Barbara Grasser

Intramyocardial Electrogram Variability in the Monitoring of Graft Rejection After Heart Transplantation

The ventricular evoked response is a well‐standardized electrophysiological signal that can be used for noninvasive, long‐term cardiac transplant monitoring. Rejection‐sensitive and infection‐specific parameters extracted from intramyocardial electrograms correlate with clinical results. The influences of pacing rate, transition from intrinsic to paced rhythm and positional changes on the diagnostic parameters were studied. Increasing the pacing rate shortened the ventricular evoked response and directly influenced the infection specific parameter. The rejection‐sensitive parameter remained stable at pacing rates between 100 and 120 beats/min. Measurements made immediately after the patient assumed a supine position and after switching to paced rhythm showed a decrease in the rejection‐sensitive parameter. A change in position from supine to upright did not influence the rejection‐sensitive parameter, but higher values were measured after returning to the supine position. In conclusion, noninvasive recordings of the ventricular evoked response for monitoring of cardiac allograft should be done at the same time of day, at the same pacing rate, and with the patient resting for at least 5 minutes before measurements are made.

Non-invasive cardiac allograft monitoring: the Graz experience

Based on previous reports by our group, initial studies on non-invasive cardiac graft monitoring have been presented recently. In this study we define new parameters to monitor rejection and infection after heart transplantation (HTX) the ventricular evoked response (VER) T-slew rate parameter is defined as the maximum negative slope in the descending part of the repolarization phase of the VER. We calculated the VER duration parameter in milliseconds and defined it as the time between the pacemaker spike and the cross-over of the baseline, with the slope line used to calculate the VER T-slew rate. During the HTX procedure, we implant wide-band telemetric pacemakers and fractally coated, epimyocardial electrodes (Physios CTM 01 and ELC 54-UP, Biotronik; Berlin, Germany). During each follow-up and on biopsy days, intramyocardial electrogram sequences were obtained and sent via the Internet to the central data-processing unit in Graz. We scored the infection status of the patients before data acquisition. The VER parameters were automatically calculated and send back within a few minutes. We prospectivly compared 1,613 follow-ups from 42 patients with biopsy (International Society of Heart and Lung Transplantation grading) and infection classification. The VER duration parameter did not change during rejection; however, we found an increase during clinically apparent infection. The VER T-slew rate parameter was lower during rejection grade 2 or higher, as well as during clinically apparent infection. The negative predictive value to rule out rejection was 99%. Our results indicate that rejection and infection cause different, reproducible effects on the electrical activity of the transplanted heart. Non-invasive cardiac graft monitoring may reduce the need for surveillance biopsies and may offer a tool to optimize immunosuppressive therapy after HTX.

Definitions of cytomegalovirus disease after heart transplantation: Antigenemia as a marker for antiviral therapy

In this prospective study, cytomegalovirus (CMV) antigenemia was defined as the marker for initiation and episodes of antigenemia as the indicator for the duration of antiviral therapy (CMV hyperimmune globulin and ganciclovir). The CMV antigenemia assay and CMV-specific IgM and IgG antibody tests were used to monitor CMV infection in 22 heart transplant recipients who, between October 1992 and July 1994, were followed up for 6 months. A total of 178 out of 627 antigenemia assays tested positive. The highest number of positive cells was greater after primary infection than after either reactivation (43.3 vs 0.3; P<0.01) or reinfection (43.3 vs 9.3; P=NS). Sixty episodes of antigenemia were observed. More episodes of antigenemia were seen after primary infection than after either reactivation (4.6 vs 0.2; P<0.01) or reinfection (4.6 vs 2.2; P=NS). The detection of antigenemia indicated the initiation of antiviral therapy within 24 h after the blood sample was harvested. Therapy was stopped immediately after a subsequent negative result became available. Our experience indicates that antigenemia directed antiviral therapy prevents CMV disease after primary and secondary infection in heart transplant recipients.

