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Background/Objectives: The literature reports high complication rates in patients with chronic thromboembolic pulmonary hypertension (CTEPH) who undergo balloon pulmonary angioplasty (BPA), especially in patients with poor pulmonary hemodynamics. Here, we describe the complications of BPA based on the new definitions. Methods: All patients with CTEPH who completed BPA treatment before 15 September 2023 were selected from the CTEPH database. Peri-procedural complications were collected and classified according to the 2023 consensus paper on BPA treatment. Complications were analyzed in subgroups of patients with pulmonary vascular resistance (PVR), ≤ or >6.6 WU, and mean pulmonary artery pressure (mPAP), ≤ or >45 mmHg, at first BPA. Results: In this analysis, 87 patients (63% women; mean age 61.1 ± 14.0 years; 62% on dual PH targeted medical therapy) underwent 426 (mean 4.9 ± 1.6 per patient) BPAs. Only non-severe complications occurred in 14% of BPA treatments and in 47% of the patients; 31% patients had a thoracic complication. The thoracic complications were mild (71%) or moderate (29%). Patients with a PVR > 6.6 WU (n = 8) underwent more BPA treatments (6.6 ± 1.5 versus 4.6 ± 1.5, p = 0.002), had more complications (88% versus 41% of patients, p = 0.020), and had more thoracic complications (17% vs. 7% of BPAs, p = 0.013) than patients with PVR ≤ 6.6 WU. Patients with mPAP > 45 mmHg (n = 13) also had more BPA treatments (6.5 ± 1.7 versus 4.6 ± 1.4, p < 0.001), more complications (77% versus 44% of patients, p = 0.027) and more thoracic complications (14% versus 8% of BPAs, p = 0.039) than patients with mPAP ≤ 45 mmHg. Conclusions: Complications occurred in 14% of BPAs and were mostly mild. Patients with severe pulmonary hemodynamics suffered more (thoracic) complications.
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AIMS: Heart failure (HF), a global pandemic affecting millions of individuals, calls for adequate predictive guidance for improved therapy. Congestion, a key factor in HF-related hospitalizations, further underscores the need for timely interventions. Proactive monitoring of intracardiac pressures, guided by pulmonary artery (PA) pressure, offers opportunities for efficient early-stage intervention, since haemodynamic congestion precedes clinical symptoms. METHODS: The BioMEMS study, a substudy of the MONITOR-HF trial, proposes a multifaceted approach integrating blood biobank data with traditional and novel HF parameters. Two additional blood samples from 340 active participants in the MONITOR-HF trial were collected at baseline, 3-, 6-, and 12-month visits and stored for the BioMEMS biobank. The main aims are to identify the relationship between temporal biomarker patterns and PA pressures derived from the CardioMEMS-HF system, and to identify the biomarker profile(s) associated with the risk of HF events and cardiovascular death. CONCLUSION: Since the prognostic value of single baseline measurements of biomarkers like N-terminal pro-B-type natriuretic peptide is limited, with the BioMEMS study we advocate a dynamic, serial approach to better capture HF progression. We will substantiate this by relating repeated biomarker measurements to PA pressures. This design rationale presents a comprehensive review on cardiac biomarkers in HF, and aims to contribute valuable insights into personalized HF therapy and patient risk assessment, advancing our ability to address the evolving nature of HF effectively.
