Familial occurrences of cardiac wild-type transthyretin amyloidosis: a case series.

Background: Cardiomyopathy caused by aggregation and deposition of transthyretin amyloid fibrils in the heart (ATTR-CM) is divided into a hereditary (ATTRv) and a wild-type (ATTRwt) forms. While ATTR-CM has been considered a rare disease, recent studies suggest that it is severely underdiagnosed and an important cause of heart failure in elderly patients. Familial occurrence is implicit in ATTRv, but it is not expected in ATTRwt. Case summary: We report a case series of two unrelated families each with two brothers diagnosed with ATTRwt. Genetic testing did not reveal mutations in the transthyretin gene. Family screening with electrocardiogram, echocardiography, and genetic testing did not raise any suspicion of ATTR in first-line family members. Discussion: Familial occurrence of a rare, non-hereditary disease is statistically unlikely. Two siblings in two different families diagnosed with ATTRwt highlight that the aetiology of ATTRwt is poorly understood, and that genetic factors distinct from mutations in the transthyretin gene, as well as environmental factors, might contribute to the pathogenesis. Identifying such factors might reveal new therapeutic targets. To investigate this further, clinicians need to be aware of the possibility of familial occurrence of ATTRwt.

Glaucoma is probably not useful as a red flag for amyloidosis.

Purpose. Transthyretin is produced in the retina and approximately one quarter of patients with variant transthyretin amyloidosis (ATTRv) develop ocular involvement. Glaucoma is the most important ocular manifestation, leading to rapid loss of vision. The usefulness of glaucoma as a red flag for cardiac amyloidosis is unknown. Materials and Methods. On a national scale, we investigated the association between glaucoma and development of amyloidosis, compared to an age- and sex-matched population from the general population. Results. The study population included 365,496 subjects (1:1 ratio). Adjusted Cox-models showed no significant association between glaucoma and future diagnosis of amyloidosis (hazard ratio: 1.16 [0.80-1.70], p = .44). Conclusion. We conclude that while ocular involvement is a possible early manifestation of ATTRv, nationwide data suggest that glaucoma is probably not useful as a red flag for cardiac amyloidosis.

Screening for Cardiac Amyloidosis 5 to 15 Years After Surgery for Bilateral Carpal Tunnel Syndrome.

BACKGROUND: Bilateral carpal tunnel syndrome (CTS) is a common extracardiac manifestation of amyloidosis and usually predates overt cardiac amyloidosis (CA) by several years. Screening studies on patients undergoing CTS surgery have shown a low yield of CA (2.0%), but high prevalence of amyloid in the carpal ligament. The proportion of patients with amyloid in the carpal ligament who later develop CA is unknown. OBJECTIVES: The authors sought to investigate the prevalence of undiagnosed CA 5 to 15 years after surgery for bilateral CTS. METHODS: Using national registries, the authors identified subjects aged 60 to 85 years with prior CTS surgery, where the first procedure on the second wrist was performed 5 to 15 years earlier. Invitations to participate in the study were sent by mail. Per international recommendations, the initial cardiac evaluation included echocardiography, 99mtechnetium-pyrophosphate scintigraphy, and assessment of monoclonal proteins in serum and urine. RESULTS: A total of 250 subjects (35.7% of those invited) participated in the study. The median age was 70.4 years, and 50% were female. CA was diagnosed in 12 patients (4.8%; 95% CI: 2.5%-8.2%), and all cases were wild-type transthyretin amyloidosis (ATTRwt). The prevalence of ATTRwt in men was 8.8% (95% CI: 4.5%-15.2%; n = 11), and 21.2% (95% CI: 11.1%-34.7%) in male subjects ≥70 years with a BMI <30 kg/m2. All but 2 patients diagnosed with ATTRwt were in the lowest disease severity score (Mayo score). CONCLUSIONS: Screening for CA in patients with prior surgery for bilateral CTS finds approximately 5% with early-stage transthyretin CA. The clinical yield was higher (>1 in 5) when focusing on nonobese men ≥70 years, showing potential for systematic screening.

Carpal Tunnel Syndrome in Patients Who Underwent Pacemaker Implantation and Relation to Amyloidosis, Heart Failure, and Mortality.

