Systemic amyloidosis from A (AA) to T (ATTR): a review.

Systemic amyloidosis is a rare protein misfolding and deposition disorder leading to progressive organ failure. There are over 15 types of systemic amyloidosis, each caused by a different precursor protein which promotes amyloid formation and tissue deposition. Amyloidosis can be acquired or hereditary and can affect various organs, including the heart, kidneys, liver, nerves, gastrointestinal tract, lungs, muscles, skin and soft tissues. Symptoms are usually insidious and nonspecific resulting in diagnostic delay. The field of amyloidosis has seen significant improvements over the past decade in diagnostic accuracy, prognosis prediction and management. The advent of mass spectrometry-based shotgun proteomics has revolutionized amyloid typing and has led to the discovery of new amyloid types. Accurate typing of the precursor protein is of paramount importance as the type dictates a specific management approach. In this article, we review each type of systemic amyloidosis to provide the practitioner with practical tools to improve diagnosis and management of these rare disorders.

Sensing with optical vortices in photonic-crystal fibers.

We demonstrate optical polarization vortex generation in a photonic-crystal fiber (PCF) by means of a CO(2) laser-induced long period grating. Vortices are a special subclass of fiber modes that result in polarization-insensitive resonances even when grating perturbations are asymmetric, as is the case with structural perturbations in single-material PCFs. The physics of vortex generation, combined with the use of structural perturbations alone, in single-material fibers, opens up a new schematic for realizing harsh-environment sensors. We show that the temperature and polarization stability of our vortex devices is maintained for prolonged periods of time (tested up to 34 h) at temperatures exceeding 1000 °C. We envisage that this demonstration opens up a new way of realizing high-temperature sensors in a cost-effective manner.

Stable low-loss optical nanofibres embedded in hydrophobic aerogel.

Nanofibres, optical fibres narrower than the wavelength of light, degrade in hours on exposure to air. We show that encapsulation in hydrophobic silica aerogel (refractive index 1.05) provides protection and stability (over 2 months) without sacrificing low attenuation, strong confinement and accessible evanescent field. The measured attenuation was <0.03 dB/mm, over 10 × lower than reported with other encapsulants. This enables many nanofibre applications based on their extreme small size and strong external evanescent field, such as optical sensors, nonlinear optics, nanofibre circuits and high-Q resonators. The aerogel is more than a waterproof box, it is a completely-compatible gas-permeable material in intimate contact with the nanofibre and hydrophobic on both the macroscopic and molecular scales. Its benefits are illustrated by experiments on gas sensing (exploiting the aerogel's porosity) and supercontinuum generation (exploiting its ultra-low index).

Silica aerogel core waveguide.

We have selectively filled the core of hollow photonic crystal fibre with silica aerogel. Light is guided in the aerogel core, with a measured attenuation of 0.2 dB/cm at 1540 nm comparable to that of bulk aerogel. The structure guides light by different mechanisms depending on the wavelength. At long wavelengths the effective index of the microstructured cladding is below the aerogel index of 1.045 and guidance is by total internal reflection. At short wavelengths, where the effective cladding index exceeds 1.045, a photonic bandgap can guide the light instead. There is a small region of crossover, where both index- and bandgap-guided modes were simultaneously observed.

Rationale, application and clinical qualification for NT-proBNP as a surrogate end point in pivotal clinical trials in patients with AL amyloidosis.

