Changes in the cardiovascular risk profile in children approaching kidney replacement therapy.

Background: Despite significant cardiovascular (CV) morbidity in children on dialysis and after kidney transplantation, data on the evolution of CV damage in children with chronic kidney disease (CKD) approaching kidney replacement therapy (KRT) is unknown. Methods: The burden, progression, and predictors of CV damage before KRT onset were explored in two prospective multicenter cohorts from Europe and Canada: Cardiovascular Comorbidity in Children with CKD (4C) and Haemodiafiltration, Heart and Height (3H) studies, conducted from 2009-19 and 2013-16, respectively. CV damage and risk factors were evaluated (i) cross sectionally at KRT-start (n = 248), and (ii) longitudinally over the 2-years preceding KRT start (n = 157; 331 patient-visits). Longitudinal analyses with mixed-effects models estimated associations of modifiable CV risk factors with change in carotid intima-media thickness (cIMT) standard deviation score (SDS), pulse wave velocity (PWV-SDS), left ventricular (LV) mass and systolic dysfunction. Findings: 248 patients, age 14.3 (12.2, 16.2) years were evaluated at median 35 (28-114) days before KRT start. Elevated cIMT-SDS and PWV-SDS were present in 43% and 25%, and LV hypertrophy and systolic dysfunction in 49% and 33%. Aortic stiffness and LV hypertrophy significantly increased, especially in the year before KRT start (adjusted odds ratio, OR 0.33, P = 0.002 and OR 0.54, P = 0.01, respectively). 79% of children had >3 modifiable CV risk factors at KRT onset. Diastolic BP and BMI were strongly associated with a linear increase in all CV measures. After controlling for CV risk factors, the time to KRT onset no longer predicted the burden of CV damage. Interpretation: This comprehensive CV evaluation shows the progressive accrual of modifiable risk factors and a high burden of CV damage in the years preceding KRT onset. CV damage in the pre-KRT period is preventable. Funding: Supported by EU4Health Programme (101085068) and Kidney Research UK (RP39/2013).

Targeted literature review exploring the predictive value of estimated glomerular filtration rate and left ventricular mass index as indicators of clinical events in Fabry disease.

BACKGROUND: Fabry disease is a rare, progressive X-linked lysosomal storage disorder. It is caused by mutations in the GLA gene resulting in deficiency of α-galactosidase A (α-Gal A), leading to peripheral neuropathy, cardiovascular disease, stroke, end-stage renal disease, gastrointestinal disorders and premature death. Given the long-term nature of disease progression, trials in Fabry disease are often not powered to capture these clinical events. Clinical measures such as estimated glomerular filtration rate (eGFR) and left ventricular mass index (LVMI) are often captured instead. eGFR and LVMI are believed to be associated with long-term Fabry disease clinical events of interest, but the precise relationships are unclear. OBJECTIVE: We aimed to identify published literature exploring the link between eGFR/LVMI and long-term clinical events in Fabry disease. METHODS: A comprehensive literature search was conducted in Embase® and MEDLINE® (using Embase.com), and a targeted literature review was conducted. Studies reporting a quantitative relationship between eGFR and/or LVMI and clinical events in Fabry disease were extracted, and narrative synthesis was conducted to understand these predictive relationships. RESULTS: Eight studies, consisting of seven patient-level retrospective analyses plus one prospective cohort study, met the inclusion criteria. Seven of these studies reported eGFR and six reported LVMI, with five reporting both. All studies presented results for either a composite measure including a range of key Fabry disease clinical events, or a composite outcome that included at least one key Fabry disease clinical event. All studies employed Cox proportional hazards survival modelling. The studies consistently reported that eGFR and LVMI are predictors of key clinical events in Fabry disease, with the findings remaining consistent regardless of the therapy received by patients in the studies. CONCLUSIONS: The evidence identified suggests that eGFR and LVMI outcomes may be appropriate indicators for long-term clinical events in Fabry disease, and all identified papers implied the same directional relationship. However, additional research is needed to further understand the specific details of these relationships and to quantify them.

Ambulatory blood pressure monitoring in children: A retrospective single-center study.