Advances in treatment warrant earlier diagnosis of cardiac amyloidosis (CA). Common cardiac and extracardiac manifestations of CA, such as pacemaker implantation and carpal tunnel syndrome (CTS), might provide screening opportunities for CA. However the association between CTS and CA in patients undergoing pacemaker implantation has not been well studied. This study examined the association between previous CTS surgery and adverse cardiovascular outcomes in patients who underwent pacemaker implantation. Using Danish nationwide registries, we identified all patients ≥50 years who underwent first-time pacemaker implantation during 2000 to 2018, examining the association between previous CTS surgery and adverse cardiovascular outcomes 5 years after pacemaker implantation. Cumulative incidence functions and Cox proportional hazard models were used to assess the differences. Among 57,315 patients who underwent pacemaker implantation, 2.2% (n = 1,266) had previous CTS surgery. Patients in the CTS cohort were older, more often female, and had more co-morbidities than patients without CTS. The cumulative 5-year mortality was higher among patients with CTS (44.6% [41.1% to 47.9%] versus 40.2% [39.7% to 40.6%], p = 0.04). In the adjusted models, previous CTS surgery was not associated with increased 5-year mortality, but it was associated with an increased rate of hospitalization for new-onset heart failure, (hazard ratio 1.32 [1.11 to 1.57], p = 0.002) and a higher risk of amyloidosis diagnosis after pacemaker implantation (hazard ratio 7.72 [2.96 to 20.10], p <0.0001), compared with no previous CTS surgery. In patients who underwent pacemaker implantation, adjusted models showed that previous CTS surgery was associated with a higher incidence of hospitalization for new-onset heart failure and amyloidosis diagnosis after pacemaker implantation. Screening for CA may be considered in patients undergoing pacemaker implantation.

Two Decades of Cardiac Amyloidosis: A Danish Nationwide Study.

BACKGROUND: Cardiac amyloidosis (CA) has been associated with poor outcomes. Screening studies suggest that CA is overlooked-especially in the elderly. Recent advances in treatment have brought attention to the disease, but data on temporal changes in CA epidemiology are sparse. OBJECTIVES: The aim of this work was to describe all patients with CA in Denmark, examining changes in patient characteristics from 1998 to 2017. METHODS: All patients with any form of amyloidosis diagnosed from 1998 to 2017, as well as their comorbidities and pharmacotherapy, were identified in Danish nationwide registries. CA was defined as any diagnosis code for amyloidosis combined with a diagnosis code for heart failure, cardiomyopathy, or atrial fibrillation or a procedural code for pacemaker implantation, regardless of the order. The index date was defined as the date of meeting those criteria. Patients were divided into 5-year periods by index date. For comparison, we also included control subjects (1:4 ratio) from the general population. RESULTS: CA criteria were met by 619 patients. Comparing 1998-2002 vs 2013-2017, the median age at baseline increased from 67.4 years (interquartile range [IQR]: 53.9-75.2 years) to 72.3 years (IQR: 66.0-79.3 years). The frequency of male patients increased from 62.1% to 66.2%. The incidence of CA rose from 0.88 to 3.56 per 100,000 person-years in the Danish population aged ≥65 years, and the 2-year mortality decreased from 82.6% (IQR: 69.9%-90.5%) to 50.2% (IQR: 43.1%-56.9%). Compared with control subjects, the mortality among CA patients was significantly higher (log-rank test: P < 0.0001). CONCLUSIONS: CA, as defined in this study, was increasingly diagnosed on a national scale. The increasing frequency of male patients and median age suggest that wild-type transthyretin amyloidosis is driving this increase. Greater recognition of earlier, less advanced cases might explain decreasing mortality.

The association of prior carpal tunnel syndrome surgery with adverse cardiovascular outcomes and long-term mortality after aortic valve replacement.

