Passive Immunization against Congenital Cytomegalovirus Infection: Current State of Knowledge.

Primary infection with the human cytomegalovirus (CMV) occurs in 1-4% of pregnancies. The rates of maternal-fetal CMV transmissions are around 25, 36, 41, and 66%, for infections occurring in the peri-conceptional weeks, first, second, and third trimester of pregnancy, respectively. On the other hand, the severity of fetal organ damage and dysfunction diminishes with increasing gestational age. Congenitally CMV-infected newborns may have neurosensory impairments like mental retardation, cerebral palsy, epilepsy, progressive hearing loss or visual defects, or even may have a fatal outcome. In in-vitro experiments, CMV specific neutralizing IgG antibodies - which are abundant in CMV specific hyperimmune globulin (HIG) products - inhibited the entry of the virus into target cells and hampered viral cell-to-cell spread. This article provides a brief overview on the epidemiology and diagnostic tools in congenital CMV infection. It also concisely summarizes the currently available study results on the safety and effectiveness of HIG treatment. Accordingly, in clinical studies HIG administration to expectant mothers following primary CMV infection (prophylactic use) was shown to lower the risk of maternal-fetal transmission of CMV compared to untreated controls. HIG was also able to ameliorate the disease sequelae in evidently infected fetuses (therapeutic use), as demonstrated by the regression or even resolution of sonographic pathologies including placental inflammation.

Glycerophosphate is interchangeable with inorganic phosphate in terms of safety and serum pharmacokinetics.

OBJECTIVE: The primary aim of the present investigation was to determine and compare the pharmacokinetic (PK) profiles of inorganic phosphate in serum and urine after intravenous administration of sodium glycerophosphate and inorganic sodium phosphate. Additionally, study product safety profiles were evaluated. SUBJECTS AND METHODS: In total, 27 healthy, white volunteers (17 male/10 female) were enrolled in this double-blinded, randomized, 2-sequence, crossover study and were assigned to receive an organic test drug (sodium glycerophosphate) and an inorganic reference preparation (sodium phosphate) on 2 occasions. Validated analytical methods were used, and concentrations of total inorganic phosphate in serum and urine were determined over 24 h following a single 4-hour continuous intravenous infusion of test and reference drugs at a dose of 80 mmol. Study days were separated by washout periods of 7 days. An analysis of variance, based on population means and 90% confidence intervals (CIs), was used for testing bioequivalence (BE; range 0.8-1.25) between investigational products. RESULTS: The geometric means of the ratio of the point estimates and corresponding 90% CIs for the area under the concentration-versus-time curve of inorganic serum phosphate from 0 to 24 h (AUC(0-24)), the phosphate's maximum concentration in serum (C(max)) and the total amount of inorganic phosphate excreted in urine over 24 h corrected for individual baseline values (Ae(0-24 bc)) were estimated. The test/reference ratios for inorganic phosphate were 1.04 (CI 1.00-1.07), 0.85 (CI 0.84-0.87) and 0.84 (CI 0.77-0.92) for AUC(0-24), C(max) in serum and Ae(0-24 bc) in urine, respectively. Hence, standard BE criteria were met for AUC(0-24) and C(max) in serum, while Ae(0-24 bc) marginally failed to demonstrate BE. After drug administration, a total of 15 subjects reported the occurrence of at least 1 treatment emergent adverse event (AE). All AEs were classified as mild to moderate in severity, and the two treatment groups were equally affected. No serious AEs occurred. CONCLUSION: The serum PK profiles of inorganic phosphate were almost superimposable following intravenous administration of equimolar doses of test and reference drugs. Thus, we conclude that the two study drugs are essentially similar in terms of serum PK profiles, safety and tolerability.

Glycerophosphate does not interact with components of parenteral nutrition.

