Danon disease presenting with early onset of hypertrophic cardiomyopathy and peripheral pigmentary retinal dystrophy in a female with a de novo novel mosaic mutation in the LAMP2 gene.

Purpose: To describe the phenotype and genotype in a young woman with Danon disease. Methods: The patient underwent an ophthalmic examination including best corrected visual acuity (BCVA), fundus photography and fundus autofluorescence (FAF), full-field electroretinography (full-field ERG), multifocal ERG, optical coherence tomography (OCT) and SAP-Humphrey 30-2 at the ages of 20 and 25. Electrooculography, fluorescein angiography (FA), indocyanine angiography and OCT angiography were performed only once. Genetic testing using a Next-Generation Sequencing panel and immunohistochemical analysis of LAMP2 protein expression were performed in the patient's explanted heart, and the patient's cardiologic and ophthalmologic records were retrospectively reviewed. Results: A de novo, novel, mosaic mutation, c.135dupA; p.(Trp46Metfs*10) was identified in exon 2 of the LAMP2 gene. Immunohistochemical investigation of the myocardium in the explanted heart revealed pronounced deficiency of LAMP2 protein in cardiomyocytes. The color photographs, FAF images and FA revealed more extensive peripheral pigmentary retinal dystrophy (PPRD) at the 5-year follow-up examination. No changes were observed in BCVA, OCT, SAP-Humphrey 30-2 or multifocal ERG findings at follow-up. Full-field ERG showed an asymmetric interocular reduction in ERG response at follow-up: the b-wave amplitude of the rod response had decreased by 29% in the right eye, but by only 6 % in the left eye. The a-wave amplitude of single-flash response had decreased by 9 % in the left eye, while it had increased by 3% in the right eye. Conclusions: Although PPRD progressed slowly, it was an important clue in the diagnosis of the life-threatening condition of Danon disease.

Characteristics and survival of adult Swedish PAH and CTEPH patients 2000-2014.

OBJECTIVES: The Swedish Pulmonary Arterial Hypertension Register (SPAHR) is an open continuous register, including pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) patients from 2000 and onwards. We hereby launch the first data from SPAHR, defining baseline characteristics and survival of Swedish PAH and CTEPH patients. DESIGN: Incident PAH and CTEPH patients 2008-2014 from all seven Swedish PAH-centres were specifically reviewed. RESULTS: There were 457 PAH (median age: 67 years, 64% female) and 183 CTEPH (median age: 70 years, 50% female) patients, whereof 77 and 81%, respectively, were in functional class III-IV at diagnosis. Systemic hypertension, diabetes, ischaemic heart disease and atrial fibrillation were common comorbidities, particularly in those >65 years. One-, 3- and 5-year survival was 85%, 71% and 59% for PAH patients. Corresponding numbers for CTEPH patients with versus without pulmonary endarterectomy were 96%, 89% and 86% versus 91%, 75% and 69%, respectively. In 2014, the incidence of IPAH/HPAH, associated PAH and CTEPH was 5, 3 and 2 per million inhabitants and year, and the prevalence was 25, 24 and 19 per million inhabitants. CONCLUSION: The majority of the PAH and CTEPH patients were diagnosed at age >65 years, in functional class III-IV, and exhibiting several comorbidities. PAH survival in SPAHR was similar to other registers.

Acute cellular rejection the first year after heart transplantation and its impact on survival: a single-centre retrospective study at Skåne University Hospital in Lund 1988-2010.

Acute cellular rejection (ACR) the first year after heart transplantation (HT) and its impact on survival was investigated. All 215 HT patients at our centre 1988-2010, including 219 HTs and 2990 first-year endomyocardial biopsies (EMBs), were studied. 'Routine' EMBs obtained 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 32, 40 and 52 weeks after HT, and 'additional clinically indicated' (ACI) EMBs, were graded according to the 1990-ISHLT-WF. The frequency and severity of first-year ACRs was low, with 6.5% of routine EMBs and 14.1% of ACI EMBs showing ACR ≥ grade 2. Proportionally more (P < 0.05) first-year ACRs ≥ grade 2 were found among EMBs in HTs performed during 1988-1999 (9.6%) than 2000-2010 (5.5%), EMBs performed during 16-52 weeks (8.8%) than 1-12 weeks (6.3%) after HT, EMBs in HTs with paediatric (11.3%) than adult (7.1%) donors, and EMBs in sex-mismatched (10.4%) than sex-matched (6.3%) HTs. Five- and ten-year survival was furthermore lower (P < 0.05) among HTs with ≥ 1 compared with 0 first-year ACRs ≥ grade 3A/3B (82% vs. 92% and 69% vs. 82%, respectively). Ten-year survival was 74% compared with 53% in the ISHLT registry. In conclusion, our results indicate that first-year ACRs ≥ grade 3A/3B affect long-term survival. We believe frequent first-year EMBs may allow early ACR detection and continuous immunosuppressive adjustments, preventing low-grade ACRs from progressing to ACRs ≥ grade 3A/3B, thereby improving survival.

Preoperative pulmonary hypertension and its impact on survival after heart transplantation.

