Simon G Williams

Neuroendocrine Effects on the Heart and Targets for Therapeutic Manipulation in Heart Failure

Chronic heart failure (CHF) involves derangements in multiple neurohormonal axes leading to a procatabolic state and wasting syndrome associated with significant mortality. Catabolic abnormalities include excess catecholamines and glucocorticoids. Anabolic defects include deficiencies of sex steroids, insulin resistance, and growth hormone (GH) resistance. These abnormalities are also correlated with increased morbidity and mortality in CHF. Anabolic axes have been augmented in pilot studies in CHF with testosterone, GH, insulin-like growth factor-1, and GH secretagogues. Results have been varied although some treatments have been associated with improved surrogate endpoints. This review article explores the current understanding of metabolic derangements in CHF and highlights potential neuroendocrine treatment strategies.

Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling

The type I interferon system is integral to human antiviral immunity. However, inappropriate stimulation or defective negative regulation of this system can lead to inflammatory disease. We sought to determine the molecular basis of genetically uncharacterized cases of the type I interferonopathy Aicardi-Goutières syndrome and of other undefined neurological and immunological phenotypes also demonstrating an upregulated type I interferon response. We found that heterozygous mutations in the cytosolic double-stranded RNA receptor gene IFIH1 (also called MDA5) cause a spectrum of neuroimmunological features consistently associated with an enhanced interferon state. Cellular and biochemical assays indicate that these mutations confer gain of function such that mutant IFIH1 binds RNA more avidly, leading to increased baseline and ligand-induced interferon signaling. Our results demonstrate that aberrant sensing of nucleic acids can cause immune upregulation.

Predicting death due to progressive heart failure in patients with mild-to-moderate chronic heart failure

OBJECTIVES The aim of this study was to explore the value of noninvasive predictors of death/mode of death in ambulant outpatients with chronic heart failure (HF). BACKGROUND Mortality in chronic HF remains high, with a significant number of patients dying of progressive disease. Identification of these patients is important. METHODS We recruited 553 ambulant outpatients age 63 +/- 10 years with symptoms of chronic HF (New York Heart Association functional class, 2.3 +/- 0.5) and objective evidence of left ventricular dysfunction (ejection fraction <45%, cardiothoracic ratio >0.55, or pulmonary edema on chest radiograph). After 2,365 patient-years of follow-up, 201 patients had died, with 76 events due to progressive HF. RESULTS Independent predictors of all-cause mortality assessed with the Cox proportional hazards model were as follows: a low standard deviation of all normal-to-normal RR intervals (SDNN); lower serum sodium and higher creatinine levels; higher cardiothoracic ratio; nonsustained ventricular tachycardia; higher left ventricular end-systolic diameter; left ventricular hypertrophy; and increasing age. Independent predictors of death specific to progressive HF were SDNN, serum sodium and creatinine levels. The hazard ratio of progressive HF death for a 10% decrease in SDNN was 1.06 (95% confidence interval [CI], 1.01 to 1.12); for a 2 mmol/l decrease in serum sodium, 1.22 (95% CI, 1.08 to 1.38); and for a 10 micromol/l increase in serum creatinine, 1.14 (95% CI, 1.09 to 1.19) (all p < 0.01). CONCLUSIONS In ambulant outpatients with chronic HF, low serum sodium and SDNN and high serum creatinine identify patients at increased risk of death due to progressive HF.

Comprehensive Validation of Cardiovascular Magnetic Resonance Techniques for the Assessment of Myocardial Extracellular Volume

