Cancer Incidence in Heart Transplant Recipients With Previous Neoplasia History.

Neoplasm history increases morbidity and mortality after solid organ transplantation and has disqualified patients from transplantation. Studies are needed to identify factors to be considered when deciding on the suitability of a patient with previous tumor for heart transplantation. A retrospective epidemiological study was conducted in heart transplant (HT) recipients (Spanish Post-Heart Transplant Tumor Registry) comparing the epidemiological data, immu-nosuppressive treatments and incidence of post-HT tumors between patients with previous malignant noncardiac tumor and with no previous tumor (NPT). The impact of previous tumor (PT) on overall survival (OS) was also assessed. A total of 4561 patients, 77 PT and 4484 NPT, were evaluated. The NPT group had a higher proportion of men than the PT group (p < 0.001). The incidence of post-HT tumors was 1.8 times greater in the PT group (95% confidence interval [CI] 1.2-2.6; p < 0.001), mainly due to the increased risk in patients with a previous hematologic tumor (rate ratio 2.3, 95% CI 1.3-4.0, p < 0.004). OS during the 10-year posttransplant period was significantly lower in the PT than the NPT group (p = 0.048) but similar when the analysis was conducted after a first post-HT tumor was diagnosed. In conclusion, a history of PT increases the incidence of post-HT tumors and should be taken into account when considering a patient for HT.

Health-related quality of life, social support, and caregiver burden between six and 120 months after heart transplantation: a Spanish multicenter cross-sectional study.

A multicenter cross-sectional study was conducted to determine the current heart transplant (HTx) outcomes in Spain. Clinical and functional status, health-related quality of life (HRQoL), social support, and caregiver burden were analyzed in 303 adult transplant recipients (77.9% males) living with one functioning graft. Mean age at time of HTx (SD) was 56.4 (11.4) years, and the reason for transplantation in all patients was congestive heart failure. All patients had received a first heart transplant 6 (± 1), 12 (± 2), 36 (± 6), 60 (± 10), or 120 (± 20) months previously. Participants completed the Kansas City Cardiomyopathy Questionnaire (KCCQ), the EQ-5D, the Duke-UNC Functional Social Support Questionnaire, and the Zarit Caregiver Burden Scale. Reasonable HRQoL, social support, and caregiver burden levels were found at all time points, although a slight decrease in HRQoL was recorded at 120 months (p ≤ 0.033). Multivariate regression analyses showed that complications, comorbidities, and hospitalizations were associated with HRQoL (EQ-5D: 48.4% of explained variance, F4,164 = 38.46, p < 0.001; KCCQ overall summary score: 45.0%, F3,198 = 54.073, p < 0.001). Patient functional capabilities and complications affected caregiver burden (p < 0.05). In conclusion, HTx patients reported reasonable levels of HRQoL with low caregiver burden. Clinical variables related to these outcomes included functional status, complications, and number of admissions.

The falling incidence of hematologic cancer after heart transplantation.

BACKGROUND: A number of changes in the management of heart transplantation (HT) patients have each tended to reduce the risk of post-HT hematologic cancer, but little information is available concerning the overall effect on incidence in the HT population. METHODS: Comparison of data from the Spanish Post-Heart-Transplantation Tumour Registry for the periods 1991-2000 and 2001-2010. RESULTS: The incidence among patients who underwent HT in the latter period was about half that observed in the former, with a particularly marked improvement in regard to incidence more than five yr post-HT. CONCLUSIONS: Changes in HT patient management have jointly reduced the risk of hematologic cancer in the Spanish HT population. Long-term risk appears to have benefited more than short-term risk.

Achievement of long-term lipid targets in a cohort of patients with acute coronary syndrome in real-world clinical practice.

INTRODUCTION AND OBJECTIVES: According to the recent European epidemiological studies, the degree of lipid control in patients with very high vascular risk is suboptimal. This study analyzes the epidemiological characteristics, cardiovascular risk factors, lipid profile, recurrence, and degree of achievement of long-term lipid targets, according to the ESC/EAS Guidelines, in a cohort of patients with acute coronary syndrome (ACS) in a real-world clinical practice setting. METHODS: This work is a retrospective cohort study of patients diagnosed with ACS admitted to the Coronary Unit of a tertiary hospital from January 1, 2012 to December 31, 2015 and followed-up on until March 2022. RESULTS: A total of 826 patients were studied. During the follow-up period, greater prescribing of combined lipid-lowering therapy was observed, mainly high- and moderate-intensity statins and ezetimibe. At 24 months after the ACS, 33.6% of living patients had LDL levels <70 mg/dl and 9.3% had LDL levels <55 mg/dl. At the end of the follow-up (101 [88-111] months), the corresponding figures were 54.5% and 21.1%. Some 22.1% of patients had a recurrent coronary event and only 24.6% achieved an LDL level <55 mg/dl. CONCLUSIONS: Achievement of the LDL targets recommended by the ESC/EAS guidelines is suboptimal in patients with ACS, both at two years and in the long-term (7-10 years), especially in patients with recurrent ACS.

