Mid-aortic Syndrome in a Pediatric Cohort.

Mid-aortic syndrome (MAS) is an uncommon condition characterized by severe narrowing of the abdominal aorta, usually involving visceral and renal arteries. Most patients are asymptomatic and typically present with incidental hypertension which might evolve into end-organ damage if untreated. Our aim was to review 8 new pediatric MAS cases. A retrospective observational study of all pediatric patients with MAS diagnosis (April 1992-November 2021) was conducted. Patients underwent systematic evaluation (medical and family history; 12-lead electrocardiogram; echocardiogram; angiography and/or computed tomography or magnetic resonance angiography). 8 pediatric patients with MAS were included. Median age at diagnosis was 2.6 [0.2-4.7] years; median follow-up time was 8.6 [6.6-10.0] years. 6/8 patients presented with incidental hypertension, 1/8 with heart murmur, and 1/8 with heart failure symptoms. All patients were on antihypertensive treatment. 1/8 patients underwent surgery and 7/8 an endovascular treatment. At the end of the study period, among the 6 patients that underwent a successful endovascular procedure, 2 achieved good blood pressure (BP) control, 2 acceptable BP control, 1 stage 1 hypertension and, another, stage 2 hypertension. There was 1 death during follow-up. BP monitoring in pediatric patients is crucial for early recognition of MAS. Treatment should be based on the individual clinical characteristics of patients with careful planning of surgical revascularisation, if possible, after adult growth is completed. Our study demonstrates that endovascular treatment might be a good alternative to surgery. Nevertheless, further trials with larger sample size and longer-term follow-up are required to determine the best treatment approach.

Hyperuricaemia Does Not Interfere with Aortopathy in a Murine Model of Marfan Syndrome.

Redox stress is involved in the aortic aneurysm pathogenesis in Marfan syndrome (MFS). We recently reported that allopurinol, a xanthine oxidoreductase inhibitor, blocked aortopathy in a MFS mouse model acting as an antioxidant without altering uric acid (UA) plasma levels. Hyperuricaemia is ambiguously associated with cardiovascular injuries as UA, having antioxidant or pro-oxidant properties depending on the concentration and accumulation site. We aimed to evaluate whether hyperuricaemia causes harm or relief in MFS aortopathy pathogenesis. Two-month-old male wild-type (WT) and MFS mice (Fbn1C1041G/+) were injected intraperitoneally for several weeks with potassium oxonate (PO), an inhibitor of uricase (an enzyme that catabolises UA to allantoin). Plasma UA and allantoin levels were measured via several techniques, aortic root diameter and cardiac parameters by ultrasonography, aortic wall structure by histopathology, and pNRF2 and 3-NT levels by immunofluorescence. PO induced a significant increase in UA in blood plasma both in WT and MFS mice, reaching a peak at three and four months of age but decaying at six months. Hyperuricaemic MFS mice showed no change in the characteristic aortic aneurysm progression or aortic wall disarray evidenced by large elastic laminae ruptures. There were no changes in cardiac parameters or the redox stress-induced nuclear translocation of pNRF2 in the aortic tunica media. Altogether, the results suggest that hyperuricaemia interferes neither with aortopathy nor cardiopathy in MFS mice.

Impact of electrocardiographic interpretability on outcome in patients referred for stress testing.

