A review and recommendations for oral chaperone therapy in adult patients with Fabry disease.

Fabry disease (FD) is a rare, X-linked lysosomal storage disorder affecting both males and females caused by genetic abnormalities in the gene encoding the enzyme α-galactosidase A. FD-affected patients represent a highly variable clinical course with first symptoms already appearing in young age. The disease causes a progressive multiple organ dysfunction affecting mostly the heart, kidneys and nervous system, eventually leading to premature death. Disease-specific management of FD includes enzyme replacement therapy with agalsidase α and ß or pharmacological oral chaperone migalastat. Migalastat is a low-molecular-mass iminosugar, that reversibly binds to active site of amenable enzyme variants, stabilizing their molecular structure and improving trafficking to the lysosome. Migalastat was approved in the EU in 2016 and is an effective therapy in the estimated 35-50% of all patients with FD with amenable GLA gene variants. This position statement is the first comprehensive review in Central and Eastern Europe of the current role of migalastat in the treatment of FD. The statement provides an overview of the pharmacology of migalastat and summarizes the current evidence from the clinical trial program regarding the safety and efficacy of the drug and its effects on organs typically involved in FD. The position paper also includes a practical guide for clinicians on the optimal selection of patients with FD who will benefit from migalastat treatment, recommendations on the optimal selection of diagnostic tests and the use of tools to identify patients with amenable GLA mutations. Areas for future migalastat clinical research have also been identified.

Sudden Cardiac Death Risk over Time in HCM Patients with Implantable Cardioverter-Defibrillator.

Background: In patients with HCM at high risk of SCD, an ICD should be considered as a standard of care. Current risk approximation algorithms recommended by ESC 2014 criteria indicate that SCD risk is not stable. The aim of the study was to investigate how the calculated SCD risk in HCM patients with an ICD implanted in the past changed over time. Methods: We analyzed 64 HCM patients with ICD for primary prevention, referred for ICD re-implantation, and 32 HCM patients referred for a first-time ICD placement during the same period. The 5-year-SCD risk was assessed for suitable patients using the recommended ESC calculator. Results: The first-time group had a higher 5-year-SCD risk than those referred for ICD re-implantation: 7.50 (IQR 5.98−10.46) vs. 4.88 (IQR 3.42−7.25), p < 0.05. Out of the patients with an initial calculated risk below 4%, the risk increased in 22% of cases, reaching the 4−6% range. In 78% of patients, the risk remained stable and low. In 31% of patients with an initial calculated SCD risk ≥ 6%, the risk decreased over time to below 6%, and in 14% of the cases, below 4%. Conclusions: SCD risk in HCM patients is usually stable or gets lower. Our data suggest it is important to re-evaluate the risk profile for patients with HCM when ICD re-implantation is considered.

Comparison of mitral regurgitation severity assessments based on magnetic resonance imaging and echocardiography in patients with hypertrophic cardiomyopathy.

Mitral regurgitation (MR), which is one of the factors responsible for heart failure symptoms and the development of atrial fibrillation, is an important feature of hypertrophic cardiomyopathy (HCM), and its presence affects which treatment options are chosen. Although cardiac magnetic resonance imaging (MRI) is considered the reference standard for assessing the regurgitant volume (RV) and fraction (RF), echocardiography is the most common method for assessing MR severity. Accordingly, the aim of this study was to compare the results of echocardiography and cardiac MRI for assessing MR severity in a cohort of patients with HCM. MR severity was assessed in 53 patients using cardiac MRI by determining the mitral RV (MRV) and mitral RF (MRF). The results were graded according to thresholds recommended in current guidelines. MR severity assessed by echocardiography was graded by integrating indices of severity. Greater than mild MR, as assessed using echocardiography, was present in 22 patients (41.5%) with HCM and in none of the control patients (p = 0.001). In all, 31 patients (58.5%) had no more than mild MR. When MR severity was assessed using different methods, either moderate (kappa = 0.44, 95% confidence interval = 0.21-0.67), poor or no agreement was found between MRI-derived and echocardiography-derived grades. HCM patients with echocardiography-derived moderate and severe MR had similar median MRVs and MRFs (p = 0.59 and p = 0.11, respectively). In HCM patients, cardiac MRI and echocardiography were at most in modest agreement in assessing MR severity. Importantly, echocardiography-derived moderate and severe MR were not distinguishable by either MRV or MRF.