Lung cancer after heart transplantation: results from a large multicenter registry.

In this study we analyzed Spanish Post-Heart-Transplant Tumour Registry data for adult heart transplantation (HT) patients since 1984. Median post-HT follow-up of 4357 patients was 6.7 years. Lung cancer (mainly squamous cell or adenocarcinoma) was diagnosed in 102 (14.0% of patients developing cancers) a mean 6.4 years post-HT. Incidence increased with age at HT from 149 per 100 000 person-years among under-45s to 542 among over-64s; was 4.6 times greater among men than women; and was four times greater among pre-HT smokers (2169 patients) than nonsmokers (2188). The incidence rates in age-at-diagnosis groups with more than one case were significantly greater than GLOBOCAN 2002 estimates for the general Spanish population, and comparison with published data on smoking and lung cancer in the general population suggests that this increase was not due to a greater prevalence of smokers or former smokers among HT patients. Curative surgery, performed in 21 of the 28 operable cases, increased Kaplan-Meier 2-year survival to 70% versus 16% among inoperable patients.

Outcomes of heart transplantation for cardiac amyloidosis: subanalysis of the spanish registry for heart transplantation.

Amyloidosis (Am), a systemic disease, has poor prognosis because of organ damage produced by protein deposition in the extracellular space. Although heart transplantation (HTx) is possible, donor availability concerns and high mortality make this approach controversial. The Spanish Registry for Heart Transplantation includes 25 Am patients (54 +/- 9 years): 13 with AL type, 2 with AA and 10 with TTR mutation. Fifteen patients (60%) died during follow-up (4.9 +/- 1.3 years): 9 AL-Am patients, both AA-Am patients and 4 with TTR-Am. HTx survival for Am patients was similar to patients without Am at 1 month but significantly worse at 5 years: 46% versus 78% (p < 0.02). Of 10 AL-Am patients undergoing successful HTx, 4 died of systemic Am. Stem cell transplantation was performed in 3 (1 died of acute rejection). Five of 10 patients with TTR-Am underwent liver transplant; 4 remained alive at the last follow-up. Findings include poor outcome for AL-Am patients despite HTx and better survival for TTR-Am patients if HTx is associated with liver transplantation. Given the shortage of donors and poor outcome for Am patients, we would recommend that HTx be reserved for patients without or with mild systemic Am and be supplemented by additional therapies as indicated.

Gastrointestinal complications in heart transplant patients: MITOS study.

INTRODUCTION: The most frequent immunosuppressive treatment complications in solid organ transplant recipients are gastrointestinal (GI) disorders. MATERIALS AND METHODS: An observational, cross-sectional study to evaluate the prevalence and management of GI complications in transplanted patients was conducted via a written questionnaire given to doctors at their practice. RESULTS: This study included 1788 patients; 181 corresponded to heart transplant recipients. The mean age for the heart transplant patients was 58.7 +/- 11.8 years. The mean time from the transplantation was 5.2 +/- 4.4 years. GI complications were seen in 38.7% of cases. Regarding the clinical management, in 72.9% of cases patients with GI complications received pharmacologic treatment, 86.3% with gastric protectors, 32.8% reduced the dose of some drug, 8.1% interrupted the drug temporarily, and 10.9% discontinued the drug permanently. The drug that was always discontinued was mycophenolate mofetil (MMF), and in 85.7% of cases in which the dose of an immunosuppressive drug was reduced, the reduced drug was also MMF. CONCLUSIONS: Almost 40% of heart transplant recipients suffered GI complications which affected daily activities in most cases. The most used strategy to manage these complications was based on a treatment with gastric protectors together with dose reduction and/or partial or definitive MMF discontinuation.