BACKGROUND: There is limited insight into the association of electrocardiographic interpretability with outcome in patients referred for stress testing. METHODS: Exercise echocardiography was performed in 8226 patients with known or suspected coronary artery disease. Electrocardiograms were considered uninterpretable in the presence of left bundle-branch block (LBBB), left ventricular hypertrophy (LVH) with strain, repolarization abnormalities because of digitalis therapy, ventricular paced rhythm, preexcitation or ST depression ≥ 0.1 mV because of other causes. End points were all-cause mortality, cardiac death and hard cardiac events (i.e. cardiac death or nonfatal myocardial infarction). RESULTS: A total of 2450 patients had uninterpretable electrocardiograms. During a follow-up period of 4.1 ± 3.5 years, there were 1011 deaths (of which 478 were cardiac deaths) and 1069 patients experienced a hard cardiac event. The 5-year rates of death, cardiac death and hard cardiac events were, respectively, 18.7%, 10.9% and 18.8% in patients with uninterpretable ECGs, compared with 9.5%, 4.1% and 10.9% in those with interpretable ECGs (P < 0.001). After covariate adjustment, lack of ECG interpretability remained an independent predictor of all-cause mortality (hazard ratio [HR] 1.25, 95% confidence interval [CI] 1.08-1.44, P = 0.002), cardiac death (HR 1.63, 95% CI 1.32-2.01, P < 0.001) and hard cardiac events (HR 1.28, 95% CI 1.11-1.47, P < 0.001). When the specific ECG abnormalities were included as covariates, LBBB, LVH and digitalis therapy remained predictors of cardiac death; LBBB and LVH were predictors of hard cardiac events, and LVH remained predictive of all-cause mortality. CONCLUSION: Uninterpretable ECGs portend a worse prognosis in patients referred for stress testing.

Unraveling Bicuspid Aortic Valve Enigmas by Multimodality Imaging: Clinical Implications.

Multimodality imaging is the basis of the diagnosis, follow-up, and surgical management of bicuspid aortic valve (BAV) patients. Transthoracic echocardiography (TTE) is used in our clinical routine practice as a first line imaging for BAV diagnosis, valvular phenotyping and function, measurement of thoracic aorta, exclusion of other aortic malformations, and for the assessment of complications such are infective endocarditis and aortic. Nevertheless, TTE is less useful if we want to assess accurately other aortic segments such as mid-distal ascending aorta, where computed tomography (CT) and magnetic resonance (CMR) could improve the precision of aorta size measurement by multiplanar reconstructions. A major advantage of CT is its superior spatial resolution, which affords a better definition of valve morphology and calcification, accuracy, and reproducibility of ascending aorta size, and allows for coronary artery assessment. Moreover, CMR offers the opportunity of being able to evaluate aortic functional properties and blood flow patterns. In this setting, new developed sequences such as 4D-flow may provide new parameters to predict events during follow up. The integration of all multimodality information facilitates a comprehensive evaluation of morphologic and dynamic features, stratification of the risk, and therapy guidance of this cohort of patients.

Arrhythmia and impaired myocardial function in heritable thoracic aortic disease: An international retrospective cohort study.

BACKGROUND: Heritable thoracic aortic diseases (HTAD), typically entailing aortic complications, can be caused by pathogenic variants or likely pathogenic variants (PV/LPVs) in several genes, including fibrillin1 (FBN1), Actin Alpha2 (ACTA2) and genes encoding components of the transforming growth factor (TGF)-ß signaling pathway. In addition to aortic complications, non-aortic cardiac disease such as impaired myocardial function and/or arrhythmia have been increasingly reported, mainly in Marfan syndrome with underlying FBN1 PV/LPVs and are acknowledged as additional causes of morbidity and mortality. The prevalence of these manifestations in the various HTAD entities is largely unknown. METHODS: This international multicentre retrospective study collected data on patients with HTAD presenting non-aortic cardiac disease. A total of 9 centers from 7 different countries participated. Patients 12 years or older carrying a PV/LPV in one of the following genes: FBN1, TGFBR1, TGFBR2, TGFB2, TGFB3, SMAD3 and ACTA2 were screened. Non-aortic cardiac disease included impaired myocardial function and/or arrhythmia. Impaired myocardial function was defined as (a)symptomatic reduced ejection fraction (EF<50%). Arrhythmias included atrial fibrillation (AF), atrial flutter (AFL), ventricular tachycardia (VT), ventricular fibrillation (VF) and (aborted) sudden cardiac death (presumed arrhythmogenic) (SCD). RESULTS: Medical records of 3219 patients with HTAD were screened (2761, 385 and 73 carrying a PV/LPV in FBN1, in a TGF-ß signaling gene and in ACTA2 respectively). Non-aortic cardiac disease was reported 142 times in 101 patients (3.1%) (age 37 [range 12-77] years, 39% female): 88 patients carrying an FBN1 PV/LPV and 13 carrying a PV/LPV in one of the TGF-ß signaling genes. Neither impaired myocardial function nor arrhythmia was reported in screened patients carrying a PV/LPV in ACTA2. Among the 142 reported non-aortic cardiac diseases, 68 (48%) were impaired myocardial function, 47 (33%) were AF/AFL and 27 (19%) were VT/VF/SCD. Among the patients with non-aortic cardiac disease, prior cardiac surgery was noted in 80% and severe valvular disease (valvular surgery or severe valvular regurgitation) in 58%, while 18% of the patients developed non-aortic cardiac disease in the absence of any of the latter. CONCLUSIONS: In patients with HTAD, arrhythmia and impaired myocardial function was reported in patients with PV/LPVs in FBN1 and in the TGF-ß signaling genes and not in patients harboring PV/LPVs in ACTA2. Though infrequent, non-aortic cardiac disease should be acknowledged as potentially severe, also occurring in young patients with no underlying significant valvular or aortic disease.