Considerations for Home-Based Treatment of Fabry Disease in Poland during the COVID-19 Pandemic and Beyond.

Current therapy for Anderson-Fabry disease in Poland includes hospital or clinic-based intravenous enzyme replacement therapy with recombinant agalsidase alpha or beta, or oral pharmacological chaperone therapy with migalastat. Some countries around the world offer such treatment to patients in the comfort of their own homes. The 2020-2021 COVID-19 pandemic has pushed global healthcare providers to evolve their services so as to minimize the risk of COVID-19 exposure to both patients and providers; this has led to advances in telemedicine services and the increasing availability of at-home treatment for various procedures including parenteral drug administration. A total of 80% of surveyed Anderson-Fabry disease patients in Poland would prefer home-based treatment, which would be a safe and convenient alternative to clinic-based treatment if patient selection is based on our proposed algorithm. Our recommendations for home-based treatments appear feasible for the long term care of Anderson-Fabry disease patients during the COVID-19 pandemic and beyond. This may also serve as a basis for home-based treatment programs in other rare and ultra-rare genetic diseases.

Is home-based therapy in Fabry disease the answer to compelling patients' needs during the COVID-19 pandemic? Survey results from the Polish FD Collaborative Group.

BACKGROUND: Fabry disease (FD) is an X-linked disorder related to a deficiency of the lysosomal enzyme alpha-galactosidase A. In Poland, enzyme replacement therapy (ERT) for FD is offered by the National Health Fund only at selected hospital infusion centers. Patients with FB are considered at a high risk of developing complications from COVID-19. Some patients omitted infusions due to fear of infection or outbreaks in hospitals. Lack of alternative infusion sites hampered the situation. OBJECTIVES: To analyze the impact of the SARS-CoV-2 pandemic on FD patients, especially their fears and expectations, the Polish FD Collaborative Group collaborated on a survey project. MATERIAL AND METHODS: Between September and November 2020, we distributed a customized survey exploring expectations and fears among FD subjects. RESULTS: Fifty-five individuals (35 receiving ongoing ERT) from different FD centers completed the study. The median age was 40 years [IQR 25; 50], and gender distribution was almost equal (27 F; 28 M). One-fourth of FD patients reported severe disability limiting transportation for infusions that, in the opinion of the other 25% of responders, consumed >4 h. Forty-four (80%) of all would prefer home infusions performed by a nurse (n = 37, 67.3%) or by a trained non-medical person (n = 7, 12.7%), while 8 (14.5%) patients would choose a local hospital. As expected, transportation time (in one direction) was longer in those preferring home infusions (89.4 ±63 vs 36.2 ±67 min; p = 0.02). Also, those with more severe FD manifestation would prefer home infusions to treatment in FD centers (p = 0.03). The vast majority of respondents (n = 46; 83%) would not change their preferences after pandemic termination. CONCLUSIONS: To maintain ERT, FD patients prefer home infusions or those given in the nearest hospital, especially during a pandemic.

Sudden cardiac death risk in hypertrophic cardiomyopathy: comparison between echocardiography and magnetic resonance imaging.

In hypertrophic cardiomyopathy (HCM) patients, left ventricular (LV) maximal wall thickness (MWT) is one of the most important factors determining sudden cardiac death (SCD) risk. In a large unselected sample of HCM patients, we aimed to simulate what changes would occur in the calculated SCD risk according to the European HCM Risk-SCD calculator when MWT measured using echocardiography was changed to MWT measured using MRI. All consecutive patients with HCM who underwent cardiac MRI were included. MWT measured with echocardiography and MRI were compared, and 5-year SCD risk according to the HCM Risk-SCD calculator was computed using four different models. The final population included 673 patients [389 (57.8%) males, median age 50 years, interquartile range (36-60)]. The median MWT was lower measured by echocardiography than by MRI [20 (17-24) mm vs 21 (18-24) mm; p < 0.0001]. There was agreement between echocardiography and MRI in the measurement of maximal LV wall thickness in 96 patients (14.3%). The largest differences between echo and MRI were - 13 mm and + 9 mm. The differences in MWT by echocardiography and MRI translated to a maximal difference of 8.33% in the absolute 5-year risk of SCD, i.e., the echocardiography-based risk was 8.33% lower than the MRI-based estimates. Interestingly, 13.7% of patients would have been reclassified into different SCD risk categories if MRI had been used to measure MWT instead of echocardiography. In conclusion, although there was high general intermodality agreement between echocardiography and MRI in the MWT measurements, the differences in MWT translated to significant differences in the 5-year risk of SCD.