Sensibilización durante la asistencia circulatoria de corta duración. Determinantes, tratamiento y pronóstico después del trasplante cardiaco / Sensitization during short-term mechanical circulatory support. Determinants, therapeutic management, and outcomes after heart transplant

Introducción y objetivos: El desarrollo de anticuerpos contra antígenos leucocitarios humanos es una complicación conocida de la asistencia ventricular de larga duración. El propósito del presente estudio es evaluar su incidencia durante el empleo de dispositivos de asistencia ventricular de corta duración (DAVC) (CentriMag), sus determinantes y su repercusión en los resultados del trasplante cardiaco. Métodos: Estudio retrospectivo con pacientes tratados con DAVC como puente al trasplante entre 2009 y 2019. Se consideró sensibilización un panel reactivo de anticuerpos calculado> 10%. Las variables de respuesta fueron supervivencia y supervivencia libre de rechazo agudo (RA). Resultados: Se trató con DAVC a 89 pacientes, con una mediana de edad de 56,0 [intervalo intercuartílico, 50,0-59,9] años y el 16,8% de mujeres, durante una mediana de 23,6 [16,6-35,0] días. El 12,4% se sensibilizó durante la asistencia. El único determinante independiente de la sensibilización fue el sexo femenino (OR=8,67; IC95%, 1,93-38,8; p=0,005). De los 89 pacientes, 21 fallecieron durante la asistencia y 68 se sometieron a trasplante. De los pacientes trasplantados, 8 (11,8%) fallecieron y 20 (29,4%) tuvieron algún episodio de RA tras un seguimiento promedio de 49,6 ±31,2 meses tras el trasplante. Tras ajuste multivariable, la sensibilización aumentó el riesgo de RA (HR=3,64; IC95%, 1,42-9,33; p=0,007), con una tendencia no significativa a mayor mortalidad (HR=4,07; IC95%, 0,96-17,3; p=0,057). Conclusiones: La sensibilización relacionada con los DAVC es posible, predomina en el sexo femenino y se asocia de manera significativa con el RA, con una tendencia no significativa a mayor mortalidad (AU)

Introduction and objectives: The development of human-leukocyte antigen antibodies is a well-known adverse effect of the use of long-term ventricular assist devices (VADs). The aim of this study was to determine the incidence of sensitization during short-term mechanical circulatory support with VAD (CentriMag), its determinants, and its impact on posttransplant outcomes. Methods: We performed a retrospective review of patients who were bridged to transplant with short-term VAD from 2009 to 2019. Sensitization was defined as a calculated panel-reactive antibody> 10%. The endpoints included overall survival and rejection-free survival. Results: A total of 89 patients (median age 56.0 [interquartile range, 50.0-59.9] years, 16.8% female) received a short-term VAD as a bridge to transplant. The median duration of support was 23.6 [interquartile range, 16.6-35.0] days. Eleven patients (12.4%) became sensitized during support. The only factor significantly associated with sensitization was female sex (OR, 8.67; 95%CI, 1.93–38.8; P=.005). Of the 89 patients, 21 patients died during support; 68 patients underwent heart transplant. After a mean follow-up of 49.6 ±31.2 months, 8 patients (11.8%) died and 20 (29.4%) had at least 1 rejection episode. On multivariate analysis, sensitization was an independent predictor of acute rejection (HR, 3.64; 95%CI, 1.42-9.33; P=.007), with a nonstatistically significant trend to higher mortality (HR, 4.07; 95%CI, 0.96-17.3; P=.057). Conclusions: Sensitization with short-term VADs can occur and is significantly associated with female sex and with rejection. Sensitization also showed a nonstatistically significant trend to higher mortality (AU)

Impacto de la variabilidad intrapaciente en la concentración sanguínea de anticalcineurínicos en los resultados del trasplante cardiaco / Impact of intrapatient blood level variability of calcineurin inhibitors on heart transplant outcomes

Introducción y objetivos: El objetivo es estudiar el impacto clínico de la variabilidad intrapaciente (VIP) de la concentración sanguínea de los anticalcineurínicos en el trasplante cardiaco, pues la información actual es escasa. Métodos: Se analizó retrospectivamente a pacientes de edad≥18 años con un trasplante cardiaco realizado entre 2000 y 2014 y con supervivencia≥1 año. La VIP se valoró mediante el coeficiente de variación de concentraciones entre los meses 4 a 12 postrasplante. El compuesto de rechazo, mortalidad o pérdida del injerto y la mortalidad o pérdida del injerto 1-5 años tras el trasplante se analizaron mediante regresión de Cox. Resultados: Se estudió a 1.581 receptores (edad, 56 años; mujeres, 21%), tratados con ciclosporina (790 pacientes) o tacrolimus (791 pacientes). En el análisis multivariable, un coeficiente de variación> 27,8% tendió a asociarse con el compuesto de rechazo/mortalidad (HR=1,298; IC95%, 0,993-1,695; p=0,056) y con la mortalidad (HR=1,387; IC95%, 0,979-1,963; p=0,065) a los 5 años. La asociación con el rechazo fue significativa al analizar a la población sin rechazos durante el primer año del trasplante (HR=1,609; IC95%, 1,129-2,295; p=0,011). El tacrolimus tuvo menos VIP que la ciclosporina, junto con unos mejores resultados por la menor influencia de la VIP. Conclusiones: La VIP de los anticalcineurínicos, especialmente con la inmunosupresión basada en el tacrolimus, se asocia solo marginalmente con los resultados a medio plazo del trasplante cardiaco, aunque puede tener influencia en los pacientes más estables durante el primer año tras el trasplante (AU)

