Uncertain diagnosis of Fabry disease: Consensus recommendation on diagnosis in adults with left ventricular hypertrophy and genetic variants of unknown significance

Background

Screening in subjects with left ventricular hypertrophy (LVH) reveals a high prevalence of Fabry disease (FD). Often, a diagnosis is uncertain because characteristic clinical features are absent and genetic variants of unknown significance (GVUS) in the α-galactosidase A (GLA) gene are identified. This carries a risk of misdiagnosis, inappropriate counselling and extremely expensive treatment. We developed a diagnostic algorithm for adults with LVH (maximal wall thickness (MWT) of > 12 mm), GLA GVUS and an uncertain diagnosis of FD.

Methods

A Delphi method was used to reach a consensus between FD experts. We performed a systematic review selecting criteria on electrocardiogram, MRI and echocardiography to confirm or exclude FD. Criteria for a definite or uncertain diagnosis and a gold standard were defined.

Results

A definite diagnosis of FD was defined as follows: a GLA mutation with ≤ 5% GLA activity (leucocytes, mean of reference value, males only) with ≥ 1 characteristic FD symptom or sign (neuropathic pain, cornea verticillata, angiokeratoma) or increased plasma (lyso)Gb3 (classical male range) or family members with definite FD. Subjects with LVH failing these criteria have a GVUS and an uncertain diagnosis. The gold standard was defined as characteristic storage in an endomyocardial biopsy on electron microscopy. Abnormally low voltages on ECG and severe LVH (MWT > 15 mm) < 20 years exclude FD. Other criteria were rejected due to insufficient evidence.

Conclusions

In adults with unexplained LVH and a GLA GVUS, severe LVH at young age and low voltages on ECG exclude FD. If absent, an endomyocardial biopsy with electron microscopy should be performed.     

Identification of Fabry Disease in a Tertiary Referral Cohort of Patients with Hypertrophic Cardiomyopathy

Background

Fabry disease is an X-linked lysosomal storage disorder caused by the deficient activity of α-galactosidase A due to mutations in the GLA gene, which may be associated with increased left ventricular wall thickness and mimic the morphologic features of hypertrophic cardiomyopathy. Management strategies for these 2 diseases diverge, with Fabry disease–specific treatment utilizing recombinant α-galactosidase A enzyme replacement therapy.

Inverse association of estimated cystatin C- and creatinine-based glomerular filtration rate with left ventricular mass: Results from the Study of Health in Pomerania

Background

Left ventricular hypertrophy (LVH) is an independent predictor of cardiovascular disease in the general population and in patients with chronic kidney disease. The objective of this study was to investigate the association of estimated glomerular filtration rate (eGFR) with left ventricular mass index (LVMI), LVH and left ventricular geometry. A question of clinical relevance is whether estimated glomerular filtration rate based on cystatin C (eGFR_cystatinC) is a better marker for cardiovascular risk than estimated glomerular filtration rate based on creatinine (eGFR_creatinine).

Methods

The study sample included 2830 individuals from the population-based Study of Health in Pomerania (SHIP). LVH was defined as echocardiographic LVMI > 48 g/m^2.7 in men and > 44 g/m^2.7 in women. Kidney function, as assessed by eGFR, was determined from established equations: the creatinine-based Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and a cystatin-based multivariable equation.

Results

We found an inverse association between eGFR and LVMI. This association was stronger in models with eGFR_cystatinC than in models with eGFR_creatinine. Subjects with moderately-to-severely decreased kidney function (defined as eGFR 15–< 60 mL/min per 1.73 m²) had higher odds for abnormal geometric patterns of the left ventricle than subjects with normal eGFR when eGFR_cystatinC was used.

Conclusions

The findings suggest that eGFR_cystatinC is superior to eGFR_creatinine for assessing the risk of cardiovascular disease.     