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Biomarcadores , Insuficiencia Cardíaca , Arteria Pulmonar , Humanos , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/sangre , Biomarcadores/sangre , Pronóstico , Arteria Pulmonar/fisiopatología , Femenino , Masculino , Péptido Natriurético Encefálico/sangre , Fragmentos de Péptidos/sangre , Anciano , Presión Esfenoidal Pulmonar/fisiología , Enfermedad Crónica , Persona de Mediana EdadRESUMEN
BACKGROUND AND AIMS: In patients with chronic heart failure (HF), the MONITOR-HF trial demonstrated the efficacy of pulmonary artery (PA)-guided HF therapy over standard of care in improving quality of life and reducing HF hospitalizations and mean PA pressure. This study aimed to evaluate the consistency of these benefits in relation to clinically relevant subgroups. METHODS: The effect of PA-guided HF therapy was evaluated in the MONITOR-HF trial among predefined subgroups based on age, sex, atrial fibrillation, diabetes mellitus, left ventricular ejection fraction, HF aetiology, cardiac resynchronization therapy, and implantable cardioverter defibrillator. Outcome measures were based upon significance in the main trial and included quality of life-, clinical-, and PA pressure endpoints, and were assessed for each subgroup. Differential effects in relation to the subgroups were assessed with interaction terms. Both unadjusted and multiple testing adjusted interaction terms were presented. RESULTS: The effects of PA monitoring on quality of life, clinical events, and PA pressure were consistent in the predefined subgroups, without any clinically relevant heterogeneity within or across all endpoint categories (all adjusted interaction P-values were non-significant). In the unadjusted analysis of the primary endpoint quality-of-life change, weak trends towards a less pronounced effect in older patients (Pinteraction = .03; adjusted Pinteraction = .33) and diabetics (Pinteraction = .01; adjusted Pinteraction = .06) were observed. However, these interaction effects did not persist after adjusting for multiple testing. CONCLUSIONS: This subgroup analysis confirmed the consistent benefits of PA-guided HF therapy observed in the MONITOR-HF trial across clinically relevant subgroups, highlighting its efficacy in improving quality of life, clinical, and PA pressure endpoints in chronic HF patients.
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Insuficiencia Cardíaca , Arteria Pulmonar , Calidad de Vida , Humanos , Insuficiencia Cardíaca/terapia , Insuficiencia Cardíaca/fisiopatología , Femenino , Masculino , Anciano , Persona de Mediana Edad , Arteria Pulmonar/fisiopatología , Enfermedad Crónica , Volumen Sistólico/fisiología , Terapia de Resincronización Cardíaca/métodos , Desfibriladores ImplantablesRESUMEN
AIMS: Despite clear guideline recommendations for initiating four drug classes in all patients with heart failure (HF) with reduced ejection fraction (HFrEF) and the availability of rapid titration schemes, information on real-world implementation lags behind. Closely following the 2021 ESC HF guidelines and 2023 focused update, the TITRATE-HF study started to prospectively investigate the use, sequencing, and titration of guideline-directed medical therapy (GDMT) in HF patients, including the identification of implementation barriers. METHODS AND RESULTS: TITRATE-HF is an ongoing long-term HF registry conducted in the Netherlands. Overall, 4288 patients from 48 hospitals were included. Among these patients, 1732 presented with de novo, 2240 with chronic, and 316 with worsening HF. The median age was 71 years (interquartile range [IQR] 63-78), 29% were female, and median ejection fraction was 35% (IQR 25-40). In total, 44% of chronic and worsening HFrEF patients were prescribed quadruple therapy. However, only 1% of HFrEF patients achieved target dose for all drug classes. In addition, quadruple therapy was more often prescribed to patients treated in a dedicated HF outpatient clinic as compared to a general cardiology outpatient clinic. In each GDMT drug class, 19% to 36% of non-use in HFrEF patients was related to side-effects, intolerances, or contraindications. In the de novo HF cohort, 49% of patients already used one or more GDMT drug classes for other indications than HF. CONCLUSION: This first analysis of the TITRATE-HF study reports relatively high use of GDMT in a contemporary HF cohort, while still showing room for improvement regarding quadruple therapy. Importantly, the use and dose of GDMT were suboptimal, with the reasons often remaining unclear. This underscores the urgency for further optimization of GDMT and implementation strategies within HF management.
