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  • Wolters Kluwer - Ovid (CrossRef)  (14)
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  • 1
    In: Circulation, 2015, Vol.132(16), pp.1570-1579
    Description: BACKGROUND—: The prognosis and treatment of the 2 main types of cardiac amyloidosis, immunoglobulin light chain (AL) and transthyretin (ATTR) amyloidosis, are substantially influenced by cardiac involvement. Cardiovascular magnetic resonance with late gadolinium enhancement (LGE) is a reference standard for the diagnosis of cardiac amyloidosis, but its potential for stratifying risk is unknown. METHODS AND RESULTS—: Two hundred fifty prospectively recruited subjects, 122 patients with ATTR amyloid, 9 asymptomatic mutation carriers, and 119 patients with AL amyloidosis, underwent LGE cardiovascular magnetic resonance. Subjects were followed up for a mean of 24±13 months. LGE was performed with phase-sensitive inversion recovery (PSIR) and without (magnitude only). These were compared with extracellular volume measured with T1 mapping. PSIR was superior to magnitude-only inversion recovery LGE because PSIR always nulled the tissue (blood or myocardium) with the longest T1 (least gadolinium). LGE was classified into 3 patterns: none, subendocardial, and transmural, which were associated with increasing amyloid burden as defined by extracellular volume (P〈0.0001), with transitions from none to subendocardial LGE at an extracellular volume of 0.40 to 0.43 (AL) and 0.39 to 0.40 (ATTR) and to transmural at 0.48 to 0.55 (AL) and 0.47 to 0.59 (ATTR). Sixty-seven patients (27%) died. Transmural LGE predicted death (hazard ratio, 5.4; 95% confidence interval, 2.1–13.7; P〈0.0001) and remained independent after adjustment for N-terminal pro-brain natriuretic peptide, ejection fraction, stroke volume index, E/E′, and left ventricular mass index (hazard ratio, 4.1; 95% confidence interval, 1.3–13.1; P〈0.05). CONCLUSIONS—: There is a continuum of cardiac involvement in systemic AL and ATTR amyloidosis. Transmural LGE is determined reliably by PSIR and represents advanced cardiac amyloidosis. The PSIR technique provides incremental information on outcome even after adjustment for known prognostic factors.
    Keywords: Medicine ; Anatomy & Physiology;
    ISSN: 0009-7322
    E-ISSN: 15244539
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  • 2
    In: Circulation, 2016, Vol.133(12), pp.e450-e451
    Description: We thank Aquaro, Cohen, and colleagues for their interest in our article.1 Cardiac involvement is a chief driver of prognosis in systemic amyloidosis, and the stratification of patients is essential for prognosis and choosing management strategies. Cardiovascular magnetic resonance with late gadolinium enhancement has good diagnostic accuracy for cardiac amyloidosis, but its prognostic impact was uncertain.2–6 This study confirms incremental prognostic information after adjusting for known prognosis factors. We note the comments of Aquaro and colleagues regarding cardiac biopsy, but point out that microscopic histological analyses of these tiny samples is not only open to sampling error, but, crucially, the presence of amyloid in heart muscle is not actually proof of cardiac amyloidosis. It is essential to make the distinction between the presence of amyloid deposits and the clinical syndromes of amyloidosis. Amyloid deposits occur widely throughout the tissues in patients with systemic amyloidosis, often without any clinical consequences, providing the basis for rectal, salivary gland, skin, and fat biopsies to support diagnosis. It is likely …
    Keywords: Medicine ; Anatomy & Physiology;
    ISSN: 0009-7322
    E-ISSN: 15244539
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  • 3
    In: Circulation, 2016, Vol.133(24), pp.2404-2412
    Description: BACKGROUND—: Cardiac transthyretin (ATTR) amyloidosis is a progressive and fatal cardiomyopathy for which several promising therapies are in development. The diagnosis is frequently delayed or missed because of the limited specificity of echocardiography and the traditional requirement for histological confirmation. It has long been recognized that technetium-labeled bone scintigraphy tracers can localize to myocardial amyloid deposits, and use of this imaging modality for the diagnosis of cardiac ATTR amyloidosis has lately been revisited. We conducted a multicenter study to ascertain the diagnostic value of bone scintigraphy in this disease. METHODS AND RESULTS—: Results of bone scintigraphy and biochemical investigations were analyzed from 1217 patients with suspected cardiac amyloidosis referred for evaluation in specialist centers. Of 857 patients with histologically proven amyloid (374 with endomyocardial biopsies) and 360 patients subsequently confirmed to have nonamyloid cardiomyopathies, myocardial radiotracer uptake on bone scintigraphy was 〉99% sensitive and 86% specific for cardiac ATTR amyloid, with false positives almost exclusively from uptake in patients with cardiac AL amyloidosis. Importantly, the combined findings of grade 2 or 3 myocardial radiotracer uptake on bone scintigraphy and the absence of a monoclonal protein in serum or urine had a specificity and positive predictive value for cardiac ATTR amyloidosis of 100% (positive predictive value confidence interval, 98.0–100). CONCLUSIONS—: Bone scintigraphy enables the diagnosis of cardiac ATTR amyloidosis to be made reliably without the need for histology in patients who do not have a monoclonal gammopathy. We propose noninvasive diagnostic criteria for cardiac ATTR amyloidosis that are applicable to the majority of patients with this disease.