Aortic flow dynamics and stiffness in Loeys-Dietz syndrome patients: a comparison with healthy volunteers and Marfan syndrome patients.

AIMS: To assess aortic flow and stiffness in patients with Loeys-Dietz syndrome (LDS) by 4D flow and cine cardiovascular magnetic resonance (CMR) and compare the results with those of healthy volunteers (HV) and Marfan syndrome (MFS) patients. METHODS AND RESULTS: Twenty-one LDS and 44 MFS patients with no previous aortic dissection or surgery and 35 HV underwent non-contrast-enhanced 4D flow CMR. In-plane rotational flow (IRF), systolic flow reversal ratio (SFRR), and aortic diameters were obtained at 20 planes from the ascending (AAo) to the proximal descending aorta (DAo). IRF and SFRR were also quantified for aortic regions (proximal and distal AAo, arch and proximal DAo). Peak-systolic wall shear stress (WSS) maps were also estimated. Aortic stiffness was quantified using pulse wave velocity (PWV) and proximal AAo longitudinal strain. Compared to HV, LDS patients had lower rotational flow at the distal AAo (P = 0.002), arch (P = 0.002), and proximal DAo (P < 0.001) even after adjustment for age, stroke volume, and local diameter. LDS patients had higher SFRR in the proximal DAo compared to both HV (P = 0.024) and MFS patients (P = 0.015), even after adjustment for age and local diameter. Axial and circumferential WSS in LDS patients were lower than in HV. AAo circumferential WSS was lower in LDS compared to MFS patients. AAo and DAo PWV and proximal AAo longitudinal strain revealed stiffer aortas in LDS patients compared to HV (P = 0.007, 0.005, and 0.029, respectively) but no differences vs. MFS patients. CONCLUSION: Greater aortic stiffness as well as impaired IRF and WSS were present in LDS patients compared to HV. Conversely, similar aortic stiffness and overlapping aortic flow features were found in Loeys-Dietz and Marfan patients.

Spanish Registry of Acute Aortic Syndrome (RESA). Changes in therapeutic management and lower mortality in acute aortic syndrome.