Introduction and objectives: Intrapatient blood level variability (IPV) of calcineurin inhibitors has been associated with poor outcomes in solid-organ transplant, but data for heart transplant are scarce. Our purpose was to ascertain the clinical impact of IPV in a multi-institutional cohort of heart transplant recipients. Methods: We retrospectively studied patients aged ≥18 years, with a first heart transplant performed between 2000 and 2014 and surviving≥ 1 year. IPV was assessed by the coefficient of variation of trough levels from posttransplant months 4 to 12. A composite of rejection or mortality/graft loss or rejection and all-cause mortality/graft loss between years 1 to 5 posttransplant were analyzed by Cox regression analysis. Results: The study group consisted of 1581 recipients (median age, 56 years; women, 21%). Cyclosporine immediate-release tacrolimus and prolonged-release tacrolimus were used in 790, 527 and 264 patients, respectively. On multivariable analysis, coefficient of variation> 27.8% showed a nonsignificant trend to association with 5-year rejection-free survival (HR, 1.298; 95%CI, 0.993-1.695; P=.056) and with 5-year mortality (HR, 1.387; 95%CI, 0.979-1.963; P=.065). Association with rejection became significant on analysis of only those patients without rejection episodes during the first year posttransplant (HR, 1.609; 95%CI, 1.129-2.295; P=.011). The tacrolimus-based formulation had less IPV than cyclosporine and better results with less influence of IPV. Conclusions: IPV of calcineurin inhibitors is only marginally associated with mid-term outcomes after heart transplant, particularly with the tacrolimus-based immunosuppression, although it could play a role in the most stable recipients (AU)

Complicaciones infecciosas relacionadas con la asistencia circulatoria mecánica de corta duración en candidatos a trasplante cardiaco urgente / Infectious complications associated with short-term mechanical circulatory support in urgent heart transplant candidates

Introducción y objetivos: El uso de dispositivos de asistencia circulatoria mecánica de corta duración como puente a trasplante es frecuente en España. Se desconocen la epidemiología y la repercusión de las complicaciones infecciosas en estos pacientes. Métodos: Descripción sistemática de la epidemiología y análisis de la repercusión pronóstica de las complicaciones infecciosas en un registro multicéntrico retrospectivo de pacientes tratados con dispositivos de asistencia circulatoria mecánica de corta duración como puente a trasplante cardiaco urgente entre 2010 y 2015 en 16 hospitales españoles. Resultados: Se estudió a 249 pacientes; 87 (34,9%) de ellos tuvieron un total de 102 infecciones. La vía respiratoria fue la localización más frecuente (n=47; 46,1%). En 78 casos (76,5%) se obtuvo confirmación microbiológica; se aislaron en total 100 gérmenes causales, con predominio de bacterias gramnegativas (n=58, 58%). Los pacientes con complicaciones infecciosas presentaron mayor mortalidad durante el periodo de asistencia circulatoria mecánica (el 25,3 frente al 12,3%; p=0,009) y menor probabilidad de recibir un trasplante (el 73,6 frente al 85,2%; p=0,025) que los pacientes sin infección. La mortalidad posoperatoria tras el trasplante fue similar en ambos grupos (con infección, el 28,3%; sin infección, el 23,4%; p=0,471). Conclusiones: Los pacientes tratados con dispositivos de asistencia circulatoria mecánica de corta duración como puente al trasplante cardiaco están expuestos a un alto riesgo de complicaciones infecciosas, las cuales se asocian con una mayor mortalidad en espera del órgano (AU)

