Background: Cardiovascular involvement among pa- tients with primary systemic amyloidosis (AL) is common and predicts poor prognosis. Different pa- rameters have been used to predict outcome. We studied the prognostic significance of clinical, ECG and echocardiographic parameters of 60 patients with tissue proven primary cardiac amyloidosis. Method and Results: Records of 60 patients with primary amyloidosis and cardiac involvement docu- mented by endomyocardial tissue biopsy were retro- spectively evaluated. Patients mean age was 57.9 ± 10.2 years. 71.6% were male and 86.6% Caucasian. Patients’ median survival was 12.2 ± 4.4 months with only 50% of patients survived for more than 1 year. 60% of patients had CHF (NYHA II-IV). CHF (NYHA II-IV), IVS, LVPW and LVEF were signifi- cant on univariate survival analysis (p < 0.05). On multivariate analysis only CHF (p = 0.027, HR 3.04 [95% CI: 1.1 - 8.1]) and IVS < 1.5 cm (p = 0.012, HR: 3.51 [95% CI: 1.3 - 9.3]) were predictors of survival. Patients with CHF had a median survival of 7.58 ± 1.74 months contrary to those without CHF who had a median survival of 31.2 ± 11.41 months. Patients with IVS ≥ 1.5 cm had a median survival of 7.0 ± 1.1 months, contrary to those with an IVS < 1.5 cm who had a median survival of 31.9 ± 12.4 months. Conclu- sion: In patients with primary amyloidosis and car- diac involvement, length of survival is strongly asso- ciated with CHF (NYHA II-IV) and IVS compared to other electrographic and echocardiographic parame- ters
Case presentation: A 60-year-old Japanese man with a history of embolic stroke and hypertrophic cardiomyopathy visited our department for heart failure. The present case exhibited only cardiomyopathy without any clinical signs of systemic amyloidosis manifested as carpal tunnel syndrome, polyneuropathy, or autonomic dysfunction. An echocardiogram revealed severe asymmetric left ventricular hypertrophy, biatrial dilatation, pericardial effusion, and preserved left ventricular ejection fraction of 50% with severe diastolic dysfunction. Technetium pyrophosphate scintigraphy indicated marked diffuse myocardial uptake of technetium pyrophosphate, strongly suggesting transthyretin cardiac amyloidosis, which was firmly confirmed by a left ventricular endomyocardial biopsy. Genetic analysis demonstrated a transthyretin C70T (Pro24Ser) heterozygous mutation. Tafamidis, a transthyretin stabilizer, was started. His cardiac symptoms remained unchanged for 12 months.
Figure 1 Diastolic function in cardiac amyloidosis (CA): diastolic parameters tend to be markedly abnormal due to stiffening of the myocardium secondary to amyloid infiltration. Aside from the classical steep deceleration time, which is consistent with restrictive diastolic dysfunction, there are other parameters that are helpful. Tissue Doppler velocity at mitral annulus (E′) are usually <6 cm/s. Also, notice the significant blunting of the systolic component of the pulmonary vein flow, suggesting high filling pressures in the absence of significant mitral regurgitation. Typically, like any other restrictive cardiomyopathy, CA will present with biatrial enlargement, reflecting the chronically elevated filling ventricular pressures.
Abstract: Cardiac amyloidosis is a rare disease that has significant sequelae if undetected and treated early. We report a case of a rare genetic mutation that leads to cardiac amyloidosis. This is a case of a 41-year-old Peruvian male without any known past medical history but with a family history of sudden death. The patient complained of episodic left-sided chest pain for 1 month that was associated with shortness of breath. A subsequent admission and workup for coronary artery disease was negative, but an echocardiogram showed global left ventricular hypokinesia. Cardiac magnetic resonance imaging (MRI) was performed which was suggestive of cardiac amyloidosis. A subsequent abdominal fat biopsy and bone marrow biopsy failed to show evidence of amyloidosis. However, the endomyocardial biopsy was consistent with cardiac amyloidosis. Familial cardiac disease was suspected because of the family history of sudden death. As such, genetic testing was performed which yielded a very rare genetic mutation corresponding to amino acid 23 of the transthyretin protein. A review of the literature shows that this gene mutation (AGT23AAT, gene sequence; Ser23Asn, protein sequence) has been described only once previously. This case is unique in that the patient’s amyloidosis was limited to the heart, without involvement of any other organ.
DOI: 10.4236/wjcd.2018.82016 167 World Journal of Cardiovascular Diseases blood, which return to normal in successful treatment. Regardless of recent ad- vances in management, long term prognosis of cardiac amyloidosis is poor, es- pecially if diagnosis is delayed . Several cases reported by Chandrashekhar et al concluded that despite intensive chemotherapy, cardiac treatment is suppor- tive and the results are often disappointing . In our case, after starting che- motherapy, patient’s heart failure symptoms relieved. The serum free light chain level was also decreased. It has been more than six months of confirmed diagno- sis and patient condition has significant improvement.