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Progresión de la Enfermedad , Insuficiencia Cardíaca , Sistema de Registros , Volumen Sistólico , Humanos , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/fisiopatología , Femenino , Masculino , Anciano , Volumen Sistólico/fisiología , Persona de Mediana Edad , Países Bajos , Guías de Práctica Clínica como Asunto , Estudios Prospectivos , Enfermedad Crónica , Antagonistas Adrenérgicos beta/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Fármacos Cardiovasculares/uso terapéutico , Quimioterapia CombinadaRESUMEN
Objectives: Acute type A aortic dissection (ATAAD) is a life-threatening cardiovascular emergency, of which the long-term impact on health-related quality of life (HRQoL) and male-female-specific insights remain inadequately clarified. Methods: Consecutive adult ATAAD patients who underwent surgery were retrospectively included between 2007 and 2017 in four referral centers in the Netherlands, and baseline data were collected. The 36-Item Short-Form (SF-36) Health Survey was sent to all survivors between 2019 and 2021 and compared to validated SF-36 scores of the Dutch general population stratified by age group and sex. Results: In total, 324/555 surviving patients returned the SF-36 questionnaire (response rate 58%), of which 40.0% were female; the median follow-up was 6.5 years (range: 1.7-13.9, IQR: 4.0-9.4) after surgery for ATAAD. In comparison to the general population, ATAAD patients scored significantly lower on 6/8 SF-36 subdomains and higher on bodily pain. Differences in HRQoL domains compared to the sex-matched data were largely comparable between sexes, apart from bodily pain. In the age-matched subgroups impaired HRQoL was most pronounced in younger patients aged 41-60 (5/8 impaired domains). Female ATAAD patients scored significantly worse on 5/8 SF-36 subdomains and the physical component summary (PCS) scores than male patients. Age at ATAAD, female sex, hypertension, COPD, and prior thoracic aortic aneurysm were associated with worse PCS scores. Conclusions: Long-term HRQoL was impaired in both male and female ATAAD patients when compared to the general population. Further studies on the nature of this impairment and on interventions to improve HRQoL after ATAAD are clearly warranted, with special attention to females and younger patients.
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BACKGROUND: Acute type B aortic dissection is a cardiovascular emergency with considerable mortality and morbidity risk. Male-female differences have been observed in cardiovascular disease; however, literature on type B aortic dissection is scarce. METHODS AND RESULTS: A retrospective cohort study was conducted including all consecutive patients with acute type B aortic dissection between 2007 and 2017 in 4 tertiary hospitals using patient files and questionnaires for late morbidity. In total, 384 patients were included with a follow-up of 6.1 (range, 0.02-14.8) years, of which 41% (n=156) were female. Women presented at an older age than men (67 [interquartile range (IQR), 57-73] versus 62 [IQR, 52-71]; P=0.015). Prior abdominal aortic aneurysm (6% versus 15%; P=0.009), distally extending dissections (71 versus 85%; P=0.001), and clinical malperfusion (18% versus 32%; P=0.002) were less frequently observed in women. Absolute maximal descending aortic diameters were smaller in women (36 [IQR: 33-40] mm versus 39 [IQR, 36-43] mm; P<0.001), while indexed for body surface area diameters were larger in women (20 [IQR, 18-23] mm/m2 versus 19 [IQR, 17-21] mm/m2). No male-female differences were found in treatment choice; however, indications for invasive treatment were different (P<0.001). Early mortality rate was 9.6% in women and 11.8% in men (P=0.60). The 5-year survival was 83% (95% CI, 77-89) for women and 84% (95% CI, 79-89) for men (P=0.90). No male-female differences were observed in late (re)interventions. CONCLUSIONS: No male-female differences were found in management, early or late death, and morbidity in patients presenting with acute type B aortic dissection, despite distinct clinical profiles at presentation. More details on the impact of age and type of intervention are warranted in future studies.
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Aneurisma de la Aorta Torácica , Disección Aórtica , Implantación de Prótesis Vascular , Procedimientos Endovasculares , Humanos , Masculino , Femenino , Aneurisma de la Aorta Torácica/cirugía , Estudios Retrospectivos , Resultado del Tratamiento , Disección Aórtica/epidemiología , Enfermedad Aguda , Factores de RiesgoRESUMEN
The current treatment algorithm for chronic thromboembolic pulmonary hypertension (CTEPH) as depicted in the 2022 European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines on the diagnosis and treatment of pulmonary hypertension (PH) includes a multimodal approach of combinations of pulmonary endarterectomy (PEA), balloon pulmonary angioplasty (BPA) and medical therapies to target major vessel pulmonary vascular lesions, and microvasculopathy. Today, BPA of >1700 patients has been reported in the literature from centers in Asia, the US, and also Europe; many more patients have been treated outside literature reports. As BPA becomes part of routine care of patients with CTEPH, benchmarks for safe and effective care delivery become increasingly important. In light of this development, the ESC Working Group on Pulmonary Circulation and Right Ventricular Function has decided to publish a document that helps standardize BPA to meet the need of uniformity in patient selection, procedural planning, technical approach, materials and devices, treatment goals, complications including their management, and patient follow-up, thus complementing the guidelines. Delphi methodology was utilized for statements that were not evidence based. First, an anatomical nomenclature and a description of vascular lesions are provided. Second, treatment goals and definitions of complete BPA are outlined. Third, definitions of complications are presented which may be the basis for a standardized reporting in studies involving BPA. The document is intended to serve as a companion to the official ESC/ERS guidelines.