Urapidil reduces elevated pulmonary vascular resistance in patients before heart transplantation

BACKGROUND Elevated pulmonary vascular resistance is a major limitation for heart transplantation. Urapidil is a centrally and peripherally acting anti-hypertensive drug, able to decrease elevated pulmonary vascular resistance in patients with either chronic obstructive pulmonary disease or heart failure. Urapidil is available as an oral or intravenous drug. In this study, we evaluated the possible beneficial effects of intravenous urapidil in patients with reversible, elevated pulmonary vascular resistance who were scheduled for heart transplantation. METHODS After approval by the Ethics Committee and written consent, 22 consecutive patients with end-stage heart failure and history of pulmonary vascular resistance >3 Wood units were enrolled into an open, prospective study. Using a (right ventricular ejection fraction) REF-Swan-Ganz catheter, hemodynamics were determined during administration of nitric oxide, and before and after 3 repeated intravenous applications of 10 mg urapidil. The treatment goal was reduction of pulmonary vascular resistance by at least 30%. RESULTS Twenty-two patients were included to obtain complete data for 14 patients. Eight patients were not treated with urapidil: 7 patients had normal pulmonary vascular resistance at baseline, and 1 patient experienced moderate pulmonary edema before the study began. Two patients did not reach the treatment goal. In patients who responded to urapidil, the following hemodynamic changes were observed: decreased pulmonary vascular resistance (-48%), decreased transpulmonary gradient (20.0 to 13.7 mm Hg), decreased mean pulmonary arterial pressure (40 to 31 mm Hg), decreased systemic vascular resistance (-27%), mean arterial pressure (80 to 72 mm Hg), and increased right heart ejection fraction (21% to 27%). Heart rate remained unchanged. CONCLUSIONS Intravenous urapidil lowered elevated pulmonary vascular resistance in patients before heart transplantation. In comparison with other vasodilative drugs, the major benefit of urapidil is its oral formulation.

Non-invasive graft monitoring after heart transplantation: rationale to reduce the number of endomyocardial biopsies.

Abstract The endomyocardial biopsy is invasive, reduces quality of life and cannot be repeated daily. Initial studies on noninvasive cardiac graft monitoring have been presented recently. During the heart transplant procedure, we implanted wideband telemetric pacemakers and fractally coated, epimyocardial electrodes. On biopsy days and during each follow‐up, intramyocardial electrogram sequences were obtained. The maximum T‐slew rate from the ventricular evoked response (VER) was automatically calculated and compared to the biopsy results (n = 331, ISHLT grading). The VER T‐slew rate was significantly lower during rejection grade 2 or higher. The negative predictive value to exclude rejection was 98%. Using a single threshold diagnosis model, 74% of the biopsies could have been avoided. Noninvasive cardiac graft monitoring can reduce the need for surveillance biopsies and may offer a tool to optimize immunosuppressive therapy after heart transplantation

Donor heart quality control. Analysis of echocardiographic (EC) findings and patient outcome

Abstract  In a retrospective analysis, 149 echocardiographic (EC) evaluations were compared with conventional clinical parameters for donor heart selection. Of these cases, 12 % were found with severe impairment of ventricular wall motion or with morphological abnormalities. Nearly half of the echocar‐diographically diagnosed pathologi cal findings in donor hearts were not detected by conventional standards for heart screening. Analysis of EC‐screened donor heart outcome showed a primary graft nonfunction rate of 3.1 %. We suggest EC as an additional screening instrument for further dynamic and morphological information about donor heart condition. Potential donors can be saved for transplantation and severe complications can be avoided by de tecting occult cardiac dysfunction. Early detection of cardiac dysfunction may have an impact on donor therapy and can avoid unnecessary and expensive transportation of the surgical team to the harvest site.

Evoked epimyocardial electrogram for rejection diagnosis after heart transplantation

An endomyocardial electrogram (ECG) was reported to be a sensitive and practicable method for rejection monitoring after heart transplantation. Long-term follow up was limited, however, by variations of signals. The repolarization part of ECG signals vary with changes of heart rate. Both can be avoided by using pacemaker-induced signals. For stimulation and sensing of the ventricular-evoked response, a new type of electrode with fractal surface structure was used. Twenty patients undergoing heart transplantation were evaluated. Amplitudes of the depolarization and repolarization part of the ventricular-evoked response signals were analyzed and related to the degree of acute rejection according to histological findings from endomyocardial biopsy. Signals were transferred by Internet and analyzed automatically. In the case of focal moderate rejection (grade 2, International Society for Heart Transplantation grading) and higher degrees of rejection, a significant amplitude decrease was found. This sensitive non-invasive method for rejection monitoring with a high level of reliability provides the possibility of reducing the number of endomyocardial biopsies.

Intramyocardial electrograms for non-invasive rejection monitoring: initial experience with an infection-specific parameter.