Conclusion: Echocardiography plays an important role in diagnosing cardiac amyloidosis. The findings of concentric left ventricular hypertrophy with preserved ejection fraction without increased in loading condition should alert the clinician towards its possibility. This is further supported by right ventricular hypertrophy and particularly longitudinal strain imaging showing apical sparing pattern.
Cardiac amyloidosis is characterized histologically by infiltration and expansion of the interstitial space with amyloid protein, along with some associated endomyo- cardial fibrosis . We have previously reported that car- diovascular magnetic resonance (CMR) frequently shows a characteristic pattern of global subendocardial late gadolinium enhancement (LGE) in cardiac amyloidosis that accords with the transmural histological distribution of amyloid . However, there are also abnormal myocar- dial and blood pool gadolinium kinetics which are likely to reflect cardiac amyloid load, and therefore might relate to prognosis in these patients. We examine here the hypothesis that LGE and gadolinium kinetics might be of prognostic value in cardiac amyloidosis.
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In the current study, more than half of cardiac amyloido- sis patients had evidence of concomitant renal disease (spe- ci ﬁ cally, a code for renal failure, nephropathy, nephrotic syndrome, dialysis, or kidney transplant) on admission, roughly consistent with smaller studies that used clinical data. 24,25 Lacking clinical data, we could not determine the speci ﬁ c type of cardiac amyloidosis or which amyloidosis type produced the cardiac and renal disease in the patients we studied, although we hope to do so in future studies. A large case series suggests two-thirds of cardiac amyloidosis patients have AL, most of the remainder have ATTRv, and under 10% have ATTRwt, 25 but these proportions could not be evaluated in the current study. Patients with both organ systems involved appear to be sicker than the group as a whole with an average LOS of nearly 10 days, compared to 7 days in patients without renal dysfunction, and costs
effusion, associated with biatrial dilatation (surface of LA of 24 cm2 and RA of 21 cm2). The LV study evaluated LVEF at 62% and an increased LV mass at 69 g/m2. The study of late enhancement (Figure 4) realized ten minutes after the injection revealed circumferential subendocardial enhancement without vascular systematization. The diagnosis of cardiac amyloidosis was therefore clarified. Periumbilical fat biopsy confirmed the presence of extracellular deposit of amyloid substance. Myocardial biopsy was not performed. Electrophoresis of serum proteins showed a monoclonal peak of Ig M lambda type (389.16 mg/l). The 24-hour Bence Jones Proteinuria was negative. Kidney function was normal. There was no digestive or neurological involvement. The diagnosis of cardiac amyloidosis secondary to Waldenstrom's disease was made. A combination of monoclonocal anti-CD20 antibodies (Rituximab) and Bendamustine was initiated which allowed improvement of cardiac symptoms with a relatively good clinical tolerance.
Simpson’s method from apical two-chamber and four- chamber windows, left atrial volume index using a biplane area-length formula, end-diastolic interventricular septal and posterior wall thickness, and LV internal dimension in diastole. LV mass index was calculated based on modelling the LV as an ellipse. The mean LV wall thickness was calcu- lated as (interventricular septum thickness + posterior wall thickness)/2. Diastolic parameters, including peak early (E) and late (A) diastolic mitral inflow velocity and its ratio (E/Ea), deceleration time, and average of the medial and lateral mitral annular diastolic velocities (Ea), were also measured according to the American Society of Echocardi- ography guidelines. All Doppler measurements were made over three cardiac cycles and averaged. In patients with atrial fibrillation, the data were averaged over five cardiac cycles. 8 LS was calculated using speckle tracking from 2D
In our study, however, in a 39 month follow- up, the survival time of patients with multiple my- eloma both complicated by amyloidosis and with- out amyloidosis did not differ significantly. also in the analysis presented by Madan, in 2010, sur- vival times in patients with myeloma complicat- ed with amyloidosis were not different from those in patients without one . also, the studies by desikan, Vela Ojeda and bahlis are noteworthy. The authors demonstrated that the prevalence of amyloidosis does not affect the results of assisted megachemotherapy followed by single or tandem autologous transplantation in myeloma patients [17, 19, 26]. The authors emphasize, however, that cardiac amyloidosis and multi-organ changes may be associated with high peritransplantation mor- tality. among our patients, none of them under- went megachemotherapy and autologous stem cell transplant.