BACKGROUND/AIMS: The primary objective of this study was to determine and compare the pharmacokinetic (PK) profiles of inorganic phosphate in the serum after continuous administration of pure glycerophosphate and glycerophosphate contained in total parenteral nutrition (TPN) emulsions. This approach was selected to identify potential PK interactions between TPN components and glycerophosphate. METHODS: The serum PK profile of inorganic phosphate after continuous intravenous administration of a sodium glycerophosphate containing TPN emulsion was determined in 10 healthy, white (5 male/5 female) volunteers. A pure sodium glycerophosphate formulation served as reference. Standard criteria of bioequivalence were applied. Subjects were enrolled in the double-blinded study and were randomly allocated to receive the test and reference preparations on two occasions in a 2-sequence crossover study design. The volunteers received 1/3 of the maximum recommended body weight- (BW) adjusted intravenous daily dosage (13.3 ml/kg BW) of the test drug over a period of 8 h. The amount of total phosphate (0.101 mmol/kg) and duration of administration were identical for the test and reference drugs. Study days were separated by washout periods of at least 88 h. Serum concentrations of total inorganic phosphate were measured serially over a 36-hour period using a validated method. A statistical mixed ANOVA, based on population averages, was used for testing bioequivalence between these study preparations. RESULTS: The 90% confidence intervals (90% CIs) of inorganic phosphate in serum were calculated for the test/reference ratios of the area under the time-concentration curve from time 0 to 36 h (AUC0₋36), the maximum concentration (C(max)) and the concentration 5 min before the end of infusion (C(ss)) for a bioequivalence range from 0.80 to 1.25. The mean test/reference ratios fell completely within the 90% CIs with values of 1.016 (90% CI 1.005-1.028), 1.013 (90% CI 0.981-1.047) and 0.932 (90% CI 0.886-0.980) for AUC(0-36), C(max) and C(ss), respectively. In total, 3 mild adverse events in the reference group were detected after starting intravenous infusion, while no adverse events were observed in the test group after treatment. CONCLUSION: Primary PK parameters were within the defined bioequivalence range of 0.8-1.25. Thus, inorganic phosphate levels were essentially similar between the two investigational medicinal products tested in the present study. These findings confirm the concept that nutritional components of the test drug do not significantly interact with glycerophosphate. The two study preparations proved to be safe during the investigation.

Prospective study of everolimus with calcineurin inhibitor-free immunosuppression in maintenance heart transplant patients: results at 2 years.

BACKGROUND: Few studies have examined everolimus therapy with calcineurin inhibitor (CNI) withdrawal in maintenance heart transplant patients. METHODS: In a prospective, single-arm, single-center study, CNI-treated heart transplant patients were converted to everolimus and were followed up for 24 months. The primary endpoints were kidney function and arterial hypertension at 12 and 24 months after conversion. RESULTS: Fifty-eight patients were recruited (mean time posttransplant 5.6±3.7 years), 55 of whom (91.7%) had renal impairment. Mean creatinine clearance increased from 43.6±21.1 mL/min to 49.5±21.2 mL/min at month 24 (P=0.02). Median blood pressure increased from 120/80 mm Hg at baseline to 122.5/80 mm Hg (P=0.008 and 0.006 for systolic and diastolic pressure, respectively). Lipid parameters did not change significantly over the 24-month follow-up. Early resolution of most non-renal CNI-related adverse events was sustained. CNI therapy was re-introduced at a mean of 309 days (range, 31-684 days) in eight patients after month 6 due to adverse events (n=13) or withdrawal of consent (n=2). No significant changes in cardiac function parameters were observed. CONCLUSIONS: CNI-free immunosuppression with everolimus is an effective and safe option in selected heart transplant maintenance patients. Most adverse effects under everolimus occurred early after conversion and generally resolved without intervention within a few weeks. Refining selection criteria may reduce the need to re-introduce CNI therapy.

Echocardiographic assessment of global left ventricular function in mice.