Introduction and objectives: Short-term mechanical circulatory support is frequently used as a bridge to heart transplant in Spain. The epidemiology and prognostic impact of infectious complications in these patients are unknown. Methods: Systematic description of the epidemiology of infectious complications and analysis of their prognostic impact in a multicenter, retrospective registry of patients treated with short-term mechanical devices as a bridge to urgent heart transplant from 2010 to 2015 in 16 Spanish hospitals. Results: We studied 249 patients, of which 87 (34.9%) had a total of 102 infections. The most frequent site was the respiratory tract (n=47; 46.1%). Microbiological confirmation was obtained in 78 (76.5%) episodes, with a total of 100 causative agents, showing a predominance of gram-negative bacteria (n=58, 58%). Compared with patients without infection, those with infectious complications showed higher mortality during the support period (25.3% vs 12.3%, P=.009) and a lower probability of receiving a transplant (73.6% vs 85.2%, P=.025). In-hospital posttransplant mortality was similar in the 2 groups (with infection: 28.3%; without infection: 23.4%; P=.471). Conclusions: Patients supported with temporary devices as a bridge to heart transplant are exposed to a high risk of infectious complications, which are associated with higher mortality during the organ waiting period (AU)

Registro español de trasplante cardiaco. XXXIII informe oficial de la Asociación de Insuficiencia Cardiaca de la Sociedad Española de Cardiología / Spanish Heart Transplant Registry. 33rd official report of the Heart Failure Association of the Spanish Society of Cardiology

Introducción y objetivos Se actualizan los datos anuales de Registro español de trasplante cardiaco con los hallazgos de los procedimientos realizados en 2021. Métodos Se describen las principales características clínicas, del tratamiento recibido y de los resultados en términos de supervivencia del año 2021 y las tendencias en el periodo 2012-2020. Resultados En 2021 se han realizado 302 trasplantes cardiacos (un 8,6% más que el año anterior). En 2021 se ha confirmado la tendencia observada en años anteriores a una disminución de los trasplantes urgentes y a la realización de estos mayoritamente con dispositivos de asistencia ventricular. Las demás características y los resultados en términos de supervivencia muestran una clara tendencia a la estabilización en la última década. Respecto a 2019, en los años de la pandemia por SARS-CoV-2 (2020 y 2021) no se detecta un impacto relevante en los resultados en la fase aguda tras el trasplante y en la serie histórica. Conclusiones En 2021 se ha recuperado la actividad de trasplante hasta cifras previas a la pandemia por SARS-CoV-2, que no ha tenido un impacto global significativo en los resultados. Las características del procedimiento y los resultados muestran una clara tendencia a la estabilización en la última década (AU)

Introduction and objectives This report updates the annual data of the Spanish heart transplant registry with the procedures performed in 2021. Methods We describe the clinical profile, therapeutic characteristics and outcomes in terms of survival of the procedures performed in 2021. Their temporal trends are updated for the 2012 to 2020 period. Results In 2021, 302 heart transplants were performed (8.6% increase versus 2020). The tendency in 2021 confirmed that of prior years, with fewer urgent transplants and a preference for the use of ventricular assist devices. The remaining characteristics and survival showed a clear trend toward stability in the last decade. Compared with 2019, the SARS-CoV-2 pandemic (2020 and 2021) did not affect short- or long-term survival. Conclusions In 2021, transplant activity returned to prepandemic levels. The SARS-CoV-2 pandemic did not significantly affect transplant outcomes. The main transplant features and outcomes have clearly stabilized in the last decade (AU)

Combined use of pulsed and color M-mode Doppler echocardiography for the estimation of pulmonary capillary wedge pressure: an empirical approach based on an analytical relation.

OBJECTIVES: We sought a noninvasive estimation of pulmonary capillary wedge pressure (Pw) by means of the information obtained from transmitral pulsed Doppler and color M-mode Doppler flow propagation velocity (FPV). BACKGROUND: Pulsed Doppler parameters have limited accuracy for the estimation of Pw because they are determined by left atrial pressure and other parameters such as ventricular relaxation. Recently, a good correlation has been found between the rate of ventricular relaxation (tau, tau) and FPV measured by color M-mode Doppler echocardiography. METHODS: We studied 20 patients who underwent invasive hemodynamic monitoring. By multilinear regression analysis, the relationships between Pw and Doppler parameters, FPV, and a noninvasive estimate (P(est)) based on the Weiss' equation (substituting tau for 1/FPV) were determined. A simplified index based on the results obtained was then tested in an additional group of 34 patients. RESULTS: By multiple regression analysis only isovolumic relaxation time (IVRT) (p = 0.0096) and P(est) (p = 0.0043) were related to Pw. A derived empirical index, 10(3)/([2 x IVRT] + FPV), was strongly correlated with Pw in the entire group according to the regression equation Pw = 4.5 x (10(3)/[[2 x IVRT] + FPV]) - 9 (r = 0.89, p < 0.0001, [standard error of the estimate] SEE = 3.3 mm Hg). The sensitivity and specificity for the prediction of Pw > 15 mm Hg were 90% and 100%, respectively. CONCLUSIONS: The combined use of FPV as a surrogate for tau and IVRT permits a close prediction of Pw.

