=NS), but less in Group 2 (59.0+/-19.9%, p=0.046 vs Group 1). There were no hemodynamic differences between Groups 4 and 5 and the infarcted myocardium was almost identical in both groups (37.7+/-18.8% and 38.7+/-19.1%, respectively, p=NS). The combined results of Groups 4 and 5, regarding the infarcted myocardium, was 38.1+/-18% (p=0.037 vs Group 2). CONCLUSIONS: In this acute coronary occlusion model, a pre-existing high-grade stenosis that maintained during reperfusion increased the amount of salvaged ischemic myocardium.

Postpericardiotomy syndrome during intensive immunosuppression after cardiac transplantation.

A 15-year-old man with end-stage heart failure due to dilated cardiomyopathy, underwent heart transplantation. In the second postoperative week, while being treated with monoclonal antibodies (OKT3), cyclosporine and azathioprine, he developed a postpericardiotomy syndrome and cardiac tamponade, which necessitated emergency pericardiocentesis. Corticosteroids, administered according to the immunosuppression protocol, resulted in the prompt subsidence of the syndrome. This is the first report of a large pericardial effusion and cardiac tamponade due to a postpericardiotomy syndrome in an adult cardiac recipient.

Synthesis and fluorescence properties of intramolecularly quenched fluorogenic p-nitroanilides containing coumarin or quinolinone derivatives as fluorophores.

Nine model intramolecularly quenched fluorogenic substrates (IQFS) of the general structure F-Phe-NH-Np, containing coumarin or quinolinone derivatives as fluorophores (F) and the p-nitroanilide group (Np) as quencher, were synthesized. The study of the fluorescence properties of the substrates synthesized and the corresponding fluorophores showed that efficient quenching of fluorescence (>89%) was observed in all cases. The combination of 7-glutarylamido-4-methyl-coumarin (Mec-NH-Glt-OH) or 7-methoxy-4-coumaryl-acetic acid (Mca) with the p-nitroanilide group gave the best results (97.2 and 98.8% quenching, respectively). These fluorophores can be used to convert peptide p-nitroanilides into IQFS, which, retaining their chromogenic properties, may be applied in both fluorometric and colorimetric assays.

Surgical repair of postinfarction ventricular septal defect: 10-year experience.

Postinfarction ventricular septal defect (PIVSD) remains a surgical challenge resulting in devastating mortality rates. We present our 10-year experience in surgical management of this catastrophic complication of acute myocardial infarction. During a decade (1987-1996) 14 patients with PIVSD were treated surgically in our department. There were 10 men and 4 women, ranging in age from 51 to 78 years. The rupture occurred within the first 4 days after the infarction in most cases (n = 10). Eight patients were supported perioperatively by intraaortic balloon counterpulsation (IABP). In all cases the surgical technique included infarctectomy and ventricular septum reconstruction with synthetic patches. Coronary artery bypass grafting was synchronously performed in four patients. Seven patients died perioperatively (mortality rate 50%) due to heart failure and to multiple organ failure. The most frequent complications were low cardiac output syndrome, hemorrhage, and respiratory and renal insufficiency. The PIVSD needs urgent surgical intervention with the patient hemodynamically stable after cardiac catheterization. Long-term results are favorable for survivors.

The efficacy of the high volume counterpulsation technique at very low levels of aortic pressure.

BACKGROUND: The objective of the present study was to identify the hemodynamic variables, that preclude the effectiveness of the counterpulsation technique. METHODS: In order to achieve high counterpulsation volume two devices were used simultaneously. The para-aortic counterpulsation device pumping 60-70 ml was implanted on the ascending aorta, and the intra-aortic balloon (20 ml) was placed in the descending aorta of 14 dogs with severe cardiogenic shock. Both devices were synchronized to provide aortic diastolic augmentation. The mechanical assistance provided by these devices was considered adequate when the mean aortic pressure during the supportive period was at least 50 mmHg, a pressure compatible with life. RESULTS: The mechanical assistance provided by the two devices was adequate in none (0%) of the cases with a systolic aortic pressure below 30 mmHg (Group I), in 71% of the cases with a systolic aortic pressure between 30-56 mmHg (Group II), and in 100% of the cases with a systolic aortic pressure above 56 mmHg (Group III). In group II the left ventricular end-diastolic pressure was higher in the cases responding adequately to mechanical assistance (Subgroup IIa) than in the ones where no adequate response was obtained (Subgroup IIb). CONCLUSIONS: The very low levels of the systolic aortic pressure was the most important factor precluding the adequate effectiveness of the counterpulsation technique.

