Roy G. Masters

Discoordinate Modulation of Natriuretic Peptides During Acute Cardiac Allograft Rejection in Humans

BACKGROUND Increased circulating levels of the cardiac polypeptide hormones atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) may be observed after orthotopic cardiac transplantation. Both the hypertrophic and inflammatory processes in the allograft may contribute to this increase, but no mechanistic explanation has been suggested for this observation. METHODS AND RESULTS Plasma immunoreactive ANF and BNP determinations were performed in 10 consecutive transplant patients. These were correlated with degree of rejection as reflected by histopathological findings at serial endomyocardial biopsies. Three patients had associated hemodynamic measurements and blood samples 24 hours before and after transplantation. All rejection episodes that received treatment were accompanied by a marked increase in BNP plasma levels to > approximately 400 pg/mL. Steadily increasing BNP levels preceded overt rejection as assessed by histopathological criteria. The increase in plasma BNP was not always accompanied by an increase in ANF, which suggests the specific upregulation of BNP gene expression during acute rejection episodes. Treatment of the acute rejection episodes led to a substantial decrease of BNP plasma levels. CONCLUSIONS The significant selective increase in plasma BNP levels found in the present study has not been previously described. This finding provides a new insight into the mechanism of allograft rejection and the modulation of natriuretic peptide synthesis and release. Furthermore, although preliminary, the data suggest that BNP plasma levels could form the basis for a new, noninvasive screening test to predict acute cardiac allograft rejection. Because treatment with the antilymphocyte monoclonal antibody OKT3 (murine monoclonal antibody to the CD3 antigen of the human T-cell) decreased BNP plasma levels, cytokine production by T-cells may mediate the selective increase in circulating BNP.

Very Long-Term Survival Implications of Heart Valve Replacement With Tissue Versus Mechanical Prostheses in Adults <60 Years of Age

Background— Several centers favor replacing a diseased native heart valve with a tissue rather than a mechanical prosthesis, even in younger adult patients. However, long-term data supporting this approach are lacking. We examined the survival implications of selecting a tissue versus a mechanical prosthesis at initial left-heart valve replacement in a cohort of adults <60 years of age who were followed for over 20 years. Methods and Results— Comorbid and procedural data were available from 6554 patients who underwent valve replacement at our institution over the last 35 years. Of these, 1512 patients contributed follow-up data beyond 20 years, of whom 567 were adults <60 years of age at first left-heart valve operation (mean survivor follow-up, 24.0±3.1 years). Late outcomes were examined with Cox regression. Valve reoperation, often for prostheses that are no longer commercially available, occurred in 89% and 84% of patients by 20 years after tissue aortic and mitral valve replacement, respectively, and was associated with a mortality of 4.3%. There was no survival difference between patients implanted with a tissue versus a mechanical prosthesis at initial aortic valve replacement (hazard ratio 0.95; 95% CI: 0.7, 1.3; P=0.7). For mitral valve replacement patients, long-term survival was poorer than after aortic valve replacement (hazard ratio 1.4; 95% CI: 1.1, 1.8; P=0.003), but again no detrimental effect was associated with use of a tissue versus a mechanical prosthesis (hazard ratio 0.9; 95% CI 0.5, 1.4; P=0.5). Conclusions— In our experience, selecting a tissue prosthesis at initial operation in younger adults does not negatively impact survival into the third decade of follow-up, despite the risk of reoperation.