Background— Extracellular matrix expansion is a key element of ventricular remodeling and a potential therapeutic target. Cardiovascular magnetic resonance (CMR) T1-mapping techniques are increasingly used to evaluate myocardial extracellular volume (ECV); however, the most widely applied methods are without histological validation. Our aim was to perform comprehensive validation of (1) dynamic-equilibrium CMR (DynEq-CMR), where ECV is quantified using hematocrit-adjusted myocardial and blood T1 values measured before and after gadolinium bolus; and (2) isolated measurement of myocardial T1, used as an ECV surrogate. Methods and Results— Whole-heart histological validation was performed using 96 tissue samples, analyzed for picrosirius red collagen volume fraction, obtained from each of 16 segments of the explanted hearts of 6 patients undergoing heart transplantation who had prospectively undergone CMR before transplantation (median interval between CMR and transplantation, 29 days). DynEq-CMR–derived ECV was calculated from T1 measurements made using a modified Look-Locker inversion recovery sequence before and 10 and 15 minutes post contrast. In addition, ECV was measured 2 to 20 minutes post contrast in 30 healthy volunteers. There was a strong linear relationship between DynEq-CMR–derived ECV and histological collagen volume fraction (P<0.001; within-subject: r=0.745; P<0.001; r 2=0.555 and between-subject: r=0.945; P<0.01; r 2=0.893; for ECV calculated using 15-minute postcontrast T1). Correlation was maintained throughout the entire heart. Isolated postcontrast T1 measurement showed significant within-subject correlation with histological collagen volume fraction (r=−0.741; P<0.001; r 2=0.550 for 15-minute postcontrast T1), but between-subject correlations were not significant. DynEq-CMR–derived ECV varied significantly according to contrast dose, myocardial region, and sex. Conclusions— DynEq-CMR–derived ECV shows a good correlation with histological collagen volume fraction throughout the whole heart. Isolated postcontrast T1 measurement is insufficient for ECV assessment.

Role of cardiac power in heart failure

The heart is a muscular mechanical pump with an ability to generate both flow (cardiac output) and pressure. The product of flow output and systemic arterial pressure is the rate of useful work done, or power output. Cardiac pumping capability can be defined as the cardiac power output (CPOmax) achieved by the heart during maximal stimulation. Cardiac reserve is the increase in power output as the cardiac performance is increased from the resting to the maximally stimulated state. Recently, several studies have shown that CPOmax, a direct indicator of overall cardiac function, measured directly or as an approximation, is a major determinant of exercise capacity and a most powerful predictor of prognosis for patients with chronic heart failure. The same holds true in acute heart failure, where it is also useful in subclassifying the conditions to select the appropriate treatment.

Germline Mutations in SUFU Cause Gorlin Syndrome–Associated Childhood Medulloblastoma and Redefine the Risk Associated With PTCH1 Mutations

PURPOSE Heterozygous germline PTCH1 mutations are causative of Gorlin syndrome (naevoid basal cell carcinoma), but detection rates > 70% have rarely been reported. We aimed to define the causative mutations in individuals with Gorlin syndrome without PTCH1 mutations. METHODS We undertook exome sequencing on lymphocyte DNA from four unrelated individuals from families with Gorlin syndrome with no PTCH1 mutations found by Sanger sequencing, multiplex ligation-dependent probe amplification (MLPA), or RNA analysis. RESULTS A germline heterozygous nonsense mutation in SUFU was identified in one of four exomes. Sanger sequencing of SUFU in 23 additional PTCH1-negative Gorlin syndrome families identified a SUFU mutation in a second family. Copy-number analysis of SUFU by MLPA revealed a large heterozygous deletion in a third family. All three SUFU-positive families fulfilled diagnostic criteria for Gorlin syndrome, although none had odontogenic jaw keratocysts. Each SUFU-positive family included a single case of medulloblastoma, whereas only two (1.7%) of 115 individuals with Gorlin syndrome and a PTCH1 mutation developed medulloblastoma. CONCLUSION We demonstrate convincing evidence that SUFU mutations can cause classical Gorlin syndrome. Our study redefines the risk of medulloblastoma in Gorlin syndrome, dependent on the underlying causative gene. Previous reports have found a 5% risk of medulloblastoma in Gorlin syndrome. We found a < 2% risk in PTCH1 mutation-positive individuals, with a risk up to 20× higher in SUFU mutation-positive individuals. Our data suggest childhood brain magnetic resonance imaging surveillance is justified in SUFU-related, but not PTCH1-related, Gorlin syndrome.

Computerized histomorphometric assessment of protocol renal transplant biopsy specimens for surrogate markers of chronic rejection.