Right and left ventricular interaction in ventricular fibrillation with mechanical maintenance of the circulation.

OBJECTIVE: To investigate the possible mechanisms of right and left ventricular interaction during ventricular fibrillation (VF) with mechanical maintenance of the circulation. EXPERIMENTAL DESIGN: In this experimental study, two para-aortic counterpulsation devices (PACDs) were implanted in 14 mongrel dogs. SETTING: The PACD is a spheroid, valveless, with one opening, 100 ml stroke volume assisting device. After midsternotomy and pericardiotomy, two PACDs were implanted on the ascending aorta and the pulmonary artery, respectively. Catheters were placed into the aortic arch, and the left and right ventricles. An electromagnetic probe was placed on the descending aorta. INTERVENTIONS: After the completion of the experimental preparation, VF was induced and the two devices were synchronized and pumped simultaneously for 10 minutes (A). Subsequently, the left sided PACD pumped alone for the same period of time (B). This sequence was repeated 1-10 times in each experiment. MEASURES: The aortic pressures, the left and right ventricular pressures and the cardiac index were obtained at the end of each intervention. RESULTS: The simultaneous pumping of the two devices (A) compared with the pumping of that implanted on the ascending aorta (B) resulted in: higher peak aortic pressure 119.1+/-32.1 mmHg (A) vs 105.7+/-36.4 mmHg (B), p<0.001, mean aortic pressure 42.1+/-13.2 mmHg vs 27.8+/-10.5 mmHg, p<0.001, mean left ventricular pressure 18.4+4.0 mmHg vs 11.7+/-3.6 mmHg, p<0.001, and cardiac index 105.7+/-40.1 ml/kg/min vs 82.0+/-39.9 ml/kg/mm, p<0.001, and lower right ventricular pressure 10.1+/-3.2 mmHg vs 13.3+/-2.6 mmHg, p<0.001. CONCLUSIONS: Maintenance of the circulation during VF with the PACD implanted on the ascending aorta results in equalization of the right and left ventricular pressures. In contrast, when both devices are pumping simultaneously, the left ventricular pressure is significantly higher than the right one and the assistance is more effective.

Total occlusion of the left main coronary artery with preserved left ventricular function.

Two patients with total occlusion of the left main coronary artery and well preserved left ventricular function are reported. Twenty one similar cases have been reported in the world literature. All the patients had angina pectoris. Twenty one of the 23 patients (including our cases) underwent coronary artery bypass graft surgery while the other two received medical treatment. All are alive for a follow-up period of 0.4-67 months. It is concluded that in patients with chronic total occlusion of the left main coronary artery and well preserved left ventricular function, collateral flow is always extensive but insufficient to prevent angina. Functional status is greatly improved by surgery, although survival is excellent in both treated and non-treated surgically patients.

Synthesis and properties of novel lipopeptides and lipid mimetics.

Lipid mimetics, synthetic molecules that resemble natural lipids either structurally or functionally, have been developed as potential medicinal substances. They have been successfully applied in the development of drug and peptide delivery systems and for the development of inhibitors or lipid metabolizing enzymes. Phospholipase A2 is considered to be involved as the rate-limiting step in the production of lipid mediators of inflammatory responses and, as such, it has been a target for drug design. A series of lipid mimetics including lipopeptides, amides and alcohols of lipidic alpha-amino acids, have been tested by bulk and monolayer assay techniques. The findings suggested the direct interaction of the tested compounds with porcine pancreatic phospholipase A2. The inactivation of the enzyme occurred in a competitive manner. The most active compound I (2-amino-N-hexadecyl-L-hexanamide) showed an apparent IC50 of 12 microM and inhibitory power Z = 13 in the monolayer assay.