    Keywords: Medicine ; Anatomy & Physiology;
    ISSN: 0009-7322
    E-ISSN: 15244539
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  • 4
    In: Circulation Research, 2014, Vol.114(4), pp.672-676
    Description: RATIONALE:: Baseline circulating concentrations of C-reactive protein (CRP) are significantly associated with cardiovascular disease risk in general populations. This modest association has been inappropriately conflated with causality, and it has been claimed that CRP is proatherogenic. Most of the known causative factors for atherosclerosis stimulate increased CRP production, but comprehensive genetic epidemiology studies provide no support for a pathogenic role of CRP. The reported proinflammatory effects of human CRP preparations on healthy cells in vitro and in healthy animals in vivo have all been produced by poorly characterized CRP preparations, demonstrably caused by impurities, or elicited by CRP made in recombinant Escherichia coli not by humans. None of the in vitro or animal findings have been reproduced with pure natural human CRP. Nevertheless, the strong proinflammatory effects of infusing recombinant bacterial CRP into humans have still been inappropriately ascribed to CRP. OBJECTIVE:: To investigate the effects of infusion into healthy adult human volunteers of pure natural human CRP. METHODS AND RESULTS:: Comprehensively characterized, pharmaceutical-grade, endotoxin-free, purified CRP, prepared to GMP standard from pooled normal human donor plasma was infused as an intravenous bolus in 7 healthy adult human volunteers at ≤2 mg/kg to provide circulating CRP concentrations ≤44 mg/L. No recipient showed any significant clinical, hematologic, coagulation, or biochemical changes, or any increase in proinflammatory cytokines or acute phase proteins. CONCLUSIONS:: The human CRP molecule itself is not proinflammatory in healthy human adults.
    Keywords: Medicine;
    ISSN: 0009-7330
    E-ISSN: 15244571
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  • 5
  • 6
    In: Circulation, 2006, Vol.114(22), pp.e612-e613
    ISSN: 0009-7322
    E-ISSN: 15244539
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  • 7
    In: Circulation: Heart Failure, 2016, Vol.9(9), pp.e003352-e003352
    Description: BACKGROUND—: It has been reported that subjects of African descent present with heart failure at a younger age and because of different causes than whites. We present contemporary data from UK Afro-Caribbean patients in London. METHODS AND RESULTS—: All patients with heart failure presenting to St George’s Hospital Heart Failure clinic between 2005 and 2012 were included (n=1392). Patients were predominantly white (71%) and male (67%), and median age at presentation was 73 years (range, 18–100 years). In 211 Afro-Caribbean patients, the most common cause of heart failure was nonischemic dilated cardiomyopathy in 27.5% (whites, 19.9%; P〈0.001). Lower rates of ischemic cardiomyopathy were observed (13% versus 41%; P〈0.001). The fourth most common cause of heart failure in Afro-Caribbeans was cardiac amyloidosis (11.4%). The prevalence may have been even higher as not all patients were tested for amyloidosis. Patients with ATTR V122I had the worst prognosis compared with other causes of Afro-Caribbean heart failure and white patients. To better understand this condition, we analyzed data from the largest international cohort of ATTR V122I patients, followed up at the UK National Amyloidosis Center (n=72). Patients presented with cardiac failure (median age, 75 [range, 59–90] years). Median survival was 2.6 years from diagnosis. CONCLUSIONS—: In London, the cause of heart failure varies depending on ethnicity and affects age of presentation and outcomes. In Afro-Caribbean patients, ATTR V122I is an underappreciated cause of heart failure, and cardiomyopathy is often misattributed to hypertension. As promising TTR therapies are in development, increased awareness and proactive detection are needed.