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Angioplastia de Balón , Cardiología , Hipertensión Pulmonar , Embolia Pulmonar , Humanos , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/terapia , Hipertensión Pulmonar/diagnóstico , Embolia Pulmonar/complicaciones , Embolia Pulmonar/terapia , Embolia Pulmonar/diagnóstico , Circulación Pulmonar , Función Ventricular Derecha , Angioplastia de Balón/métodos , Arteria Pulmonar/cirugía , Enfermedad CrónicaRESUMEN
PURPOSE OF REVIEW: In recent years new recommendations have been published about organ assessment in the diagnosis of sarcoidosis. RECENT FINDINGS: Screening for pulmonary, cardiac, ocular, neurologic and renal involvement and hypercalcemia is recommended in the work-up for sarcoidosis, additionally, screening for hypercalciuria at the time of the diagnosis might be beneficial. SUMMARY: One of the goals in the work-up of sarcoidosis is to assess the extent and severity of organ involvement. Timely and accurate assessment leads to determination of treatment indication. Screening for pulmonary involvement should include pulmonary imaging and pulmonary function tests. Screening for cardiac involvement should include a clear history including palpitations and collapse and a baseline electrocardiogram or 24-h Holter monitoring. At diagnosis, ophthalmological assessment is recommended. Furthermore, serum calcium level and serum creatinine level should be obtained. Although routine 24-h urinary calcium excretion is not included in the guidelines, performing this test routinely can be considered. On indication, neurologic, rheumatologic or dermatologic assessment can be performed.
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Calcio , Sarcoidosis , Humanos , Sarcoidosis/diagnóstico , Pruebas de Función Respiratoria , PulmónRESUMEN
Importance: It is suggested that patients with Cutibacterium acnes endocarditis often present without fever or abnormal inflammatory markers. However, no study has yet confirmed this statement. Objective: To assess the clinical characteristics and outcomes of patients with C acnes endocarditis. Design, Setting, and Participants: A case series of 105 patients presenting to 7 hospitals in the Netherlands and France (4 university hospitals and 3 teaching hospitals) with definite endocarditis according to the modified Duke criteria between January 1, 2010, and December 31, 2020, was performed. Clinical characteristics and outcomes were retrieved from medical records. Cases were identified by blood or valve and prosthesis cultures positive for C acnes, retrieved from the medical microbiology databases. Infected pacemaker or internal cardioverter defibrillator lead cases were excluded. Statistical analysis was performed in November 2022. Main Outcomes and Measures: Main outcomes included symptoms at presentation, presence of prosthetic valve endocarditis, laboratory test results at presentation, time to positive results of blood cultures, 30-day and 1-year mortality rates, type of treatment (conservative or surgical), and endocarditis relapse rates. Results: A total of 105 patients (mean [SD] age, 61.1 [13.9] years; 96 men [91.4%]; 93 patients [88.6%] with prosthetic valve endocarditis) were identified and included. Seventy patients (66.7%) did not experience fever prior to hospital admission, nor was it present at hospitalization. The median C-reactive protein level was 3.6 mg/dL (IQR, 1.2-7.5 mg/dL), and the median leukocyte count was 10.0 × 103/µL (IQR, 8.2-12.2 × 103/µL). The median time to positive blood culture results was 7 days (IQR, 6-9 days). Surgery or reoperation was indicated for 88 patients and performed for 80 patients. Not performing the indicated surgical procedure was associated with high mortality rates. Seventeen patients were treated conservatively, in accordance with the European Society of Cardiology guideline; these patients showed relatively high rates of endocarditis recurrence (5 of 17 [29.4%]). Conclusions and Relevance: This case series suggests that C acnes endocarditis was seen predominantly among male patients with prosthetic heart valves. Diagnosing C acnes endocarditis is difficult due to its atypical presentation, with frequent absence of fever and inflammatory markers. The prolonged time to positivity of blood culture results further delays the diagnostic process. Not performing a surgical procedure when indicated seems to be associated with higher mortality rates. For prosthetic valve endocarditis with small vegetations, there should be a low threshold for surgery because this group seems prone to endocarditis recurrence.
