Light chain amyloidosis (AL) is associated with high mortality. The aim was to identify echocardiographic parameters that predict AL long-term mortality.Methods/Results-42 biopsy-proven AL subjects (43% females; 61±12 years) had echocardiography and followed 29±16 (median 29.4) months. Standard echocardiographic and clinical parameters and heart failure (HF) class were tested using univariate/multivariable Cox proportional hazard regression analyses to identify markers of mortality. 23 subjects died with 1-year mortality of 44%. Univariate predictors of mortality were HF class (p<0.001), left ventricular systolic ejection time (ET, p=0.002), alkaline phosphatase (p<0.001), aspartate and alanine aminotransferase (p=0.003 each). On multivariable analysis, only HF Class (hazards ratio, 95% confidence interval, p-value: 4.86, 1.58-14.9, p=0.006), ET (10 ms increase, 0.87, 0.78-0.97, p=0.01) and alkaline phosphatase (10 U/L increase, 1.04, 1.01-1.06, p=0.01) were prognostic. ET≤240 ms had sensitivity/specificity of 61/90% in predicting 1-year mortality and 73/90% in predicting 1-year cardiac mortality.Conclusions-AL amyloidosis was associated with high long-term mortality. Among echocardiographic and clinical parameters, only ET and alkaline phosphatase had incremental value to HF class in predicting mortality. This may be useful to identify high-risk patients.Light chain or primary amyloidosis (AL) is a plasma cell dyscrasia with monoclonal production and extracellular deposition of immunoglobulin light chains in multiple organs [1][2][3] . The accumulation of fibrillar amyloid deposits in the heart, kidneys, liver and nervous system leads to organ failure and death. It is associated with poor prognosis with median survival reduced to 4 months in patients with heart failure 4, 5 . The early identification of high risk patients is important for risk stratification. Echocardiography is an important noninvasive tool to assess cardiac involvement with classic findings of ventricular thickening and diastolic dysfunction with often preserved left ventricular ejection fraction [6][7][8] . However, early systolic dysfunction is increasingly recognized with more sensitive techniques such as strain imaging 9, 10 and regional systolic dyssynchrony or hypersynchrony has recently been reported in AL subjects Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. 11,12 . Prior retrospective studies of AL patients demonstrated prognostic value for echocardiography-derived abnormal deceleration time, ratio of peak early mitral inflow to late mitral inflow velocity (E/A ratio) as well as th...

The candidate gene approach to pharmacogenetics is hypothesis driven, and anchored in biological plausibility. Whole genome scanning is hypothesis generating, and it may lead to new biology. While both approaches are important, the scientific community is rapidly reallocating resources toward the latter. We propose a step-wise approach to large-scale pharmacogenetic association studies that begins with candidate genes, then uses a pathway-based intermediate step, to inform subsequent analyses of data generated through whole genome scanning. Novel computational strategies are explored in the context of two clinically relevant examples, cholesterol synthesis and lipid signaling.

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Statin use can be accompanied by a variety of musculoskeletal complaints. We describe the clinical characteristics of case subjects experiencing adverse statin-induced musculoskeletal symptoms within a large, population based cohort in Central Wisconsin. Case status was determined based upon elevated serum creatine kinase (CK) levels and the presence of at least one physician note reflecting an increased index of suspicion for statin intolerance. From the medical records of nearly 2 million unique patients, we identified more than 20,000 potential study subjects (∼1%) having CK data and at least one exposure to a statin drug. Manual screening was completed on 2,227 subjects with CK levels in the upper 10th percentile. Of those screened, 267 met inclusion criteria (12.0% eligibility), and 218 agreed to participate in a retrospective study characterizing the risk determinants of statin-induced muscle toxicity. Three categorical pain variables were graded retrospectively (distribution, location, and severity of pain). The presenting complaints of these case subjects were extremely heterogeneous. The number of subjects with a compelling pain syndrome (diffuse, proximal muscle pain of high intensity) increased at higher serum CK levels; the number of subjects with indeterminate pain variables decreased at higher serum CK levels. The lines reflecting these relationships cross at a CK level of approximately 1,175 U/l, approximately half the threshold level needed to make a clinical diagnosis of “myopathy” (i.e., CK > 10-fold upper limit).

Patent foramen ovale (PFO) is an anatomical variant of the interatrial septum with an overall prevalence of 27% in autopsy studies. PFOs have a potential role in causation of stroke, platypneaorthodeoxia, decompression sickness, right to left shunt and migraine headaches. Data regarding percutaneous closure of PFO in low volume tertiary care centers is lacking. Retrospective review of 14 percutaneous PFO closures done in our facility from March 2005 to August 2006 was performed for efficacy of procedure and safety.All patients received clopidogrel for a period of 3 months, and aspirin and subacute bacterial endocarditis prophylaxis for 6 months. Mean age of the study population was 54 years. Fifty percent (7 of 14) of patients experienced an atrial septal aneurysm and 14% (2 patients) exhibited a hypercoagulable state.The indication for closure in 13 patients was transient ischemic attacks or strokes, while one patient had persistent hypoxia due to a severe right to left shunt at PFO. Patients received either a CardioSEAL or Amplatzer device. Deployment rate was 100%. All patients completed a minimum of 6 months of follow-up, with a mean follow-up time of 14.9 ± 7.6 months. No immediate or late bleeding complication occurred in any patient. One patient developed paroxysmal atrial fibrillation and one patient developed thrombotic complications at 7 months post-procedure secondary to the progression of her anal carcinoma and subsequently died. Pending the results of the four large randomized trials that are enrolling patients, percutaneous closure of PFO for cryptogenic strokes is an attractive alternative to lifelong anticoagulation with relatively few complications, even in low volume centers.There are many challenges in the management of this subset of patients, the foremost being the selection of a target patient population. Role of PFO in migraines is less clear. Pat ent foramen ovale (PFO) is an anatomical variant of the interatrial septum, which until recently was believed to be of no clinical importance. Evidence emerging over the past 15 years suggests a role for PFO in cryptogenic stroke, platypnea-orthodeoxia, decompression sickness, right to left shunt and migraine headaches. Better diagnostic modalities for its detection and improved methods of closure, including percutaneous approach have become available for clinical practice.PFO is a congenital defect occurring in the septum separating the two atrial chambers. PFO provides communication between the atrial chambers of the heart through fossa ovalis on the right side and the ostium secundum on the left side. Septum primum acts as a one-way valve allowing blood flow from the right to left atria, bypassing the lungs. 1 This septum normally remains patent before birth and closes with the first breath of air that a baby takes because of increased left sided pressures. Anatomical closure usually occurs by 2 years of age. However, it remains patent in a subset of the population. Autopsy studies have shown an overall prevalence of 27% in the general populat...