Impact of cardiac magnetic resonance on the diagnosis of hypertrophic cardiomyopathy - a 10-year experience with over 1000 patients.

OBJECTIVES: To assess the value of cardiac MRI in comparison to echocardiography in consecutive patients with previously diagnosed and new suspected hypertrophic cardiomyopathy (HCM). METHODS: All MRI studies of patients with HCM or suspected disease performed at our centre within a 10-year time period were evaluated. Initial diagnoses (echocardiography-based) and final (MRI-based) diagnoses were compared in subgroups, and the discrepancies were recorded. RESULTS: A total of 1006 subjects with HCM or suspected HCM were identified (61% males, 39% females; median age, 49.1 years; interquartile range, 34.9-60.4). In 12 (2.2%) out of 550 patients with known HCM, MRI indicated a diagnosis other than HCM, including but not limited to the subaortic membrane (n = 1, 8.3%) or mild left ventricular hypertrophy (n = 5, 41.7%). Among all patients with suspected HCM (n = 456), MRI diagnosis was different from HCM in 5.3% (n = 24) of patients. In an additional 20.4% of patients (n = 93), no significant hypertrophy was present. In total, among patients with suspected HCM, MRI led to clear HCM diagnosis in 204 (44.7%) patients. Among patients with a history of uncontrolled hypertension suspected of having HCM, MRI aided in identifying cardiomyopathy in 47.9% of patients. This subgroup contained the largest proportion of patients with an ambiguous diagnosis, namely, 29.6% compared with 13.8% in the remaining groups of patients with suspected HCM (p = 0.0001). CONCLUSIONS: In a small but important group of patients with ultrasound-based HCM, cardiac MRI can diagnose previously unknown conditions and/or refute suspected cardiomyopathy. The diagnostic yield of MRI when compared to echocardiography in patients suspected of having HCM is 44.7%. KEY POINTS: • Out of 550 patients previously diagnosed with echocardiography but without magnetic resonance imaging (MRI) as having hypertrophic cardiomyopathy (HCM), we diagnosed a different disease in 12 (2.2%) patients using MRI. • Among patients with suspected HCM based on echocardiography, MRI led to clear HCM diagnosis in 44.7% of patients. • In patients with a history of uncontrolled hypertension suspected, based on an echocardiogram, of having HCM, MRI aided in identifying cardiomyopathy in 47.9% of patients. This subgroup contained the largest proportion of patients with an ambiguous diagnosis.

Cardiac Lipomatosis: A Rare Form of Left Ventricular Hypertrophy.

A 30-year-old female patient was referred to our centre due to an abnormal electrocardiography showing left ventricular hypertrophy. The physical examination was normal, and the patient was asymptomatic. Echocardiography was performed, revealing an atypical pattern of left ventricular hypertrophy with heterogeneous echogenicity of the left ventricular walls. A cardiac magnetic resonance examination revealed marked thickening of the interventricular septum and left and right ventricular walls. The signal intensity of the thickened ventricular walls was increased and was similar to that of subcutaneous fat. Follow-up echocardiography and cardiac magnetic resonance showed no progression of left ventricular hypertrophy.

Predictors of right ventricular function and size in patients with hypertrophic cardiomyopathy.

