Sodium-glucose cotransporter 2 inhibitor Dapagliflozin attenuates diabetic cardiomyopathy.

BACKGROUND: Diabetes mellitus type 2 (DM2) is a risk factor for developing heart failure but there is no specific therapy for diabetic heart disease. Sodium glucose transporter 2 inhibitors (SGLT2I) are recently developed diabetic drugs that primarily work on the kidney. Clinical data describing the cardiovascular benefits of SGLT2Is highlight the potential therapeutic benefit of these drugs in the prevention of cardiovascular events and heart failure. However, the underlying mechanism of protection remains unclear. We investigated the effect of Dapagliflozin-SGLT2I, on diabetic cardiomyopathy in a mouse model of DM2. METHODS: Cardiomyopathy was induced in diabetic mice (db/db) by subcutaneous infusion of angiotensin II (ATII) for 30 days using an osmotic pump. Dapagliflozin (1.5 mg/kg/day) was administered concomitantly in drinking water. Male homozygous, 12-14 weeks old WT or db/db mice (n = 4-8/group), were used for the experiments. Isolated cardiomyocytes were exposed to glucose (17.5-33 mM) and treated with Dapagliflozin in vitro. Intracellular calcium transients were measured using a fluorescent indicator indo-1. RESULTS: Angiotensin II infusion induced cardiomyopathy in db/db mice, manifested by cardiac hypertrophy, myocardial fibrosis and inflammation (TNFα, TLR4). Dapagliflozin decreased blood glucose (874 ± 111 to 556 ± 57 mg/dl, p < 0.05). In addition it attenuated fibrosis and inflammation and increased the left ventricular fractional shortening in ATII treated db/db mice. In isolated cardiomyocytes Dapagliflozin decreased intracellular calcium transients, inflammation and ROS production. Finally, voltage-dependent L-type calcium channel (CACNA1C), the sodium-calcium exchanger (NCX) and the sodium-hydrogen exchanger 1 (NHE) membrane transporters expression was reduced following Dapagliflozin treatment. CONCLUSION: Dapagliflozin was cardioprotective in ATII-stressed diabetic mice. It reduced oxygen radicals, as well the activity of membrane channels related to calcium transport. The cardioprotective effect manifested by decreased fibrosis, reduced inflammation and improved systolic function. The clinical implication of our results suggest a novel pharmacologic approach for the treatment of diabetic cardiomyopathy through modulation of ion homeostasis.

Use of Encapsulated Stem Cells to Overcome the Bottleneck of Cell Availability for Cell Therapy Approaches.

Nowadays cell-based therapy is rarely in clinical practice because of the limited availability of appropriate cells. To apply cells therapeutically, they must not cause any immune response wherefore mainly autologous cells have been used up to now. The amount of vital cells in patients is limited, and under certain circumstances in highly degenerated tissues no vital cells are left. Moreover, the extraction of these cells is connected with additional surgery; also the expansion in vitro is difficult. Other approaches avoid these problems by using allo-or even xenogenic cells. These cells are more stable concerning their therapeutic behavior and can be produced in stock. To prevent an immune response caused by these cells, cell encapsulation (e.g. with alginate) can be performed. Certain studies showed that encapsulated allo- and xenogenic cells achieve promising results in treatment of several diseases. For such cell therapy approaches, stem cells, particularly mesenchymal stem cells, are an interesting cell source. This review deals on the one hand with the use of encapsulated cells, especially stem cells, in cell therapy and on the other hand with bioreactor systems for the expansion and differentiation of mesenchymal stem cells in reproducible and sufficient amounts for potential clinical use.

Monitoring lung fluid content in CHF patients under intravenous diuretics treatment using bio-impedance measurements.

A pulmonary edema monitoring system (PulmoTrace, CardioInspect, Tel-Aviv University, Israel) was evaluated for tracking lung resistivity during diuretics treatment in congestive heart failure (CHF) patients. The system incorporates a bio-impedance measurement algorithm and enables, by employing an eight-electrode thoracic belt, the assessment of both the left- and right-lung resistivity values. A clinical study was conducted on a group of 13 CHF patients under intravenous diuretics treatment. The group was measured twice-before the beginning of treatment and following a period of a couple of hours. An increase of 8% of the mean lung resistivity (median value) was found between the two measuring sessions, which indicates a dehydration of the lungs, and a significant correlation (R=0.73, p=0.004) was found between the lung resistivity change and the urine output. In conjunction with previously reported results, which demonstrated the system's reproducibility and long-term monitoring capabilities, this study further supports the diagnostics value of the system.