Doppler-echocardiographic assessment of cardiovascular structure and function in murine models has developed into one of the most commonly used non-invasive techniques during the last decades. Recent technical improvements even expanded the possibilities. In this review, we summarize the current options to assess global left ventricular (LV) function in mice using echocardiographic techniques. In detail, standard techniques as structural and functional assessment of the cardiovascular phenotype using one-dimensional M-mode echocardiography, two-dimensional B-mode echocardiography and spectral Doppler signals from mitral inflow respective aortal outflow are presented. Further pros and contras of recently implemented techniques as three-dimensional echocardiography and strain and strain rate measurements are discussed. Deduced measures of LV function as the myocardial performance index according to Tei, estimation of the mean velocity of circumferential fibre shortening, LV wall stress and different algorithms to estimate the LV mass are described in detail. Last but not least, specific features and limitations of murine echocardiography are presented. Future perspectives in respect to new examination techniques like targeted molecular imaging with advanced ultrasound contrast bubbles or improvement of equipment like new generation matrix transducers for murine echocardiography are discussed.

Daptomycin: a review 4 years after first approval.

Daptomycin is the first approved member of a new class of antibiotics, namely the cyclic lipopeptides. Daptomycin has rapid bactericidal activity against Gram-positive pathogens. It acts by penetrating into the bacterial cell wall with consecutive formation of pores, loss of electrical membrane potential and inhibition of peptidoglycan synthesis. As the mode of action of daptomycin is 'concentration-dependent', the pharmacokinetic/pharmacodynamic indices that correlate best with its activity are the ratios of the peak concentration (C(max)) to minimum inhibitory concentration (MIC) or the area under the curve (24-hour AUC) to MIC. Daptomycin should be administered intravenously once daily, because adverse effects on skeletal muscle associated with an increase in plasma levels of creatine phosphokinase and myopathy were observed more frequently at shorter dosing intervals. Overall, the rate of adverse events during daptomycin therapy is comparable to that of other standard regimens. Daptomycin was shown to be not inferior to antimicrobial standard therapy and therefore was approved for complicated skin and skin structure infections at a dose of 4 mg/kg, for Staphylococcus aureus bacteremia and right-sided endocarditis at a dose of 6 mg/kg. Dosage regimens remain a matter of discussion, and an increase in the currently approved doses from 4-6 to 6-8 mg/kg per day for severe infections seems promising. Though not approved up to now, daptomycin appears to be a treatment alternative for Gram-positive bone and joint infections based on clinical observations. Large international studies showed high susceptibility of relevant Gram-positive pathogens to daptomycin, even in multidrug-resistant strains. Thus, treatment of infections caused by Gram-positive cocci resistant to other antimicrobial drugs is a potential indication of daptomycin. Since glycopeptides and daptomycin have the same target site, there appears to be a risk of reduced susceptibility to both drugs after consecutive use. Therefore, daptomycin should be used with caution for treatment of vancomycin-resistant isolates or after prior vancomycin (glycopeptide) therapy. This review describes the history, mechanism of action, susceptibility, recent discoveries and clinical experience regarding daptomycin, discussing its current role in the field of infectious diseases.

Daptomycin does not exert immunomodulatory effects in an experimental endotoxin model of human whole blood.

BACKGROUND: Recent studies have shown that distinct classes of antimicrobial agents might exert immunomodulatory effects in experimental settings. Daptomycin is the first member of the class of cyclic lipopeptide antibiotics, which exert their antimicrobial activity via a unique mode of action on the bacterial cytoplasmic membrane. Thus, we tested its ability to influence pro-inflammatory cytokines by use of an established experimental model of human endotoxemia. METHODS: A controlled experimental study design with 4 parallel groups was used. Whole blood from 10 healthy male volunteers was incubated either with saline (negative control), daptomycin (40 microg/ml, control), lipopolysaccharide (LPS; 50 pg/ml, positive control), or the combination of daptomycin plus LPS for 4 h. Real-time polymerase chain reaction was utilized for the measurement of selected pro-inflammatory cytokines, namely IL-1 beta, IL-6 (high sensitivity) and TNF-alpha on the mRNA level. Protein concentrations of these respective cytokines were measured in the supernatant using a commercially available ELISA. RESULTS: Incubation of whole blood with LPS significantly increased protein and mRNA levels of cytokines compared to baseline (p < 0.05). However, the combination of daptomycin plus LPS did not exert any significant effect on mRNA and protein levels of IL-1 beta, IL-6 (high sensitivity) and TNF-alpha after 2 and 4 h of incubation compared to LPS incubation alone. CONCLUSION: Daptomycin does not affect pro-inflammatory cytokines in the early phase of endotoxemia. This is most likely due to the unique mode of action of daptomycin, its low potential to penetrate into human cells and its high affinity to bacterial cytoplasmic membranes.