We investigated factors associated with right ventricular (RV) function and size in hypertrophic cardiomyopathy (HCM) patients. Two hundred fifty-three consecutive HCM patients and 20 healthy volunteers underwent cardiac magnetic resonance examination. In addition to measuring RV function (ejection fraction-RVEF) and size (end-diastolic volume-RVEDV), each image was inspected for the presence of RV and left ventricular (LV) hypertrophy, and the maximal wall thickness of the left and right ventricles was recorded. HCM patients had higher RVEF and lower RVEDV than healthy volunteers and similar RV mass. The mean RV wall thickness was higher in HCM patients than in controls. LV late gadolinium enhancement (LGE) was present in 89.7% of patients, and RV LGE was present in 3.1% of patients (p < 0.0001). Univariate and multivariable analyses revealed that LVEF, peak LV outflow tract gradient, LV LGE, maximal LV wall thickness, and tricuspid regurgitation (TR) volume by magnetic resonance imaging were positive predictors of RVEF. In addition to TR volume, the only independent predictor of RVEF < 45% was LVEF (odds ratio = 0.80, 95% confidence interval 0.67-0.95). Multivariable analysis revealed that LVEDV and TR volume were positive predictors of RVEDV, whereas negative predictors were RVEF, maximal RV wall thickness, LV LGE, and age. Neither estimated systolic pulmonary artery pressure nor TR grade by echocardiography proved to be predictors of RVEF. There were no differences in either the maximal RV wall thickness or the maximal left ventricular (LV) wall thickness in patients stratified according to NYHA functional class (p = 0.93 and p = 0.15, respectively). There were no differences in mean RV wall thickness in patients categorised based on the number of clinical risk factors for sudden cardiac death (SCD), i.e., non-sustained ventricular tachycardia, family history of SCD, or unexplained syncope (p = 0.79). On the other hand, there was a weak positive association between RV hypertrophy and the estimated probability of SCD at 5 years (rho = 0.16, p = 0.01). RV systolic dysfunction measured as decreased RVEF was uncommon in HCM and was associated with poor LV systolic function. LV also had a significant impact on RV size.

Improvement in long-term survival with acute kidney recovery after a successful transcatheter aortic valve replacement.

INTRODUCTION: Chronic kidney disease (CKD) is frequent in patients treated with transcatheter aortic valve replacement. Yet, the procedure can improve kidney function, that is, it can lead to acute kidney recovery (AKR). OBJECTIVES: The aim of the study was to assess kidney function changes after transcatheter aortic valve replacement and their impact on long­term outcomes. PATIENT AND METHODS: In 432 patients (median age, 83 years; female sex, 63.4% ), estimated glomerular filtration rate (eGFR) was measured before and after the procedure. Chronic kidney disease was defined as a prior diagnosis or baseline eGFR of less than 60 ml/min/1.73 m2. Median (interquartile range [IQR]) follow­up was 44.7 (31.2-48) months. RESULTS: Overall, 66.7% of patients had CKD. An increase in eGFR of 10% or greater at 48 hours (median [IQR], 39.8% [26.2%-51.8%]) was observed in 55.2% of patients with CKD and lasted until discharge (31.8% [17.8%-49%]) in 35.8% (the AKR group). In 17.4% of patients (64.3% with CKD), there was a drop in eGFR of 10% or greater at 48 hours, which remained at discharge in 6.5% of patients (the AKI group; median [IQR] eGFR drop, -22.8% [-40.6% to -14.9%] and -22.8% [-37.5% to -16.2%], respectively). There was a stepwise increase in AKR prevalence from CKD stage 1 and 2 (11.5%) to 4 (52%) (P = 0.03). In­hospital mortality (P = 0.01) was highest with AKI (10.7%); intermediate with CKD but no AKR (6.6%); and lowest with neither CKD nor AKI (1.5%) or with AKR (1%). Estimated 4­year mortality was correspondingly different (46.9%, 47.2%, 25.5%, 35.4%, respectively; P <0.001). The nonperipheral access was associated with more AKI and less AKR. Acute kidney recovery was more frequent with a history of stroke or transient ischemic attack or a newer generation self-expanding valves. CONCLUSIONS: Transcatheter aortic valve replacement led to acute kidney recovery in a substantial number of patients with CKD and an improved 4­year survival.

Anterior mitral leaflet length and mitral annulus diameter impact the echocardiographic outcome after isolated myectomy.