Parametric EIT for monitoring cardiac stroke volume.

The bio-impedance technique appears appropriate for non-invasive cardiac stroke volume (SV) measurement, as the thoracic conductivity distribution is altered during the cardiac cycle due to the heart contraction and blood perfusion. In the present work, the feasibility of a parametric electrical impedance tomography (EIT) for assessing the cardiac SV was studied. An impedance model of the thorax was constructed from segmented axial MRI images along 19 phases of the cardiac cycle. The heart was simulated as an ellipsoid, with its axes' lengths set as the reconstruction parameters, while all other tissues' geometry and conductivity values were kept fixed. A Newton-Raphson parametric optimization scheme was utilized, yielding a correlation between the reconstructed and anatomical left ventricular volumes of 0.97 (p = 2 x 10(-11)). An analysis of noise sensitivity showed that the proposed algorithm requires an SNR greater than 65 dB. The simulation results were compared to physical data, collected with a portable EIT system (PulmoTrace, CardioInspect). The validation study was employed for a group of N = 28 healthy patients, and a comparison with impedance cardiography measurements (BioZ, Cardiodynamics) was made, showing a correlation of r = 0.86 (p = 4 x10(-9)). The preliminary results demonstrate that parametric EIT has the potential to measure SV, and may be applicable for both clinical and home environment usage.

The distinction between coronary and myocardial reperfusion after thrombolytic therapy by clinical markers of reperfusion.

OBJECTIVES: We sought to examine the hypothesis that rapid resolution of ST-segment elevation in acute myocardial infarction (AMI) patients with early peak creatine kinase (CK) after thrombolytic therapy differentiates among patients with early recanalization between those with and those without adequate tissue (myocardial) reperfusion. BACKGROUND: Early recanalization of the epicardial infarct-related artery (IRA) during AMI does not ensure adequate reperfusion on the myocardial level. While early peak CK after thrombolysis results from early and abrupt restoration of the coronary flow to the infarcted area, rapid ST-segment resolution, which is another clinical marker of successful reperfusion, reflects changes of the myocardial tissue itself. METHODS: We compared the clinical and the angiographic results of 162 AMI patients with early peak CK (< or =12 h) after thrombolytic therapy with (group A) and without (group B) concomitant rapid resolution of ST-segment elevation. RESULTS: Patients in groups A and B had similar patency rates of the IRA on angiography (anterior infarction: 93% vs. 93%; inferior infarction: 89% vs. 77%). Nevertheless, group A versus B patients had lower peak CK (anterior infarction: 1,083+/-585 IU/ml vs. 1,950+/-1,216, p < 0.01; and inferior infarction: 940+/-750 IU/ml vs. 1,350+/-820, p=0.18) and better left ventricular ejection fraction (anterior infarction: 49+/-8, vs. 44+/-8, p < 0.01; inferior infarction: 56+/-12 vs. 51+/-10, p=0.1). In a 2-year follow-up, group A as compared with group B patients had a lower rate of congestive heart failure (1% vs. 13%, p < 0.01) and mortality (2% vs. 13%, p < 0.01). CONCLUSIONS: Among patients in whom reperfusion appears to have taken place using an early peak CK as a marker, the coexistence of rapid resolution of ST-segment elevation further differentiates among patients with an opened culprit artery between the ones with and without adequate myocardial reperfusion.

Acute myocardial infarction with isolated ST-segment elevation in posterior chest leads V7-9: "hidden" ST-segment elevations revealing acute posterior infarction.

