Lawreen H. Connors

Bio: Lawreen H. Connors is an academic researcher from Boston University. The author has contributed to research in topics: Amyloidosis & Transthyretin. The author has an hindex of 36, co-authored 127 publications receiving 4586 citations. Previous affiliations of Lawreen H. Connors include Boston Medical Center & University of New Hampshire.

Tabulation of human transthyretin (TTR) variants, 2003.

Abstract: (2003). Tabulation of human transthyretin (TTR) variants, 2003. Amyloid: Vol. 10, No. 3, pp. 160-184.

Human amyloidogenic light chains directly impair cardiomyocyte function through an increase in cellular oxidant stress.

Abstract: Primary amyloidosis is a systemic disorder characterized by the clonal production and tissue deposition of immunoglobulin light chain (LC) proteins. Congestive heart failure remains the greatest cause of death in primary amyloidosis, due to the development of a rapidly progressive amyloid cardiomyopathy. Amyloid cardiomyopathy is largely unresponsive to current heart failure therapies, and is associated with a median survival of less than 6 months and a 5-year survival of less than 10%. The mechanisms underlying this disorder, however, remain unknown. In this report, we demonstrate that physiological levels of human amyloid LC proteins, isolated from patients with amyloid cardiomyopathy (cardiac-LC), specifically alter cellular redox state in isolated cardiomyocytes, marked by an increase in intracellular reactive oxygen species and upregulation of the redox-sensitive protein, heme oxygenase-1. In contrast, vehicle or control LC proteins isolated from patients without cardiac involvement did not alter cardiomyocyte redox status. Oxidant stress imposed by cardiac-LC proteins further resulted in direct impairment of cardiomyocyte contractility and relaxation, associated with alterations in intracellular calcium handling. Cardiomyocyte dysfunction induced by cardiac-LC proteins was independent of neurohormonal stimulants, vascular factors, or extracellular fibril deposition, and was prevented through treatment with a superoxide dismutase/catalase mimetic. This study suggests that cardiac dysfunction in amyloid cardiomyopathy is directly mediated by LC protein-induced cardiomyocyte oxidant stress and alterations in cellular redox status, independent of fibril deposition. Antioxidant therapies or treatment strategies aimed at eliminating circulating LC proteins may therefore be beneficial in the treatment of this fatal disease.

Senile Systemic Amyloidosis Presenting With Heart Failure A Comparison With Light Chain-Associated Amyloidosis

Abstract: Background:Small deposits of amyloid are often found intheheartsofelderlypatients.However,extensivedepositionoftransthyretin-derivedamyloidfibrilsintheheart (senile systemic amyloidosis [SSA]) can cause heart failure. The clinical features of SSA that involve the heart are ill defined, and the condition may be overlooked as a cause of heart failure. We sought to better define the clinical,echocardiographic,andelectrocardiographicfeaturesofcardiacinvolvementinSSAandtocomparethem with the findings in patients with light chain–associated (AL) amyloidosis that affects the heart. Methods: Eighteen consecutive patients with SSA and heart failure evaluated at a tertiary referral center for the diagnosis and treatment of amyloidosis were compared with 18 randomly selected patients with AL amyloidosisthatinvolvedtheheart.Allpatientsunderwentacomplete clinical and biochemical evaluation. Echocardiogramsandelectrocardiogramswereinterpretedbyblinded investigators. Results:PatientswithSSAwereolderthanthosewithAL amyloidosis and were all male. Proteinuria (protein outputof1gper24hours)wascommoninALamyloidosis butwasnotpresentinSSA.Leftventricularwallthickness was greater in patients with SSA than those with AL amyloidosis,butdespitethickerwallsandolderage,theseverity of heart failure was less in the SSA group and the mediansurvivalwasmuchlonger(75vs11months;P=.003). Conclusions: Senile systemic amyloidosis is a disorder of elderly men and is characterized by amyloidosis clinically limited to the heart. In contrast to the rapid progression of heart failure in AL amyloidosis, SSA results in slowly progressive heart failure. The difference in survival, despite evidence of more myocardial disease in the senile group, suggests that heart failure in AL amyloidosis may have a toxic component, possibly related to the circulating monoclonal light chain. Arch Intern Med. 2005;165:1425-1429

Amyloidogenic light chains induce cardiomyocyte contractile dysfunction and apoptosis via a non-canonical p38α MAPK pathway