BACKGROUND: Myectomy remains the standard surgical treatment of patients with hypertrophic cardiomyopathy (HOCM). New surgical methods developed in the last decades mainly address the mitral valve and are controversial because of their conflicting assumptions. This study assesses the influence of anterior mitral valve leaflet (AML) length and the anterior-posterior diameter of the mitral annulus (MAD) on dynamic left ventricle outflow tract obstruction and mitral regurgitation (MR) after extended myectomy. METHODS: We retrospectively analysed the transthoracic echocardiograms (TTE) of 36 patients. AML length and MAD were obtained from TTE performed before the operation. The greatest maximal left ventricle outflow tract (LVOT) gradient and MR registered in follow-up were analysed. After surgery, patients were divided into two groups; those with moderate or milder MR and/or an LVOT gradient < 30 mmHg (responders), and those with more than moderate MR and/or an LVOT gradient ≥30 mmHg (non-responders). RESULTS: Patients in responders group had significantly longer AML: 32.3 ± 2.3 mm vs 30.0 ± 3.8 mm (p = 0.03) [parasternal long axis view - PLAX view], 25.9 ± 2.3 mm vs 23.5 ± 2.7 mm (p = 0.008) [four chamber view - 4CH view] and larger anterior-posterior mitral annulus diameter 28.1 ± 2.8 mm vs 25.4 ± 3.2 mm (p = 0.011) than those in non-responders group. Among all analysed patients longer anterior mitral leaflet was correlated with lower postoperative LVOT gradient when measured in PLAX view (p = 0.02) and lower degree of MR due to systolic anterior motion (SAM) when measured in 4CH view (p = 0.009). Greater [AML x mitral annulus] ratio correlated with lower postoperative LVOT gradient in both projections: 4CH (p = 0.025), PLAX (p = 0.012). There was significant reduction in NYHA Class after surgery (p = 0.000). There were no significant differences in NYHA class after surgery (p = 0.633) neither in NYHA class reduction (p = 0.475) between patients divided into responders and non-responders group according to echocardiographic parameters. CONCLUSIONS: Patients with a longer AML and a greater diameter of the mitral annulus are less likely to have mitral regurgitation due to residual SAM and increased LVOT gradient after an extended myectomy. Division of patients according to echocardiographic criteria into responders and non-responders was not in concordance with clinical improvement. TRIAL REGISTRATION: Retrospective study. Approved by ethics committee (IK-NPIA-0021-21/1763/19) at 16.01.2019.

Long-term follow-up and safety assessment of angiogenic gene therapy trial VIF-CAD: Transcatheter intramyocardial administration of a bicistronic plasmid expressing VEGF-A165/bFGF cDNA for the treatment of refractory coronary artery disease.

There have been a number of angiogenic gene therapy trials, yielding mixed results as to efficacy, but demonstrating uniform short-term treatment safety. Data regarding long-term safety of angiogenic gene therapy are limited. Double-blind VIF-CAD trial (NCT00620217) assessed myocardial perfusion and clinical data in 52 refractory coronary artery disease (CAD) patients randomized into treatment (VIF; n = 33) and Placebo (n = 19) arms. VIF group received electromechanical system NOGA-guided intramyocardial injections of VEGF-A165/bFGF plasmid (VIF) into ischemic regions, while the Placebo group-placebo plasmid injections. Full 1-year follow-up data have been published. This study presents the results of over 10-year (median 133 months, range 95-149) safety follow-up of VIF-CAD patients. Overall, 12 (36.4%) patients died in VIF and 8 (42.1%) in Placebo group (P = .68). Cardiovascular mortality was 12/33 (36.4%) in the VIF group and 6/19 (31.6%) in Placebo group (P = .73). Two Placebo patients died due to malignancies, but no VIF patients (P = .17). The Kaplan-Meier curves of combined endpoint: cardiovascular mortality, myocardial infarction and stroke were similar for both patient groups (P = .71). Odds ratio of Placebo group increasing (reaching a worse) their CCS class versus VIF was non-significant (OR 1.28, 95% CI = 0.66-2.45; P = .47). However, CCS class improved in time irrespectively of treatment-OR of reaching a less favorable CCS class per each year of follow-up was 0.74 (95% CI 0.685-0.792; P < .0001, pooled data). There were no differences in readmission rates. Intramyocardial VEGF-A165/bFGF plasmid administration appears safe, with no evidence of an increase in the incidence of death, malignancy, myocardial infarction or stroke during 10-year follow-up in this limited patient population.