Left ventricular hypertrophy reduction and clinical events. A meta-regression analysis of 14 studies in 12,809 hypertensive patients

Background

Left ventricular hypertrophy (LVH) is an independent risk factor for clinical events (CE), and regression of LVH is associated with reduction of cardiovascular risk. However, whether a continuous relationship between reduction of LVH and risk of CE exists has not been investigated.

Methods

Randomized clinical trials evaluating LVH at baseline and reporting quantitative LVH changes and CE, stroke or new onset heart failure) were included. Meta-regression analysis was performed to test the relationship between changes in LVH and incidence of the composite outcome (all-cause death, MI, stroke or new onset heart failure) and between changes of LVH and occurrence of each component of the composite outcome. Analysis of potential confounder variables was also performed.

Results

Fourteen trials including 12,809 participants and reporting 2259 events were included. Follow-up ranged from 0.50 to 5 years, with mean 1.97 ± 1.50 years. Mean age was 62 ± 5 years and 52% of patients were women. The composite outcome was significantly reduced by active treatments (OR: 0.851, IC: 0.780 to 0.929, p < 0.001), as well stroke (OR: 0.756, IC: 0.638 to 0.895, p < 0.001) whereas MI and new onset heart failure were not significantly reduced by treatments. LVH changes did not predict the reduction of CE. No significant influence on the association of baseline patients and studies characteristics was found.

Conclusions

A significant continuous relationship between LVH changes and CE could not be demonstrated in hypertensive patients, independently on the technique or drug used. Ad hoc designed studies should further explore the relationship between LVH modification and outcomes in hypertensive patients.     

Awareness of Fabry disease in cardiology: A gap to be filled

Introduction

In adults, unexplained left ventricular hypertrophy is usually due to sarcomeric hypertrophic cardiomyopathy (HCM). Fabry disease (FD) is rare but may mimic sarcomeric HCM, and has an adverse prognosis in the absence of specific treatment. We aimed to assess cardiologists’ awareness of FD based on data from the Portuguese Registry of Hypertrophic Cardiomyopathy.

Clusters of AMI risk factors and their association with left ventricular hypertrophy: A population-based study within the Skaraborg Project,Sweden

Objectives

Risk factors for acute myocardial infarction (AMI) are known to cluster and to be differently distributed in men and women. The aim of this study was to sex-specifically explore clusters of acknowledged AMI risk factors by factor analysis, and to study whether such clusters are associated with left ventricular hypertrophy (LVH), used as a subclinical measure of CHD.

Methods

In 2001–2005, 2328 subjects (30–74 years) were randomly selected from two municipalities in Sweden (participation-rate 76%) and were assessed with regard to cardiovascular risk factors; 852 participants also had an echocardiographic examination performed.

Results

Factor analysis identified three identical factors in men and women. WHR, HOMA-ir, systolic blood pressure, and ApoB/ApoA1 loaded significantly on the principal “metabolic factor”, leisure-time physical activity and self-rated health loaded significantly on the “vitality factor”, and smoking and alcohol consumption loaded significantly on the “addiction factor”. The metabolic factor was associated with LVH in both men (P < 0.001) and women (P < 0.001), whereas the addiction factor was associated with LVH solely in men (P = 0.002).

Conclusions

The consistent pattern in the clustering of acknowledged AMI risk factors suggests common underlying mechanisms in both men and women. However, whereas the metabolic factor was paramount in both men and women in the association with LVH, the addiction factor had an impact solely in men. As LVH often precedes AMI, a deeper understanding of risk factors for LVH, including consideration of the supposed sex differences, can be useful in order to explore prevention strategies for AMI.     

In vivo effect of proton-pump inhibitors on gastric plasmin-dependent fibrinolysis: A study in a porcine model

Introduction

Alkalization of gastric fluids could inhibit plasmin-mediated and/or pepsin-mediated fibrinolysis. We evaluated the gastric antifibrinolytic effect of proton pump inhibitors in a live porcine model.