Abstract: Patients with primary (AL) cardiac amyloidosis suffer from progressive cardiomyopathy with a median survival of less than 8 months and a 5-year survival of <10%. Contributing to this poor prognosis is the fact that these patients generally do not tolerate standard heart failure therapies. The molecular mechanisms underlying this deadly form of heart disease remain unclear. Although interstitial amyloid fibril deposition of Ig light chain proteins is a major cause of cardiac dysfunction in AL cardiac amyloidosis, we have previously shown that amyloid precursor proteins directly impair cardiac function at the cellular and isolated organ levels, independent of fibril formation. In this study, we report that amyloidogenic light chain (AL-LC) proteins provoke oxidative stress, cellular dysfunction, and apoptosis in isolated adult cardiomyocytes through activation of p38 mitogen-activated protein kinase (MAPK). AL-LC–induced p38 activation was found to be independent of the upstream MAPK kinase, MKK3/6, and instead depends upon transforming growth factor-β-activated protein kinase-1 binding protein-1 (TAB1)-mediated p38α MAPK autophosphorylation. Treatment of cardiomyocytes with SB203580, a selective p38 MAPK inhibitor, significantly attenuated AL-LC–induced oxidative stress, cellular dysfunction, and apoptosis. Our data provide a unique mechanistic insight into the pathogenesis of AL-LC cardiac toxicity and suggest that TAB1-mediated p38α MAPK autophosphorylation may serve as an important event leading to cardiac dysfunction and subsequent heart failure.

Infusion of Light Chains From Patients With Cardiac Amyloidosis Causes Diastolic Dysfunction in Isolated Mouse Hearts

Abstract: Background Primary (AL) amyloidosis is a plasma cell dyscrasia characterized by clonal production of immunoglobulin light chains (LC) resulting in the subsequent systemic deposition of extracellular amyloid fibrils. Cardiac involvement is marked by the hemodynamic pattern of impaired diastolic filling and restrictive cardiomyopathy. Although cardiac death in patients with AL amyloidosis is usually associated with extensive myocardial infiltration, the infiltration alone does not correlated with the degree of heart failure or survival. We hypothesized that circulating monoclonal LC may directly impair cardiac function, in addition to any mechanical effects of amyloid fibril deposition. Therefore, we examined the effects of amyloid LC proteins on diastolic and systolic cardiac function, as measured in an isolated mouse heart model. Methods and Results LC were obtained from patients with nonamyloid disease or from those with noncardiac, mild cardiac, and severe cardiac involved AL amyloidosis. Saline or LC (...

Definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL): A consensus opinion from the 10th International Symposium on Amyloid and Amyloidosis

Abstract: We undertook this study to develop uniformly accepted criteria for the definition of organ involvement and response for patients on treatment protocols for immunoglobulin light-chain amyloidosis (AL). A consensus panel was convened comprising 13 specialists actively involved in the treatment of patients with amyloidosis. Institutional criteria were submitted from each, and a consensus was developed defining each organ involved and the criteria for response. Specific criteria have been developed with agreed on definitions of organ and hematologic response as a result of discussions at the 10th International Symposium on Amyloid and Amyloidosis held in Tours, France, April 2004. These criteria now form the working definition of involvement and response for the purposes of future data collection and reporting. We report criteria that centers can now use to define organ involvement and uniform response criteria for reporting outcomes in patients with light-chain AL.

Safety and efficacy of RNAi therapy for transthyretin amyloidosis

Abstract: BACKGROUND: Transthyretin amyloidosis is caused by the deposition of hepatocyte-derived transthyretin amyloid in peripheral nerves and the heart. A therapeutic approach mediated by RNA interference (RNAi) could reduce the production of transthyretin. METHODS: We identified a potent antitransthyretin small interfering RNA, which was encapsulated in two distinct first- and second-generation formulations of lipid nanoparticles, generating ALN-TTR01 and ALN-TTR02, respectively. Each formulation was studied in a single-dose, placebo-controlled phase 1 trial to assess safety and effect on transthyretin levels. We first evaluated ALN-TTR01 (at doses of 0.01 to 1.0 mg per kilogram of body weight) in 32 patients with transthyretin amyloidosis and then evaluated ALN-TTR02 (at doses of 0.01 to 0.5 mg per kilogram) in 17 healthy volunteers. RESULTS: Rapid, dose-dependent, and durable lowering of transthyretin levels was observed in the two trials. At a dose of 1.0 mg per kilogram, ALN-TTR01 suppressed transthyretin, with a mean reduction at day 7 of 38%, as compared with placebo (P=0.01); levels of mutant and nonmutant forms of transthyretin were lowered to a similar extent. For ALN-TTR02, the mean reductions in transthyretin levels at doses of 0.15 to 0.3 mg per kilogram ranged from 82.3 to 86.8%, with reductions of 56.6 to 67.1% at 28 days (P<0.001 for all comparisons). These reductions were shown to be RNAi-mediated. Mild-to-moderate infusion-related reactions occurred in 20.8% and 7.7% of participants receiving ALN-TTR01 and ALN-TTR02, respectively. CONCLUSIONS: ALN-TTR01 and ALN-TTR02 suppressed the production of both mutant and nonmutant forms of transthyretin, establishing proof of concept for RNAi therapy targeting messenger RNA transcribed from a disease-causing gene. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov numbers, NCT01148953 and NCT01559077.).