OBJECTIVES: This study was done to determine whether electrocardiographic (ECG) isolated ST-segment elevation (ST) in posterior chest leads can establish the diagnosis of acute posterior infarction in patients with ischemic chest pain and to describe the clinical and echocardiographic characteristics of these patients. BACKGROUND: The absence of ST on the standard 12-lead ECG in many patients with acute posterior infarction hampers the early diagnosis of these infarcts and thus may result in inadequate triage and treatment. Although 4% of all acute myocardial infarction (AMI) patients reveal the presence of isolated ST in posterior chest leads, the significance of this finding has not yet been determined. METHODS: We studied 33 consecutive patients with ischemic chest pain suggestive of AMI without ST in the standard ECG who had isolated ST in posterior chest leads V7 through V9. All patients had echocardiographic imaging within 48 h of admission, and 20 patients underwent coronary angiography. RESULTS: Acute myocardial infarction was confirmed enzymatically in all patients and on discharge ECG pathologic Q-waves appeared in leads V7 through V9 in 75% of the patients. On echocardiography, posterior wall-motion abnormality was visible in 97% of the patients, and 69% had evidence of mitral regurgitation (MR), which was moderate or severe in one-third of the patients. Four patients (12%), all with significant MR, had heart failure, and one died from free-wall rupture. The circumflex coronary artery was the infarct related artery in all catheterized patients. CONCLUSIONS: Isolated ST in leads V7 through V9 identify patients with acute posterior wall myocardial infarction. Early identification of those patients is important for adequate triage and treatment of patients with ischemic chest pain without ST on standard 12-lead ECG.

Significance of ST segment elevations in posterior chest leads (V7 to V9) in patients with acute inferior myocardial infarction: application for thrombolytic therapy.

OBJECTIVES: This study was designed to examine whether ST segment elevation in posterior chest leads (V7 to V9) during acute inferior myocardial infarction (MI) identifies patients with a concomitant posterior infarction and whether these patients might benefit more from thrombolysis. BACKGROUND: Because the posterior wall is faced by none of the 12 standard electrocardiographic (ECG) leads, the ECG diagnosis of posterior infarction is problematic and has often remained undiagnosed, especially in the acute phase. METHODS: Eighty-seven patients with a first inferior infarction who were treated with recombinant tissue-type plasminogen activator were stratified according to the presence (Group A [46 patients]) or absence (Group B [41 patients]) of concomitant ST segment elevation in posterior chest leads V7 to V9. RESULTS: Patients in Group A had a higher incidence of posterolateral wall motion abnormalities (p < 0.001) on radionuclide ventriculography, a larger infarct area (as evidenced by higher peak creatine kinase levels) (p < 0.02) and a lower left ventricular ejection fraction (LVEF) at hospital discharge (p < 0.008) than those in Group B. ST segment elevation in leads V7 to V9 was associated with a higher incidence of at least one of the following adverse clinical events: reinfarction, heart failure or death (p = 0.05). Although patency of the infarct-related artery (IRA) in Group A resulted in an improved LVEF at discharge (p < 0.012), LVEF was unchanged in Group B, regardless of the patency status of the IRA. CONCLUSIONS: ST segment elevation in leads V7 to V9 identifies patients with a larger inferior MI because of concomitant posterolateral involvement. Such patients might benefit more from thrombolytic therapy.

Atrial emptying with orthotopic heart transplantation using bicaval and pulmonary venous anastomoses: a magnetic resonance imaging study.

OBJECTIVES: We hypothesized that orthotopic heart transplantation with bicaval and pulmonary venous anastomoses preserves atrial contractility. BACKGROUND: The standard biatrial anastomotic technique of orthotopic heart transplantation causes impaired function and enlargement of the atria. Cine magnetic resonance imaging (MRI) allows assessment of atrial size and function. METHODS: We studied 16 patients who had undergone bicaval (n = 8) or biatrial (n = 8) orthotopic heart transplantation without evidence of rejection and a control group of 6 healthy volunteers. For all three groups, cine MRI was performed by combining coronal and axial gated spin echo and gradient echo cine sequences. Intracardiac volumes were calculated with the Simpson rule. Atrial emptying fraction was defined as the difference between atrial diastolic and systolic volumes, divided by atrial diastolic volume, expressed in percent. All patients had right heart catheterization. RESULTS: Right atrial emptying fraction was significantly higher in the bicaval (mean [+/- SD] 37 +/- 9%) than in the biatrial group (22 +/- 11%, p < 0.05) and similar to that in the control group (48 +/- 4%). Left atrial emptying fraction was significantly higher in the bicaval (30 +/- 5%) than in the biatrial group (15 +/- 4%, p < 0.05) and significantly lower in both transplant groups than in the control group (47 +/- 5%, p < 0.05). The left atrium was larger in the biatrial than in the control group (p < 0.05). Cardiac index, stroke index, heart rate and blood pressure were similar in the transplant groups. CONCLUSIONS: Left and right atrial emptying fractions are significantly depressed with the biatrial technique and markedly improved with the bicaval technique of orthotopic heart transplantation. The beneficial effects of the latter technique on atrial function could improve allograft exercise performance.