Material and methods

Six pigs were randomly assigned to treatment with proton pump inhibitors vs no treatment. After endoscopic mucosal resection, 8 μm sections were incubated on fibrin films. Fibrinolytic activity was assessed through focal lysis time. One-hundred-and-forty-two mucosal sections and 129 submucosal sections were analysed. Twenty-four additional sections were analysed on plates containing tranexamic acid to explore pepsin-mediated fibrinolysis.

Results

Focal lysis times in treated vs control groups were 21.0 min vs 21.2 min (p = 0.39) in the mucosa, and 22.2 min vs 20.2 min (p = 0.56) in the submucosa. No lysis could be seen on the plasmin-inhibited fibrin plates.

Conclusion

Only plasmin-mediated fibrinolysis was observed. Proton pump inhibitors had no significant plasmin-dependant antifibrinolytic effect. They may enhance haemostasis through different pathways.     

Lamin A/C mutation is independently associated with an increased risk of arterial and venous thromboembolic complications

Background

Lamin A/C (LMNA) mutation carriers suffer from a variety of clinical phenotypes, including dilated cardiomyopathy (DCM). Although it has been suggested that carriers are at risk for thromboembolic complications, it is unknown whether this risk is higher than can be expected from the underlying cardiac abnormalities. The purpose of this study was to determine whether a LMNA mutation is associated with an increased risk of thromboembolic complications.

Methods

We compared a cohort of 76 LMNA mutation carriers with a cohort of 224 idiopathic DCM patients without a LMNA mutation, with respect to the prevalence of arterial and venous thromboembolic complications. Furthermore, we carried out a case–control study to explore whether a prothrombotic phenotype was present in LMNA mutation carriers without DCM or atrial tachyarrhythmias (n = 14) and compared this with mutation negative relatives (n = 13).

Results

The prevalence of thromboembolic complications was higher in the cohort of LMNA mutation carriers than in DCM patients (22 vs 11%; p < 0.05), after respectively mean follow-up of 42 ± 12 and 49 ± 12 years. After adjustment for possible confounders, including atrial tachyarrhythmias and left ventricular ejection fraction, LMNA mutation carriership was independently associated with an increased risk of thromboembolic complications (HR 4.8, 95% CI: 2.2–10.6). The results of the case–control study suggested a prothrombotic phenotype in LMNA mutation carriers, as reflected by an altered platelet function and increased thrombin generation.

Conclusions

LMNA mutation is independently associated with an increased risk of arterial and venous thromboembolic complications. Laboratory research in LMNA mutation carriers without severe cardiac abnormalities suggests a prothrombotic phenotype.     

Influence of left ventricular remodeling on atrial fibrillation recurrence and cardiovascular hospitalizations in patients undergoing rhythm-control therapy

Background

Atrial fibrillation (AF) patients with left ventricular hypertrophy (LVH) and diastolic dysfunction may derive benefit from being in sinus rhythm but no data are available to support this strategy in them. We sought to investigate effect of left ventricular remodeling on cardiovascular outcomes in AF patients undergoing rhythm control strategy.

Methods

We identified 1088 patients with echocardiographic data on left ventricular mass (LVM) enrolled in the AFFIRM trial. Using the American Society of Echocardiography (ASE) criteria, patients were divided into 4 categories: 1) normal geometry, 2) concentric remodeling, 3) eccentric hypertrophy, and 4) concentric hypertrophy. The primary endpoint was AF recurrence and the secondary endpoint was cardiovascular hospitalization (CVH).

Results

In rhythm control arm, median time to recurrence in patients with concentric LVH was 13.3 months (95% CI 8.2–24.5) vs. 28.3 months (95% CI 20.2–48.6) in patients without LVH. Concentric left ventricular hypertrophy (LVH) was independently predictive of AF recurrence (HR 1.49, 95% CI 1.10–2.01, p = 0.01) in rhythm control arm, but not in overall population or rate control arm. Both concentric and eccentric LVH were independently predictive of cardiovascular hospitalization (CVH) in the overall population, with respective HRs of 1.36 (1.04–1.78, p = 0.03) and 1.38 (1.02–1.85, p = 0.04).