Observational study with everolimus (Certican) in combination with low-dose cyclosporine in de novo heart transplant recipients.

BACKGROUND/METHODS: This observational study reports on immunosuppression with cyclosporine (CsA) in 38 de novo heart transplant recipients receiving everolimus compared with 14 patients receiving mycophenolate mofetil (MMF). RESULTS: Mean (+/- SD) everolimus C0 blood levels remained stable within 5 to 7 ng/ml. Mean CsA C0 blood levels were reduced by 47%, from 240 +/- 57 ng/ml at 2 weeks post-transplant to 128 +/- 38 ng/ml at Month 6 and by 58% to 101 +/- 26 ng/ml at Month 12 in the everolimus group, compared to 18% from 246 +/- 54 ng/ml at 2 weeks post-transplant to 201 +/- 48 ng/ml at Month 6 and by 35% to 160 +/- 41 ng/ml in MMF patients. Efficacy was high with a rejection rate of 23.6% (everolimus) vs 28.5% (MMF) by Month 12. Mean pre-transplant serum creatinine levels of 1.67 +/- 0.59 mg/dl decreased to 1.53 +/- 0.57 mg/dl under everolimus and increased from 1.22 +/- 0.36 to 1.99 +/- 0.75 mg/dl in the MMF group by Month 12 post-transplant. However, calculated GFR declined in both groups by Month 12 (everolimus: from 71 +/- 29 to 57 +/- 27 ml/min/1.73 m2; MMF: from 73 +/- 22 to 44 +/- 24 ml/min/1.73 m2), with stabilization after 3 to 6 months in everolimus-treated patients and after 6 to 9 months in MMF-treated patients. CONCLUSIONS: Everolimus allows marked reduction of CsA exposure without significant loss of efficacy and also provides early protection of renal function.

Transmitral flow patterns and the presence of chronic kidney disease provide independent and incremental prognostic information in patients with heart failure and systolic dysfunction.

BACKGROUND: Transmitral flow patterns derived from Doppler echocardiography carry prognostic information in patients with chronic heart failure and systolic dysfunction. In such patients, chronic kidney disease (CKD) defined as a reduction in estimated glomerular filtration rate less than 60 mL/min/1.73 m(2) is frequent, but its prognostic impact relative to that of transmitral flow patterns is unknown. METHODS: This prospective study enrolled 292 patients with stable chronic heart failure and systolic dysfunction (mean ejection fraction 30 +/- 10), of whom 148 had CKD. Echocardiographic measurements comprised left ventricular dimensions/volumes, ejection fraction, the ratio of early (E) to late (A) transmitral flow velocity, deceleration time, and tissue Doppler mitral annular velocities. The mitral filling pattern (FP) was classified as either restrictive FP (RFP) or non-RFP. A cardiac event (cardiac death or urgent cardiac transplantation) was defined as combined study end point. RESULTS: During a follow-up of 497 +/- 373 days, 45 patients had a cardiac event (cardiac death, n = 42; urgent cardiac transplantation, n = 3). On multivariate Cox analysis including clinical and echocardiographic variables, independent prognostic predictors were RFP (hazard ratio: 2.77, 95% confidence interval 1.28-6.09), CKD (hazard ratio: 2.79, 95% confidence interval 1.24-6.28), and left atrial diameter. In patients with RFP, the prognosis was markedly worse in the presence of CKD as compared with the absence (event-free survival of 23% vs 83%, P = .03). Similarly, in patients with non-RFP, outcome was worse in the presence of CKD (event-free survival of 71% vs 88%, P = .003). CONCLUSIONS: In patients with chronic heart failure and systolic dysfunction, the presence of CKD adds incremental value to transmitral flow patterns in determining the prognosis.