INTRODUCTION AND OBJECTIVES: The Spanish Registry of Acute Aortic Syndrome (RESA) was launched in 2005 to identify the characteristics of acute aortic syndrome (AAS) in Spain. The aim of this study was to analyze the differences in management and mortality in the 3 RESA iterations. METHODS: We analyzed data from patients with AAS prospectively included by 24 to 30 tertiary centers during the 3 iterations of the registry: RESA I (2005-2006), RESA-II (2012-2013), and RESA III (2018-2019). RESULTS: AAS was diagnosed in 1902 patients (74% men; age, 60.7±12.5 years): 1329 (69.9%) type A and 573 (30.1%) type B. Comparison of the 3 periods revealed that the use of computed tomography increased as the first diagnostic technique (77.1%, 77.9%, and 84.2%, respectively; P=.001). In type A, surgical management increased (79.6%, 78.7%, and 84.5%; P=.045) and overall mortality decreased (41.2%, 34.5%, and 31.2%; P=.002), due to a reduction in surgical mortality (33.4%, 25.1%, and 23.9%; P=.003). In type B, endovascular treatment increased (22.8%, 32.8%, and 38.7%; P=.006), while medical and surgical treatment decreased. Overall type B mortality also decreased (21.6%, 16.1%, and 12.0%; P=.005) in line with a reduction in mortality with medical (16.8%, 13.8%, and 8.8%, P=.030) and endovascular (27.0%, 18.0%, and 9.2%; P=.009) treatments. CONCLUSIONS: The iterations of RESA show a decrease in mortality from type A AAS, coinciding with an increase in surgical treatment and a reduction in surgical mortality. In type B, the use of endovascular treatment was associated with improved survival, allowing better management in patients with complications.

Aortic Branch Aneurysms and Vascular Risk in Patients With Marfan Syndrome.

BACKGROUND: Aortic branch aneurysms are not included in the diagnostic criteria for Marfan syndrome (MFS); however, their prevalence and eventual prognostic significance are unknown. OBJECTIVES: The goal of this study was to assess the prevalence of aortic branch aneurysms in MFS and their relationship with aortic prognosis. METHODS: MFS patients with a pathogenic FBN1 genetic variant and at least one magnetic resonance or computed tomography angiography study assessing aortic branches were included. Aortic events and those related to aneurysm complications were recorded during follow-up. RESULTS: A total of 104 aneurysms were detected in 50 (26.7%) of the 187 patients with MFS (mean age 37.9 ± 14.4 years; 54% male) included in this study, with the iliac artery being the most common location (45 aneurysms). Thirty-one patients (62%) had >1 peripheral aneurysm, and surgery was performed in 5 (4.8%). Patients with aneurysms were older (41.9 ± 12.7 years vs. 36.7 ± 14.8 years; p = 0.040) and had more dilated aortic root (42.2 ± 6.4 mm vs. 38.8 ± 8.0 mm; p = 0.044) and dyslipidemia (31.0% vs. 9.7%; p = 0.001). In a subgroup of 95 patients with no previous aortic surgery or dissection followed up for 3.3 ± 2.6 years, the presence of arterial aneurysms was associated with a greater need for aortic surgery (hazard ratio: 3.4; 95% confidence interval: 1.1 to 10.3; p = 0.028) in a multivariable Cox analysis adjusted for age and aortic diameter. CONCLUSIONS: Aortic branch aneurysms are present in one-quarter of patients with MFS and are related to age and aortic dilation, and they independently predict the need for aortic surgery. The systematic use of whole-body vascular assessment is recommended to identify other sites of vascular involvement at risk for complications and to define the subgroup of patients with more aggressive aortic disease.

Are Aortic Root and Ascending Aorta Diameters Measured by the Pediatric versus the Adult American Society of Echocardiography Guidelines Interchangeable?

Ascending aorta diameters have important clinical value in the diagnosis, follow-up, and surgical indication of many aortic diseases. However, there is no uniformity among experts regarding ascending aorta diameter quantification by echocardiography. The aim of this study was to compare maximum aortic root and ascending aorta diameters determined by the diastolic leading edge (DLE) and the systolic inner edge (SIE) conventions in adult and pediatric patients with inherited cardiovascular diseases. Transthoracic echocardiograms were performed in 328 consecutive patients (260 adults and 68 children). Aorta diameters were measured twice at the root and ascending aorta by the DLE convention following the 2015 American Society of Echocardiography (ASE) adult guidelines and the SIE convention following the 2010 ASE pediatric guidelines. Comparison of the diameters measured by the two conventions in the overall population showed a non-significant underestimation of the diameter measured by the SIE convention at root level of 0.28 mm (CI -1.36; 1.93) and at tubular ascending aorta level of 0.17 mm (CI -1.69; 2.03). Intraobserver and interobserver variability were excellent. Maximum aorta diameter measured by the leading edge convention in end-diastole and the inner edge convention in mid-systole had similar values to a mild non-significant underestimation of the inner-to-inner method that permits them to be interchangeable when used in clinical practice.