Amyloid light-chain (LC) amyloidosis (AL amyloidosis) is a rare and fatal disease for which there are no approved therapies. In patients with AL amyloidosis, LC aggregates progressively accumulate in organs, resulting in organ failure that is particularly lethal when the heart is involved. A significant obstacle in the development of treatments for patients with AL amyloidosis, as well as for those with any disease that is rare, severe and heterogeneous, has been satisfying traditional clinical trial end points (for example, overall survival or progression-free survival). It is for this reason that many organizations, including the United States Food and Drug Administration through its Safety and Innovation Act Accelerated Approval pathway, have recognized the need for biomarkers as surrogate end points. The international AL amyloidosis expert community is in agreement that the N-terminal fragment of the pro-brain natriuretic peptide (NT-proBNP) is analytically validated and clinically qualified as a biomarker for use as a surrogate end point for survival in patients with AL amyloidosis. Underlying this consensus is the demonstration that NT-proBNP is an indicator of cardiac response in all interventional studies in which it has been assessed, despite differences in patient population, treatment type and treatment schedule. Furthermore, NT-proBNP expression is directly modulated by amyloidogenic LC-elicited signal transduction pathways in cardiomyocytes. The use of NT-proBNP will greatly facilitate the development of targeted therapies for AL amyloidosis. Here, we review the data supporting the use of NT-proBNP, a biomarker that is analytically validated, clinically qualified, directly modulated by LC and universally accepted by AL amyloidosis specialists, as a surrogate end point for survival.

Pregnancy among women with congenitally corrected transposition of great arteries.

OBJECTIVES: The outcome of pregnancy in congenitally corrected transposition of the great vessels was studied in 22 women. BACKGROUND: Women with congenitally corrected transposition of the great vessels often reach childbearing age. Although reports on the outcome of pregnancy in these women are available, the number of patients is small. METHODS: The medical and surgical databases at the Mayo Clinic were reviewed, and 36 women >16 years old with congenitally corrected transposition of the great vessels were identified. All of them were contacted, and 22 who had pregnancies were identified and the outcome of pregnancy was evaluated. RESULTS: Twenty-two women had 60 pregnancies resulting in 50 live births (83%). Forty-four deliveries (88%) were vaginal and 6 (12%) were by cesarean section. One delivery was premature at 29 weeks. There was one successful twin pregnancy. There were 11 unsuccessful pregnancies. One patient developed congestive heart failure late in pregnancy because of systemic atrioventricular valve regurgitation and required valve replacement in the early postpartum period. One patient had a total of 12 pregnancies, including 1 twin pregnancy and 2 unsuccessful pregnancies. She had multiple pregnancy-related complications, including toxemia, congestive heart failure, endocarditis and myocardial infarction (single coronary artery). No other serious pregnancy-related maternal complications and no pregnancy-related deaths occurred. The mean birth weight of the infants (n = 32) was 3.2 +/- 0.4 kg. None of the 50 live offspring have been diagnosed with congenital heart disease. CONCLUSIONS: Successful pregnancy can be achieved in most women with congenitally corrected transposition of the great arteries. The rate of fetal loss and maternal cardiovascular morbidity is increased. Because of the small number of births, the risk of congenital heart disease in offspring of women with congenitally corrected transposition of the great arteries is uncertain.

Long-term outcome of patients with biopsy-proved myocarditis: comparison with idiopathic dilated cardiomyopathy.

OBJECTIVES: The study objectives were 1) to assess the long-term outcome of patients with biopsy-proved lymphocytic myocarditis (Dallas criteria), and 2) to compare the outcome of these patients with that of patients with idiopathic dilated cardiomyopathy. BACKGROUND: Endomyocardial biopsy is frequently performed in patients presenting with dilated cardiomyopathy to identify lymphocytic myocarditis. Most previous studies of the natural history of myocarditis were performed before the establishment of the Dallas criteria. Thus, it is important to evaluate the prognostic value of positive endomyocardial biopsy findings in patients presenting with dilated cardiomyopathy, using standardized criteria for lymphocytic myocarditis. METHODS: All endomyocardial biopsy results from the Mayo Clinic (October 1979 to April 1988) with a diagnosis of myocarditis were reclassified according to the Dallas criteria. Patients whose biopsy specimens showed borderline or lymphocytic myocarditis were included in the study group; those with systemic inflammatory diseases known to be associated with myocardial involvement were excluded. Study group survival was compared with that for a cohort of patients with idiopathic dilated cardiomyopathy seen at the Mayo Clinic from 1976 to 1987 who had endomyocardial biopsy findings negative for myocarditis. RESULTS: Biopsy specimens from 41 patients met the Dallas criteria for a diagnosis of myocarditis (n = 28) or borderline myocarditis (n = 13). Of these 41 patients, 9 were excluded because of the presence of systemic diseases known to be associated with myocarditis, and 5 patients were excluded because of lack of available follow-up data. The myocarditis study group therefore included 27 patients (10 with borderline myocarditis, 17 with myocarditis). Fifty-eight patients with a diagnosis of idiopathic dilated cardiomyopathy who underwent endomyocardial biopsy served as the comparison cohort. Ejection fraction was lower in patients with idiopathic dilated cardiomyopathy ([mean +/- SD] 25 +/- 11%) than in those with myocarditis (38 +/- 19%, p = 0.001), even though a higher proportion of myocarditis group patients were in New York Heart Association functional class III or IV (63%) than patients in the dilated cardiomyopathy group (30%, p = 0.005). There was no difference in 5-year survival rate between the myocarditis and idiopathic dilated cardiomyopathy groups (56% vs. 54%, respectively). CONCLUSIONS: This study demonstrates that the long-term outcome of patients with biopsy-proved myocarditis seen in a referral setting is poor, although no different from that of patients with idiopathic dilated cardiomyopathy. With the current lack of proved effective treatment for lymphocytic myocarditis and no demonstration of survival benefit for patients with myocarditis, these data suggest that endomyocardial biopsy performed to exclude myocarditis is of limited prognostic value in the routine evaluation of dilated cardiomyopathy.