Guided de-escalation of DAPT in acute coronary syndrome patients undergoing percutaneous coronary intervention with BVS implantation: a post-hoc analysis from the randomized TROPICAL-ACS trial.

To investigate the safety and efficacy of an early platelet function testing (PFT)-guided de-escalation of dual antiplatelet treatment (DAPT) in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) with bioresorbable vascular scaffolds (BVS). Early DAPT de-escalation is a new non-inferior alternative to 12-months DAPT in patients with biomarker positive ACS treated with stent implantation. In this post-hoc analysis of the TROPICAL-ACS trial, which randomized 2610 ACS patients to a PFT-guided DAPT de-escalation (switch from prasugrel to clopidogrel) or to control group (uniform prasugrel), we compared clinical outcomes of patients (n = 151) who received a BVS during the index PCI. The frequency of the primary endpoint (cardiovascular death, myocardial infarction, stroke or BARC ≥ 2 bleeding) was 8.8% (n = 6) in the de-escalation group vs. 12.0% (n = 10) in the control group (HR 0.72, 95% CI 0.26-1.98, p = 0.52) at 12 months. One early definite stent thrombosis (ST) occurred in the control group (day 19) and 1 possible ST (sudden cardiovascular death) in the de-escalation group (day 86), both despite prasugrel treatment and in a background of high on-treatment platelet reactivity assessed at day 14 after randomization (ADP-induced platelet aggregation values of 108 U and 59 U, respectively). A PFT-guided DAPT de-escalation strategy could potentially be a safe and effective strategy in ACS patients with BVS implantation but the level of platelet inhibition may be of particular importance. This hypothesis-generating post-hoc analysis requires verification in larger studies with upcoming BVS platforms.

Reduction of left ventricular mass, left atrial size, and N-terminal pro-B-type natriuretic peptide level following alcohol septal ablation in patients with hypertrophic obstructive cardiomyopathy.

BACKGROUND: Alcohol septal ablation (ASA) is an alternative to surgical treatment in patients with hypertrophic obstructive cardiomyopathy (HOCM). Through alcohol-induced necrosis, ASA leads to an increase in left ventricular outflow tract (LVOT) diameter and a decrease in LVOT pressure gradient. AIM: We sought to assess the effect of ASA on left ventricular (LV) wall thickness and mass, left atrial (LA) size, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) level. METHODS: The study cohort consisted of 50 patients with HOCM (30 in the ASA group, 20 in the optimal pharmacotherapy group [OPG]). Transthoracic echocardiography (TTE), cardiac magnetic resonance (CMR), and NT-proBNP level analysis were performed at baseline and at six months. RESULTS: All parameters are presented as means. In the ASA group, the maximal LVOT pressure gradient decreased from 122.7 to 54.8 mmHg directly after ASA and to 37.2 mmHg after a further six months (p < 0.0001). The NT-proBNP level decreased from 2174.4 to 1103.4 pg/mL (p < 0.001). On TTE, the interventricular septum (IVS) thickness decreased to from 23.6 to 19.4 mm (p < 0.0001) and the lateral wall (LW) thickness decreased from 15.9 to 14.2 mm (p < 0.007). On CMR, basal IVS thickness decreased from 23.7 to 18.0 mm (p < 0.0001) and the LW thickness decreased from 13.2 to 12.2 mm (p = 0.02). IVS mass reduced from 108.9 to 91.5 g (-16%; p < 0.001). All of the above parameters remained unchanged in the OPG. CONCLUSIONS: Successful ASA reduces LV hypertrophy and improves parameters of the LV overload, resulting in LV wall hy-pertrophy regression, and LA size and NT-proBNP level reduction. The above parameters may be as useful in assessing the efficacy of ASA as the LVOT gradient itself.