Objectives: (1) Compare 24-hour ambulatory blood pressure monitoring (ABPM) diagnoses in a pediatric population with the new 2022 guidelines to the original diagnoses with the 2014 guidelines. (2) Determine whether findings of hypertension from ABPM could be predicted from prior patient data. (3) Determine whether ABPM readings could predict left ventricular mass index (LVMI) in patients who obtained an echocardiogram (ECHO). Study design: Single-center retrospective study on patients referred to Pediatric Nephrology Clinic for evaluation of elevated blood pressure who underwent ABPM from 2015 to 2018. Predictions of hypertension were obtained using a logistic regression model, and predictions of LVMI were performed using regression models including (a) the wake systolic and diastolic BP indices, or (b) additionally including the standard deviation (SD) of wake SBP and DBP. Results: With the change in 2022 to new ABPM guidelines from the AHA, comparing the old and new guidelines led to 70% of previous pre-hypertensive diagnoses now meeting criteria for diagnosis of hypertension, and a rise from 21% of the ABPMs meeting criteria for hypertension to 51% now meeting criteria. In a logistic regression model, prior patient data were not predictive of a diagnosis of hypertension from ABPM (Nagelkerke's R 2 = 0.04). Among the individual variables studied, none were statistically significant. For prediction of LVMI, the SD of wake SBP and DBP were significantly associated with increased LVMI, but the wake SBP and DBP indices were not. Conclusions: In our patient population, the new ABPM guidelines led to a significant increase in diagnoses of hypertension. Prior patient data was not sufficient to predict a diagnosis of hypertension by ABPM, supporting the need for evaluation by ABPM as the gold standard. Our analysis of the relationship between ABPM readings and LVMI supports the hypothesis that BP variability contributes to increased LVMI. These data are consistent with growing evidence in the adult literature that BP variability detected by ABPM is associated with left-ventricular hypertrophy.

The significance of central blood pressure for cardiovascular target organ damage in children and adolescents after kidney transplantation.

BACKGROUND: Cardiovascular (CV) complications are important causes of morbidity and mortality in children after kidney transplantation (KTx). In adults, central blood pressure (cBP) is an accepted predictor of CV sequelae. We aimed to assess the prognostic value of cBP over peripheral blood pressure (pBP) for existing CV damage. METHODS: We measured cBP and pBP in 48 pediatric KTx recipients (mean age: 13.5 ± 4.2 years). Assessment of left ventricular mass index (LVMI) and aortic pulse wave velocity (PWV) allowed detection of CV target organ damage. LVMI and PWV were used as endpoints in multivariable linear regression models, in which cBP and pBP were compared for their predictive value. RESULTS: Using cBP z-scores, we identified a larger number of patients with uncontrolled or untreated hypertension compared to pBP (36% vs. 7%). Central systolic blood pressure (cSBP) was a significant independent predictor of LVMI, while peripheral systolic blood pressure (pSBP) was not. Comparing central (cDBP) and peripheral (pDBP) diastolic blood pressure for their predictive value on PWV revealed a greater estimate for cDBP (0.035 vs. 0.026 for pDBP) along with a slightly better model fit for cDBP. CONCLUSIONS: Our data in a small group of patients provide first evidence that cBP measurements in pediatric KTx recipients might be helpful in identifying patients at risk for the development of CV sequelae. Investigating a larger patient number, ideally repeatedly, is needed to create further evidence supporting our findings. In light of available devices measuring cBP noninvasively, the implementation of such clinical studies post-KTx care should be feasible. A higher resolution version of the Graphical abstract is available as Supplementary information.

FGF23 and Cardiovascular Structure and Function in Advanced Chronic Kidney Disease.

Background: Fibroblast growth factor 23 (FGF23) is a bone-derived phosphatonin that is elevated in chronic kidney disease (CKD) and has been implicated in the development of cardiovascular disease. It is unknown whether elevated FGF23 in CKD is associated with impaired cardiovascular functional capacity, as assessed by maximum exercise oxygen consumption (VO2Max). We sought to determine whether FGF23 is associated with cardiovascular functional capacity in patients with advanced CKD and after improvement of VO2Max by kidney transplantation. Methods: We performed secondary analysis of 235 patients from the Cardiopulmonary Exercise Testing in Renal Failure and After Kidney Transplantation (CAPER) cohort, which recruited patients with stage 5 CKD who underwent kidney transplantation or were waitlisted and hypertensive controls. All patients underwent cardiopulmonary exercise testing (CPET) and echocardiography and were followed longitudinally for 1 year after study enrollment. Results: Patients across FGF23 quartiles differed in BMI (P=0.004) and mean arterial pressure (P<0.001) but did not significantly differ in sex (P=0.5) or age (P=0.08) compared with patients with lower levels of FGF23. Patients with higher FGF23 levels had impaired VO2Max (Q1: 24.2±4.8 ml/min per kilogram; Q4: 18.6±5.2 ml/min per kilogram; P<0.001), greater left ventricular mass index (LVMI; P<0.001), reduced HR at peak exercise (P<0.001), and maximal workload (P<0.001). Kidney transplantation conferred a significant decline in FGF23 at 2 months (P<0.001) before improvement in VO2Max at 1 year (P=0.008). Multivariable regression modeling revealed that changes in FGF23 was significantly associated with VO2Max in advanced CKD (P<0.001) and after improvement after kidney transplantation (P=0.006). FGF23 was associated with LVMI before kidney transplantation (P=0.003), however this association was lost after adjustment for dialysis status (P=0.4). FGF23 was not associated with LVMI after kidney transplantation in all models. Conclusions: FGF23 levels are associated with alterations in cardiovascular functional capacity in advanced CKD and after kidney transplantation. FGF23 is only associated with structural cardiac adaptations in advanced CKD but this was modified by dialysis status, and was not associated after kidney transplantation.