Recommendations for the use of everolimus (Certican) in heart transplantation: results from the second German-Austrian Certican Consensus Conference.

Everolimus (Certican; Novartis Pharma AG, Basel, Switzerland) represents the latest generation of proliferation signal inhibitors (PSIs). Everolimus is indicated for use as an immunosuppressive drug in renal and heart transplantation. This report reflects the recommendations of the second German-Austrian Certican Consensus Conference, held in January 2006, for the clinical use of everolimus.

Calcineurin inhibitor-free immunosuppression using everolimus (Certican) in maintenance heart transplant recipients: 6 months' follow-up.

BACKGROUND: Everolimus is a proliferation signal-inhibitor recently introduced in heart transplant recipients. To date, little is known about calcineurin inhibitor (CNI)-free immunosuppression using everolimus. This study reports the results of CNI-free immunosuppression using everolimus. METHODS: During a continuous 9-month period, 60 heart transplant recipients were enrolled. Reasons for switching to everolimus were side effects associated with prior CNI immunosuppression. All patients underwent standardized switching protocols and completed 6 months of follow-up. Blood was obtained for lipid status, renal function, routine controls, and levels of immunosuppressive agents. Echocardiography and a physical examination were performed on Days 0, 14, 28, and then every 3 months. RESULTS: After switching to everolimus, most patients recovered from the side effects associated with CNIs. Renal function improved significantly after 6 months (creatinine, 2.1 +/- 0.6 vs 1.5 +/- 0.9 mg/dl, p = 0.001; creatinine clearance, 42.2 +/- 21.6 vs 61.8 +/- 23.4 ml/[min x 1.73 m2], p = 0.018). Arterial hypertension improved after 3 months and remained decreased during the observation period. Tremor, peripheral edema, hirsutism, and gingival hyperplasia markedly improved. Adverse events occurred in 8 patients (13.3%), including interstitial pneumonia (n = 2), skin disorders (n = 2), reactivated hepatitis B (n = 1), and fever of unknown origin (n = 3). CONCLUSION: Preliminary data suggest that CNI-free immunosuppression using everolimus is safe, with excellent efficacy in maintenance heart transplant recipients. Arterial hypertension and renal function improved significantly. CNI-induced side effects such as tremor, peripheral edema, hirsutism, and gingival hyperplasia markedly improved in most patients.

Doppler echocardiography and tissue Doppler imaging in the healthy rabbit: differences of cardiac function during awake and anaesthetised examination.

OBJECTIVE: In the past years, Doppler echocardiography has evolved into a commonly used technique. More recent sophisticated advances in imaging quality have substantially improved spatial and temporal resolution allowing the adaptation of this technique to small animal models, particularly in rabbits but even in mice. Recently, parameters obtained by Tissue Doppler Imaging (TDI) have been shown to be more independent of pre- and afterload than classic hemodynamic Doppler measurements. Exploration of animal models may require anaesthesia but there is only very little information on the effect of anaesthesia on echocardiographic parameters in rabbits. METHODS: We therefore performed Doppler-echocardiographic examinations of 20 wild-type New Zealand White rabbits in awake state and under light ketamine-xylazine anaesthesia. Special focus was put on the evaluation of global and regional left ventricular systolic and diastolic function using TDI and the myocardial performance index (Tei-index). RESULTS: Doppler-echocardiographic measurements including TDI in rabbits were feasible to assess cardiac morphology and function within a short examination time. There were some distinct changes of functional parameters during anaesthesia. Exemplary for systolic function, fractional shortening, cardiac output and systolic TDI velocity of the lateral wall decreased distinctly. Global left ventricular function measured by the Tei-index deteriorated. CONCLUSIONS: Doppler echocardiography and TDI can be performed easily, quickly and safely in the rabbit. Anaesthesia with the cardiodepressive ketamine-xylazine shows some distinct Doppler-echocardiographically measurable negative effects on cardiac function. Thus, echocardiography with less cardiodepressive anaesthetic regimes or even without anaesthesia after training of the animals should be considered as alternatives whenever possible.