Natriuretic Peptide System Gene Expression in Human Coronary Arteries

The natriuretic peptides (NPs) ANF, BNP, and CNP have potent anti-proliferative and anti-migratory effects on vascular smooth muscle cells (SMCs). These properties make NPs relevant to the study of human coronary atherosclerosis because vascular cell proliferation and migration are central to the pathophysiology of atherosclerosis. However, the existence and cytological distribution of NPs and their receptors in human coronary arteries remain undetermined. This has hampered the development of hypotheses regarding the possible role of NPs in human coronary disease. We determined the pattern of expression of NPs and their receptors (NPRs) in human coronary arteries with atherosclerotic lesions classified by standard histopathological criteria as fatty streak/early atherosclerotic lesions, intermediate plaques, or advanced lesions. The investigation was carried out using a combination of immunocytochemistry (ICC), in situ hybridization (ISH), and semiquantitative polymerase chain reaction (PCR). Both by ICC and ISH, ANF was found in the intimal and medial layers of all lesions. BNP was highly expressed in advanced lesions where it was particularly evident by a strong ISH signal but weak ICC staining. CNP was demonstrable in all types of lesions, giving a strong signal by ISH and ICC. This peptide was particularly demonstrable in the endothelium, as well as in the SMCs of the intima, media, and vasa vasorum of the adventitia and in macrophages. By ISH, NPR-A was not detectable in any of the lesions but both NPR-B and NPR-C were found in the intimal and the inner medial layers. By RT-PCR, mRNA levels of all NPs tended to be increased in macroscopically diseased arteries, but only the values for BNP were significantly so. No significant changes in NPR mRNA levels were detected by PCR. In general, the signal intensity given by the NPs and their receptors by ICC or ISH appeared dependent on the type of lesion, being strongest in intermediate plaques and decreasing with increasing severity of the lesion. This study constitutes the first demonstration of NPs and NPR mRNAs in human coronary arteries and supports the existence of an autocrine/paracrine NP system that is actively modulated during the progression of atherosclerotic coronary disease. This suggests that the coronary NP system is involved in the pathobiology of intimal plaque formation in humans and may be involved in vascular remodeling.

Giant cell myocarditis: clinical presentation, bridge to transplantation with mechanical circulatory support, and long-term outcome

BACKGROUND The multicenter Giant Cell Myocarditis Registry recorded 64 cases from 36 centers before 1996. The median transplant-free survival of 30 patients without immunosuppression was 3 months. Of 34 patients who received heart transplantations, 9 experienced recurrence of giant cell myocarditis in their transplanted hearts and 1 patient died. METHODS We reviewed our experience in 340 heart transplantations since 1984. Unexpected giant cell myocarditis was found in the explanted hearts of 7 patients (6 men and 1 female, aged 18-65 years). RESULTS The duration from the onset of symptoms to assist-device implant or transplantation ranged from 11 days to 9 years, whereas the time interval from referral or deterioration ranged from 2 days to 4 months. Four patients required mechanical circulatory support before surgery (total artificial hearts in 2 and left ventricular assist devices in 2), and 3 patients required inotropic drugs. Six patients are alive with no sign of recurrent giant cell myocarditis at 12 to 113 months after surgery. One patient died suddenly 75 months after surgery, and autopsy showed severe graft vascular disease with no recurrence of giant cell myocarditis. Surveillance, right ventricular endomyocardial biopsy specimens showed recurrent asymptomatic giant cell myocarditis in 3 patients at 5 to 13 months after surgery, and found recurrence in 1 patient 30 months after surgery. This patient received augmented immunosuppression. CONCLUSIONS Giant cell myocarditis often is not diagnosed before transplantation. It can present as dilated cardiomyopathy with late deterioration, or it can present with rapid hemodynamic deterioration. In our experience, these patients can be bridged successfully to transplant with mechanical circulatory assist. Giant cell myocarditis may recur after transplantation but may respond to augmented immunosuppression.

Reoperation of Left Heart Valve Bioprostheses According to Age at Implantation

Background— Evidence supporting the use of bioprostheses for heart valve replacement in young adults is accumulating. However, reoperation data, which may help guide clinical decision making in young patients, remains poorly defined in the literature. Methods and Results— We examined the need for reoperation in 3975 patients who underwent first-time bioprosthetic aortic valve replacement (AVR) (n=3152) or mitral valve replacement (MVR) (n=823). There were 895 patients below the age of 60 years at bioprosthesis implant (AVR, n=636; MVR, n=259). The median interval to reoperation of contemporary, stented aortic bioprostheses was 7.74 years (95% CI 7.28 to 9.97 years) in patients less than 40 years, and 12.93 years (95% CI 11.10 to 15.76 years) in patients between 40 and 60 years of age. Multivariable risk factors associated with reoperation following bioprosthetic AVR include age (hazard ratio [HR] 0.94 per year, 95% CI 0.91 to 0.96, P<0.001) and concomitant coronary artery bypass grafting (HR 0.34, 95% CI 0.11 to 0.99, P=0.04). The median interval to reoperation of contemporary mitral bioprostheses was 8.11 years (95% CI 5.79 to 16.50 years) in patients less than 40 years, and 10.14 years (95% CI 8.64 to 11.14 years) in patients between 40 and 60 years of age. As for AVR, age (HR 0.96 per year, 95% CI 0.95 to 0.98, P<0.001) and concomitant coronary artery bypass grafting (HR 0.55, 95% CI 0.32 to 0.93, P=0.03) were associated with decreased reoperation risk following bioprosthetic MVR. Conclusions— These data constitute clinically relevant age-specific prognostic information regarding reoperation in young patients, who may wish to select a bioprosthesis at initial left heart valve replacement.