Conclusion

Concentric LVH is predictive of AF recurrences when a predominantly pharmacologic rhythm-control strategy is employed. Different patterns of LVH seem to be important determinants of outcomes (AF recurrence and CVH). These findings may have important clinical implications for the management of patients with AF and LVH. Further studies are warranted to confirm our findings.     

Left ventricular geometry and outcomes in patients with atrial fibrillation: The AFFIRM Trial

Background

Echocardiographically determined left ventricular hypertrophy (LVH) is a marker of cardiovascular disease related to prognosis and clinical outcomes. We sought to determine if LVH is a measure of outcomes in atrial fibrillation (AF) patients.

Methods

We performed a post-hoc analysis of patients with echocardiographic data enrolled in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Trial. Patients were stratified based on gender-adjusted echocardiography derived interventricular septal (IVS) thickness, relative wall thickness (RWT), gender-adjusted LV mass, and type of LV remodeling (normal LV geometry, concentric hypertrophy, eccentric hypertrophy, and concentric remodeling).

Results

Of 4060 patients in AFFIRM, echocardiographic data were available in 2433 patients (60%). Multivariate analysis revealed that LVH defined as moderately or severely abnormal IVS thickness was an independent predictor of both all cause mortality (HR 1.46, 95%CI 1.14–1.86, p = 0.003) and stroke (HR 1.89, 95%CI 1.17–3.08, p = 0.01). This association was confirmed when IVS thickness was assessed as continuous or categorical variable. Concentric LV hypertrophy was associated with the highest rates of all cause mortality (HR 1.53; 95%CI 1.11–2.12; p = 0.009).

Conclusion

An easily obtained echocardiographic index of LVH (IVS thickness) may enhance risk stratification of patients with AF, and raise the possibility that LVH regression should be a therapeutic target in this population.     

The utility of urinary myo-inositol as a marker of glucose intolerance

Objective

The most common screening tests for glucose intolerance are fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c). Because it reflects the current status of hyperglycemia, urinary myo-inositol (UMI) may be useful. We evaluated UMI as a screening tool for glucose intolerance.

Design and methods

A cross-sectional, community-based population study of 1057 Japanese residents. 173 with an FPG level between 5.5 and 6.9 mmol/L and an HbA1c under 6.5% had an oral glucose tolerance test. We measured UMI level before (fasting UMI) and 2 h after (2 h-UMI) glucose ingestion. Δ-UMI was defined as the difference between fasting UMI and 2 h-UMI.

Results

Δ-UMI, 2 h-UMI and HbA1c levels significantly increased as glucose intolerance worsened. Δ-UMI level was significantly positively correlated with 2 h-UMI level (r = 0.896, p < 0.001). Using cutoff levels from receiver operating characteristic (ROC) analyses, the sensitivity of Δ-UMI (82.1%) and 2 h-UMI (79.3%) were higher than that of HbA1c (48.3%). The area under the ROC curve values for Δ-UMI (0.903) and 2 h-UMI (0.891) were higher than that for HbA1c (0.785).

Conclusions

2 h-UMI is useful as a non-invasive screening of glucose intolerance.     

Endoscopic ultrasonography-guided brushing increases cellular diagnosis of pancreatic cysts: A prospective study

Background

The diagnosis of pancreatic cystic lesions is still a challenge.

Aim

To prospectively investigate the usefulness and safety of EUS-guided cytology brushing (EUS BR) in the cellular diagnosis of pancreatic cysts.

Methods

Cysts >15 mm were sampled with a 19G needle. The fluid was aspirated and processed for cytology. The brush was introduced to scrub the cystic wall and processed as standard brushings. Antibiotic prophylaxis was administered. Complications were assessed in the first 24 h and 7 days after the procedure.