The significance of persistent ST elevation versus early resolution of ST segment elevation after primary PTCA.

OBJECTIVES: To determine the prevalence and clinical significance of early ST segment elevation resolution after primary percutaneous transluminal coronary angioplasty (PTCA) for acute myocardial infarction (AMI). BACKGROUND: Despite angiographically successful restoration of coronary flow early during AMI, adequate myocardial reperfusion might not occur in a substantial portion of the jeopardized myocardium due to microvascular damage. This phenomenon comprises the potentially beneficial effect of early recanalization of the infarct related artery (IRA). METHODS: Included in the study were 117 consecutive patients who underwent angiographically successful [Thrombolysis in Myocardial Infarction (TIMI III)] primary PTCA. The patients were classified based on the presence or absence of reduction > or =50% in ST segment elevation in an ECG performed immediately upon return to the intensive cardiac care unit after the PTCA in comparison with ECG before the intervention. RESULTS: Eighty-nine patients (76%) had early ST segment elevation resolution (Group A) and 28 patients (24%) did not (Group B). Group A and B had similar clinical and hemodynamic features before referring to primary PTCA, as well as similar angiographic results. Despite this, ST segment elevation resolution was associated with better predischarge left ventricular ejection fraction (LVEF) (44.7 +/- 8.0 vs. 38.2 +/- 8.5, p < 0.01). Group B patients, as compared with those of Group A, had a higher incidence of in-hospital mortality (11% vs. 2%, p = 0.088), congestive heart failure (CHF) [28% vs. 19%, odds ratio (OR) = 4, 95% confidence interval (CI) 1 to 15, p = 0.04], higher long-term mortality (OR = 7.3, 95% CI 1.9 to 28, p = 0.004 with Cox proportional hazard regression analysis) and long-term CHF rate (OR = 6.5, 95% CI 1.3 to 33, p = 0.016 with logistic regression). CONCLUSIONS: Absence of early ST segment elevation resolution after angiographically successful primary PTCA identifies patients who are less likely to benefit from the early restoration of flow in the IRA, probably because of microvascular damage and subsequently less myocardial salvage.

The clinical significance of antibodies to human vascular endothelial cells after cardiac transplantation.

BACKGROUND: Vascular endothelial cells are primary targets for injury during both cellular and humoral allograft rejection (AR). In cardiac transplantation, the role of humoral immunity in mediating AR has not been extensively characterized. METHODS: Antibodies against human vascular endothelial cells (AECA) were measured using a cellular ELISA developed from human umbilical vein endothelial cells in 80 consecutive patients after cardiac transplantation. The aim was to determine the incidence of AECA formation after transplantation and their association with different types of AR, graft survival, and development of cardiac allograft vasculopathy (CAV). At least eight serum samples obtained from each patient were examined for AECA and an endomyocardial biopsy was performed at regular intervals during the first year after transplantation. RESULTS: Of the 80 patients examined, 31 were AECA (+) and 49 patients were AECA (-). There were no significant differences between the AECA (+) and (-) groups when examined for age, sex, and pretransplantation ischemia time. A significant correlation was found between the presence of AECA and humoral AR (P<0.015). AECA positivity did not correlate with the presence of cellular AR or the number of rejection episodes. In addition, allograft survival at 2 years after transplantation was significantly better in the AECA (-) group compared with that in the AECA (+) group (89.8% vs. 71.0%, P<0.0004). The persistence of AECA positivity during the first year after transplantation was also associated with a significantly greater incidence of CAV when compared with the patients who were AECA (-) (25.8% vs. 14.3%, P<0.004). CONCLUSIONS: AECA may be important in the mediation of humoral AR, may decrease allograft survival, and may identify a high-risk group for CAV.

Combined antiviral and immunoglobulin therapy as prophylaxis against cytomegalovirus infection after heart transplantation.