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Cardiac amyloidosis, which occurs as a complication of primary amyloidosis, is a result of cardiac deposition of insol- uble, monoclonal immunoglobulin light chain fragments. This is observed in about 50% of patients with light chain amyloidosis predominantly after 40 years of age with higher prevalence in men than in women. The development of restrictive cardiomyopathy, complicated by progressive left ventricular or biventricular dysfunction, represents a major determinant of adverse outcome for these patients who typically die as a result of progressive heart failure or sudden cardiac death.
Because pulmonary impairment rarely dominates the clinical picture, pathologists most often encounter diffuse alveolar-septal amyloidosis as a post mortem finding. Post mortem series have confirmed that diffuse parenchymal amyloid is common in systemic AL amyloidosis. In an autopsy series, pulmonary involvement was found in 30% of 223 cases of patients with amyloidosis, including 14% with ATTRwt cardiac amyloidosis, 10% with AL amyloidosis and 4% with multiple myeloma . In the series reported by B ROWNING et al. , lung involvement was present at histological examination of post mortem tissue specimens in 18 (90%) out of 20 patients with AL amyloidosis and in eight (33%) out of 24 patients with AA. In a recent report from the Mayo Clinic , the authors reviewed the demographic and clinical features of 76 patients with autopsy-proven pulmonary amyloidosis. The diagnosis of AL amyloidosis was the most frequent and nearly all were diagnosed ante mortem; however, ATTR was mostly diagnosed at autopsy. In this series, alveolar septal involvement was seen in 59 patients (78%; AL n=44, ATTRwt n=11, ATTRm (mutated transthyretin) n=3 and apolipoprotein A-IV n=1). An ante mortem diagnosis of pulmonary AL amyloidosis was rendered only in one case. Interestingly, the authors concluded that the most common cause of death was cardiac amyloidosis . Upon autopsy, the lungs are rubbery and their cut sections have a uniform spongelike appearance. Typically, all lobes are involved. The visceral pleura may be affected and pleural effusion is common. Diffuse alveolar septal amyloidosis manifests with widespread amyloid deposition involving the small vessels and the interstitium, with reticular opacities, interlobular septal thickening, micronodules and, less frequently, ground-glass opacification, traction bronchiectasias and honeycombing at high-resolution computed tomography (CT)  (figure 1). Diffuse amyloidosis is sometimes accompanied by mediastinal lymphadenopathy . However, interstitial opacities may be subtle even in patients with overt clinical manifestations [43 – 45]. Factors that influence the pattern of amyloid deposition in amyloidosis remain unclear. However, in patients with systemic amyloidosis, pulmonary involvement is commonly demonstrable histopathologically at autopsy, but generally not diagnosed clinically . Another autopsy study reported involvement of the lung parenchyma and vasculature in 11 out of 12 patients with AL, of whom only four were symptomatic, including one patient who died of pulmonary amyloidosis . The lesions are typically hypocellular, but scant plasma cells may be present. Giant cells are not usually seen with diffuse alveolar-septal amyloidosis.
Systemic AL amyloidoisis should be distinguished from other forms of amyloidosis, related to different protein precursors bearing an unstable tertiary structure enabling the formation of fibrils. Various mechanisms of amyloid deposition are involved in systemic amyloidosis: increased serum levels of serum amyloid A protein (SAA) in AA amyloidosis during chronic inflammatory or infectious diseases, or increased β2microglobulin levels in chronic dialysis patients. In hereditary amyloidosis, a mutation in the gene encoding for the precursor results in increased amyloidogenicity of the mutant protein. Although the transmission of all types of hereditary amyloidosis is autosomal dominant, a suggestive family history is often lacking due to incomplete penetrance of the mutation . Therefore, in the absence of unequivocal staining with an anti-LC antibody, additional immunofluores- cence and immunohistochemistry studies should be per- formed to verify the absence of staining with antibodies specific for amyloid precursors found in hereditary amyl- oidosis (i.e. lysozyme, apolipoprotein A1, apoliprotein A2, fibrinogen, gelsolin and transthyretin). Moreover, genetic studies seeking for an amyloidogenic mutation of the genes encoding for the precursors cited above should be rapidly undertaken, with, if available, mass spectrometry-based proteomic analysis of biopsy samples after laser microdissection.
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Case presentation: We report the case of a 60-year-old Moroccan woman, complaining of dyspnea and wheezing for three years, who was treated at our institution for management of severe asthma. A bronchoscopy revealed a tumor formation of her trachea; multiples biopsies were performed and a diagnosis made of amyloid light-chain amyloidosis. She successfully received an endoscopic resection.