Newborn screening for Pompe disease in Italy: Long-term results and future challenges.

Pompe disease (PD) is a progressive neuromuscular disorder caused by a lysosomal acid α-glucosidase (GAA) deficiency. Enzymatic replacement therapy is available, but early diagnosis by newborn screening (NBS) is essential for early treatment and better outcomes, especially with more severe forms. We present results from 7 years of NBS for PD and the management of infantile-onset (IOPD) and late-onset (LOPD) patients, during which we sought candidate predictive parameters of phenotype severity at baseline and during follow-up. We used a tandem mass spectrometry assay for α-glucosidase activity to screen 206,741 newborns and identified 39 positive neonates (0.019%). Eleven had two pathogenic variants of the GAA gene (3 IOPD, 8 LOPD); six carried variants of uncertain significance (VUS). IOPD patients were treated promptly and had good outcomes. LOPD and infants with VUS were followed; all were asymptomatic at the last visit (mean age 3.4 years, range 0.5-5.5). Urinary glucose tetrasaccharide was a useful and biomarker for rapidly differentiating IOPD from LOPD and monitoring response to therapy during follow-up. Our study, the largest reported to date in Europe, presents data from longstanding NBS for PD, revealing an incidence in North East Italy of 1/18,795 (IOPD 1/68,914; LOPD 1/25,843), and the absence of mortality in IOPD treated from birth. In LOPD, rigorous long-term follow-up is needed to evaluate the best time to start therapy. The high pseudodeficiency frequency, ethical issues with early LOPD diagnosis, and difficulty predicting phenotypes based on biochemical parameters and genotypes, especially in LOPD, need further study.

Independent prognostic value of left ventricular mass index in patients with light-chain amyloidosis.

BACKGROUND: Echocardiographic-determined left ventricular mass index (LVMI) provides quantitative information on left-ventricular structure. However, its prognostic value on light-chain (AL) amyloidosis has not been clearly defined. METHODS: We included 99 patients with newly diagnosed AL amyloidosis between July 2013 and March 2022. Clinical features and echocardiographic parameters were collected. RESULTS: LVMI ≥113.4 g/m2 was predictive for overall survival (OS) and progression-free survival (PFS) with respective hazard ratios (HRs) of 2.87 (95% CI: 1.04-7.79) and 2.91 (95% CI: 1.25-6.68). Patients in the LVMI-high group had higher NT-proBNP, cTnT, and FLC-diff levels. They were more likely to be cardiac involved and have increased mean left ventricular wall thickness, decreased left ventricular ejection fraction, and higher proportion of patients with pericardial effusion. In subgroup analysis, LVMI-high group was associated with a reduced OS [HR: 4.74 (95% CI: 1.26-17.77)] and PFS [HR: 7.16 (95% CI: 2.10-24.40)] in patients with cardiac amyloidosis (CA). Besides, LVMI-high was associated with a reduced OS [HR: 3.58 (95% CI: 1.17-11.02)] and PFS [HR: 4.79 (95% CI: 1.77-12.94), p = 0.00] among patients staged of II or III (Mayo 2004), as well as reduced OS [HR: 22.65 (95% CI: 1.66-299.31)] and PFS [HR: 18.73 (95% CI: 2.36-148.35)] among patients staged of III or IV (Mayo 2012). CONCLUSIONS: LVMI is a reliable prognostic indicator of survival. A cut-off of LVMI (113.4 g/m2) was prognostic for OS and PFS. Importantly, LVMI was able to identify a subset of patients with poorer prognosis in the context of CA or in the late stages according to the biomarker staging systems.

Echocardiographic Investigation of Low-Flow State in a Hispanic/Latino Population.