BACKGROUND: Cytomegalovirus is a frequent cause of infection and morbidity after heart transplantation, especially in patients treated with antilymphocytic drugs where the incidence may be as high as 50%. METHODS: To determine the efficacy of combined antiviral and intravenous immune globulin therapy for prevention of cytomegalovirus disease in transplant recipients receiving OKT3 and to compare two different antiviral drug regimens, we reviewed 115 transplant recipients from December 1988 to December 1993 who survived for more than 30 days. Of these, 29 received oral acyclovir for 3 months (group A) and 86 received intravenous ganciclovir for 2 weeks followed by oral acyclovir up to 3 months (group G); all received six infusions of 5% intravenous immune globulin over 2 months. All patients had OKT3 for 10 to 14 days and triple-drug immunosuppression. RESULTS: Cytomegalovirus disease (pneumonitis, gastroenteritis, or leukopenia with fever) occurred in 10% of patients (12 of 115 patients) and was confirmed by positive culture, typical microscopic inclusions, or polymerase chain reaction. In 91 seropositive recipients, there was a trend to less cytomegalovirus disease in group G (3.0%, 2 of 67 patients) than in group A (12.5%, 3 of 24 patients) (p = 0.11), which was more apparent in recipients with seropositive donors where the incidence was reduced from 16.7% (group A) to 2.4% (group G; p = 0.08). In 24 seronegative recipients, cytomegalovirus disease incidence was higher overall and not significantly less in group G (26%, 5 of 19 patients) than in group A (40%, two of five patients) (p = Not significant). CONCLUSIONS: Prophylaxis with combined antiviral and immune globulin therapy produces a low (10%) incidence of cytomegalovirus disease in OKT3-treated heart transplant recipients. In seropositive recipients treated with combined therapy, ganciclovir may be more effective than acyclovir. Larger trials and more aggressive prophylactic strategies are needed in seronegative patients who receive hearts from seropositive donors.

Hearts from donors with chronic alcohol use: a possible risk factor for death after heart transplantation.

BACKGROUND: Careful donor and recipient selection are important factors for the success of heart transplantation. Currently, donors with a history of alcohol use are routinely accepted despite the potential deleterious effects of alcohol on the heart. METHODS: We examined the frequency of chronic alcohol use (> 2 ounces of pure alcohol daily for > or = 3 months) among organ donors and the outcome of the receipients after heart transplantation. Of 99 consecutive patients who underwent transplantation between December 1988 and August 1993 with an adequate donor history, 17 (17%) had a history of chronic alcohol use (alcohol group), and 82 (83%) did not (nonalcohol group). All recipients received triple-drug immunosuppression, and 10 to 14 days of OKT3. RESULTS: Survival rates at 1 and 2 years were significantly lower in the alcohol group (61% +/- 13% and 61$ +/- 13%) than in the nonalcohol group (95% +/- 3% and 91% +/-4%, p = 0.0001). Most deaths in the alcohol group occurred within 3 months after transplantation. The incidence of rejection episodes did not differ significantly. Fatal rejection occurred more frequently in the alcohol group and was associated with severe ventricular dysfunction before death. Cox multiple regression analysis identified donor alcohol use as an independent risk factor for death after heart transplantation. CONCLUSIONS: A substantial proportion (17%) of heart donors have a history of chronic alcohol use. The unfavorable early outcome of patients receiving hearts from alcoholic donors suggests the presence of a subclinical alcoholic cardiomyopathy before transplantation and poor tolerance of rejection episodes after transplantation. Larger prospective studies are needed to determine the mechanism of fatal rejection and whether such hearts can be used safely for transplantation.

The effect of chronic alcohol use on the heart before and after transplantation in an experimental model in the rat.