OBJECTIVES: Pulmonary hypertension (PH) due to left heart disease may impair outcome after heart transplantation (HT). To evaluate to what extent previous, and present, haemodynamic criteria discriminate the impact of pre-operative-PH on survival, we characterized the PH in our HT-patients according to ESC's guidelines, ISHLT's summary statement and ISHLT's relative contraindications and criteria for early risk of death after HT. DESIGN: Records from the 215 HT-patients in Lund during 1988-2010 were reviewed. Subsequent analysis included adults (n = 94) evaluated with right-heart-catheterization at our lab, at rest before HT. End of follow-up was 30th of June 2012. RESULTS: Survival (mean, n) did not differ (p = ns) for the 94 HT-patients; without (13.0 years, n = 28) or with (13.9 years, n = 66) PH, passive (13.8 years, n = 50) or reactive (12.2 years, n = 13) post-capillary-PH, "modified" passive (13.1 years, n = 40), mixed (16.6 years, n = 23), "modified" reactive (12.6 years, n = 7) or non-reactive (12.2 years, n = 8) post-capillary-PH; or for ISHLT's relative contraindications (12.0 years, n = 22) or increased risk of right-heart-failure and early death (16.5 years, n = 23) after HT. CONCLUSIONS: As previous and present haemodynamic criteria did not sufficiently discriminate the impact of pre-operative-PH for survival after HT at our centre, larger multi-centre studies are encouraged to redefine criteria that may influence outcome.

Desensitization and heart transplantation of a patient with high levels of donor-reactive anti-human leukocyte antigen antibodies.

BACKGROUND: To prepare a highly immunized recipient for heart transplantation, reduction of high levels of cytotoxic antibodies against human leukocyte antigen (HLA) was deemed essential to prevent antibody-mediated graft failure. METHODS: Antibodies were analyzed by lymphocytotoxic and solid-phase assays. The pretransplant desensitization treatment protocol included daily tacrolimus and mycophenolate mofetil, weekly protein-A immunoadsorption (IA), intravenous immunoglobulin, and daclizumab. Posttransplant treatment consisted of tacrolimus, mycophenolate mofetil, prednisolone, IA, and daclizumab. RESULTS: During pretransplant desensitization, each of the weekly immunoadsorption treatments reduced anti-HLA antibody levels by 50% to 70%, but they returned to the pretreatment level within 1 week as measured by flow cytometry. Cytotoxic antibodies remained reduced. After perioperative immunoadsorption, the donor-reactive antibodies (DRAs) were reduced to low levels. The patient underwent successful heart transplantation after 6 weeks on a waiting list. During the first week posttransplant, DRAs remained low. However, after the first week, anti-HLA DRAs reappeared and increased slightly over a 3-week period and then decreased slowly. Cytotoxic crossmatches were negative before and 3 week after transplantation. No clinical rejection was encountered. The patient was doing well 3 years after transplantation, and yearly clinical cardiac investigations were all normal. Three hyperimmunized patients have now undergone successful heart transplantation at our center using this desensitization protocol. CONCLUSIONS: IA in combination with pretransplant immunosuppressive drug treatment temporarily reduces antibody levels. The therapeutic levels of drug treatment at the time of transplantation may be of crucial importance. The treatment protocol resulted in freedom from rejection and other clinical adverse events.

Heart transplantation across the antibodies against HLA and ABO.

We have intentionally performed heart transplantation in a 5-year-old child, despite the most unfavourable risk factors for patient survival; the presence of high level of antibodies against donor's human leucocyte antigen (HLA) class I/II and blood group antigens. Pretransplant treatment by mycophenolate mofetil, prednisolone, tacrolimus, intravenous immunoglobulin, rituximab, protein-A immunoadsorption (IA) and plasma exchange reduced antibody titres against the donor's lymphocytes from 128 to 16 and against the donor's blood group antigen from 256 to 0. The patient was urgently transplanted with a heart from an ABO incompatible donor (A(1) to O). A standard triple-drug immunosuppressive protocol was used. No hyperacute rejection was seen. Antibodies against the donor's HLA antigens remained at a low level despite three acute rejections. Rising anti-A(1) blood group antibodies preceded the second rejection and were reduced by two blood group-specific IAs and remained at a low level. The patient is doing well despite the persistence of donor-reactive antibodies.

Is growth hormone deficiency contributing to heart failure in patients with beta-thalassemia major?

A 21-year-old woman with beta-thalassemia major (beta-TM) and GH deficiency developed end-stage heart failure, New York Heart Association (NYHA) functional class IV, within 3 months after withdrawal of recombinant human growth hormone (GH). A myocardial biopsy excluded myocarditis and showed moderate iron deposit in the heart. Before her admission, intensified treatments with digoxin, angiotensin-converting enzyme inhibitor, diuretics and extra chelation therapy (desferrioxamine (DFO)) had not improved her progressive heart failure. At admission, GH was reinstituted together with intensified treatment of cardiac drugs and low doses of DFO, and her heart failure reversed. Four months later, NYHA functional class II was reached and within 1 year her cardiac function was normalised. We suggest that GH deficiency due to iron-induced damage to the hypothalamic-pituitary axis can contribute to heart failure in adult patients with beta-TM.