The structure of amyloid fibrils by electron microscopy and X-ray diffraction.

Abstract: Publisher Summary The chapter discusses the structural analysis of amyloid fibrils by electron microscopy and X-ray diffraction A method to isolate amyloid fibrils from tissue was developed, and such preparations of purified fibrils exhibited the classic staining and birefringent characteristics of crude amyloid samples The further use of high-resolution electron microscopy, examining ultrathin sections of tissue and isolated material, confirmed the fibrillar form as the characteristic appearance of amyloid in the electron microscope With the ability to prepare samples of isolated amyloid fibrils it began to be possible to probe the molecular structure of the fibrils using X-ray diffraction The initial use of this technique produced diffraction patterns that showed that the fibrils were composed of polypeptide chains, extended in the so-called cross-β-conformation Subsequent analyses by X-ray diffraction on a variety of amyloids and also by NMR analysis have confirmed that the protein chains in all amyloid fibrils are predominantly in the cross-β-conformation The structures of the soluble, globular forms of several amyloidogenic proteins have been determined by the single crystal X-ray crystallography The origins of the different amyloidoses appear quite diverse, with some arising from a genetic mutation and others apparently from polypeptide misprocessing or from an unusual accumulation of full-length wild-type protein

An introduction to quadrupole-time-of-flight mass spectrometry.

Abstract: A brief introduction is presented to the basic principles and application of a quadrupole–time-of-flight (TOF) tandem mass spectrometer. The main features of reflecting TOF instruments with orthogonal injection of ions are discussed. Their operation and performance are compared with those of triple quadrupoles with electrospray ionization and matrix-assisted laser desorption/ionization (MALDI) TOF mass spectrometers. Examples and recommendations are provided for all major operational modes: mass spectrometry (MS) and tandem MS (MS/MS), precursor ion scans and studies of non-covalent complexes. Basic algorithms for liquid chromatography/MS/MS automation are discussed and illustrated by two applications. Copyright  2001 John Wiley & Sons, Ltd.

Diagnosis and Management of the Cardiac Amyloidoses

Abstract: Cardiac amyloidosis is a manifestation of one of several systemic diseases known as the amyloidoses.1,2 This uncommon disease is probably underdiagnosed, and even when a diagnosis of amyloidosis of the heart is made, the fact that there are several types of amyloid, each with its unique features and treatment, is often unrecognized. This can lead to errors in management and in the information conveyed to the patient. The purpose of this review is to familiarize the reader with the clinical features of amyloidosis and to address the approach to the patient with this disease, focusing on the various types of amyloidosis, their prognosis and treatment. The common feature of this group of diseases is the extracellular deposition of a proteinaceous material that, when stained with Congo red, demonstrates apple-green birefringence under polarized light and that has a distinct color when stained with sulfated Alcian blue (Figure 1). Viewed with electron microscopy, the amyloid deposits are seen to be composed of a β-sheet fibrillar material (Figure 2). These nonbranching fibrils have a diameter3 of 7.5 to 10 nm and are the result of protein misfolding.4,5 Cardiac involvement in amyloidosis may be the predominant feature or may be found on investigation of a patient presenting with another major organ involvement. The presence of cardiac amyloidosis and its relative predominance varies with the type of amyloidosis. Thus, senile systemic amyloidosis and some forms of transthyretin amyloidosis invariably affect the heart, whereas cardiac involvement ranges from absent to severe in amyloidosis derived from a light-chain precursor (AL amyloidosis). Secondary amyloidosis almost never affects the heart in any clinically significant manner.6 The specific composition of the fibrils differs in the different types of amyloid7 and are outlined in the Table. Both on the basis of common usage and for …