BACKGROUND: Alcohol has potential deleterious effects on donor heart function. This study was conducted in rats to determine whether long-term alcohol ingestion produces impaired hemodynamic performance while maintaining a normal left ventricular ejection fraction in donor hearts before transplantation and whether donor cardiac function is affected after heart transplantation. METHODS: Rats fed 30% alcohol in their drinking water for 12 weeks were compared with rats fed a normal diet. Left ventricular ejection fraction was measured by echocardiography with Simpson and single plane Dodge formulas in living sedated rats after 10 and 12 weeks of alcohol feeding. Explanted heart function was assessed before and 3 days after heterotopic heart transplantation (no immunosuppression) with a Langendorff preparation. RESULTS: Blood ethanol levels at 4 and 8 weeks were 0.08 +/- 0.04 and 0.08 +/- 0.09 gm/dl. Left ventricular ejection fraction was similar in the group fed an alcohol diet for 12 weeks when compared with the control group (65.4% +/- 1.6% vs. 66.5% +/- 2.9%, p = 0.33). Explanted alcohol-fed hearts before transplantation had significantly lower maximum and developed pressures and had a blunted response to 0.1 ml 10(-9) mol/L isoproterenol. After transplantation alcohol-fed hearts had significantly lower maximum and developed pressures and decreased maximum rates of pressure rise and pressure decline. Allografts (ACI to Lewis) exhibited decreased function in comparison with isografts (ACI to ACI). CONCLUSIONS: Alcohol feeding for 12 weeks in rats does not affect pretransplantation left ventricular ejection fraction, but it impairs explanted heart function, both before and after transplantation, resulting in a subclinical cardiomyopathy that is worsened by the presence of allograft rejection. Long-term alcohol exposure and rejection have independent, additive detrimental effects on left ventricular performance of the transplanted heart. Alcohol-exposed hearts may not be suitable donors.

Pathogenesis of Quilty lesion in cardiac allografts: relationship to reduced endocardial cyclosporine A.

BACKGROUND: Endocardial lymphocytic infiltrates, known as Quilty effect, are a common finding of uncertain pathogenesis in cardiac allografts. Quilty effect was not observed before the use of cyclosporine A for immunosuppression and is not generally regarded as a manifestation of rejection. We hypothesized that the endocardial localization of Quilty effect may be related to a relative absence of cyclosporine A in this region. METHODS: We used an indirect immunofluorescence staining method with rabbit polyclonal anti-cyclosporine A antibodies to detect cyclosporine A in fresh frozen sections of 27 cardiac allograft endomyocardial biopsies. Staining was graded 0 to +3. Negative controls were from untreated transplant candidates and from biopsies with the primary antibody omitted. RESULTS: On comparison of endocardial and myocardial fluorescence in biopsy specimens from patients treated with cyclosporine A, there was less endocardial (0.7 +/- 1.1, p < 0.0001) than myocardial (2.2 +/- 0.5) staining. However, in biopsy specimens with Quilty effect (n = 12), this difference was significantly greater (endocardial = 0.2 +/- 0.6 versus myocardial = 2.3 +/- 0.5; p = 0.005) than in specimens without Quilty effect (n = 10) (endocardial = 1.4 +/- 1.2 versus myocardial = 2.1 +/- 0.6; p = 0.7). Endocardial thickness as measured by ocular micrometry was significantly greater in regions with (32 +/- 19 microns) than without (7 +/- 4 microns) Quilty effect, with involved regions showing increased connective tissue (p < 0.0001). In patients with and without Quilty effect, no differences in donor or recipient demographics, prevalence of diabetes, or plasma cyclosporine A levels were found. CONCLUSIONS: Although it has been postulated that Quilty effect is due to the presence of cyclosporine A in cardiac tissue (toxic effect or immunologic reaction), these data suggest that Quilty effect is related to reduced endocardial presence of cyclosporine A, leading to localized, contained, and usually not clinically significant endocardial rejection.

Donors with a history of cocaine use: effect on survival and rejection frequency after heart transplantation.