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Enfermedades Transmisibles , Endocarditis Bacteriana , Endocarditis , Prótesis Valvulares Cardíacas , Humanos , Masculino , Persona de Mediana Edad , Endocarditis Bacteriana/diagnóstico , Endocarditis Bacteriana/epidemiología , Endocarditis Bacteriana/terapia , Prótesis Valvulares Cardíacas/efectos adversos , Endocarditis/complicaciones , ElectrocardiografíaRESUMEN
Voltage imaging using genetically encoded voltage indicators (GEVIs) has taken the field of neuroscience by storm in the past decade. Its ability to create subcellular and network level readouts of electrical dynamics depends critically on the kinetics of the response to voltage of the indicator used. Engineered microbial rhodopsins form a GEVI subclass known for their high voltage sensitivity and fast response kinetics. Here we review the essential aspects of microbial rhodopsin photocycles that are critical to understanding the mechanisms of voltage sensitivity in these proteins and link them to insights from efforts to create faster, brighter and more sensitive microbial rhodopsin-based GEVIs.
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OBJECTIVE: Acute type B aortic dissection (ATBD) is a rare yet serious cardiovascular event that potentially has an impact on health related quality of life (HRQoL). However, long term follow up data on this topic are scarce. This study aimed to review the long term HRQoL among patients treated for ATBD. METHODS: In this multicentre, cross sectional survey study, consecutive treated patients with ATBD between 2007 and 2017 in four referral centres in the Netherlands were retrospectively included and baseline data were collected. Between 2019 and 2021 the 36 Item Short Form Survey (SF-36) was sent to all surviving patients (n = 263) and was compared with validated SF-36 scores in the Dutch general population stratified by age and sex. RESULTS: In total, 144 of 263 surviving patients completed the SF-36 (response rate 55%). Median (IQR) age was 68 (61, 76) years at completion of the questionnaire, and 40% (n = 58) were female. Initial treatment was medical in 55% (n = 79), endovascular in 41% (n = 59), and surgical in 4% (n = 6) of ATBD patients. Median follow up time was 6.1 (range 1.7-13.9; IQR 4.0, 9.0) years. Compared with the general population, patients scored significantly worse on six of eight SF-36 subdomains, particularly physical domains. Apart from bodily pain, there were no substantial differences in HRQoL between male and female ATBD patients. Compared with sex matched normative data, females scored significantly worse on five of eight subdomains, whereas males scored significantly lower on six subdomains. Younger patients aged 41-60 years seemed more severely impaired in HRQoL compared with the age matched general population. Treatment strategy did not influence HRQoL outcomes. Follow up time was associated with better Physical and Mental Component Summary scores. CONCLUSION: Long term HRQoL was impaired in ATBD patients compared with the Dutch general population, especially regarding physical status. This warrants more attention for HRQoL during clinical follow up. Rehabilitation programmes including exercise and physical support might improve HRQoL and increase patients' health understanding.
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Disección Aórtica , Calidad de Vida , Humanos , Masculino , Femenino , Estudios Transversales , Estudios Retrospectivos , Encuestas y Cuestionarios , Disección Aórtica/cirugíaRESUMEN
BACKGROUND: Sexual health related quality of life (SHRQoL) is an important pillar of health related quality of life (HRQoL). The aim of this study was to investigate sexual functioning in men and women with pulmonary hypertension (PH). METHODS AND RESULTS: In this cross-sectional study, a total of 78 patients were included, 49 were diagnosed with pulmonary arterial hypertension and 29 with chronic thromboembolic pulmonary hypertension (median age 53 [IQR: 46-67 years], 66.7% female). All patients completed SHRQoL questionnaires; for women: ASEX, FSFI, and FSDS and for men: ASEX and IIEF. A PH-specific SHRQoL questionnaire was created based on 4 semi-structured interviews to investigate PH-specific barriers in sexuality. More than half of the patients experienced symptoms during sexual activity, mainly dyspnea (52.6%) and palpitations (32.1%). Sexual dysfunction was present, according to the FSFI-questionnaire, in 63.0% of women. All of the men experienced at least mild dysfunction in one of the domains of the IIEF and erectile dysfunction was present in 48.0%. Sexual dysfunction occurred more often in both men and women with PH than in the general population. PAH-specific medication was not associated with sexual dysfunction, nor was subcutaneous or intravenous pump therapy (OR 1.14, 95%-CI: 0.75-1.73). Diuretics were associated with sexual dysfunction in women (OR 4.01, 95%-CI: 1.04-15.41). Of all patients committed in a relationship, 69.0% would like to discuss sexuality with their healthcare provider. CONCLUSION: This study showed a high prevalence of sexual dysfunction in men and women with PH. It is important for healthcare providers to discuss sexuality with patients.