Changes in the diagnosis and management of acute aortic syndrome and associated mortality in the last 20 years.

INTRODUCTION AND OBJECTIVES: Mortality is high in acute aortic syndrome (AAS), which therefore requires early treatment. This study aimed to analyze changes in the diagnosis and treatment of AAS over 20 years at our center. METHODS: From 1999 to 2018, 451 patients diagnosed with AAS (336 men; mean age, 60.9±12.4 years) were prospectively included (270 type A and 181 type B). Clinical variables, diagnosis, treatment, and in-hospital complications were analyzed. RESULTS: The use of computed tomography (CT) as the first-line diagnostic technique increased from 62.8% to 94.2% (P <.001). Surgical treatment of type A AAS rose from 67.4% to 82.5% (P=.09). Mortality from type A AAS decreased significantly from 53.1% to 26.3% (P <.001) as a result of the fall in mortality from surgical treatment (from 45.4% to 17.0%; P <.001). The use of medical treatment alone for type B AAS decreased from 91.8% to 61.7% (P <.001) due to the greater use of endovascular treatment. Mortality from type B AAS showed no significant reduction (16.2% to 10.6%; P=.15). CONCLUSIONS: The diagnosis and treatment of AAS has changed substantially in the last 2 decades. CT has become the first-line diagnostic technique for AAS. In type A AAS, mortality has fallen significantly due to improvements in the results of surgical treatment. In type B AAS, the use of medical treatment alone has decreased due to the expansion of endovascular treatment, although in-hospital mortality has not decreased significantly.

Clinical profile and outcome of cardiac amyloidosis in a Spanish referral center.

INTRODUCTION AND OBJECTIVES: Cardiac amyloidosis (CA) is produced by amyloid fiber deposition in the myocardium. The most frequent forms are those caused by light chains (AL) and transthyretin (ATTR). Our objective was to describe the diagnosis, treatment and outcomes of CA in a specialized Spanish center. METHODS: We included all patients diagnosed with CA in Hospital Universitario Puerta de Hierro Majadahonda from May 2008 to September 2018. We analyzed their clinical characteristics, outcomes, and survival. RESULTS: We included 180 patients with CA, of whom 64 (36%) had AL (50% men; mean age, 65±11 years) and 116 had ATTR (72% men; mean age 79±11 years; 18 with hereditary ATTR). The most common presentation was heart failure in both groups (81% in AL and 45% in ATTR, P <.01). Other forms of presentation in ATTR patients were atrial arrhythmias (16%), conduction disorders (6%), and incidental finding (6%); 70 patients (40%), had a previous alternative cardiac diagnosis. Diagnosis was noninvasive in 75% of ATTR patients. Diagnostic delay was higher in ATTR (2.8±4.3 vs 0.6±0.7 years, P <.001), but mortality was greater in AL patients (48% vs 32%, P=.028). Independent predictors of mortality were AL subtype (HR, 6.16; 95%CI, 1.56-24.30; P=.01), female sex (HR, 2.35; 95%CI, 1.24-4.46; P=.01), and NYHA functional class III-IV (HR, 2.07; 95%CI, 1.11-3.89; P=.02). CONCLUSIONS: CA is a clinical challenge, with wide variability in its presentation depending on the subtype, leading to diagnostic delay and high mortality. Improvements are needed in the early diagnosis and treatment of these patients.

Clinical Risk Prediction in Patients With Left Ventricular Myocardial Noncompaction.