Objective: To assess the prevalence of low-flow state (LFS) with left ventricular (LV) stroke volume index of less than 35 mL/m2 and the demographics, clinical and echocardiographic characteristics associated with LV remodeling and function in a Hispanic/Latino population. Participants and Methods: The study included 1346 asymptomatic participants from the Hispanic Community Health Study/Study of Latinos with normal LV ejection fraction (≥55%) and no valvular heart disease. LV volume, mass and left atrial volume, LV ejection fraction, global longitudinal strain, and myocardial contraction fraction were measured by echocardiography. The participants were divided into LFS or normal flow state (NFS: stroke volume index ≥35 mL/m2). Demographics, clinical and echocardiographic characteristics, and measures of LV remodeling and function were compared between the LFS and NFS groups. Results: The prevalence of LFS was 41%. In comparison with NFS, the LFS had lower LV mass index (77.2±0.96 g/m2 vs 84.6±0.86 g/m2; P<.001), left atrial volume index (20.6±0.35 mL/m2 vs 23.5±0.37 mL/m2; P<.001), global longitudinal strain (-16.8±0.16% vs -17.7±0.17%; P<.001), and myocardial contraction fraction (43.3±0.63% vs 55.7±0.64%; P<.001). There was no significant difference in the relative wall thickness (LFS: 0.40±0.004 vs NFS: 0.40±0.005; P=.57). The LFS group had significantly higher hemoglobin A1c (6.18±0.07% vs 5.97±0.04%; P=.01) than the NFS group. Conclusion: A high prevalence of LFS associated with echocardiographic characteristics reflecting unfavorable LV remodeling and function was observed in a Hispanic/Latino population. Further studies of the prognostic significance of LFS in a large multiethnic population are warranted.

Serial changes of coronary flow reserve over one year after transcatheter aortic valve implantation in patients with severe aortic stenosis.

Background: Impaired coronary flow reserve (CFR) portends a poor prognosis in patients with aortic stenosis. The present study aims to investigate how CFR changes over one year after transcatheter aortic valve implantation (TAVI) in patients with severe aortic stenosis, and to explore factors related to the changes. Methods: Consecutive patients undergoing TAVI were registered. CFR in the left anterior descending artery was measured by transthoracic echocardiography on three occasions pre-TAVI, one-day post-TAVI, and one-year post-TAVI. Results: A total of 59 patients were enrolled, 46 of whom completed one-year follow-up. CFR was impaired in 35 (59.3%) patients pre-TAVI, but the impairment was only seen in 2 patients (4%) one-year post-TAVI. CFR value improved from 1.75 (1.50-2.10) cm/s pre-TAVI, to 2.00 (1.70-2.30) one-day post-TAVI, and further to 2.60 (2.30-3.10) one-year post-TAVI (P < 0.001). The median difference in CFR between pre-TAVI and one-year post-TAVI was 0.90 (0.53-1.20). Patients with significant improvement of CFR (more than the median value of 0.9) had larger aortic valve area (1.55 [1.38-1.92] vs. 1.36 cm2 [1.26-1.69], P = 0.042) and greater improvement in left ventricular ejection fraction (3.10 [-1.67-4.24] vs. -1.46 [-3.42-1.48] percentage points, P = 0.019) than those without. Conclusions: CFR is impaired in a considerable proportion of patients with severe aortic stenosis, but improvement is seen immediately after TAVI, and one year later. Patients with significant improvement of CFR had larger aortic valve area and greater increase in left ventricular ejection fraction after TAVI.

Understanding and modifying Fabry disease: Rationale and design of a pivotal Phase 3 study and results from a patient-reported outcome validation study.

The use of available treatments for Fabry disease (FD) (including enzyme replacement therapy [ERT]) may be restricted by their limited symptom improvement and mode of administration. Lucerastat is currently being investigated in the MODIFY study as oral substrate reduction therapy for the treatment of FD. By reducing the net globotriaosylceramide (Gb3) load in tissues, lucerastat has disease-modifying potential to improve symptoms and delay disease progression. MODIFY is a multicenter, double-blind, randomized, placebo-controlled, parallel-group Phase 3 study (ClinicalTrial.gov: NCT03425539); here we present the rationale and design of this study. Eligible adults with a genetically confirmed diagnosis of FD and FD-specific neuropathic pain entered screening. Patients were randomized (2:1) to receive either oral lucerastat twice daily or placebo for 6 months; treatment allocation was stratified according to sex and ERT treatment status. The main objectives of MODIFY are to assess the effects of lucerastat on neuropathic pain, gastrointestinal (GI) symptoms, FD biomarkers, and determine its safety and tolerability. Neuropathic pain and GI symptoms are key features of FD that have a significant impact on quality of life. Despite various tools available to assess pain and GI symptoms, there are currently limited tools available to assess neuropathic and GI symptoms in FD, validated according to health authority guidelines. Based on FDA recommendations, we undertook a patient-reported outcome (PRO) validation study, using a novel eDiary-based PRO tool to assess the validity of evaluating neuropathic pain as a primary efficacy endpoint in MODIFY. Results from the PRO validation study are included. To date, MODIFY is the largest Phase 3 clinical study conducted in patients with FD. Enrollment to MODIFY is now complete, with 118 patients randomized. Results will be presented in a separate publication. Long-term effects of lucerastat are being assessed in the ongoing open-label extension study (NCT03737214).