Sirolimus as an alternative to anticalcineurin therapy in heart transplantation: experience of a single center.

We report a series of 26 heart transplant recipients with renal impairment in which sirolimus was used as the basic immunosuppresive drug (without associated calcineurin inhibitors) to avoid further nephrotoxicity. Sirolimus (trough levels 10 to 12 ng/mL, average daily dose 3 mg) was used in two settings: de novo in 7 patients with significant preexistent renal impairment and as a chronic conversion in 19 stable patients with established renal failure (creatinine level >2 mg/dL). In all de novo patients (n = 7), the renal function significantly improved. Creatinine fell from 2.95 +/- 0.9 mg/dL to 1.41 +/- 0.4 mg/dL at follow-up (P = .0017). One patient died suddenly of a massive pulmonary embolism. Only one patient experienced histologic but reversible rejection. In one patient, anemia and diarrhea prompted sirolimus withdrawal. Five patients had infectious episodes: three bacterial pneumonias, one mediastinitis, and two CMV infections. In the chronic conversion group (n = 19), the improvement was mostly limited to patients with moderate renal failure (creatinine < or =2.5 mg/dL) in which creatinine fell from 2.24 +/- 0.2 to 1.9 +/- 0.27 mg/dL, P = .009). When basal creatinine was over 2.5 mg/dL, only one third of the patients improved after conversion. Two patients died: terminal renal failure and cerebrovascular accident. There were no clinical episodes of rejection. Secondary effects prompted the discontinuation of sirolimus in five patients: two definite and one possible interstitial pneumonitis and two cases of anemia). The symptoms resolved after sirolimus withdrawal. Six patients had infection: four pneumonias, one sepsis, and one cutaneous abscess. Sirolimus is an interesting alternative to calcineurin inhibitors in selected patients with renal impairment. It prevents renal failure in de novo recipients at high risk of catastrophic renal damage and ameliorates renal dysfunction in chronic patients with moderate renal dysfunction. Given the high incidence of secondary effects, the adequate dosage and the secondary effects profile needs further study.

cis-[PtCl2(4,7-H-5-methyl-7-oxo[1,2,4]triazolo[1,5-a]pyrimidine)2]: a sterically restrictive new cisplatin analogue. Reaction kinetics with model nucleobases, DNA interaction studies, antitumor activity, and structure-activity relationships.

The formation and isolation of the antitumor drug cisplatin analogue cis-[PtCl2(Hmtpo-N3)2].2H2O (1) (where Hmtpo = 4,7-H-5-methyl-7-oxo[1,2,4]triazolo[1,5-a]pyrimidine) by reaction of Hmpto with K2[PtCl4] in HCl (0.5 N) is reported. This complex crystallizes in the monoclinic space group P21/c with unit cell dimensions a = 15.215(2) A, b = 9.629(1) A, c = 13.115(3) A, beta = 97.40(2) degrees, and Z = 4. The molecular structure shows that Pt is in an almost square planar environment, PtN2Cl2, which has a cis configuration. The Hmpto ligands show a head to head orientation in the solid state and nonrestricted rotation about the Pt-N bonds in solution. The reactivity of the complex to model nucleobases 9-ethylguanine (9-EtGH) and 1-methylcytosine (1-MeC) has been investigated by 1H NMR spectroscopy at 45 degrees C in aqueous media. The results show that 1 reacts slowly with 9-EtGH (t1/2 approximately 5 days) by displacement of Cl-, producing cis-[Pt(mtpo-N3)2(9-EtGH-N7)2], which is similar to the major cross-link adduct of cisplatin with DNA. However, 1 gives no reaction with 1-MeC. This appears to be due to the lesser reactivity of 1-MeC and to competition between the cross-link reaction and dimerization of 1 to [Pt2(mu-mtpo-N3,N4)4]. Circular dichroism studies of DNA in the presence of 1 show that the platinum complex reacts efficiently after 48 h at a optimum ratio of 0.25 Pt atom/mol of DNA nucleotide. These results and those obtained from reaction of 1 with 9-EtGH suggest that the platinum compound binds the N7 atoms of two guanines of the same strand, forming intrastrand cross-linked adducts. Chelation of DNA bases by 1 causes important conformational changes, bringing the guanines close together. The anticancer activity of complex 1 has been tested against the human cancer cell lines MCF-7 breast carcinoma and A121 ovarian carcinoma. Results indicate a moderate antitumor activity against breast carcinoma and a marked and selective cytotoxic effect against ovarian carcinoma.