AIMS: Patients undergoing aortic valve replacement (AVR) for severe aortic stenosis have a 6-16% prevalence of occult cardiac amyloidosis. Carpal tunnel syndrome (CTS) is common in cardiac amyloidosis, but whether prior CTS surgery has a prognostic impact in patients undergoing AVR is unknown. This study examined the association between prior CTS surgery and adverse cardiovascular outcomes in patients treated with AVR. METHODS AND RESULTS: Using Danish nationwide registries, we retrospectively identified patients undergoing first-time AVR from 2005 to 2018, examining the association between previous CTS and adverse cardiovascular outcomes the following 5 years after the AVR procedure. Cumulative incidence functions and adjusted Cox proportional hazard models were used to assess differences. Among 19,211 patients undergoing AVR, 2.5% (n = 472) had prior CTS surgery. Patients in the CTS-cohort were significantly older (median age 75.7 [IQR 68.1-82.3] vs 73.7 [IQR 66.0-79.6]), more often female and had more comorbidities. Prior CTS surgery was not associated with differences in hospitalization for heart failure (11.2% [95% CI 8.3-14.7] vs 9.4% [95% CI 9.0-9.9]), atrial fibrillation (11.1% [95% CI 8.2-14.5] vs 11.2% [95% CI 10.8-11.7]) or pacemaker implantation (6.2% [95% CI 4.0-9.0] vs 5.1% [95% CI 4.8-5.5]). The 5-year mortality (32.8% [27.6-38.0] vs 25.2% [24.5-25.9]) was higher in the CTS-cohort. CTS was significantly associated with increased 5-year mortality (HR 1.27 [1.05-1.53]) in crude models, however, after multivariable adjustment prior CTS surgery was not associated with adverse cardiovascular outcomes. CONCLUSION: Previous CTS surgery was not associated with increased risk for adverse cardiovascular outcomes after AVR.

Recurrent Episodes of Pericardial Effusion as Isolated Manifestation of Tuberculosis: Case Report.

BACKGROUND: Recurrent episodes of isolated pericardial effusion due to tuberculosis, leading to reduced Left Ventricle Ejection Fraction (LVEF), are uncommon. METHODS: This is a case report of a previously healthy 32-years old male with tuberculous induced pericardial effusion as isolated manifestation. The only known exposure of tuberculosis was a brother with whom the patient did not have physical contact during the last year. The pericardial effusion repeatedly appeared after being drained a total of three times. Due to recurrent episodes of pericardial effusion, severe thickening of the pericardium, pericardial adherences and increasing affection on the heart, pericardiectomy was ultimately performed. RESULTS: Biochemical examination, chest X-ray, computed tomography of thorax and abdomen and cytology report did not reveal any signs of malignancy, connective tissue disease or other infections including extra-pulmonary/pulmonary tuberculosis. However, the pericardial biopsy was Polymerase Chain Reaction positive (PCR) for tuberculosis DNA and showed granulomatous inflammation with necrosis. After 6 months anti-tuberculous therapy, biochemical parameters, LVEF and the clinical condition of the patient were normalized. CONCLUSION: Tuberculosis can be difficult to diagnose when it only manifests as pericardial effusion especially if the time for exposure is long before the appearance of symptoms and admission.

Soluble Urokinase Plasminogen Activator Receptor (suPAR) as a Predictor of Incident Atrial Fibrillation.

Soluble urokinase plasminogen activator receptor (suPAR) is a biomarker of chronic low-grade inflammation and a potent predictor of cardiovascular events. We hypothesized that plasma suPAR levels would predict new-onset atrial fibrillation (AF) in a large cohort of con-secutively admitted acute medical patients during long-term follow-up. In 14,764 acutely ad-mitted patients without prior or current AF, median suPAR measured upon admission was 2.7 ng/ml (interquartile range (IQR) 1.9-4.0). During a median follow-up of 392 days (IQR 218-577), 349 patients (2.4%) were diagnosed with incident AF. suPAR levels at admission significantly predicted subsequent incident AF (HR per doubling of suPAR: 1.21, 95% CI 1.05-1.41, adjusted for age and sex). After further adjustment for Charlson score, plasma C-reactive protein (CRP), plasma creatinine and blood hemoglobin-levels, the result remained essentially unaltered (HR per doubling of suPAR: 1.20, 95% CI: 1.01-1.42). In multivariate ROC curve analysis, combining age, sex, Charlson score, CRP, creatinine, and hemoglobin (AUC 0.77, 95% CI 0.75-0.79), the addition of suPAR did not improve the prediction of incident AF (AUC 0.77, 95% CI 0.75-0.79, P=0.89). Plasma suPAR is independently associated with subsequent new-onset AF in a population of recently hospitalized patients, but the addition of suPAR to baseline risk markers appears not to improve the prediction of AF.

Posterior corneal astigmatism in refractive lens exchange surgery.