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Disfunción Eréctil , Hipertensión Pulmonar , Disfunciones Sexuales Fisiológicas , Masculino , Humanos , Femenino , Persona de Mediana Edad , Calidad de Vida , Hipertensión Pulmonar/diagnóstico , Hipertensión Pulmonar/epidemiología , Estudios Transversales , Disfunción Eréctil/tratamiento farmacológico , Disfunción Eréctil/epidemiología , Disfunciones Sexuales Fisiológicas/epidemiología , Disfunciones Sexuales Fisiológicas/etiología , Encuestas y Cuestionarios , Conducta SexualRESUMEN
BACKGROUND: Side effects limit the long-term use of glucocorticoids in cardiac sarcoidosis (CS), and methotrexate has gained attention as steroid sparing agent although the supporting evidence is poor. This study compared prednisone monotherapy, methotrexate monotherapy or a combination of both, in the reduction of myocardial Fluorine-18 fluorodeoxyglucose (FDG) uptake and clinical stabilization of CS patients. METHODS AND RESULTS: In this retrospective cohort study, 61 newly diagnosed and treatment naïve CS patients commenced treatment with prednisone (N = 21), methotrexate (N = 30) or prednisone and methotrexate (N = 10) between January 2010 and December 2017. Primary outcome was metabolic response on FDG PET/CT and secondary outcomes were treatment patterns, major adverse cardiovascular events, left ventricular ejection fraction, biomarkers and side effects. At a median treatment duration of 6.2 [5.7-7.2] months, 71.4% of patients were FDG PET/CT responders, and the overall myocardial maximum standardized uptake value decreased from 6.9 [5.0-10.1] to 3.4 [2.1-4.7] (P < 0.001), with no significant differences between treatment groups. During 24 months of follow-up, 7 patients (33.3%; prednisone), 6 patients (20.0%; methotrexate) and 1 patient (10.0%; combination group) experienced at least one major adverse cardiovascular event (P = 0.292). Left ventricular ejection fraction was preserved in all treatment groups. CONCLUSIONS: Significant suppression of cardiac FDG uptake occurred in CS patients after 6 months of prednisone, methotrexate or combination therapy. There were no significant differences in clinical outcomes during follow-up. These results warrant further investigation of methotrexate treatment in CS patients.
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Cardiomiopatías , Miocarditis , Sarcoidosis , Humanos , Prednisona/uso terapéutico , Fluorodesoxiglucosa F18/uso terapéutico , Metotrexato/uso terapéutico , Tomografía Computarizada por Tomografía de Emisión de Positrones , Estudios Retrospectivos , Volumen Sistólico , Cardiomiopatías/diagnóstico por imagen , Cardiomiopatías/tratamiento farmacológico , Cardiomiopatías/complicaciones , Radiofármacos/uso terapéutico , Función Ventricular Izquierda , Sarcoidosis/diagnóstico por imagen , Sarcoidosis/tratamiento farmacológico , Sarcoidosis/complicaciones , Tomografía de Emisión de Positrones/métodos , Miocarditis/complicacionesRESUMEN
BACKGROUND: Clinical factors are used to estimate late complication risk in adults after atrial switch operation (AtrSO) for transposition of the great arteries (TGA), but heterogeneity in clinical course remains. We studied whether common genetic variants are associated with outcome and add value to a clinical risk score in TGA-AtrSO patients. METHODS AND RESULTS: This multicenter study followed 133 TGA-AtrSO patients (aged 28 [IQR 24-35] years) for 13 (IQR 9-16) years and examined the association of genome-wide single-nucleotide polymorphisms (SNPs) with a composite endpoint of symptomatic ventricular arrhythmia, heart failure hospitalization, ventricular assist device implantation, heart transplantation, or mortality. Thirty-two patients (24%) reached the endpoint. The genome-wide association study yielded one genome-wide significant (p < 1 × 10-8) locus and 18 suggestive loci (p < 1 × 10-5). A genetic risk score constructed on the basis of independent SNPs with p < 1 × 10-5 was associated with outcome after correction for the clinical risk score (HR = 1.26/point increase [95%CI 1.17-1.35]). Risk stratification improved with a combined risk score (clinical score + genetic score) compared to the clinical score alone (p = 2 × 10-16, C-statistic 0.95 vs 0.85). In 51 patients with a clinical intermediate (5-20%) 5-year risk of events, the combined score reclassified 32 patients to low (<5%) and 5 to high (>20%) risk. Stratified by the combined score, observed 5-year event-free survival was 100%, 79% and 31% for low, intermediate, and high-risk patients, respectively. CONCLUSIONS: Common genetic variants may explain some variation in the clinical course in TGA-AtrSO and improve risk stratification over clinical factors alone, especially in patients at intermediate clinical risk. These findings support the hypothesis that including genetic variants in risk assessment may be beneficial.