Left ventricular dysfunction due to atrial fibrillation in patients initially believed to have idiopathic dilated cardiomyopathy.

Ten patients aged 22 to 80 years (median 57) with severe left ventricular (LV) dysfunction and atrial fibrillation (AF) with rapid ventricular response were evaluated after therapy. Because most patients were unaware of their arrhythmia, duration was usually unknown. All patients had heart failure symptoms; 9 presented with New York Heart Association class III or IV disability, and 1 with class II disability. Initial LV ejection fraction ranged from 12 to 30% (median 25). No patient had symptomatic coronary artery disease (4 underwent angiography). Myocarditis and infiltrative processes were excluded by biopsy in 5 patients. All patients were considered initially to have idiopathic dilated cardiomyopathy with secondary AF. Ventricular rate was controlled in all patients, with sinus rhythm restored in 5. At follow-up (median 30 months, range 3 to 56), all patients were asymptomatic. LV ejection fraction after treatment ranged from 40 to 64% (median 52). It is concluded that in some patients initially considered to have idiopathic dilated cardiomyopathy, AF with rapid ventricular response may be the primary cause rather than the consequence of severe LV dysfunction. LV dysfunction may be completely reversible with ventricular rate control.

Endomyocardial biopsy-proven light chain amyloidosis (AL) without echocardiographic features of infiltrative cardiomyopathy.

Amyloid cardiomyopathy may exist when echocardiography does not suggest infiltration. Clinicians should be alert for the presence of a monoclonal protein, nephrotic range proteinuria, or peripheral neuropathy in a patient with heart failure.

Five or more years of survival in patients with primary systemic amyloidosis and biopsy-proven cardiac involvement.

Survival of > or =5 years was seen in 8 of 153 patients (5%) with primary systemic amyloidosis and cardiac involvement. All patients with survival of >5 years received chemotherapy and all but 1 had an objective chemotherapeutic response.

Long-term prognostic value of clinically evident noncoronary vascular disease in patients undergoing coronary revascularization in the Bypass Angioplasty Revascularization Investigation (BARI).

In the general population, peripheral atherosclerosis is a strong predictor of cardiovascular disease and death. In patients with known coronary artery disease, it is unclear whether the presence of additional noncoronary atherosclerosis is of further prognostic value. In the Bypass Angioplasty Revascularization Investigation, 5-year outcome was compared between patients with and without clinically evident noncoronary atherosclerosis. Within the subgroup with noncoronary atherosclerosis, surgery, and angioplasty treatment strategies were compared. Noncoronary atherosclerosis was defined as claudication, peripheral vascular surgery, abdominal aortic aneurysm, history of cerebral ischemia, or carotid disease. Among 1,816 patients, 303 (17%) had noncoronary atherosclerosis. These patients were more likely to have a history of congestive heart failure, diabetes, and hypertension, and were more likely to smoke. Coronary angiographic variables were similar between the 2 groups. Five-year survival was 75.8% for patients with noncoronary atherosclerosis and 90.2% for those without (p < 0.001). The adjusted relative risk of death was 1.7 for any noncoronary atherosclerosis, 1.5 for lower extremity disease alone, 1.7 for cerebral disease alone, and 2.3 for both conditions. Among the 303 patients with noncoronary atherosclerosis, the adjusted relative risk of death for surgery versus angioplasty was 0.87 (p = 0.40). However, the study has limited power to detect a treatment effect in this small subgroup. Thus, patients with combined coronary and clinically evident noncoronary atherosclerosis are a high-risk group with significantly worse long-term outcome compared patients with isolated coronary disease.