High stroke volume para-aortic counterpulsation device versus centrifugal pump in cardiogenic shock: experimental study.

During the last decades a number of left ventricular assist devices has been used especially for patients resistant to pharmacologic treatment and to intraaortic balloon pump (IABP) support for left ventricular failure. A high stroke volume para-aortic counterpulsation device (PACD) has been developed utilizing the principle of the diastolic counterpulsation technique. In this study the hemodynamic effects of the valveless PACD were compared to those of the centrifugal blood pump (CBP) in nine dogs in acute experimental cardiogenic shock. Hemodynamic measurements were obtained at baseline with both devices off, PACD on and CBP off, or PACD off and CBP on. There was no difference in mean aortic pressure between PACD on (60.0 +/- 11.5 mmHg) and CBP on (69.0 +/- 26.8 mmHg). Similarly, there was no difference in left ventricular end-diastolic pressure with the PACD on (11.9 +/- 5.4 mmHg) versus the CBP on (9.9 +/- 5.2 mmHg) or the cardiac index with the PACD on (84 +/- 36 ml/kg/min) versus the CBP on (77 +/- 36 ml/kg/min). However, the left ventricular systolic pressure (55.0 +/- 19.0 with PACD versus 73.0 +/- 26.0 with CBP,p < 0.001), the tension time index (712 +/- 381 versus 1333 +/- 694,p < 0.01), and the double product (5629 +/- 2574 versus 7440 +/- 3294,p < 0.01) were significantly lower during assistance with the PACD than with the CBP. It was concluded that PACD is at least as effective as CBP for restoring hemodynamic status during acute experimental cardiogenic shock. Moreover, the PACD unloads the left ventricle more effectively than CBP, making it suitable for left ventricular mechanical support in cases with reversible myocardial damage.

A valveless high stroke volume counterpulsation device restores hemodynamics in patients with congestive heart failure and intractable cardiogenic shock awaiting heart transplantation.

The paraaortic counterpulsation device is a round pumping chamber with one valveless opening 20 mm in diameter and a 100 ml stroke volume. The paraaortic counterpulsation device was implanted on the ascending aorta of three male patients with intractable cardiogenic shock. Patients were assisted for 4 hours and 8 and 54 days, respectively; the first patient died as a result of nonresponding peripheral vasodilation and the other two died of septic shock. The two patients who were assisted for 8 and 54 days were conscious and able to function in a limited manner during the mechanical assistance. Discontinuation of the mechanical support for a few seconds was followed by low systolic arterial pressure (30 to 60 mm Hg) and syncopal episodes. Biochemical tests and autopsy results in these patients showed no evidence of blood cell destruction, thrombus formation, brain infarction, or other distal emboli. In conclusion, satisfactory hemodynamic effects, excellent biocompatibility, and simplicity of the implantation procedure in these patients encourage the use of the paraaortic counterpulsation device as a bridge to heart transplantation.

Maintenance of circulation during ventricular fibrillation with the simultaneous use of two "counterpulsation" devices.

Two valveless, single orifice counterpulsation devices, with pumping stroke volumes of 65 ml each, were implanted on the ascending aorta and pulmonary artery of seven open chest anesthetized dogs. After completion of the preparation, ventricular fibrillation was induced. The devices were synchronized to pump simultaneously at a rate of 85-100 bpm. The combined use of the counterpulsation devices provided maximal aortic pressure of 111.4 +/- 25.1 mmHg during ventricular fibrillation for a period of 15-60 min. The mean left ventricular pressure was 17.7 +/- 4.4 mmHg, and the cardiac index 64.5 +/- 23.6 ml/kg/min. Cardioversion of ventricular fibrillation to sinus rhythm restored normal hemodynamics. The counterpulsation device implanted on the ascending aorta was not able to maintain circulation for more than 5 min after the induction of ventricular fibrillation, if used alone. In conclusion, the use of two counterpulsation devices implanted on the ascending aorta and pulmonary artery was able to maintain circulation in experimental animals during ventricular fibrillation.