BACKGROUND: Left ventricular noncompaction (LVNC) is a heterogeneous entity with uncertain prognosis. OBJECTIVES: This study sought to develop and validate a prediction model of major adverse cardiovascular events (MACE) and to identify LVNC cases without events during long-term follow-up. METHODS: This is a retrospective longitudinal multicenter cohort study of consecutive patients fulfilling LVNC criteria by echocardiography or cardiovascular magnetic resonance. MACE were defined as heart failure (HF), ventricular arrhythmias (VAs), systemic embolisms, or all-cause mortality. RESULTS: A total of 585 patients were included (45 ± 20 years of age, 57% male). LV ejection fraction (LVEF) was 48% ± 17%, and 18% presented late gadolinium enhancement (LGE). After a median follow-up of 5.1 years, MACE occurred in 223 (38%) patients: HF in 110 (19%), VAs in 87 (15%), systemic embolisms in 18 (3%), and 34 (6%) died. LVEF was the main variable independently associated with MACE (P < 0.05). LGE was associated with HF and VAs in patients with LVEF >35% (P < 0.05). A prediction model of MACE was developed using Cox regression, composed by age, sex, electrocardiography, cardiovascular risk factors, LVEF, and family aggregation. C-index was 0.72 (95% confidence interval: 0.67-0.75) in the derivation cohort and 0.72 (95% confidence interval: 0.71-0.73) in an external validation cohort. Patients with no electrocardiogram abnormalities, LVEF ≥50%, no LGE, and negative family screening presented no MACE at follow-up. CONCLUSIONS: LVNC is associated with an increased risk of heart failure and ventricular arrhythmias. LVEF is the variable most strongly associated with MACE; however, LGE confers additional risk in patients without severe systolic dysfunction. A risk prediction model is developed and validated to guide management.

Multiparametric Echocardiography Scores for the Diagnosis of Cardiac Amyloidosis.

OBJECTIVES: This study aimed to investigate the accuracy of a broad range of echocardiographic variables to develop multiparametric scores to diagnose CA in patients with proven light chain (AL) amyloidosis or those with increased heart wall thickness who had amyloid was suspected. We also aimed to further characterize the structural and functional changes associated with amyloid infiltration. BACKGROUND: Cardiac amyloidosis (CA) is a serious but increasingly treatable cause of heart failure. Diagnosis is challenging and frequently unclear at echocardiography, which remains the most often used imaging tool. METHODS: We studied 1,187 consecutive patients evaluated at 3 referral centers for CA and analyzed morphological, functional, and strain-derived echocardiogram parameters with the aim of developing a score-based diagnostic algorithm. Cardiac amyloid burden was quantified by using extracellular volume measurements at cardiac magnetic resonance. RESULTS: A total of 332 patients were diagnosed with AL amyloidosis and 339 patients with transthyretin CA. Concentric remodeling and strain-derived parameters displayed the best diagnostic performance. A multivariable logistic regression model incorporating relative wall thickness, E wave/e' wave ratio, longitudinal strain, and tricuspid annular plane systolic excursion had the greatest diagnostic performance in AL amyloidosis (area under the curve: 0.90; 95% confidence interval: 0.87 to 0.92), whereas the addition of septal apical-to-base ratio yielded the best diagnostic accuracy in the increased heart wall thickness group (area under the curve: 0.80; 95% confidence interval: 0.85 to 0.90). CONCLUSIONS: Specific functional and structural parameters characterize different burdens of CA deposition with different diagnostic performances and enable the definition of 2 scores that are sensitive and specific tools with which diagnose or exclude CA.

Clinical Features and Natural History of PRKAG2 Variant Cardiac Glycogenosis.