PURPOSE: To assess the anterior, posterior and total corneal spherical and astigmatic powers in patients undergoing refractive lens exchange (RLE) surgery. METHODS: In 402 consecutive patients planned for RLE at Koskelas Eye Clinic, Luleå, Sweden, right eye data from pre- and postoperative subjective refraction, preoperative IOLMaster(®) biometry and Pentacam HR(®) measurements were collected. Postoperative Pentacam HR(®) data were collected for 54 of the patients. The spherical and astigmatic powers of the anterior and posterior corneal surfaces and for the total cornea were assessed and compared, and surgically, induced astigmatism was calculated using vector analysis. RESULTS: The spherical power of the anterior corneal surface was 48.18 ± 1.69D with an astigmatic power of 0.83 ± 0.54D. The corresponding values for the posterior surface were -6.05 ± 2,52D and 0.26 ± 0.15D, respectively. The total corneal spherical power calculated with ray tracing was 42.47 ± 2.89D with a 0.72 ± 0.48D astigmatic power, and the corresponding figures obtained by estimating the posterior corneal surface were 43.25 ± 1.51D (p < 0.001) with a 0.75 ± 0.49D astigmatic power (p = 0.003). In eyes with anterior astigmatism with-the-rule, the total corneal astigmatism is overestimated if the posterior corneal surface is estimated; in eyes, with against-the-rule astigmatism it is underestimated. Had the posterior corneal surface been measured in this material, 14.7% of the patients would have received a spheric instead of a toric IOL, or vice versa. CONCLUSION: Estimating the posterior corneal surface in RLE patients leads to systematic measurement errors that can be reduced by measuring the posterior surface. Such an approach can potentially increase the refractive outcome accuracy in RLE surgery.

Gender differences in refractive prediction in refractive lens exchange surgery.

PURPOSE: To compare the refractive outcomes after refractive lens exchange (RLE) surgery with regards to gender and intraocular lens (IOL) power calculation formula. METHODS: A cohort of consecutive patients operated with bilateral same-day RLE surgery at a private eye clinic (n = 512) was studied. Target refraction was emmetropia in all cases and Haigis formula was used for all IOL power calculations. One month after surgery, subjective refraction was assessed and the absolute refractive prediction error (RPEAbs), as well as the refractive prediction error with correct signs (RPESign), was calculated, as were the refractive outcomes with the SRK/T formula. RESULTS: For the whole cohort, the Haigis formula rendered a significantly smaller RPEAbs than the SRK/T formula (0.16 ± 0.26 D vs 0.32 ± 0.30 D; p<0.001). No gender difference in RPEAbs was seen. A slight myopic error was seen with the SRK/T formula in women, and a slight hyperopic error in men (-0.06 ± 0.47 D vs + 0.16 ± 0.39 D; p<0.001). No similar gender difference was seen with the Haigis formula (+0.05 ± 0.29 D vs +0.05 ± 0.31 D; p = NS). Axial length, anterior chamber depth, and corneal steepness differed significantly between the sexes. CONCLUSIONS: The Haigis formula generally performed better in this RLE cohort. The SRK/T formula generates a small myopic error in women and a hyperopic error in men, associated with flatter corneas, longer axial lengths, and deeper anterior chambers in the latter.

Epidemiology and outcomes in refractive lens exchange surgery.

PURPOSE: To assess demographics and refractive outcomes in patients undergoing refractive lens exchange surgery (RLE), with a population of cataract patients as a reference. METHODS: A RLE cohort from a private eye clinic (n = 675) and a cataract cohort from the outcome registration of the Swedish National Cataract Register were studied and compared from an epidemiological perspective regarding age, gender, preoperative refraction and postoperative refractive outcome. RESULTS: The RLE patients were younger (52.1 ± 7.7 versus 73.84 ± 9.32 years) with a smaller percentage of women (45.28% versus 60.46%; p < 0.001) and were more often myopic than the cataract patients. Astigmatism and hyperopia did not differ between the cohorts. Uncorrected visual acuity after RLE equalled the best corrected visual acuity in best cases after cataract surgery. The absolute biometry prediction was more accurate in RLE (0.17 ± 0.27 D versus 0.40 ± 0.58 D; p < 0.001), particularly in patients given a customized toric IOL (0.12 ± 0.27 D; p < 0.05). In cataracts, the Haigis' formula showed higher accuracy than the SRK/T formula (0.39 ± 0.53 D versus 0.43 ± 0.61 D; p < 0.01). Postoperatively after RLE, Laser Epithelial Keratomileusis was performed in 9.04% and Yttrium Aluminium Garnet capsulotomy in 7.41% of the eyes. Other reoperations were performed in three cases, and five postoperative retinal detachments occurred after RLE. CONCLUSION: Compared with patients undergoing cataract surgery, we see many similarities, but also many interesting differences in patients undergoing RLE. Basic information about the growing population choosing to undergo RLE can help us plan future ophthalmic care.