Chronic kidney disease in patients with chronic heart failure--impact on intracardiac conduction, diastolic function and prognosis.

BACKGROUND: In patients with chronic heart failure (CHF), chronic kidney disease (CKD) is associated with increased morbidity and mortality, but contributing mechanisms are not well defined. This study tested the impact of CKD on intracardiac conduction, diastolic function and prognosis in patients with underlying CHF. METHODS: We prospectively enrolled 269 patients with stable CHF, of whom 135 had CKD (estimated glomerular filtration rate (eGFR)<60 ml/min/1.73 m(2)). Echo measurements comprised left ventricular dimensions/volumes, ejection fraction, mitral E/A-ratio, deceleration time and tissue Doppler mitral annular velocities (S', E', A'). PQ and QRS intervals were derived from the 12-lead ECG. A cardiac event (cardiac death or urgent cardiac transplantation) was defined as combined study end point. RESULTS: Patients with CKD had longer PQ and QRS intervals, and were in a poorer NYHA functional class as compared to patients without CKD. In patients with CKD, the mitral annular E' velocity was lower, the mitral E/E'-ratio was higher and a restrictive mitral filling pattern was more frequent. By linear regression analysis, PQ and QRS intervals and the mitral E/E'-ratio were inversely related to the eGFR. During a follow-up of 507+/-375 days, 39 patients suffered a cardiac event. In CKD patients, outcome was markedly poorer as compared to those without CKD (event-free survival rate 51% vs. 87% in those without KD, p=0.001) CONCLUSIONS: In patients with CHF, CKD is associated with impaired intracardiac conduction and progressive diastolic dysfunction. Both mechanisms may contribute to increased morbidity and mortality of such patients.

Cardiovascular characterization of Pkd2(+/LacZ) mice, an animal model for the autosomal dominant polycystic kidney disease type 2 (ADPKD2).

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1 or PKD2. Patients with ADPKD have an increased incidence of cardiac valve abnormalities and left ventricular hypertrophy. Systematic analyses of cardiovascular involvement have so far been performed only on genetically unclassified patients or on ADPKD1 patients, but not on genetically defined ADPKD2 patients. Even existing Pkd1 or Pkd2 mouse models were not thoroughly analyzed in this respect. Therefore, the aim of this project was the noninvasive functional cardiovascular characterization of a mouse model for ADPKD2. METHODS: Pkd2(+/LacZ) mice and wildtype controls were classified into 8 groups with respect to gender, age and genotype. In addition, two subgroups of female mice were analyzed for cardiac function before and during advanced pregnancy. Doppler-echocardiographic as well as histological studies were performed. RESULTS: Doppler-echocardiography did not reveal significant cardiovascular changes. Heart rate and left ventricular (LV) length, LV mass, LV enddiastolic and LV endsystolic diameters did not differ significantly among the various groups when comparing wildtype and knockout mice. There were no significant differences except for a tendency towards higher maximal early and late flow velocities over the mitral valve in old wildtype mice. CONCLUSIONS: Non-invasive phenotyping using ultrasound did not reveal significant cardiovascular difference between adult Pkd2(+/LacZ) and WT mice. Due to the lack of an obvious renal phenotype in heterozygous mice, it is likely that in conventional ADPKD knock out mouse models severe cardiac problems appear too late to be identified during the reduced lifespan of the animals.

Prevalence and prognostic impact of comorbidities in patients with severe aortic valve stenosis.