Diet drug-related cardiac valve disease: the Mayo Clinic echocardiographic laboratory experience.

OBJECTIVE: To describe the prevalence of diet drug-related valvular disease among our referral population and the association of valvular disease with duration of exposure to fenfluramine and phentermine in combination and to dexfenfluramine alone. PATIENTS AND METHODS: In this retrospective review of clinical and echocardiographic data, charts of patients referred for treatment of toxic effects of diet drugs were reviewed, and telephone interviews were conducted. RESULTS: Between June and December 1997, 191 patients (164 women, 27 men; mean age, 47 years) were referred for possible diet drug-related valvular disease. Twenty-eight (28%) of the 99 asymptomatic patients and 40 (43%) of the 92 symptomatic patients had abnormal echocardiographic findings. Valvular lesions among the 68 patients with abnormal echocardiographic findings included mild (or greater) aortic regurgitation in 55 patients (81%), moderate (or greater) mitral regurgitation in 12 (18%), and moderate (or greater) tricuspid regurgitation in 7 (10%). The Food and Drug Administration case definition of diet drug-related valvulopathy was noted in 31 % of this referral population. Of patients with valvulopathy, mean duration of therapy with fenfluramine and phentermine in combination and dexfenfluramine alone was 9 months and 5 months, respectively. Duration of therapy was not associated with presence or absence of disease. Five patients had surgical intervention for severe valvulopathy: 3 had mitral valve repair, 1 had mitral valve replacement, and 1 had aortic valve replacement. Pulmonary hypertension (>40 mm Hg) was found in 24 patients (13%), and 17 (71 %) had pulmonary hypertension in association with valvulopathy. CONCLUSION: This study demonstrated a 31% (60/191) prevalence of valvulopathy in patients with a history of diet drug exposure who were referred for echocardiographic evaluation. The most common finding was mild aortic regurgitation. Twenty-eight percent of asymptomatic patients had abnormal echocardiographic findings. This study emphasizes the spectrum of diet drug-related cardiac disease and the potential for valvulopathy in asymptomatic patients.

Echocardiographic improvement over time after cessation of use of fenfluramine and phentermine.

OBJECTIVE: To determine the echocardiographic changes over time of valvular heart lesions in patients who took the weight loss drugs fenfluramine and phentermine. SUBJECTS AND METHODS: This prospective cohort study began at the termination of a randomized, double-blind, placebo-controlled weight loss trial of 18 obese women and 13 obese men (mean age, 42 years; mean body mass index, 33.4 kg/m2) who had been assigned randomly to treatment with fenfluramine and phentermine or to placebo. Echocardiograms were obtained at termination of the trial when fenfluramine was withdrawn from the market and 6 months later. They were interpreted independently by 3 cardiologists blinded to treatment assignment and temporal sequence of the echocardiograms. The main outcome measure was the change in drug-related valvular disease over time. RESULTS: One subject assigned to receive the drugs was lost to follow-up, and 3 subjects who did not meet a weight loss goal of 10 kg crossed over from placebo to drug treatment. Echocardiograms were obtained in 19 subjects who received the drugs and 11 subjects who received placebo, and 6-month follow-up echocardiograms were obtained in 15 subjects who received the drugs and 3 who received placebo. Subjects had taken fenfluramine and phentermine a mean of 41 weeks (range, 8-73 weeks). Five of 19 subjects who received the drugs (26%; 95% confidence interval, 7%-46%) and 1 of 11 who received placebo (9%) (odds ratio, 3.6; 95% confidence interval, 0.4-35.6) had findings that met criteria established for drug-related valvular disease. All 5 subjects (4 women and 1 man) receiving the drugs had mild aortic regurgitation, and 1 also had pulmonary hypertension (estimated pulmonary artery pressure, 59 mm Hg). Six months later, the echocardiographic findings had improved in all 5 subjects (P=.06), and 3 no longer met the criteria for drug-related valvular disease. Pulmonary artery pressures decreased to near normal in the subject with pulmonary hypertension (37 mm Hg). Overall, the echocardiographic valvular features improved in 8 of 15 subjects who received the drugs and had echocardiograms performed at both time periods (P=.008). CONCLUSIONS: Valvular heart disease did not appear to progress after cessation of use of fenfluramine and phentermine, and echocardiographic valvular features appeared to improve over time.