The frequency of cocaine use among donors is currently unknown. Cocaine has cardiotoxic effects and could affect the outcome of heart transplantation. To examine the frequency of nonintravenous cocaine use in organ donors and the outcome of heart transplantation with such donors, we retrospectively analyzed the clinical, biopsy, and donor information on 112 consecutive patients who underwent transplantation between December 1988 and August 1993. Ten patients were excluded because of incomplete information regarding the donor's cocaine status. Of the remaining 102 patients, 16 (16%) had a positive donor history for nonintravenous cocaine use (cocaine group) and 86 patients (84%) had a negative history (noncocaine group). Survival, frequency of cellular rejection (grade > or = 1B), and humoral rejection were compared between the two groups. Survival rates at 30 days (100% versus 97% +/- 2%) and at 1 year (93 +/- 7% versus 89 +/- 3%) were similar (p = not significant, cocaine versus noncocaine group). Freedom from rejection was similar at 30 days (81% +/- 10% versus 79% +/- 4% cellular rejection-free, 33% +/- 14% versus 60% +/- 6% humoral-free) and 6 months (34% +/- 12% versus 55% +/- 5% cellular-free, 16% +/- 11% versus 36% +/- 6% humoral-free) (p = not significant). No significant difference was found in donor inotropic support before procurement, ischemic time, length of stay in intensive care unit, or total stay in the hospital. In conclusion, a high incidence of nonintravenous cocaine use exists among donors. The outcome of patients who receive transplanted hearts obtained from nonintravenous cocaine users is favorable, suggesting that the use of such hearts is safe.

Heart transplantation for Q fever endocarditis.

A 30-year-old man underwent aortic and mitral valve replacement for the treatment of Q fever endocarditis. Postoperatively, paravalvular leak of the mitral prosthesis, progressive deterioration in cardiac function, and intractable heart failure developed. As a result, the patient underwent orthotopic heart transplantation 15 months after his initial valve operation. The patient is clinically well 14 months after transplantation.

Orthotopic heart transplantation with bicaval and pulmonary venous anastomoses.

We present our experience with an alternative technique for orthotopic heart transplantation. It consists of total excision of the recipient's atria, with the donor's heart implantation performed using bicaval end-to-end anastomoses as well as pulmonary venous anastomoses. Forty consecutive patients receiving transplants in this fashion were compared with 64 patients who underwent orthotopic transplantation with the standard technique. The incidence of postoperative tricuspid regurgitation was reduced in patients receiving transplants with the new surgical approach (p = 0.003). In addition, the need for pacemaker implantation for severe bradyarrhythmia in the early (0 to 6 weeks) posttransplantation period (p = 0.003) was eliminated. Although not statistically significant, there was a trend in the reduction of postoperative mitral regurgitation in patients who received transplants by the modified technique. Based on this experience, we believe this modified technique for orthotopic heart transplantation has an anatomic and physiologic advantage that may improve long-term hemodynamic results.

In vivo liposome-mediated transfection of HLA-DR alpha-chain gene into pig hearts.

UNLABELLED: Scarcity of suitable donor organs remains a major problem for organ transplantation. Transfer of recipient HLA-genes into animal donor-organs during harvest could induce graft-tolerance without suppressing the recipient immune system. OBJECTIVE: This pilot study aimed to test the feasibility of an in vivo gene transfer into pig hearts by intracoronary infusion of DNA:liposome-complexes and to detect the gene product by immunohistochemistry. METHODS: The pcDV1-pL2-vector, containing the basesequence for HLA-DR alpha-chain in plasmids (1.3 kb) was selected. The plasmids were isolated with ethidiumbromide and incubated with lipofectin in a 1:3-ratio for 10 min. The DNA:lipofectin-complex was diluted to 10 cc with physiologic saline and delivered into the left anterior descending artery of 6 farm pigs over 10 min. As a control within the same animal, the same amount of lipofectin alone was infused into the first diagonal branch. Three pigs were sacrificed after 24 h, the other 3 after 48 h. Delivery of DNA:liposome-complexes was detected by oil red 0 staining, expression of HLA-DR alpha-chain-antigen with a monoclonal anti-HLA-DR alpha-antibody. RESULTS: Transfection of the HLA-class-II DR-alpha-chain occurred in endothelial cells. Infiltrating cells around capillaries stained positively for HLA-DR-alpha. These infiltrating cells were negative for the pan B- and the pan T-cell-marker L26 and UCHL-1. There was no transfection and hypercellularity in the myocardium around the first diagonal branch. CONCLUSIONS: In vivo intracoronary infusion of the HLA-DR alpha-chain-DNA:lipofectin-complex leads to expression of the corresponding antigen on pig endothelium for 48 h. The infiltrating cells require further characterization.

Resting hemodynamics after total versus standard orthotopic heart transplantation in patients with high preoperative pulmonary vascular resistance.