In patients with severe aortic valve stenosis (valve area 41.8 ml/min/1.73 m(2) (event-free survival rate of 38% vs 93%, p = 0.004). Thus, in patients with severe AS, comorbidities are frequent, and particularly kidney disease significantly impacts longterm outcome.

N-terminal pro-brain natriuretic peptide, kidney disease and outcome in patients with chronic heart failure.

BACKGROUND: In patients with chronic heart failure (CHF), N-terminal pro-brain natriuretic peptide (NT-proBNP) provides relevant prognostic information, but its usefulness in the presence of kidney disease has been questioned. METHODS: We prospectively enrolled 142 patients with stable CHF and a wide spectrum of renal function (estimated glomerular filtration rates [eGFRs] ranging from 17.1 to 100.3 ml/min/1.73 m2). Chronic kidney disease, defined as eGFR < 60 ml/min/1.73 m2, was present in 63 patients (44%). NT-proBNP measurements were carried out on a bench-top analyzer (Elecsys 2010). Cardiac death or urgent cardiac transplantation were considered as a combined study end-point. RESULTS: During a follow-up of 383 +/- 237 days, 19 patients underwent a cardiac event (cardiac death, n = 17; urgent cardiac transplantation, n = 2). By multivariate Cox analysis, including clinical and laboratory variables, NT-proBNP and serum hemoglobin were independent prognostic predictors. In patients with NT-proBNP > 1,129 pg/ml, outcome was significantly worse compared to patients with NT-proBNP < 1,129 pg/ml (event-free survival rate 67% vs 94% in those with NT-proBNP < 1,129 pg/ml, p = 0.001). By linear regression analysis, NT-proBNP levels were related to New York Heart Association (NYHA) functional class (R = 0.41, p < 0.001), and inversely related to eGFR (R = -0.29, p = 0.001) and to left ventricular ejection fraction (R = -0.43, p < 0.001). CONCLUSIONS: In CHF patients with and without kidney disease, NT-proBNP provides independent prognostic information. In such patients, NT-proBNP levels are not only reflective of a reduced clearance (i.e., a lower eGFR) but also of the severity of the underlying structural heart disease.

Risk stratification in chronic heart failure: independent and incremental prognostic value of echocardiography and brain natriuretic peptide and its N-terminal fragment.

BACKGROUND: It was the aim of this study to compare the prognostic impact of echocardiography and brain natriuretic peptide and its N-terminal fragment (NT-proBNP) in patients with chronic heart failure (CHF). METHODS: In all, 73 patients with CHF underwent conventional 2-dimensional/Doppler echocardiography and Doppler tissue analysis of systolic, early and late diastolic mitral annular velocities. The mitral filling pattern was classified as restrictive or nonrestrictive. NT-proBNP measurements were carried out on a bench-top analyzer. A cardiac event (rehospitalization caused by worsening CHF, cardiac death, urgent cardiac transplantation) was defined as combined study end point. RESULTS: During follow-up of 226 +/- 169 days, 27 patients had an event (rehospitalization because of CHF, n = 18; cardiac death, n = 7; urgent transplantation, n = 2). On multivariate Cox regression analysis, a restrictive filling pattern, NT-proBNP, the ratio of peak early diastolic mitral flow to mitral annular E' velocity were independent prognostic predictors. A risk stratification model based on the 3 strongest independent predictors separated groups into those with good, intermediate, and poor outcome (event-free survival of 78%, 46%, and 0%, respectively). CONCLUSIONS: In patients with CHF, Doppler echocardiography, Doppler tissue imaging, and NT-proBNP provide independent and incremental prognostic information. A combined use of echocardiography and NT-proBNP may help to improve risk stratification in this patient population.

Partial left ventriculectomy and mitral valve repair: favorable short-term results in carefully selected patients with advanced heart failure due to dilated cardiomyopathy.