Enantioselective synthesis of alpha-amino nitriles from N-benzhydryl imines and HCN with a chiral bicyclic guanidine as catalyst.

[formula: see text] A novel catalytic enantioselective Strecker synthesis of chiral alpha-amino nitriles and alpha-amino acids is described and analyzed with regard to the possible mechanistic basis for stereoselectivity. Key features of the enantioselective process include (1) the use of the chiral bicyclic guanidine 1 as catalyst and (2) the use of the N-benzhydryl substituent on the imine substrate.

The value of follow-up of patients with early breast cancer treated with conservative surgery and radiation therapy.

A retrospective study of 438 women with Stage I or II breast cancer who were treated with conservation therapy and followed in accordance with a 'minimal' follow-up programme was conducted to identify a follow-up schedule to optimize detection of salvageable recurrence and/or contralateral new primary breast cancer, and to rationalize cost. Data from 104 women were used to establish the cost of detecting a salvageable event and to model the efficacy of 13 theoretical follow-up schedules. Among women followed for 5 years, 21% relapsed, and 19% of recurrences were salvageable. Only 0.1% of 1294 follow-up visits resulted in the detection of a salvageable event, at an average cost per woman of A $802. A simulated follow-up programme involving monthly visits for 5 years, costing A $3870 per woman, was the most successful in facilitating the detection of a salvageable recurrence but was also prohibitively expensive. Three-monthly visits for 4 years and 12-monthly for 1 year was more efficacious, but a better understanding of the psychosocial impact and patients' preferences for follow-up is required before any programme is implemented.

High sensitivity cardiac troponin T in patients with immunoglobulin light chain amyloidosis.

OBJECTIVES: To define whether the high sensitivity cardiac troponin T (hs-cTnT) assay in patients with immunoglobulin light chain amyloidosis (AL) improves risk prediction. BACKGROUND: Cardiac involvement is the major cause of death in patients with AL amyloidosis. Risk stratification is facilitated by cardiac biomarkers such as cardiac troponin T (cTnT) and N-terminal pro B-type natriuretic peptide (NT-proBNP). METHODS: Stored serum from patients with newly diagnosed AL was used to measure hs-cTnT, cTnT, and NT-proBNP. Survival modelling was performed. RESULTS: The direct numeric result from hs-cTnT measurement cannot merely be substituted for a cTnT measurement in the Mayo AL staging system. The performance of the receiver operator curve derived an hs-cTnT cut-point of 54 ng/L which improves on the value of 35 ng/L validated with the prior iteration of the assay. An alternate staging option using hs-cTnT alone-using the two thresholds 14 ng/L and 54 ng/L-performs as well as either the original Mayo AL staging system or other systems incorporating hs-cTnT. On multivariate analysis, an hs-cTnT alone staging system was independent of period of diagnosis, type of therapy, and NT-proBNP value, the last of which dropped out of the model. Alternate models were explored, but none performed better than the original system or the new hs-cTnT system. Thus, hs-cTnT can be used alone for the staging of disease prognosis. CONCLUSIONS: A survival model based on hs-cTnT improves the prognostic staging of patients with AL amyloidosis, relegating NT-proBNP to a measure of cardiac response.