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Operación de Switch Arterial , Transposición de los Grandes Vasos , Adulto , Humanos , Operación de Switch Arterial/efectos adversos , Transposición de los Grandes Vasos/genética , Transposición de los Grandes Vasos/cirugía , Transposición de los Grandes Vasos/complicaciones , Estudio de Asociación del Genoma Completo , Estudios de Seguimiento , Arterias , Medición de Riesgo , Progresión de la Enfermedad , Estudios RetrospectivosRESUMEN
BACKGROUND: Pulmonary hypertension (PH) is a severe complication of sarcoidosis in a minority of patients. Several genetic defects are known to cause hereditary or sporadic PH, but whether variants in PH-associated genes are also involved in sarcoidosis-associated PH (SAPH) is unknown. METHODS: 40 patients with SAPH were individually matched to 40 sarcoidosis patients without PH (SA). Whole exome sequencing was performed to identify rare genetic variants in a diagnostic PH gene panel of 13 genes. Additionally, an exploratory analysis was performed to search for other genes of interest. From 572 genes biologically involved in PH pathways, genes were selected in which at least 15% of the SAPH patients and no more than 5% of patients without PH carried a rare variant. RESULTS: In the diagnostic PH gene panel, 20 different rare variants, of which 18 cause an amino-acid substitution, were detected in 23 patients: 14 SAPH patients carried a variant, as compared to 5 SA patients without PH (p = 0.018). Most variants were of yet unknown significance. The exploratory approach yielded five genes of interest. First, the NOTCH3 gene that was previously linked to PH, and furthermore PDE6B, GUCY2F, COL5A1, and MMP21. CONCLUSIONS: The increased frequency of variants in PH genes in SAPH suggests a mechanism whereby the presence of such a genetic variant in a patient may increase risk for the development of PH in the context of pulmonary sarcoidosis. Replication and studies into the functionality of the variants are required for further understanding the pathogenesis of SAPH.
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The prognosis of pulmonary arterial hypertension (PAH) remains dismal. Over the years, multiple therapeutic advances have been introduced. This study evaluates the evolution of PAH survival over the past 15 years. We included 293 consecutive adult patients diagnosed with PAH between 2005 and 2019 (median age: 61.8 years, 70.3% female). Patients were divided into three cohorts based on the time of diagnosis: 2005-2009, 2010-2014, and 2015-2019 (2005-2009: n = 56; 2010-2014: n = 111; 2015-2019: n = 126). Transplant-free survival was measured from the date of right heart catheterization until patients reached the composite endpoint of lung transplant or death. Multivariable cox-pulmonary hypertension regression was used to study the effect of the time of diagnosis. The final cox model was fitted in both younger and older patients to evaluate the difference between these groups. During a median follow-up time of 4.1 (interquartile range: 2.2-7.3) years, 9 patients underwent lung transplantation and 151 patients died. The median overall transplant-free survival was 6.2 (5.5-8.0) years. Patients older than 56 years at baseline who were diagnosed in 2005-2009 showed better survival compared to patients diagnosed in 2010-2014 and 2015-2019 with an adjusted hazard ratio of, respectively, 2.12 (1.11-4.03) and 2.83 (1.41-5.69). Patients younger than 56 years showed neither an improved nor deteriorated survival over time. In conclusion, survival in patients with PAH did not improve over time, despite more available therapeutic options. This might be partly due to the changed demographic characteristics of the PAH patients and a still important diagnostic delay.