Screening endoscopic biopsies of the gastrointestinal tract are diagnostic in most cases of systemic amyloido- sis. A variety of mucosal abnormalities are observed in the GI tract by endoscopy; involvement of the small in- testine is especially common (Figure 2). The lesions may appear as a fine granular, granular and nodular mu- cosa, polypoid protrusions, erosions, ulcerations, muco- sal friability, and bowel wall thickening [3,6,57,60]. Tada et al. reported endoscopic appearances of gastrointestinal amyloidosis at different location . In their study, en- doscopic findings of the esophagus, stomach, duodenum, and colorectum were assessed in 37 patients with amy- loidosis involving the gastrointestinal tract. Endoscopic examinations revealed fine granular appearance, poly- poid protrusions, erosions, ulcerations, and mucosal fri- ability in many cases. These findings were most marked and noticed most often in the second portion of the duo- denum. The frequency of amyloid deposition in the bi-
In the current observational study, 50 newly diagnosed cases of primary cutaneous amyloidosis, attending the OPD of a tertiary care center were recruited from December, 2012 to June, 2014. As the prevalence of cutaneous amyloidosis in the literature is 0.2- 0.3%, it will require a very large sample size. Therefore, we included all 22,127 patients attending dermatology OPD during the study period of one and half year to have the maximum sample size possible to increase the accuracy of the estimation process [7,8]. All the patients suspected to be suffering from cutaneous amyloidosis on the basis of clinical symptoms and signs were included in the study, after obtaining an informed written consent. Patients having any systemic disease were excluded from the study. The study was approved by Ethical Committee of SS Institute of Medical Sciences and Research Centre, India.
Diflunisal, a generic nonsteroidal anti-inflammatory drug (NSAID), also slows the rate of amyloidogenesis by preventing the dissociation, misfolding, and misassembly of mutated TTR tetramers. Diflunisal preferentially sta- bilizes TTR tetramers by increasing the tetramer dissoci- ation barrier via small molecule binding and by binding to the 99% unoccupied L-thyroxine binding sites in TTR [139, 140]. Because of high serum concentrations after oral administration, diflunisal imposes kinetic stability on TTR heterotetramers exceeding that of the wild-type homotetramer and compensates for its modest binding affinity and selectivity to TTR over all other serum pro- teins. Thus, diflunisal is the most promising NSAID for the treatment of TTR amyloidosis . Diflunisal ad- ministered at a dose of 250 mg twice a day is sufficient to impose kinetic stabilization on the tetrameric native state of TTR and achieves kinetic stabilization under very demanding denaturing conditions. In an inter- national randomized, double-blind, placebo-controlled study conducted among 130 ATTR-FAP patients in Sweden, Italy, Japan, England, and the United States from 2006 through 2012, polyneuropathy progression (measured by the Neuropathy Impairment Score plus 7 nerve tests [NIS+7]) was significantly less (NIS+7 score: 8.7 [95% confidence interval (CI), 3.3–14.1] vs 25.0 [95% CI, 18.4–31.6]) in patients receiving diflunisal. Also, pa- tients on diflunisal showed significant improvement in quality of life measures than patients on placebo in whom quality of life deteriorated. Further, a greater proportion of patients receiving diflunisal (29.7% vs 9.4%) exhibited neurological stability at 2 years (<2-point increase in NIS +7 score; p = 0.007) . A retrospective analysis of off-
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Successful treatment of the underlying inflammatory process can lead to stabilization or improvement in renal function, reduction in protein excretion, and partial resolution of amyloid deposits [4-6]. There have been cases reported in the literature in which there was remission of nephrotic syndrome following treatment of tuberculosis [7,8] but this is certainly rare. Even in our second patient, remission was seen. But most patients with renal amyloidosis ultimately progress to chronic renal failure and once kidney involvement is extensive, anti-TB treatment will not cause any regression in the course of renal amyloidosis. Even despite being treated adequately with effective ATT, patients may present with renal amyloidosis and this could be attributed to posttubercular bronchiectasis or an irreversible process of amyloid deposition that had initiated earlier .
Amyloidosis is a spectrum of diseases associ- ated with abnormal extracellular deposition of amyloid, and autologus fibrillar protein materi- al. Histochemically, this protein binds with Congo red, revealing green birefringence under polarized light. In 1842, Rokitansky first des- cribed such deposits in tissue . Virchow was the first to use the term amyloid because of the starch-like reaction when treated with iodine and sulphuric acid . In 1851, Borow docu- mented the first case of laryngeal amyloidosis in 1973 . The cause of amyloidosis has not been elucidated. The protein of amyloid fibrils may be light chains synthesized by increased plasma cells and secreted extracellularly, cleaved by lysosomal enzymes in tissue macro- phages, polymerized into immunoglobulin light chain amyloid fibrils, and then deposited. Amyloidosis is a rare benign process and the larynx is the common site of localized amyloido- sis in the head and neck region , Laryngeal