Hearing loss in fabry disease: A 16 year follow-up study of the Danish nationwide cohort.

Background: Fabry disease (FD) is a lysosomal storage disorder resulting in systemic accumulation of globotriaosylceramide (Gb3) causing multi-organ dysfunction. The audiologic involvement in FD has been neglected in previous studies; while not a lethal aspect of the disease, hearing loss can have a significantly negative impact on quality of life. Objective: To investigate hearing loss from baseline through 16 years follow-up of the Danish FD cohort and to compare audiometric data to other clinical variables. Methods: Data was collected prospectively and assessed retrospectively during a period of 16 years from 83 patients (age: 9-72 years; sex: 29 males and 54 females). 55 patients underwent treatment. Air conduction thresholds was assessed at six frequencies between 0.25 and 8 kHz bilaterally. Data was analyzed using multilinear models. Results: Mean follow-up period for patients undergoing a FD specific treatment was 7.8 years (0-12.8 years, SD 3.8 years, n = 55). Hearing thresholds for FD patients deviated from healthy individuals at all frequencies for both sexes (p < 0.001). Males had more profound hearing loss than females at high frequencies (4,8 kHz) (p = 0.025). There was no improvement in hearing with treatment (p = 0.343♂, p = 0.256♀). No associations between hearing loss and measured glomerular filtration rate, left ventricular wall thickness or cerebral white matter lesions were found. Lower plasma Gb3 concentration correlated with better hearing (p = 0.046) in males. Conclusion: Our findings demonstrated significant hearing loss in FD patients compared to audiologically healthy individuals at all frequencies, and no change in hearing during treatment. Lower plasma Gb3 concentrations correlated with better hearing in males.

Missense Variant E1295K of Sodium Channel SCN5A Associated With Recurrent Ventricular Fibrillation and Myocardial Inflammation.

SCN5A was considered an exclusively cardiac expressed ion channel but discovered to also act as a novel innate immune sensor. We report on a young SCN5A variant carrier with recurrent ventricular fibrillation and massive myocardial inflammation whose peculiar clinical course is highly suggestive of such a dual role of SCN5A. (Level of Difficulty: Advanced.).

Cardiovascular Research in Friedreich Ataxia: Unmet Needs and Opportunities.

Friedreich Ataxia (FRDA) is an autosomal recessive disease in which a mitochondrial protein, frataxin, is severely decreased in its expression. In addition to progressive ataxia, patients with FRDA often develop a cardiomyopathy that can be hypertrophic. This cardiomyopathy is unlike the sarcomeric hypertrophic cardiomyopathies in that the hypertrophy is associated with massive mitochondrial proliferation within the cardiomyocyte rather than contractile protein overexpression. This is associated with atrial arrhythmias, apoptosis, and fibrosis over time, and patients often develop heart failure leading to premature death. The differences between this mitochondrial cardiomyopathy and the more common contractile protein hypertrophic cardiomyopathies can be a source of misunderstanding in the management of these patients. Although imaging studies have revealed much about the structure and function of the heart in this disease, we still lack an understanding of many important clinical and fundamental molecular events that determine outcome of the heart in FRDA. This review will describe the current basic and clinical understanding of the FRDA heart, and most importantly, identify major gaps in our knowledge that represent new directions and opportunities for research.

Mid-aortic syndrome is associated with increased left ventricular mass index in Takayasu arteritis.