Left ventricular assist devices as bridge to heart transplantation in congestive heart failure with pulmonary hypertension.

Severe pulmonary hypertension (PH) has been considered a significant contraindication to cardiac transplantation. Ongoing clinical experience, however, has shown that temporary support using left ventricular assist devices (LVADs) in these patients can result in significant reductions in PH. A comprehensive review of the available literature regarding the use of LVADs in heart failure patients with PH was conducted. The existing literature to date supports the use of LVADs in heart failure patients with PH and demonstrates that significant reductions in PH in these patients can be achieved. This subsequently allows for safe and effective cardiac transplantation in patients who were previously excluded from this modality. For heart failure patients with severe PH, the use of LVADs can provide significant benefits by significantly reducing PH and allowing subsequent staged transplantation.

Gender differences in the long-term outcomes after valve replacement surgery

Objective: To compare the long-term outcomes in women and men after valve replacement surgery. Design: Observational study. Setting: Postoperative aortic valve replacement (AVR) or mitral valve replacement (MVR). Patients: 3118 patients (1261 women, 1857 men) who underwent AVR or MVR between 1976 and 2006 (2255 AVR, 863 MVR), with mean follow-up of 5.6 (4.5) years. Main outcome measures: The independent effect of gender on the risk of long-term complications (reoperation, stroke and death) after valve replacement surgery using multivariate actuarial methods. Results: After implantation of an aortic valve bioprosthesis, women had a significantly lower rate of reoperation compared to men (comorbidity-adjusted hazard ratio (HR) 0.4; 95% confidence intervals (CI) 0.2 to 0.9). In contrast, if an aortic mechanical prosthesis had been implanted, women were more at risk for late stroke compared to men (HR 1.7; CI 1.1 to 2.7). After adjustment for age and co-morbidities, women had significantly better long-term survival compared to men after bioprosthetic AVR (HR 0.5; CI 0.3 to 0.6), but there was no survival difference between genders after mechanical AVR. Trends existed towards better survival for women after bioprosthetic MVR (HR 0.6; CI 0.4 to 1.0) and mechanical MVR (HR 0.8; CI 0.5 to 1.1). Conclusion: The long-term outcomes after valve replacement surgery differ between women and men. Although women have more late strokes after valve replacement, they undergo fewer reoperations and have better overall long-term survival compared to men.

Statin Therapy and Saphenous Vein Graft Disease After Coronary Bypass Surgery: Analysis From the CASCADE Randomized Trial

BACKGROUND Current guidelines recommend statin therapy after coronary artery bypass grafting (CABG) to attain low-density lipoprotein (LDL) levels less than 100 mg/dL. Whether achieving LDL levels less than 70 mg/dL improves postoperative graft patency remains unknown. METHODS The CASCADE (Clopidogrel after Surgery for Coronary Artery Disease) trial was a randomized study that evaluated the addition of clopidogrel to aspirin on the development of saphenous vein graft disease after CABG. Patients received the standard of care regarding postoperative statin therapy with targeted LDL levels less than 100 mg/dL. Twelve months postoperatively, patients returned for a coronary angiogram and saphenous vein graft (SVG) intravascular ultrasonogram. In this post hoc analysis, the impact of statin therapy on graft patency and vein graft intimal hyperplasia was assessed. RESULTS LDL levels significantly declined over the period of the trial (p = 0.002). Twelve months postoperatively, 58.4% patients achieved LDL levels less than 70 mg/dL. Twelve-month graft patency was higher for patients with LDL levels less than 100 mg/dL (96.5%) compared with patients with LDL levels >100 mg/dL (83.3%, p = 0.03), even after adjustment in multivariate analysis (odds ratio [OR], 5.2; 95% confidence interval [CI], 1.3-21.6; p = 0.02). However, no improvement in graft patency was noted with further LDL reduction to less than 70 mg/dL (p = 1.00). Consistent statin use throughout the trial period was independently associated with less vein graft intimal hyperplasia documented by intravascular ultrasound at 12 months (p = 0.04). CONCLUSIONS Statin therapy to achieve LDL levels less than 100 mg/dL was independently associated with improved graft patency in the CASCADE trial. Randomized clinical trials are warranted to prospectively evaluate postoperative LDL reduction to less than 70 mg/dL and its impact on graft patency after CABG.