BACKGROUND: PRKAG2 gene variants cause a syndrome characterized by cardiomyopathy, conduction disease, and ventricular pre-excitation. Only a small number of cases have been reported to date, and the natural history of the disease is poorly understood. OBJECTIVES: The aim of this study was to describe phenotype and natural history of PRKAG2 variants in a large multicenter European cohort. METHODS: Clinical, electrocardiographic, and echocardiographic data from 90 subjects with PRKAG2 variants (53% men; median age 33 years; interquartile range [IQR]: 15 to 50 years) recruited from 27 centers were retrospectively studied. RESULTS: At first evaluation, 93% of patients were in New York Heart Association functional class I or II. Maximum left ventricular wall thickness was 18 ± 8 mm, and left ventricular ejection fraction was 61 ± 12%. Left ventricular hypertrophy (LVH) was present in 60 subjects (67%) at baseline. Thirty patients (33%) had ventricular pre-excitation or had undergone accessory pathway ablation; 17 (19%) had pacemakers (median age at implantation 36 years; IQR: 27 to 46 years), and 16 (18%) had atrial fibrillation (median age 43 years; IQR: 31 to 54 years). After a median follow-up period of 6 years (IQR: 2.3 to 13.9 years), 71% of subjects had LVH, 29% had AF, 21% required de novo pacemakers (median age at implantation 37 years; IQR: 29 to 48 years), 14% required admission for heart failure, 8% experienced sudden cardiac death or equivalent, 4% required heart transplantation, and 13% died. CONCLUSIONS: PRKAG2 syndrome is a progressive cardiomyopathy characterized by high rates of atrial fibrillation, conduction disease, advanced heart failure, and life-threatening arrhythmias. Classical features of pre-excitation and severe LVH are not uniformly present, and diagnosis should be considered in patients with LVH who develop atrial fibrillation or require permanent pacemakers at a young age.

Negative screening of Fabry disease in patients with conduction disorders requiring a pacemaker.

Identification of Fabry disease (FD) in cardiac patients has been restricted so far to patients with left ventricular hypertrophy. Conduction problems are frequent in FD and could precede other manifestations, offering a possible earlier diagnosis.We studied the prevalence of FD in 188 patients < 70 years with conduction problems requiring pacemaker implantation. Although classical manifestations of FD were not rare, no patient with FD was identified. Screening efforts should not be conducted in this population.

Clinical Findings and Prognosis of Danon Disease. An Analysis of the Spanish Multicenter Danon Registry.

INTRODUCTION AND OBJECTIVES: Danon disease (DD) is caused by mutations in the LAMP2 gene. It is considered a multisystemic disease characterized by hypertrophic cardiomyopathy with pre-excitation and extreme hypertrophy, intellectual disability, myopathy, childhood presentation, and worse prognosis in men. There are scarce data on the clinical characteristics and prognosis of DD. METHODS: We analyzed the clinical records of patients with DD from 10 Spanish hospitals. RESULTS: Twenty-seven patients were included (mean age, 31 ± 19 years; 78% women). Male patients showed a high prevalence of extracardiac manifestations: myopathy (80%), learning disorders (83%), and visual alterations (60%), which were uncommon findings in women (5%, 0%, and 27%, respectively). Although hypertrophic cardiomyopathy was the most common form of heart disease (61%), the mean maximum wall thickness was 15 ± 7 mm and dilated cardiomyopathy was present in 12 patients (10 women). Pre-excitation was found in only 11 patients (49%). Age at presentation was older than 20 years in 16 patients (65%). After a median follow-up of 4 years (interquartile range, 2-9), 4 men (67%) and 9 women (43%) died or required a transplant. Cardiac disease and adverse events occurred later in women (37 ± 9 vs 23 ± 16 and 36 ± 20 vs 20 ± 11 years, respectively). CONCLUSIONS: The clinical characteristics of DD differ substantially from traditional descriptions: age at presentation of DD is older, the disease is not multisystemic in women, and pre-excitation is infrequent.

Prevalence of cardiac amyloidosis among elderly patients with systolic heart failure or conduction disorders.