BACKGROUND: Mid-aortic syndrome (MAS) may induce changes in cardiac structure among patients with Takayasu arteritis (TA). METHODS: Consecutive adult patients with TA (January 1, 2011 to January 1, 2018) were enrolled and their data was retrospectively analyzed. RESULTS: Patients were divided into MAS group (100/457 patients, 21.8%) and non-MAS group (357, 78.1%). The left ventricular mass index (LVMI) was higher in the MAS group than the non-MAS (113.78±26.82 versus 100.74±23.66 g/m2, respectively; P<0.001). The MAS group showed higher prevalence than the non-MAS group of mild-to-severe mitral regurgitation (9.0% and 3.9%, respectively; P=0.040) and aortic regurgitation (26% and 14.8%, respectively; P=0.003). No difference was found in the rates of heart failure (27.0% and 19.9% for MAS and non-MAS, respectively; P=0.126). The MAS group also showed lower estimated glomerular filtration rates than the non-MAS group (89.93±18.89 versus 96.16±21.60 mL/min/1.73 m2, respectively; P=0.009) and higher prevalence of renal artery stenosis (57% versus 43.7%; P=0.018). MAS was independently related to greater LVMI in both unadjusted model [ß=12.60; 95% confidence interval (CI): 7.09-18.11; P<0.001] and the model adjusted for multiple indices (ß=9.91; 95% CI: 4.57-15.25; P<0.001) in multivariate linear analysis. The LVMI significantly decreased from 111.49±25.65 to 100.36±22.91 g/m2 (P<0.001) among 55 patients who underwent successful revascularization treatment for MAS, while no significant difference (P=0.635) was observed among patients treated with medicine alone. CONCLUSIONS: TA-induced MAS is a potential independent risk factor for increased LVMI, and revascularization therapy for MAS is effective in reversing structural changes in the heart.

Long-term follow-up of renal function in patients treated with migalastat for Fabry disease.

The effect of migalastat on long-term renal outcomes in enzyme replacement therapy (ERT)-naive and ERT-experienced patients with Fabry disease is not well defined. An integrated posthoc analysis of the phase 3 clinical trials and open-label extension studies was conducted to evaluate long-term changes in renal function in patients with Fabry disease and amenable GLA variants who were treated with migalastat for ≥2 years during these studies. The analysis included ERT-naive (n = 36 [23 females]; mean age 45 years; mean baseline estimated glomerular filtration rate (eGFR), 91.4 mL/min/mL/1.73 m2) and ERT-experienced (n = 42 [24 females]; mean age, 50 years; mean baseline eGFR, 89.2 mL/min/1.73m2) patients with amenable variants who received migalastat 123 mg every other day for ≥2 years. The annualized rate of change from baseline to last observation in estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation (eGFRCKD-EPI) was calculated by both simple linear regression and a random coefficient model. In ERT-naive patients, mean annualized rates of change from baseline in eGFRCKD-EPI were - 1.6 mL/min/1.73 m2 overall and - 1.8 mL/min/1.73 m2 and - 1.4 mL/min/1.73 m2 in male and female patients, respectively, as estimated by simple linear regression. In ERT-experienced patients, mean annualized rates of change from baseline in eGFRCKD-EPI were - 1.6 mL/min/1.73 m2 overall and - 2.6 mL/min/1.73 m2 and - 0.8 mL/min/1.73 m2 in male and female patients, respectively. Mean annualized rate of change in eGFRCKD-EPI in ERT-naive patients with the classic phenotype (defined by white blood cell alpha galactosidase A [α-Gal A] activity of <3% of normal and multiorgan system involvement) was -1.7 mL/min/1.73 m2. When calculated using the random coefficient model, which adjusted for sex, age, and baseline renal function, the annualized eGFRCKD-EPI change was minimal (mean: -0.1 and 0.1 mL/min/1.73 m2 in ERT-naive and ERT-experienced patients, respectively). In conclusion, patients with Fabry disease and amenable GLA variants receiving long-term migalastat treatment (≤8.6 years) maintained renal function irrespective of treatment status, sex, or phenotype.

Challenges in choosing the appropriate guidelines for use in children and adolescents with hypertension.