BACKGROUND Chronic transplant rejection has emerged as the commonest cause of long-term renal allograft failure, and early identification of those grafts at risk could allow the targeting of specific therapies aimed at delaying this process. This study explores the usefulness of quantitative immunohistochemistry in defining biopsy-based surrogate markers of allograft damage. METHODS A consecutive series of 52 renal transplant recipients immunosuppressed with cyclosporine were studied. Needle core transplant biopsies were performed at 1, 3, and 6 months postoperatively. Immunostaining for collagen III, and smooth muscle actin, tenascin, and infiltrating leukocytes was performed using an indirect immunoperoxidase technique. The interstitial area stained (%) was measured using a semiautomatic image analysis system. The results were related to glomerular filtration rates (GFR) measured at 6, 12, and 24 months after transplantation using rank correlation coefficients. RESULTS The area fraction of immunostained collagen III correlated with 6-month GFR (r=-0.42, P=0.005) and was predictive of 12-month GFR (r=-0.32, P=0.03). An area fraction of immunostained collagen III of >40% at 6 months was associated with a significantly lower GFR at 24 months, compared with a percentage area of < or =40% (31+/-4 versus 45+/-4 ml/min/1.73 m2, P=0.01). Furthermore, a collagen III of >40% at 6 months identified patients who were at risk of progressive deterioration in graft function. CONCLUSIONS Grafts with poorer long-term function can be predicted using 6-month protocol biopsy specimens immunostained for collagen III. This should prove to be a useful ad interim surrogate marker of allograft damage in studies addressing the effects of new immunosuppressive agents on the development of chronic rejection.

UK guidelines for referral and assessment of adults for heart transplantation

Patients with advanced heart failure have a dismal prognosis and poor quality of life. Heart transplantation provides an effective treatment for a subset of these patients. This article provides cardiologists with up-to-date information about referral for transplantation, the role of left ventricular assist devices prior to transplant, patient selection, waiting-list management and donor heart availability. Timing is of central importance; patients should be referred before complications (eg, cardiorenal syndrome or secondary pulmonary hypertension) have developed that will increase the risk of, or potentially contraindicate, transplantation. Issues related to heart failure aetiology, comorbidity and adherence to medical treatment are reviewed. Finally, the positive role that cardiologists can play in promoting and facilitating organ donation is discussed.

Spinal c-fos induction by sensory stimulation in neonatal rats

C-fos immunocytochemistry was used to investigate the functional connectivity between primary afferent nociceptive fibres and second-order neurons in the spinal cord of the anaesthetised neonatal rat. Subcutaneous injection of 50 mg/kg capsaicin potently induced c-fos in the spinal cord on the first postnatal day (P1), whilst plantar injection of dilute formalin was much less effective until P3. In contrast with the adult, there was no c-fos response of the neonatal rat spinal cord to cutaneous application of the C-fibre irritant, mustard oil. It is concluded that spinal c-fos expression induced by noxious sensory stimulation can occur before the development of mature functional synaptic contact with first-order neurones.

Randomised study of endoscopic biliary endoprosthesis versus duct clearance for bileduct stones in high-risk patients

BACKGROUND The value of an endoprosthesis for long-term management of bileduct stones has not been formally established. The main theoretical advantage of endoprosthesis insertion (BE) over conventional endoscopic duct clearance (DC) is the prevention of stone impaction, with obstruction and consequent cholangitis or pancreatitis. In a randomised study we compared the results of these two methods in patients with symptomatic bileduct stones who were at high risk because of old age (> 70 yr) or serious debilitating disease. METHODS 43 high-risk patients were randomised to BE with a 7F double-pigtail endoprosthesis and < 0.75 cm sphincterotomy, and 43 to DC with standard 1.25-1.50 cm sphincterotomy and stone extraction by balloon or basket, with or without mechanical lithotripsy. The principal endpoint was the rate of biliary related complications. FINDINGS In the BE group biliary drainage was achieved in the first session in all but one patient (who required 2 sessions). In the DC group, 24 patients had duct clearance at the first attempt and 35 (81%) after a median of 2 sessions (range 2-4); eight of this group had an endoprosthesis inserted to maintain long-term drainage. At 72 h the complication rates were 7% in the BE group and 16% in the DC group (p = 0.18). However, the long-term complication rate for BE was higher: by Kaplan-Meier analysis, at a median of 20 months the proportions free of biliary complications were 64% BE and 86% DC (p = 0.03, log-rank test). INTERPRETATION For immediate bileduct drainage, endoprosthesis insertion proved a safe and effective alternative to duct clearance. Because of the risk of subsequent cholangitis, its use as a definitive treatment should be confined to highly selected cases.