Perivalvular abscesses associated with endocarditis. Clinical features and diagnostic accuracy of two-dimensional echocardiography.

OBJECTIVE: To determine the clinical implications of the development of a perivalvular abscess in the course of an infective endocarditis and evaluate the utility of two-dimensional echocardiography in the diagnosis of this complication. DESIGN: Retrospective clinical review. Investigator-blinded comparative echographic case-control study. SETTING: Tertiary referral center. PATIENTS: Forty patients with infective endocarditis and a histologically proved diagnosis of perivalvular abscess. INTERVENTION: Two-dimensional echocardiograms corresponding to 36 of these 40 patients were blindly compared with two-dimensional echocardiograms of 20 randomly chosen patients with infective endocarditis in whom myocardial abscesses had not been demonstrated during surgery. MEASUREMENTS AND MAIN RESULTS: During surgery or at autopsy, 40 patients had a total of 41 definite perivalvular abscesses. Native valve endocarditis was present in 27 patients, and prosthetic valve endocarditis was present in 13 patients. Abscesses were more frequent in aortic-valve endocarditis (57.5 percent) than in infections of other valves, and the infecting organism was more often Staphylococcus (42.5 percent of cases). The hospital mortality rate was 90 percent in the 10 patients who did not receive surgical treatment, as compared with 26.6 percent in the 30 operated-on patient (p < 0.001). Sensitivity and specificity for the detection of abscesses associated with endocarditis were 80.5 percent and 85 percent, respectively, for transthoracic two-dimensional echocardiography. CONCLUSIONS: Our data indicate that transthoracic echocardiography remains an accurate method for the diagnosis of abscesses associated with endocarditis, even in the presence of a prosthetic valve, and it could help to indicate early surgery in these patients.

Nitrate/nitrite reductase activity of sulfido/selenido bridged dinuclear ruthenium(III) complexes.

Series of dinuclear species [Ru(2)(L)(2)(LH)(2)-mu-S(2)Cl(2)], [Ru(2)(L)(2)(LH)(4)-mu-Se(2)Cl(2)] (L=L(1)H and L(3)H) and [Ru(2)(L(2))(2)(L(2)H)-mu-Se(2)Cl(2)].2H(2)O, where L(1)H, L(2)H and L(3)H represent for 2-mercapto-5-phenyl-1,3,4-oxadiazole, 2-mercapto-benzimidazole and 2-mercapto-benzothiazole, respectively, have been prepared and characterized by their elemental analyses and spectral (IR, UV-visible, 1H NMR and FAB mass) data. The diamagnetism of these complexes are indicative of an exchange coupled dinuclear ruthenium(III) species containing S(2)(2-) and Se(2)(2-) bridges. The complexes along with free heterocycles (L(1)H-L(3)H) as well as RuCl(3) x 3H(2)0 were tested for their nitrate and nitrite reductase activities. The electrochemical behaviour of the complexes showed irreversible oxidation peaks at +(1.04-1.40) V quite comparable to those reported for sulphido bridged complexes.

Intramolecular stacking interactions in ternary copper(II) complexes formed with 2,2'-bipyridine or 1,10-phenanthroline and 9-(4-phosphonobutyl)adenine (dPMEA), the carba relative of the antiviral nucleotide analogue 9.

The stability constants of the mixed ligand complexes formed between Cu(Arm)2+, where Arm=2,2'-bipyridine (Bpy) or 1,10-phenanthroline (Phen), and the monoanion or the dianion of 9-(4-phosphonobutyl)adenine (dPMEA=3'-deoxa-PMEA), which is the carba analogue of the antivirally active 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA), were determined by potentiometric pH titrations in aqueous solution at 25 degrees C and I=0.1 M (NaNO3). Detailed stability constant comparisons reveal that in the monoprotonated ternary Cu(Arm)(H;dPMEA)+ complexes the proton is at the phosphonate group and that stacking between Cu(Arm)2+ and H(dPMEA)- plays a significant role. For the Cu(Arm)(dPMEA) complexes a large increase in complex stability (compared to the stability expected on the basis of the basicity of the phosphonate group) is observed, which is due to intramolecular stack formation between the aromatic ring systems of Phen or Bpy and the purine moiety of dPMEA2-. The formation degree of the stacked isomer in the Cu(Arm)(dPMEA) systems is on the order of 90%, though it is somewhat more pronounced with Phen than with Bpy. Comparisons of the Cu(Arm)(N) systems, where N=dPMEA2- and PMEA2- or adenosine 5'-monophosphate (AMP2-), reveal that the stacking properties of dPMEA2- and PMEA2-resemble closely those of their parent nucleotide AMP2-.