BACKGROUND: This study was designed to observe the effect of antihypertensive treatment on blood pressure (BP) and target organ damage in patients followed up according to the American Academy of Pediatrics Hypertension Guidelines (AAPG). The results were also assessed in comparison with the definitions and target organ damage according to the European Society of Hypertension Guidelines 2016 (ESHG). MATERIALS AND METHODS: A total of 44 (34 male) out of 140 patients were enrolled in the study and the mean age was 14±3.19years. The follow-up period was at least 12months. All patients underwent the following assessments: anthropometrical measurements of body mass index (BMI), left ventricular mass index (LVMI), and biochemical parameters according to the relevant guidelines. The pre-treatment and post-treatment datasets collected were compared. RESULTS: The frequency of symptomatic patients decreased from 88% to 30%. After treatment, 29.4% (n=13) of patients still had elevated and stage 1 hypertension (HT) according to the AAPG. These patients were older and had higher BMI z-scores, LVMI z-scores, mean BP indices, and also had longer symptom duration than normotensive patients (P<0.001). When patients were assessed according to the ESHG, 34.1% (n=15) of patients had high-normal stage 1 and stage 2 HT. While 53.3% (n=8) of the patients aged 13-15years were classified as having high-normal stage 1 and stage 2 HT according to the ESHG, 33.3% (n=5) were classified as having elevated BP and stage 1 HT according to the AAPG. Additionally, 36.4% (n=4) of the patients aged≥16years were classified as having high-normal and stage 1 HT according to the ESHG, whereas 45.5% (n=5) were classified as having elevated BP and stage 1 HT according to the AAPG. CONCLUSION: To control HT in children with higher BMI z-scores, higher LVMI z-scores, and higher BP indices, an earlier and more intensive approach is needed. Considering that the duration of exposure to HT may also affect the LVMI, adjusting age and gender or decreasing the current thresholds for LVMI may lead to an earlier diagnosis for more patients. According to the present classifications, the ESHG covers more children aged between 13 and 15years in contrast to the AAPG, which covers more patients aged≥16years. However, further studies are needed to confirm these results.

The impact of body mass index on left ventricular mass index, right ventricular function, and cardiac dimension of children with sickle cell anemia in Enugu City.

BACKGROUND: Body mass index is a major determinant of cardiac annular valvar dimension and left ventricular mass index in children with sickle cell anemia. OBJECTIVES: The study is aimed at ascertaining the impact of Body Mass Index on Left ventricular mass index, right ventricular function and cardiac dimension of children with sickle cell anemia. METHODS: A case control study in which echocardiographic measurement of cardiac function and structures were ascertained among children with sickle cell anemia compared with hemoglobin AA genotype. RESULTS: There were 51 subjects and 50 controls. The subjects comprised 54.9% males and controls, 52.0% male. There was a strong positive correlation between BMI and most cardiac structure diameters among children with normal hemoglobin genotype (Pearson's correlation coefficient value, P < 0.001) There was also statistically significant positive correlation between BMI and LV mass among the subjects (n = 50, r = 0.5, P < 0.001). There was significant positive correlation between BMI and TAPSE in both subjects and controls as well as between BMI and RVSP among the subjects, but not the controls (p < 0.001). There was no significant difference in the number with left ventricular hypertrophy (LVH) based on their nutritional status (n = 51, χ^2 = 7.03, P = 0.32). The BMI correlated negatively with left ventricular mass index (LVMI) among the subjects, but the correlation was not statistically significant (r = -0.1, P = 0.53). CONCLUSION: There was significant positive correlation between BMI and TAPSE in both subjects and controls as well as between BMI and RVSP among the subjects, but not the controls. Body mass index correlated negatively with left ventricular mass index (LVMI) among the subjects.

Left atrial volume and left ventricular mass indices in heart failure with preserved and reduced ejection fraction.

AIMS: Two key echocardiographic parameters that are currently used to diagnose heart failure (HF) with preserved ejection fraction (HFpEF) are left atrial volume index (LAVi) and left ventricular mass index (LVMi). We investigated whether patients' characteristics, biomarkers, and co-morbidities are associated with these parameters and whether the relationships differ between patients with HFpEF or HF with reduced ejection fraction (HFrEF). METHODS: We consecutively enrolled 831 outpatients with typical signs and symptoms of HF and elevated N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels and categorized patients based upon left ventricular ejection fraction (LVEF): LVEF < 40% (HFrEF), LVEF between 40% and 50% (HF with mid-range ejection fraction), and LVEF ≥ 50% (HFpEF). The study includes consecutively enrolled HF patients from an HF outpatient clinic at a tertiary medical centre in the Netherlands. All patients underwent baseline characterization, laboratory measurements, and echocardiography. RESULTS: Four hundred sixty-nine patients had HFrEF, 189 HF with mid-range ejection fraction, and 173 HFpEF. The patients with HFrEF were rather male [HFrEF: 323 (69%); HFpEF: 80 (46%); P < 0.001], and the age was comparable (HFrEF 67 ± 13; HFpEF 70 ± 14; P = 0.069). In HFpEF, more patients had hypertension [190 (40.5%); 114 (65.9%); P < 0.001], higher body mass indices (27 ± 8; 30 ± 7; P < 0.001), and atrial fibrillation [194 (41.4); 86 (49.7); P = 0.029]. The correlation analyses showed that in HFrEF patients, LAVi was significantly associated with age (ß 0.293; P < 0.001), male gender (ß 0.104; P = 0.042), body mass index (ß -0160; P = 0.002), diastolic blood pressure (ß -0.136; P < 0.001), New York Heart Association (ß 0.174; P = 0.001), atrial fibrillation (ß 0.381; P < 0.001), galectin 3 (ß 0.230; P < 0.001), NT-proBNP (ß 0.183; P < 0.001), estimated glomerular filtration rate (ß -0.205; P < 0.001), LVEF (ß -0.173; P = 0.001), and LVMi (ß 0.337; P < 0.001). In HFpEF patients, only age (ß 0.326; P < 0.001), atrial fibrillation (ß 0.386; P < 0.001), NT-proBNP (ß 0.176; P = 0.036), and LVMi (ß 0.213; P = 0.013) were associated with LAVi. CONCLUSIONS: Although LVMi and LAVi are hallmark parameters to diagnose HFpEF, they only correlate with a few characteristics of HF and mainly with atrial fibrillation. In contrast, in HFrEF patients, LAVi relates strongly to several other HF parameters. These findings underscore the complexity in visualizing the pathophysiology of HFpEF and question the relation between cardiac structural remodeling and the impact of co-morbidities.