OBJECTIVE: Pretransplant pulmonary vascular resistance > or = 4 Wood-units predisposes to right ventricular failure after heart transplantation. Total orthotopic heart transplantation with bicaval and pulmonary venous anastomoses offers synchronous contractions of the atria and a normal ventricular filling pattern, but requires longer ischemic time than standard orthotopic heart transplantation. To test if total orthotopic heart transplantation improves resting hemodynamics in pts with high preoperative pulmonary vascular resistance, we analyzed 65 pts with standard and 65 with total orthotopic heart transplantation transplanted between 12/88 and 7/94. Of these, 18 with total and 15 with standard orthotopic heart transplantation had a preoperative pulmonary vascular resistance > or = 4 Wood-units. METHODS: Right heart catheterization data were obtained at each endomyocardial biopsy. All data from biopsies at both 2 weeks and 1 year posttransplant that were free from humoral or greater than 1A cellular rejection (9 versus 13 pts) were included in a two way ANOVA. Pts with postop pacemakers, atrial fib or beta-blocker therapy at the time of biopsy were excluded. RESULTS: Ischemic time was different (172 +/- 44 versus 142 +/- 28 min, P = 0.03). Demographics, NYHA class, pre-TX hemodynamics, donor age and inotropes were similar. Cardiac output and index were higher in the total orthotopic group at 2 weeks (6.5 +/- 1.7 versus 5.1 +/- 1.0 l/min; 3.4 +/- 0.9 versus 2.8 +/- 0.6 l/min per m2) and 1 year (7.1 +/- 2.0 versus 4.9 +/- 1.1 l/min, P = 0.002; 3.6 +/- 1.1 versus 2.6 +/- 0.5 l/min per m2, P = 0.009). Right atrial and pulmonary arterial mean pressure (mmHg) were lower with total orthotopic heart transplantation at 2 weeks (6 +/- 4 versus 9 +/- 5, P = 0.04; 22 +/- 3 versus 25 +/- 7, P = 0.1) and 1 year (5 +/- 2 versus 7 +/- 3, P = 0.02; 19 +/- 4 versus 25 +/- 7, P = 0.03). Pulmonary capillary wedge pressure (mmHg) was borderline nonsignificant (11 +/- 4 versus 13 +/- 7 at 2 weeks, 8 +/- 3 versus 14 +/- 5 at 1 year, P = 0.055), as well as pulmonary vascular resistance (1.9 +/- 1 versus 2.5 +/- 1 at 2 weeks, 1.5 +/- 0.6 versus 2.7 +/- 1.7 WU at 1 year, P = 0.051). CONCLUSIONS: Total orthotopic heart transplantation improves cardiac output and index in pts with high preoperative pulmonary vacular resistance. There is a lower mean RA and PA pressure perhaps due to less tricuspid and mitral regurgitation. In view of the frequently observed restrictive filling pattern after cardiac transplantation, total orthotopic heart transplantation can be beneficial until this pattern has subsided by preserving atrioventricular synchrony and offering better atrial transport.

Does total orthotopic heart transplantation offer improved hemodynamics during cellular rejection events?

BACKGROUND: We hypothesized that total orthotopic heart transplantation (TOHT) improves hemodynamics during cellular rejection compared with biatrial transplantation (SOHT). METHODS: We reviewed 1942 biopsies from 134 patients (pts) and right heart catheterization data obtained at endomyocardial biopsy. Biopsies that displayed cellular rejection grade 1B as classified according to International Society for Heart and Lung Transplantation (ISHLT) criteria were analyzed. Pts with pacemakers, atrial fibrillation, or beta-blocker therapy at the time of biopsy were excluded. Twenty-three pts after TOHT and 38 after SOHT were identified to match these criteria. RESULTS: Demographic data and pretransplant hemodynamics were similar. TOHT pts had a higher mean cardiac index than SOHT recipients (3.3 +/- 0.8 vs 2.7 +/- 0.5 L/min/m(2); P =.002). Right atrial mean pressure was lower after TOHT (8 +/- 4 vs 11 +/- 4 mm Hg; P =.006). Pulmonary pressures, pulmonary vascular resistance, and heart rate were similar. CONCLUSIONS: TOHT offers improved hemodynamics during cellular rejection grade 1B as evidenced by higher cardiac output and index with lower right atrial pressures. Future studies must examine the potential benefits of TOHT during more severe rejection events.