Solution studies of the antitumor complex dichloro 1,2-propylendiaminetetraacetate ruthenium (III) and of its interactions with proteins.

A mixed complex of ruthenium (III) with 1,2-propylendiaminetetraacetate (PDTA) and chloride--RAP hereafter--has been found to exhibit favorable anticancer properties in vivo. To get some insight into the possible mechanism of action of this ruthenium (III) complex, its solution behavior and reactivity with proteins were investigated through absorption, circular dichroism and 1H NMR spectroscopies. Under physiological conditions RAP slowly looses the two coordinated chlorine atoms to produce a number of ruthenium (III) reactive species; a description of the distribution of these species on the dependence of pH has been obtained through 1H NMR studies of the hyperfine shifted signals. Remarkably, through the different solution conditions employed in this study, the ruthenium ion always remains in the 3+ oxidation state and the PDTA ligand is always bound to the metal. Upon reaction with albumin, apotransferrin or diferric transferrin, at a 1:1 ratio, RAP rapidly binds to these proteins to produce substantially equivalent and relatively stable adducts. This behavior is tentatively interpreted in terms of a tight interaction between RAP and surface residues of these proteins. The implications of these findings for the biological action of this novel ruthenium (III) compound are discussed.

Assessment of tricuspid regurgitation by Doppler color flow imaging: angiographic correlation.

The correlation between data obtained by Doppler color flow imaging and angiographic severity has been investigated in mitral and aortic regurgitation. However, similar studies have not been performed for tricuspid regurgitation (TR). This study was performed to establish the correlation between measurements of regurgitant jet area by Doppler color flow imaging and the angiographic severity of TR. Fifty-four patients with rheumatic heart disease who underwent right ventriculography and transthoracic Doppler color flow imaging were studied. The regurgitant jet area was measured as the largest clearly definable flow disturbance in apical four-chamber and right ventricle inflow views, and expressed in both views as the absolute jet area or as the ratio of maximal jet area to right atrial area. Correlation of all Doppler color flow measurements with angiographic grades of TR were comparable, absolute jet area in apical four-chamber view being closest at r = 0.80. A regurgitant jet area in apical four-chamber view < 5 cm2 predicted minimal or mild TR by angiography with a sensitivity of 78% and a specificity of 100%, whereas a regurgitant jet area > 10 cm2 predicted severe TR with a sensitivity of 92% and a specificity of 91%. Values between 5 and 10 cm2 predicted moderate TR with a sensitivity of 89% and a specificity of 89%. Sensitivity and specificity were not improved with use of the ratio of jet area to right atrial area or with use of right ventricle inflow view. Thus, Doppler color flow jet measurements correlate closely with angiographic results in the evaluation of TR.(ABSTRACT TRUNCATED AT 250 WORDS)

[Evaluation using serial exercise tests of verapamil alone and combined with isosorbide dinitrate in exertional angina]. / Valoración mediante pruebas de esfuerzo seriadas del verapamil solo y combinado con dinitrato de isosorbide en la angina de esfuerzo.

The response to verapamil alone and combined with isosorbide dinitrate in a group of 12 patients with severe ischemic heart disease and stable effort angina was assessed by means of serial treadmill testing. The study was randomized, of a square latin design and double-blind. The tested drugs and dosages were 120 mg of verapamil, 120 mg of verapamil plus 20 mg of isosorbide dinitrate and placebo. Patients were serially tested (Bruce protocol) over three consecutive days at 8-9-12 and 16 hours. A significative improvement was observed in several ischemic parameters both with verapamil alone and combined with isosorbide dinitrate, but this improvement was remarkably enhanced with the combination of drugs. The mean exercise time to produce angina improved from 268 +/- 18 sec (basal) to 379 +/- 19 sec (verapamil plus isosorbide dinitrate) and the time for 1 mm ST segment depression from 163 +/- 22 sec (basal) to 257 +/- 19 sec (verapamil plus isosorbide dinitrate) when measured at the last daily test (8 hours after drug administration). It is concluded that both verapamil alone and combined with isosorbide dinitrate at the chosen doses are clinically efficient, significantly improving the ischemic parameters. The combination of verapamil and isosorbide dinitrate resulted in a remarkably better improvement in this group of patients with stable effort angina.