BACKGROUND: Because of the scarcity of donor hearts, surgical alternatives to heart transplantation, such as partial left ventriculectomy (PLV), were introduced for treatment of advanced heart failure. Here, we report our experience with this procedure performed in combination with mitral valve repair. METHODS: Twelve patients with dilated cardiomyopathy (DCM), New York Heart Association (NYHA) class exceeding III on maximal medical therapy, cardiac index of 2.5 liter/min/m2 or less, VO2max of 14 ml/kg/min or less, left ventricular end-diastolic diameter (LVEDD) of 7.0 cm or more, and grade II or greater mitral incompetence, were selected for PLV and mitral valve reconstruction (MVR). Echocardiography, hemodynamics, spiroergometry, and clinical assessment were performed before and 1 year after the operation. RESULTS: One-year survival was 83.3%. All 10 surviving patients were free from failure of the procedure 1 year post-operatively. From pre-operatively to 1 year post-operatively, NYHA functional class improved from 3.3 +/- 0.3 to 1.9 +/- 0.2 (p < 0.001), cardiac index increased from 2.0 +/- 0.2 liter/min/m2 to 2.9 +/- 0.2 liter/min/m2 (p < 0.001), stroke volume index from 25.9 +/- 4.8 ml/m2 to 40.3 +/- 7.3 ml/m2 (p = 0.008), and VO2max from 10.9 +/- 2.4 ml/kg/min to 16.0 +/- 3.6 ml/kg/min (p = 0.016), whereas LVEDD decreased from 8.4 +/- 0.6 cm to 6.6 +/- 0.3 cm (p < 0.001), left ventricular end-systolic diameter from 6.8 +/- 0.8 cm to 5.3 +/- 0.5 cm (p < 0.001), and mitral incompetence from 2.4 +/- 0.6 to 0.9 +/- 0.6 (p < 0.001). Pulmonary pressures and fractional shortening did not change significantly (p > 0.05). Four patients received an implantable cardioverter/defibrillator as a result of their pathologic electrophysiologic examination. CONCLUSIONS: In carefully selected patients, PLV combined with MVR achieves short-term results comparable to that after heart transplantation. However, long-term results and multicenter evaluation will be needed to define its place in the treatment of advanced heart failure.

Long-term support of 9 patients with the DeBakey VAD for more than 200 days.

OBJECTIVE: Pulsatile left ventricular assist devices serving as mechanical circulatory support for patients with end-stage heart failure are associated with complications, including bleeding, thromboembolism, and infection. Axial-flow pumps might overcome some of these shortcomings. Here we report our experience with long-term application of the DeBakey VAD (MicroMed Technology, Inc, Houston, Tex). METHODS: Nine male transplant candidates (37 +/- 14 years) with severe hemodynamic compromise (cardiac index, 1.6 +/- 0.5 L . min(-1) x m(-2); pulmonary capillary wedge pressure, 27 +/- 6 mm Hg) and beginning end-organ failure despite inotropic and intra-aortic balloon pump support received the DeBakey VAD. Clinical outcome was evaluated. RESULTS: Cumulative support was 7.8 years, and the mean duration of support was 314 +/- 75 days (range, 229-438 days). Eight patients were transplanted, and one died from intracerebral bleeding. Peripheral circulation and end-organ function recovered rapidly after implantation. Continuous flow was able to maintain adequate organ perfusion over the long term. Eight patients were discharged during support, with good quality of life. There were no early bleedings, but there were late bleedings in 3 patients caused by excessive anticoagulation and platelet inhibition. Neurologic events occurred in 4 patients. Three patients recovered completely from symptoms, and one had lethal intracerebral bleeding. Because of thrombus formation, the device was exchanged in 4 patients. With increasing experience, thrombolysis was performed in similar situations. All such patients underwent successful transplantation. Hemolysis occurred, with events indicating thrombus formation. Device-related infection was found in one patient. CONCLUSIONS: The DeBakey VAD demonstrated its potential for long-term bridge to transplantation. The risk for thrombus formation needs to be addressed by improvement of pump technology and new strategies for platelet inhibition.