Objective: Cardiac amyloid infiltration can lead to systolic heart failure (HF) or to conduction disorders (CD). Patients with transthyretin (ATTR) amyloidosis are particularly exposed. We sought to determine the prevalence of ATTR and AL among patients >60 years admitted with CD or unexplained systolic HF and increased wall thickness. Materials and Methods: We studied 143 patients (57% males, 79 ± 9 years) with HF (N = 28) or CD requiring pacemaker implantation (N = 115). In total, 139 (97%) patients (28 with HF and 111 with CD) underwent 99mTc-DPD scintigraphy to detect ATTR, and 105 (73%; 19 HF and 86 CD) underwent AL screening. Results: Five patients (4%; 95%CI:0-7%) exhibited wild-type ATTR (ATTRwt) amyloidosis, 2 (2%; 95%CI:0-4%) had CD and 3 (11%; 95%CI:0-23%) HF. No patient showed AL. The 2 ATTRwt patients with CD were previously asymptomatic, did not show classical ECG signs and exhibited mild LV hypertrophy with preserved LVEF. By contrast, all ATTRwt patients with HF had ECG and echocardiographic signs of amyloid. During a mean follow-up of 18 ± 11 months, 3(60%) patients with ATTRwt amyloidosis (1 CD and 2 HF) and 14(10.4%) without died. Conclusion: Prevalence of ATTRwt amyloidosis in patients with CD requiring pacemaker is low. Although, additional studies are needed, prevalence seems to be higher in elderly patients with systolic HF.

Late graft failure in heart transplant recipients: incidence, risk factors and clinical outcomes.

AIM: To analyse the incidence, risk factors and clinical outcomes of late graft failure after heart transplantation. METHODS AND RESULTS: We conducted an observational, single-centre study based on 547 patients who underwent cardiac transplantation from 1991 to 2014 and who survived the in-hospital postoperative period. Late graft failure was defined as the first hospitalization due to this condition after discharge. Over a mean follow-up of 8.4 ± 6 years, 178 (32.5%) patients were hospitalized due to late graft failure [incidence rate: 3.6 cases per 100 patient-years, 95% confidence interval (CI) 3.1-4.2]. Pre-transplant diabetes, higher pre-transplant transpulmonary pressure gradient and lower donor-recipient weight ratio were independently associated with higher risk of graft failure. Cardiac allograft vasculopathy, cellular rejection grade ≥1R, and antibody-mediated rejection grade ≥1 were detected in 50.6%, 44.9% and 19.2% patients, respectively, admitted due to graft failure. Left ventricular ejection fraction was ≥50% in 60.1% of these patients. Re-transplant free survival 1, 5, 10 and 15 years after the diagnosis of late graft failure was 72.2%, 38.4%, 18.4%, and 7.5%, respectively; the incidence rate of re-hospitalization due to decompensated heart failure was 40.9 episodes per 100 patient-years (95% CI 36.6-46.1). The need for inotropes, the presence of cardiac allograft vasculopathy, higher creatinine serum levels, lower ejection fraction and lower sodium serum levels were independent predictors of worse outcomes. CONCLUSIONS: Late graft failure is frequent after heart transplantation, as it is associated with poor outcomes. Rejection and cardiac allograft vasculopathy are the most frequent underlying causes.

Diagnosis and Treatment of Transthyretin Cardiac Amyloidosis. Progress and Hope.

Cardiac amyloidosis is an infiltrative disorder caused by extracellular protein deposition. Transthyretin is a proamyloidotic protein that produces one of the most frequent forms of cardiac amyloidosis, either through mutations or a wild-type form (previously known as senile amyloidosis). Until very recently, diagnosis of transthyretin amyloidosis (ATTR) was very uncommon and histological confirmation was mandatory, making diagnosis of ATTR a real challenge in daily clinical practice. Moreover, the specific therapeutic options to alter the clinical course of the disease were very limited. However, advances in cardiac imaging and diagnostic strategies have improved recognition of ATTR. In addition, several compounds able to modify the natural history of the disease are in the final phases of research, with promising results. Given that effective therapies are on the horizon, cardiologists should be well-versed in this disease and be familiar with its diagnosis and treatment. This review describes the broad clinical spectrum of ATTR in detail, as well as recent advances in the diagnosis and treatment of this condition.