William H. Frist

Chronic injury of human renal microvessels with low-dose cyclosporine therapy

Physiologic and morphologic techniques were used to study kidneys of cardiac transplant recipients treated with either low-dose (low-CsA) or high-dose (high-CsA) cyclosporine. After 12 months both low-CsA (4.6 +/- 0.4) and high-CsA (6.3 +/- 0.3 mg/Kg/24 hr, p less than 0.01) were associated with azotemia and hypertension; GFR with each regimen was depressed below values in a third group treated without CsA (no-CsA) by 40-47%, while corresponding renal vascular resistance was elevated greater than 2-fold (P less than 0.01). Morphologic changes in both CsA groups included an obliterative arteriolopathy with downstream collapse or sclerosis of glomeruli. Determination of renal arcuate vein occlusion pressure revealed an increasing renal artery-to-peritubular capillary pressure gradient between 1 and 12 months of CsA therapy. Fractional clearances of dextrans of graded size were elevated at each time compared with the no-CsA group. Analysis of dextran transport with an isoporous membrane model indicates that transglomerular hydraulic pressure difference (delta P) approximated 39 with no-CsA, but was reduced with low-CsA therapy to about 30 at 1 month, and about 34 mmHg after 12 months. We conclude that chronic CsA therapy induces constriction and eventual occlusion of afferent arterioles, causing downstream glomerular damage that is irreversible. Low versus high dosage of CsA confers only marginal protection against this serious microvascular injury.

Predictors of operative mortality in critical valvular aortic stenosis presenting in infancy

Congenital aortic stenosis presenting within the first 6 months of life is a highly lethal anomaly. Although aortic valvotomy has offered excellent palliation in many instances, the operative risk remains substantial. To better understand the factors associated with a poor operative result, the records of all patients less than 6 months of age undergoing aortic valvotomy at our institution from 1972 through 1986 were analyzed. Nineteen patients (58%) (Group I) survived operation; 14 (42%) (Group II) died. The following variables were analyzed in an attempt to define those with prognostic significance: mean pulmonary artery pressure (PAP), left ventricular (LV) peak systolic pressure, LV end-diastolic pressure, peak systolic aortic valve gradient, LV end-diastolic volume (LVEDV), LV ejection fraction, and age at operation. The only variables that were significantly different in the two groups were mean PA (Group I, 29 +/- 3 mm Hg, and Group II, 54 +/- 3 mm Hg; p less than 0.001) and LVEDV (Group I, 50 +/- 8 ml/m2, and Group II, 20 +/- 4 ml/m2; p less than 0.05). No patient with an LVEDV of 20 ml/m2 or less survived operation. We conclude that small LV dimension and elevation of PAP may be predictive of a poor surgical result in patients with severe aortic stenosis presenting in infancy.

Induction of acidic fibroblast growth factor and full-length platelet-derived growth factor expression in human cardiac allografts. Analysis by PCR, in situ hybridization, and immunohistochemistry.

BackgroundFurther understanding of cardiac allograft vasculopathy (CAV) is needed to improve long-term survival after cardiac transplantation. The diffuse hyperplasia of coronary intima characteristic of CAV suggests that growth factors may play a role in the development of CAV. Fibroblast growth factor (FGF) and platelet-derived growth factor (PDGF) are potent mitogens for smooth muscle cells (SMCs), and PDGF is an important cofactor in the pathogenesis of native coronary atherosclerosis. Methods and ResultsReverse transcriptase/polymerase chain reaction (RT/PCR), in situ hybridization, and immuno-histochemistry were used to determine whether transplantation results in increased cardiac expression of acidic (a)FGF, basic (b)FGF, and PDGF-A and -B chains. Sixty-eight myo-cardial biopsies from 36 heart transplant recipients and 7 normal hearts were analyzed by PCR. aFGF mRNA was present in 54 of 61 allograft biopsies and was not found in any normal heart. In situ hybridization and immunohistochemistry demonstrated diffuse, intense expression of aFGF mRNA and protein in allograft biopsies, predominantly in myocytes and vascular walls. Only scattered aFGF expression was observed in normal hearts. mRNA for the full-length isoform of PDGF-A chain was found in 43 of 61 allograft biopsies and was not detected in any normal heart. In situ hybridization and immunohistochemistry confirmed that full-length PDGF-A chain mRNA and PDGF protein were present in myocytes and vascular walls. ConclusionsExpression of aFGF and PDGF-A chain is significantly increased in cardiac allografts. Cardiac myocytes and vascular walls are the predominant sources of aFGF and PDGF. Diffuse expression of these growth factors in cardiac allografts may be important in the pathogenesis of CAV.