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Haploinsufficiency for Endoglin (ENG) and activin A receptor type II-like I (ACVRL1/ALK1) lead to the formation of weak and abnormal vessels in hereditary hemorrhagic telangiectasia (HHT). These cause epistaxis (nosebleeds) and/or gastrointestinal blood loss. In vitro in cultured endothelial cells, tacrolimus has been shown to increase ENG and ALK1 expression. It is, therefore, a potential treatment option. We report here a proof-of-concept study in patients with HHT and severe epistaxis and/or gastrointestinal bleeding who were treated daily with orally-administered tacrolimus for twenty weeks. Twenty-five patients with HHT (11 females (44%)) and median age of 59 years were enrolled. Five patients (20%) stopped the trial prematurely-four due to (serious) adverse events ((S)AE). Twenty patients were included in further analyses. Hemoglobin levels increased during tacrolimus treatment from 6.1 (IQR 5.2-6.9) mmol/L at baseline (9.8 g/dL) to 6.7 (6.5-7.1) mmol/L (10.8 g/dL), p = 0.003. The number of blood transfusions over the twenty weeks decreased from a mean of 5.0 (±9.2) to 1.9 (±3.5), p = 0.04. In 64% of the patients, at least one AE occurred. Oral tacrolimus, thus, significantly increased hemoglobin levels and decreased blood transfusion needs, epistaxis and/or gastrointestinal bleeding in patients with HHT. However, side-effects were common. Further investigation of the potential therapeutic benefit is justified by the outcome of the study.
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Hereditary haemorrhagic telangiectasia (HHT) is a rare vascular multisystemic disease that leads to epistaxis, anaemia due to blood loss, and arteriovenous malformations (AVMs) in organs such as the lungs, liver and brain. HHT prevalence is estimated at 1/6000, i.e. around 85,000 European citizens, and is served by the European Reference Network for Rare Multisystemic Vascular Diseases (VASCERN). HHT treatments depend on clinical manifestations, and span multiple different medical, surgical and interventional disciplines. Separate to local treatments in the nose, in severe settings, intravenous bevacizumab has been proposed as treatment option, and the purpose of the current article is to assess the use of intravenous bevacizumab in patients with HHT in 2022 according to available data.
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Malformaciones Arteriovenosas , Telangiectasia Hemorrágica Hereditaria , Bevacizumab/uso terapéutico , Epistaxis/tratamiento farmacológico , Humanos , Enfermedades Raras , Telangiectasia Hemorrágica Hereditaria/tratamiento farmacológicoRESUMEN
BACKGROUND: Multiple biomarkers have been investigated in the risk stratification of patients with pulmonary arterial hypertension (PAH). This systematic review and meta-analysis is the first to investigate the prognostic value of (NT-pro)BNP in patients with PAH. METHODS: A systematic literature search was performed using MEDLINE, Embase, Web of Science, the Cochrane Library and Google scholar to identify studies on the prognostic value of baseline (NT-pro)BNP levels in PAH. Studies reporting hazard ratios (HR) for the endpoints mortality or lung transplant were included. A random effects meta-analysis was performed to calculate the pooled HR of (NT-pro)BNP levels at the time of diagnosis. To account for different transformations applied to (NT-pro)BNP, the HR was calculated for a 2-fold difference of the weighted mean (NT-pro)BNP level of 247 pmol/L, for studies reporting a HR based on a continuous (NT-pro)BNP measurement. RESULTS: Sixteen studies were included, representing 6999 patients (mean age 45.2-65.0 years, 97.3% PAH). Overall, 1460 patients reached the endpoint during a mean follow-up period between 1 and 10 years. Nine studies reported HRs based on cut-off values. The risk of mortality or lung transplant was increased for both elevated NT-proBNP and BNP with a pooled HR based on unadjusted HRs of 2.75 (95%-CI: 1.86-4.07) and 3.87 (95% CI 2.69-5.57) respectively. Six studies reported HRs for (NT-pro)BNP on a continues scale. A 2-fold difference of the weighted mean NT-proBNP resulted in an increased risk of mortality or lung transplant with a pooled HR of 1.17 (95%-CI: 1.03-1.32). CONCLUSIONS: Increased levels of (NT-pro)BNP are associated with a significantly increased risk of mortality or lung transplant in PAH patients.