Abstract Non‐invasive rejection monitoring based on the analysis of paced intramyocardial electrograms enables repeated or even daily graft surveillance. The rejection‐sensitive parameter is calculated from the maximum slope of the descending part of the t wave. Biopsy‐proven rejection grade 2 or higher (ISHLT classification) can safely be detected. Nevertheless, infection influences the rejection‐sensitive parameter in the same manner as does rejection (99% negative predictive value for rejection grade 2 or higher, 17 % positive predictive value). We defined the infection‐specific parameter as the time on the O line between the pacemaker stimulus and the crossover with the maximum slope of the descending part of the t wave. Patients were classified prospectively according to infection status: patients without infection and those with clinically apparent infection. Patients with clinically apparent infections had a significantly longer infection‐specific parameter. A simultaneous decrease of the rejection‐sensitive parameter and an increase in the infection‐specific parameter was observed during clinical infection; a decrease in the rejection‐sensitive parameter and no changes in the infection‐specific parameter were observed during rejection. This preliminary analysis revealed that discrimination of rejection and infection might be possible by the analysis of intramyocardial electrograms.

Prostaglandins in Heart Transplantation

Heart transplant recipients with secondary pulmonary hypertension (PH) are prone to acute right ventricular (RV) graft failure after orthotopic heart transplantation (oHTX). A suitable donor heart of a healthy individual is not adapted to elevated RV afterload caused by PH. In contrast, the majority of potential heart transplant recipients suffer from chronic left ventricular (LV) failure. LV insufficiency requires elevated filling pressures to maintain cardiac output (CO), (LV backwards failure) and causes systemic hypotension (LV forward failure) which induces systemic and pulmonary vasoconstriction. This increases systemic (SVR) and pulmonary vascular resistance (PVR), induces RV hypertrophy and secondary PH. After oHTX, the unadapted transplanted RV is exposed to the recipients PVR, RV afterload mismatch results in acute RV failure when the patient is weaned from cardiopulmonary bypass. RV volume overload, dilatation and structural damage are followed by RV failure and death. The preoperative estimation of PVR and of the reactivity of the pulmonary vascular bed to pulmonary vasodilators permits the selection of patients with reversible PH that are still suitable for oHTX. Many attempts failed to define a clear borderline beyond which oHTX is not feasible. In fact, RV failure after oHTX is caused by both, the elevated RV afterload of the recipient and by insufficient RV performance. Reduction of RV afterload by pulmonary vasodilator therapy reduces the risk of RV failure resulting from RV forward failure. The risk of inadequate myocardial function remains.

Right ventricular pathophysiology and function monitoring during heart transplantation

Summary After orthotopic heart transplantation, right ventricular failure resulting from right ventricular afterload mismatch remains a significant complication. Heart transplant recipients suffer from chronic left ventricular failure which requires elevated filling pressures to maintain cardiac output. Systemic hypotension induces systemic and pulmonary vasoconstriction. This induces right ventricular hypertrophy and secondary pulmonary hypertension. After oHTX, the unadapted transplanted RV is exposed to the recipients PVR, and RV afterload mismatch results in acute RV failure. The preoperative estimation of PVR and of the reactivity of the pulmonary vascular bed to pulmonary vasodilators permits the selection of patients with reversible PH who are still suitable for oHTX. Reduction of RV afterload by pulmonary vasodilator therapy reduces the risk of RV failure. Right ventricular function monitoring after orthotopic heart transplantation is done using invasive hemodynamic monitoring, computer tomography (fast evolution CT), echocardiography, troponin T and CHARM (computerized heart allograft recipient monitoring).Zusammenfassung Nach Herztransplantation ist rechtsventrikuläres Versagen wegen „Afterload Mismatch” eine häufige Komplikation. Patienten auf der Warteliste für eine Herztransplantation leiden an chronischer linksventrikulärer Insuffizienz und halten das Herzzeitvolumen durch Erhöhung des Füllungsdruckes aufrecht. Hypotension erzeugt jedoch periphere und pulmonale Vasokonstriktion, die Folgen sind rechtsventrikuläre Hypertrophie und sekundärer pulmonaler Hypertonus. Nach der Transplantation ist der nicht adaptierte rechte Ventrikel des Spenderherzens dem erhöhten pulmonalen Widerstand des Empfängers ausgesetzt, gefolgt von Rechtsherzinsuffizienz. Die präoperative Abschätzung des pulmonalen Gefäßwiderstandes und die Reaktion auf pulmonale Vasodilatatoren erlaubt eine ungefähre Abschätzung des Risikos und die Auswahl von Patienten mit reversiblem pulmonalen Hypertonus. Die Senkung des rechtsventrikulären Afterloads nach der Transplantation reduziert das Risiko des rechtsventrikulären Versagens. Das Monitoring der rechtventrikulären Funktion besteht aus invasiver Druckmessung, Computertomographie (fast evolution CT), Echocardiographie, Troponin T and CHARM (Computerized heart allograft recipient monitoring).