Cardiac surgery in patients age 80 years or older.

Between February 1978 and August 1989, forty patients aged 80 years or older underwent cardiac surgery at this institution. Patient age varied from 80 to 87 years (mean, 82.4 years). Operative indications were angina pectoris or congestive heart failure. Twenty-eight patients underwent coronary artery bypass (CAB) alone and 12 underwent valve replacement(s) with or without CAB. The operative mortality rate was 10%. Postoperative hospitalization averaged 14 days. There were three late cardiac deaths at 13, 36, and 48 months after operation and one late noncardiac death. Thirty-two survivors have been followed from 1 to 86 months (mean, 20 months). All experienced sustained improvement in functional status and minimal late morbidity. All survivors remained in NYHA class 1 or 2. Cardiac surgical procedures in patients older than 80 years can be performed with increased but acceptable mortality and morbidity rates. Most patients achieve sustained symptomatic improvement and excellent long-term survival.

Expression of cytokine genes in human cardiac allografts: correlation of IL‐6 and transforming growth factor‐beta (TGF‐β) with histological rejection

Cytokines may play critical roles in allograft rejection. Currently, a clear pattern of cytokine production that correlates with rejection has not emerged. Our preliminary studies suggested a trend toward increased IL‐6 and TGF‐β gene expression in cardiac allografts during rejection. We have extended these studies using reverse transcriptase/polymerase chain reaction (RT/PCR) to detect the expression of IL‐6. TGF‐β, and T cell receptor β chain constant region (TCR‐β genes in 21 additional consecutive myocardial biopsies obtained from six heart transplant patients and from five pre‐transplant donor hearts. Cytokine gene expression was compared with histological diagnosis of rejection. There was strong correlation between IL‐6 as well as TGF‐β gene expression, and histological rejection (6/8 biopsies with versus 0/7 without rejection (P = 0.006) and 7/9 biopsies with versus 0/7 without rejection (P=0.003) respectively). Neither IL‐6 nor TGF‐β transcripts were detected in any pre‐transplant donor heart. TCR‐β chain mRNA was found in all allograft biopsies regardless of the presence of rejection, but was absent in pre‐transplant donor hearts. Our results indicate that expression of IL‐6 and TGF‐β is highly correlated with allograft rejection and thus may play an important role in regulation of cardiac ailograft rejection. T cell infiltration of allografted myocardium is invariably detected by PCR regardless of histological rejection. The long‐term functional significance of these cells in transplanted hearts needs further investigation.

The expression of acidic fibroblast growth factor (heparin-binding growth factor-1) and cytokine genes in human cardiac allografts and T cells.

The purpose of this study was to investigate the role of cytokines and growth factors in cardiac allograft rejection and vasculopathy (CAV). The polymerase chain reaction (PCR) was used to detect the expression of IL-1, IL-2, IL-4, IL-5, IL-6, TNF-alpha, IFN-gamma, TGF-beta, TCR-beta chain and aFGF genes in 21 myocardial biopsies obtained from 9 heart transplant patients. There was no statistically significant correlation between cytokine gene expression and rejection, although a trend toward increased IL-6 and TGF-beta expression was noted with rejection (6 of 10 biopsies with vs. 1 of 7 without rejection, and 4 of 9 biopsies with vs. none of 7 without rejection, respectively). IL-2 gene expression was detected in only 2 of 21 biopsies, both positive for rejection. IL-1, IL-4, IL-5, CD8, IFN-gamma, and TNF-alpha were not detected in any of the biopsies. TCR-beta chain mRNA was found in all biopsies, indicating the invariable presence of T cells regardless of histologic diagnosis of rejection. The aFGF gene was expressed in the majority (18 of 21) of biopsies, and its presence was not correlated with rejection. In addition to mRNA for the complete coding sequence of aFGF, two alternatively spliced mRNAs for aFGF were present in myocardial biopsies. Because aFGF and TCR beta genes were expressed in most biopsies, we determined whether aFGF mRNA was expressed in T cells; aFGF transcripts were found in 2 of 5 T-cell clones examined. Thus, aFGF mRNA in cardiac allografts may have been induced within the myocardium or elaborated by infiltrating T cells. The presence of mRNA for aFGF, a potent endothelial and smooth muscle cell mitogen, in allograft myocardium suggests that aFGF may play a role in the pathogenesis of CAV.