    Keywords: Medicine;
    ISSN: 1941-3289
    E-ISSN: 19413297
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  • 8
    In: Circulation: Cardiovascular Imaging, 2013, Vol.6(1), pp.34-39
    Description: BACKGROUND—: Cardiac involvement predicts outcome in systemic AL amyloidosis and influences therapeutic options. Current methods of cardiac assessment do not quantify myocardial amyloid burden. We used equilibrium contrast cardiovascular magnetic resonance (EQ-CMR) to quantify the cardiac interstitial compartment, measured as myocardial extracellular volume (ECV) fraction, hypothesizing it would reflect amyloid burden. METHODS AND RESULTS—: Sixty patients with systemic AL amyloidosis (65% men, median age 65 years) underwent conventional clinical cardiovascular magnetic resonance, including late enhancement, equilibrium contrast cardiovascular magnetic resonance, and clinical cardiac evaluation, including ECG, echocardiography, assays of N-terminal pro-brain natriuretic peptide and Troponin T, and functional assessment comprising the 6-minute walk test in ambulant individuals. Cardiac involvement in the amyloidosis patients was categorized as definite, probable, or none, suspected by conventional criteria. Findings were compared with 82 healthy controls. Mean ECV was significantly greater in patients than healthy controls (0.25 versus 0.40, P〈0.001) and correlated with conventional criteria for characterizing the presence of cardiac involvement, the categories of none, probable, definite corresponding to ECV of 0.276 versus 0.342 versus 0.488, respectively (P〈0.001). ECV was correlated with cardiac parameters by echocardiography (eg, Tissue Doppler Imaging [TDI] S-wave R=0.52, P〈0.001) and conventional cardiovascular magnetic resonance (eg, indexed left ventricular mass R=0.56, P〈0.001). There were also significant correlations with N-terminal pro-brain natriuretic peptide (R=0.69, P〈0.001) and Troponin T (R=0.53, P=0.006). ECV was associated with smaller QRS voltages (R=0.57, P〈0.001) and correlated with poorer performance in the 6-minute walk test (R=0.36, P=0.03). CONCLUSIONS—: Myocardial ECV measurement has potential to become the first noninvasive test to quantify cardiac amyloid burden.
    Keywords: Gadolinium Dtpa ; Amyloid -- Metabolism ; Amyloidosis -- Diagnosis ; Heart Diseases -- Diagnosis ; Magnetic Resonance Imaging, Cine -- Methods ; Myocardium -- Pathology;
    ISSN: 1941-9651
    E-ISSN: 19420080
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  • 9
    Language: English
    In: Journal of the American Heart Association, 22 April 2013, Vol.2(2), pp.e000098
    Description: Cardiac amyloidosis is a fatal disease whose prognosis and treatment rely on identification of the amyloid type. In our aging population transthyretin amyloidosis (ATTRwt) is common and must be differentiated from other amyloid types. We report the clinical presentation, natural history, and prognostic features of ATTRwt compared with cardiac-isolated AL amyloidosis and calculate the probability of disease diagnosis of ATTRwt from baseline factors. All patients with biopsy-proven ATTRwt (102 cases) and isolated cardiac AL (36 cases) seen from 2002 to 2011 at the UK National Amyloidosis Center were included. Median survival from the onset of symptoms was 6.07 years in the ATTRwt group and 1.7 years in the AL group. Positive troponin, a pacemaker, and increasing New York Heart Association (NYHA) class were associated with worse survival in ATTRwt patients on univariate analysis. All patients with isolated cardiac AL and 24.1% of patients with ATTRwt had evidence of a plasma cell dyscrasia. Older age and lower N-terminal pro-B-type natriuretic peptide (NT pro-BNP) were factors significantly associated with ATTRwt. Patients aged 70 years and younger with an NT pro-BNP 〈183 pmol/L were more likely to have ATTRwt, as were patients older than 70 years with an NT pro-BNP 〈1420 pmol/L. Factors at baseline associated with a worse outcome in ATTRwt are positive troponin T, a pacemaker, and NYHA class IV symptoms. The age of the patient at diagnosis and NT pro-BNP level can aid in distinguishing ATTRwt from AL amyloidosis.