Results

30 patients were included. In 8 patients the technique failed for technical reasons. EUS BR provided with a cellular diagnosis in 20/22 cases (91%). The EUS BR was superior to the aspirated fluid for detecting diagnostic cells (73% vs. 36%, p = 0.08) and mucinous cells (50% vs. 18%, p = 0.016). In the 8 patients operated on, the specimen was consistent with EUS BR diagnosis. Three patients (10%) had complications, one of them a subacute retroperitoneal haemorrhage in a patient on anticoagulation therapy who died for complications 1 month later.

Conclusions

EUS BR increases cellular diagnosis of pancreatic cystic lesions as compared with fluid analysis, mainly in mucinous lesions. Its use is not recommended in patients under anticoagulation therapy.     

High definition plus colonoscopy combined with i-scan tone enhancement vs. high definition colonoscopy for colorectal neoplasia: A randomized trial

Background

High definition endoscopy is the accepted standard in colonoscopy. However, an important problem is missed polyps.

Aims

Our objective was to assess the additional adenoma detection rate between high definition colonoscopy with tone enhancement (digital chromoendoscopy) vs. white light high definition colonoscopy.

Methods

In this prospective randomized trial patients were included to undergo a tandem colonoscopy. The first exam was a white light colonoscopy with removal of all visualized polyps. The second examination was randomly assigned in a 1:1 ratio as either again white light colonoscopy (Group A) or colonoscopy with tone enhancement (Group B). Primary endpoint was the adenoma detection rate during the second withdrawal (sample size calculation – 40 per group).

Results

67 lesions (Group A: n = 34 vs. Group B: n = 33) in 80 patients (mean age 61 years, male 64%) were identified on the first colonoscopy. The second colonoscopy detected 78 additional lesions: n = 60 with tone enhancement vs. n = 18 with white light endoscopy (p < 0.001). Tone enhancement found more additional adenomas (A n = 20 vs. B n = 6, p = 0.006) and identified significantly more missed adenomas per subject (0.5 vs. 0.15, p = 0.006).

Conclusions

High definition plus colonoscopy with tone enhancement detected more adenomas missed by white light colonoscopy.     

Prevalence of low phospholipid-associated cholelithiasis in young female patients

Background and aims

We evaluated the prevalence of low phospholipid-associated cholelithiasis, a specific form of cholelithiasis associated with at least 2 of the 3 following criteria: first symptoms before the age of 40; intrahepatic comet tail artefacts, sludge or microlithiasis on ultrasound imaging; and recurrence of symptoms after cholecystectomy.

Methods

We prospectively studied the cases of 60 consecutive female patients under 30 with symptomatic cholelithiasis.

Results

A diagnosis of low phospholipid-associated cholelithiasis was made in 14/60 patients (23%). The molecular analysis showed ABCB4 (n = 4) and ABCB11 (n = 4) gene mutations. Low phospholipid-associated cholelithiasis was frequently observed in non-overweight patients [13/27 (48%)], was present in most patients whose biliary symptoms occurred before the age of 18 [7/10 (70%)] and was often associated with cholangitis or acute pancreatitis [9/14 (64%), p < 0.05] while “common” cholelithiasis was mainly associated with cholecystitis [16/46 (35%), p < 0.05].

Conclusion

Nearly one quarter of the female patients under the age of 30 admitted for symptomatic cholelithiasis had low phospholipid-associated cholelithiasis; particularly if body weight was normal, the symptoms began before the age of 18 or in the presence of severe biliary complications.     

Coronary artery calcification correlates with the presence and severity of valve calcification

Aim

To investigate the prevalence of coronary artery calcification (CAC) in symptomatic individuals with CT evidence for left heart valve calcification, aortic valve (AVC), mitral valve (MAC) or both.

Methods

This is a retrospective study of 282 consecutive patients with calcification in either the aortic valve or mitral annulus. Calcium scoring of the coronary artery, aortic and mitral valve was measured using the Agatston score.