Vital Directions for Health and Health Care: Priorities From a National Academy of Medicine Initiative

Importance Recent discussion has focused on questions related to the repeal and replacement of portions of the Affordable Care Act (ACA). However, issues central to the future of health and health care in the United States transcend the ACA provisions receiving the greatest attention. Initiatives directed to certain strategic and infrastructure priorities are vital to achieve better health at lower cost. Objectives To review the most salient health challenges and opportunities facing the United States, to identify practical and achievable priorities essential to health progress, and to present policy initiatives critical to the nation’s health and fiscal integrity. Evidence Review Qualitative synthesis of 19 National Academy of Medicine–commissioned white papers, with supplemental review and analysis of publicly available data and published research findings. Findings The US health system faces major challenges. Health care costs remain high at

MRI Complements Standard Assessment of Right Ventricular Function After Lung Transplantation

3.2 trillion spent annually, of which an estimated 30% is related to waste, inefficiencies, and excessive prices; health disparities are persistent and worsening; and the health and financial burdens of chronic illness and disability are straining families and communities. Concurrently, promising opportunities and knowledge to achieve change exist. Across the 19 discussion papers examined, 8 crosscutting policy directions were identified as vital to the nation’s health and fiscal future, including 4 action priorities and 4 essential infrastructure needs. The action priorities—pay for value, empower people, activate communities, and connect care—recurred across the articles as direct and strategic opportunities to advance a more efficient, equitable, and patient- and community-focused health system. The essential infrastructure needs—measure what matters most, modernize skills, accelerate real-world evidence, and advance science—were the most commonly cited foundational elements to ensure progress. Conclusions and Relevance The action priorities and essential infrastructure needs represent major opportunities to improve health outcomes and increase efficiency and value in the health system. As the new US administration and Congress chart the future of health and health care for the United States, and as health leaders across the country contemplate future directions for their programs and initiatives, their leadership and strategic investment in these priorities will be essential for achieving significant progress.

Modification of alternative messenger RNA splicing of fibroblast growth factor receptors in human cardiac allografts during rejection.

BACKGROUND Changes in right ventricular mass and ejection fraction after single-lung transplantation for pulmonary hypertension are poorly understood. METHODS To complement functional data provided by echocardiography, radionuclide ventriculography, and right heart catheterization, magnetic resonance imaging was used to assess right ventricular function in 5 single-lung transplant recipients with preoperative pulmonary hypertension and right ventricular dysfunction (right ventricular ejection fraction, 0.21 +/- 0.09). The right and left ventricular mass, ejection fraction, and mass ratio (left ventricular mass/right ventricular mass) were calculated from the magnetic resonance images. RESULTS The mean pulmonary artery pressure fell from 72 +/- 18 to 21 +/- 8 mm Hg after transplantation. At 3 months after transplantation both the left ventricular and right ventricular ejection fractions approached normal values, as shown by both radionuclide ventriculography and magnetic resonance imaging, but the right ventricular mass remained abnormally high with slightly low mass ratios. By 1 year both the left ventricular and right ventricular masses had regressed to normal with near-normal mass ratios. CONCLUSIONS Right ventricular performance returns to nearly normal early after transplantation, but the right ventricular mass regresses over a more prolonged time. Cine magnetic resonance imaging provides a noninvasive means of assessing changes in right ventricular function and mass after lung transplantation.

Confirmation of alternatively spliced platelet-derived growth factor-A chain and correlation with expression of PDGF receptor-alpha in human cardiac allografts.

Accelerated coronary atherosclerosis in cardiac transplants (cardiac allograft vasculopathy, CAV) is characterized by coronary intimal hyperplasia. Acidic fibroblast growth factor (aFGF) is a potent mitogen for vascular smooth muscle cells and endothelial cells, and its expression is increased in cardiac allografts, suggesting it may play a role in the pathogenesis of CAV. The activity of aFGF is dependent on binding to transmembrane receptors. To investigate whether receptors for aFGF are also induced after transplantation, polymerase chain reaction, in situ hybridization, and immunohistochemistry were used to analyze expression of four receptors for aFGF (FGFR1-FGFR4). Expression of mRNA encoding extracellular immunoglobulin-like domains of FGFR1 was increased 35-fold in cardiac allografts compared with normal hearts and was predominantly present in cardiac myocytes and vascular structures. Alternatively spliced mRNA that encodes transmembrane forms of FGFR1, which contain the signal-transducing tyrosine kinase domains, was induced in allografts during rejection, in infiltrating cells, vascular structures, and myocytes. In vitro experiments showed that differential expression of FGF receptor isoforms was induced by aFGF, and also by IL-6 and TGF-beta, which are expressed in cardiac allografts during rejection. The results show that expression of both aFGF and its receptors is altered in cardiac allografts and suggest that these events are important in the pathogenesis of CAV.