Additional salutary hemodynamic effects of the combined use of the paraaortic counterpulsation device and intraaortic balloon pump versus a paraaortic counterpulsation device alone.

The hemodynamic effects of the combined use of the paraaortic counterpulsation device (PACD) (stroke volume 65 ml) implanted on the ascending aorta, and a 20 ml intraaortic balloon pump (IABP) placed in the descending aorta, were compared with the PACD working alone in 12 dogs after the induction of heart failure. Heart failure was characterized by left ventricular end-diastolic pressure (LVEDP) greater than 18 mmHg and systolic aortic pressure (SAP) in stage A: 116 mmHg greater than or equal to SAP greater than 70 mmHg; in stage B: 70 mmHg greater than or equal to SAP greater than 30 mmHg; and in stage C: SAP less than or equal to 30 mmHg. Both modalities of mechanical assistance produced significant salutary hemodynamic effects in stages A and B. No difference was observed in stage C. In conclusion, the combined use of PACD and IABP is more effective than the use of either of these devices alone. This modality of mechanical assistance may easily be applied in patients that cannot be weaned from extracorporeal circulation, and in whom IABP was unsuccessfully applied.

Preclinical evaluation of the abdominal aortic counterpulsation device.

A valveless, single-orifice abdominal aortic counterpulsation device (AACD) was implanted retroperitoneally on the abdominal aorta and was pumped continuously, providing aortic diastolic augmentation for 45 +/- 4.9 days in four calves (group A). The hematocrit, lactate dehydrogenase (LDH), bilirubin, blood urea nitrogen, and creatinine were obtained before implantation and weekly thereafter. Biocompatibility data were compared to those obtained from 11 calves (group B) that received a total artificial heart (TAH) and were electively terminated 50.0 +/- 19.5 days after implantation. The hematocrit values in the first week were 20.9 +/- 11.5% and 39.8 +/- 11.5% below control values for group A and group B, respectively (p less than 0.02); in the sixth week they were 5.1 +/- 14.6% above control values (group A) and 22.6 +/- 9.0% below control values (group B) (p less than 0.05). LDH did not change in group A, while in group B it was constantly about 100% above control values. Autopsy revealed one to three infarcts 1 to 3 mm in diameter in 63% of the kidneys in group A, while in all of group B kidneys there were multiple infarcts of more than 10 mm. After the induction of left ventricular (LV) failure, the AACD decreased the LV end-diastolic pressure (EDP) by 21.2% (p less than 0.005) and the aortic (AO) EDP by 18% (p less than 0.005). It increased the endocardial viability ratio by 300% (p less than 0.0005), and the cardiac index by 66.9% (p less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamic effects of a counterpulsation device implanted on the ascending aorta in severe cardiogenic shock.

A valveless, single orifice counterpulsation device (CD) with maximum stroke volume of 100 ml was implanted on the ascending aorta of nine dogs. Its pneumatic driver was gaited by the ECG to provide aortic diastolic augmentation, with a stroke volume of 60-70 ml. In the same animals a 20 ml intraaortic balloon (IAB) was placed into the descending aorta. An attempt was made to evaluate the effectiveness of the CD on severe cardiogenic shock and to compare its hemodynamic effects with those of the IABP. Severe cardiogenic shock was induced by coronary artery ligation, propranolol administration, and fluid infusion and was characterized by a LVEDP of 22.2 +/- 6.4 mmHg, ASP less than 70 mmHg and greater than or equal to 30 mmHg, and a reduction of CI by 71.7%. The CD had a significant beneficial effect in all measured parameters. The LVEDP decreased by a mean of 44.3% (P less than 0.001) below control value, and the AEDP by 60.2% (P less than 0.001). The PADA increased by 108.5% (P less than 0.001), and the CI by 155.8% (P less than 0.004). The IABP did not significantly change any of the hemodynamic variables. In conclusion, the CD has significant salutary hemodynamic effects in severe cardiogenic shock where IABP is ineffective.