Results

AVC was more prevalent than MAC (64% vs. 2.5%, p < 0.001), with 34% having both. Absence of CAC was noted in 12.7% of the study population. AVC + CAC were observed in 53.5%, MAC and CAC in 2.1%, and combined AVC, MAC and CAC in 31.6%. The median CAC score was higher in individuals with combined AVC + MAC, followed by those with AVC and lowest was in the MAC group. The majority (40%) of individuals with AVC had CAC score > 400, and only in 16% had CAC = 0. The same pattern was more evident in individuals with AVC + MAC, where 70% had CAC score > 400 and only 6% had CAC score of 0. These results were irrespective of gender. There was no correlation between AVC and MAC but there was modest correlation between CAC score and AVC score (r = 0.28, p = 0.0001), MAC (r = 0.36, p = 0.0001) and with combined AVC + MAC (r = 0.5, p = 0.0001). AVC score of 262 had a sensitivity of 78% and specificity of 92% for the prediction of presence of CAC.

Conclusion

The presence and extent of calcification in the aortic valve or/and mitral valves are associated with severe coronary artery calcification.     

Molecular epidemiology of fluoroquinolone resistance in invasive clinical isolates of Streptococcus pneumoniae in Seville

Introduction

Due to the emergence of drug-resistant pneumococcal isolates, new fluoroquinolones have been recommended for the treatment of pneumococcal infections. The purpose of this study was to establish surveillance, and to conduct molecular characterization, of fluoroquinolone-resistant Streptococcus pneumoniae in Seville.

Method

Norfloxacin-resistant S. pneumoniae isolates were characterized by quinolone resistance-determining region (QRDR) substitutions, reserpine-sensitive efflux, serotype and by pulsed-field gel electrophoresis (PFGE) patterns.

Results

Fourteen isolates (5.1%) showed an MIC > 16 μg/ml to norfloxacin. Eight of 10 adult isolates were susceptible to levofloxacin. The 4 infant isolates with norfloxacin MIC > 16 μg/ml were susceptible to levofloxacin. Seven of these 12 low-level-resistant isolates had mutations in ParC, while mutations both in ParC and GyrA genes were only detected in one of the two high-level-resistant isolates. All the isolates without QRDR substitutions that remained norfloxacin-resistant were positive for reserpine-inhibited efflux. The serotyping and PFGE revealed significant heterogeneity. We obtained 9 different profiles, 3 of which had two isolates each. Two of the isolates with the same pulsotype were from the same patient. The first isolate showed a mutation in the QRDR of ParC, and the second one had an additional GyrA mutation.

Conclusion

In our study a levofloxacin resistance rate of 0.7% was found among invasive isolates. Although resistance level is low, surveillance is necessary, especially to prevent cases of in vivo resistance development as reported.     

Enhanced recognition of ischemia by three variable analysis of the exercise stress test

Background

ECG ST-segment deviations have been the standard measure of coronary artery disease (CAD) during the exercise stress test (EST). Our past research has shown other ECG variables to be significant in EST. This study evaluates the benefit of routinely combining these variables in the detection of CAD.

Methods

Sequential patients (n = 439) with suspected CAD referred for EST had their cases reviewed. Clinical and ECG variables were associated with myocardial perfusion imaging (MPI) scintigrams used to detect ischemia during maximum EST.

Results

An increase in P-wave duration was the most sensitive predictor of ischemia with a sensitivity of 64.3%, a specificity of 86.5%, and a positive predictive power (PPP) of 57.8%. ST elevation ≥ 1 mm in lead AVR had a sensitivity of 53.1%, a specificity of 78.3%, and a PPP of 41.3%. ST depression ≥ 1 mm in leads V₄–V₆ had a sensitivity of 11.2%, a specificity of 94.7%, and a PPP of 37.9%. When these variables were combined, specificity and PPP increased to 100% (p < 0.001).

Conclusions

EST evaluation solely by ST deviation fails to identify a significant portion of ischemic cases. Combinations of ΔPWD, ST elevation in AVR, and ST depression improved the identification of ischemia.