Relationship between natriuretic peptides and inflammation: proteomic evidence obtained during acute cellular cardiac allograft rejection in humans.

BACKGROUND Cardiac natriuretic peptides (NPs) atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) are polypeptide hormones secreted by the heart. Previously, we found that BNP, but not ANF, plasma levels may increase during an acute cellular cardiac allograft rejection episode. In vitro, the pro-inflammatory cytokines interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) produced a selective increase of BNP gene expression and secretion. Other pro-inflammatory cytokines had no such effects. METHODS We identified cytokines associated with the selective upregulation of BNP during cardiac allograft rejection using a proteomics approach to measure 120 cytokines and related substances in the plasma of 16 transplant patients before, during and after an acute rejection episode. The values obtained were correlated with BNP plasma levels. Cytokines identified as being significantly related to BNP plasma levels were tested in neonatal rat ventricular cardiocytes in culture for their ability to selectively promote BNP secretion. The signaling pathway related to this phenomenon was pharmacologically characterized. RESULTS Regulated-on-activation, normal T-expressed and secreted (RANTES), neutrophil-activating protein-2 (NAP-2) and insulin growth factor binding protein-1 (IGFBP-1) had significant correlations with BNP plasma levels during Grade 3A (Grade 2 revised [2R]) or above rejection as diagnosed by endomyocardial biopsy score according to the International Society for Heart and Lung Transplantation (ISHLT) grading system. In rat neonatal ventricular cardiocyte cultures, IGFBP-1 and RANTES were capable of promoting BNP, but not ANF secretion, as observed in rejecting patients. The BNP-promoting secretion activity of the identified cytokines was abolished by SB203580, a specific p38 MAP kinase inhibitor. CONCLUSIONS This work shows that cytokines other than pro-inflammatory cytokines correlate with BNP plasma levels observed during acute cardiac allograft rejection, and that the substances identified have in common p38 signaling. This finding provides a unifying mechanistic explanation regarding the relationship between inflammation and cardiac hormone production in acute cardiac allograft rejection.

A transcutaneous energy and information transfer system for implanted medical devices.

During the last four decades there has been a rapid increase in the development and usage of medical devices. Currently, there are more than 500,000 devices on the market and 25,000 new devices enter the market each year. Many medical devices are now designed to be implantable (pacemakers, defibrillators, circulatory assist devices, artificial hearts, cochlear implants, neuromuscular stimulators, biosensors, etc.). Almost all of the active devices (those that perform work) and many of the passive devices (those that do not perform work) require a source of power. In addition, these devices need to be monitored and controlled, which can be accomplished by utilizing remote communication methods. A transcutaneous energy transfer system combined with a remote communications system has been developed and evaluated in vitro and in vivo (bovine, porcine, and human cadaver experiments). The energy transfer system can deliver up to 60 W with power transfer efficiencies between 60 and 83%. An automatically tuned, resonant frequency tracking method is used to obtain optimum power transfer over a range of operating conditions. The remote communications system can transfer digital data bidirectionally through intact skin at rates up to 9600 baud. The system transmits information by frequency modulating an 890 nm infrared carrier signal. The system has demonstrated satisfactory performance during multicenter evaluation with ventricular assist and total artificial heart devices. Design improvements have been identified, which will be implemented to produce an optimized system for energy transfer to and remote communications with various implantable medical devices.