    Keywords: Amyloid -- Classification ; Amyloidosis -- Diagnosis ; Cardiomyopathies -- Diagnosis ; Myocardium -- Metabolism
    E-ISSN: 2047-9980
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  • 10
    In: Circulation: Cardiovascular Imaging, 2016, Vol.9(8), pp.e005066-e005066
    Description: BACKGROUND—: Calcific aortic stenosis (cAS) affects 3% of individuals aged 〉75 years, leading to heart failure and death unless the valve is replaced. Wild-type transthyretin cardiac amyloid is also a disorder of ageing individuals. Prevalence and clinical significance of dual pathology are unknown. This study explored the prevalence of wild-type transthyretin amyloid in cAS by myocardial biopsy, its imaging phenotype and prognostic significance. METHODS AND RESULTS—: A total of 146 patients with severe AS requiring surgical valve replacement underwent cardiovascular magnetic resonance and intraoperative biopsies; 112 had cAS (75±6 years; 57% men). Amyloid was sought histologically using Congo red staining and then typed using immunohistochemistry and mass spectrometry; patients with amyloid underwent clinical evaluation including genotyping and TC-3,3-diphosphono-1,2-propanodicarboxylic-acid (DPD) bone scintigraphy. Amyloid was identified in 6 of 146 patients, all with cAS and 〉65 years (prevalence 5.6% in cAS 〉65). All 6 patients had wild-type transthyretin amyloid (mean age 75 years; range, 69–85; 4 men), not suspected on echocardiography. Cardiovascular magnetic resonance findings were of definite cardiac amyloidosis in 2, but could be explained solely by AS in the other 4. Postoperative DPD scans demonstrated cardiac localization in all 4 patients who had this investigation (2 died prior). At follow-up (median, 2.3 years), 50% with amyloid had died (versus 7.5% in cAS; 6.9% in age 〉65 years). In univariable analyses, the presence of transthyretin amyloidosis amyloid had the highest hazard ratio for death (9.5 [95% confidence interval, 2.5–35.8]; P=0.001). CONCLUSIONS—: Occult wild-type transthyretin cardiac amyloid had a prevalence of 6% among patients with AS aged 〉65 years undergoing surgical aortic valve replacement and was associated with a poor outcome.
    Keywords: Aged–Analysis ; Aged, 80 and Over–Diagnostic Imaging ; Amyloid–Epidemiology ; Amyloid Neuropathies, Familial–Genetics ; Aortic Valve–Mortality ; Aortic Valve Stenosis–Diagnostic Imaging ; Biopsy–Surgery ; Cardiomyopathies–Diagnostic Imaging ; Echocardiography–Mortality ; Female–Surgery ; Genetic Predisposition to Disease–Diagnostic Imaging ; Heart Valve Prosthesis Implantation–Epidemiology ; Humans–Genetics ; Immunohistochemistry–Mortality ; Kaplan-Meier Estimate–Adverse Effects ; London–Mortality ; Magnetic Resonance Imaging–Chemistry ; Male–Pathology ; Mass Spectrometry–Genetics ; Mutation–Genetics ; Myocardium–Genetics ; Phenotype–Genetics ; Prealbumin–Genetics ; Predictive Value of Tests–Genetics ; Proportional Hazards Models–Genetics ; Risk Factors–Genetics ; Severity of Illness Index–Genetics ; Tomography, Emission-Computed, Single-Photon–Genetics ; Treatment Outcome–Genetics ; Amyloid ; Prealbumin ; Congo Red ; Aortic Stenosis, Calcific ; Aortic Valve Stenosis ; Biopsy ; Mass Spectrometry;
    ISSN: 1941-9651
    E-ISSN: 19420080
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