Effect of Sex on Mortality and Left Ventricular Remodeling After Transcatheter Aortic Valve Implantation.

BACKGROUND: The effect of sex on mortality is controversial; furthermore, sex differences in left ventricular (LV) remodeling after transcatheter aortic valve implantation (TAVI) remain unknown.Methods and Results:This study included 2,588 patients (1,793 [69.3%] female) enrolled in the Optimized CathEter vAlvular iNtervention (OCEAN)-TAVI Japanese multicenter registry between October 2013 and May 2017. We retrospectively analyzed the effect of sex on mortality, and evaluated changes in the LV mass index (LVMI) after TAVI. Female sex was significantly associated with lower all-cause and cardiovascular mortality (log-rank P<0.001 for both). Multivariate analysis showed that female sex was independently associated with lower cumulative long-term mortality (hazard ratio 0.615; 95% confidence interval 0.512-0.738; P<0.001). Regression in the LVMI was observed in both sexes, and there was no significant difference in the percentage LVMI regression from baseline to 1 year after TAVI between women and men. Women had a survival advantage compared with men among patients with LVMI regression at 1 year, but not among patients with no LVMI regression. CONCLUSIONS: We found that female sex is associated with better survival outcomes after TAVI in a large Japanese registry. Although LVMI regression was observed in women and men after TAVI, post-procedural LV mass regression may be related to the sex differences in mortality.

A randomised controlled trial to examine the effects of cinacalcet on bone and cardiovascular parameters in haemodialysis patients with advanced secondary hyperparathyroidism.

BACKGROUND: Secondary hyperparathyroidism may lead to increased cardiovascular risk. The use of cinacalcet may improve bone and cardiovascular health with improved parathormone (PTH) and phosphate control. METHODS: This is an open-label prospective randomised controlled trial to compare progression of cardiovascular and chronic kidney disease mineral and bone disorder (CKD-MBD) parameters. Patients were randomised to receive cinacalcet alongside standard therapy or standard therapy alone. Thirty-six haemodialysis patients who had > 90 days on dialysis, iPTH > 300 pg/mL, calcium > 2.1 mmol/L and age 18-75 years were included. Following randomization, all 36 patients underwent an intensive 12-week period of bone disease management aiming for iPTH 150-300 pg/mL. The primary outcome was change in vascular calcification using CT agatston score. Secondary outcomes included pulse wave velocity (PWV), left ventricular mass index (LVMI), carotid intima-media thickness (CIMT), augmentation index (Aix) and bone measurements. The above measurements were obtained at baseline and 12 months. RESULTS: There was no evidence of a group difference in the progression of calcification (median change (IQR) cinacalcet: 488 (0 to1539); standard therapy: 563 (50 to 1214)). In a post hoc analysis combining groups there was a mean (SD) phosphate reduction of 0.3 mmol/L (0.7) and median (IQR) iPTH reduction of 380 pg/mL (- 754, 120). Regression of LVMI and CIMT was seen (P = 0.03 and P = 0.001) and was significantly associated with change of phosphate on multi-factorial analyses. CONCLUSIONS: With a policy of intense CKD-MBD parameter control, no significant benefit in bone and cardiovascular markers was seen with the addition of cinacalcet to standard therapy over one year. Tight control of hyperphosphataemia and secondary hyperparathyroidism may lead to a reduction in LVMI and CIMT but this needs further investigation. Although the sample size was small, meticulous trial supervision resulted in very few protocol deviations with therapy.