Effectiveness of a cardiac rehabilitation program on biomechanical, imaging, and physiological biomarkers in elderly patients with heart failure with preserved ejection fraction (HFpEF): FUNNEL + study protocol.

BACKGROUND: Patients with heart failure with preserved ejection fraction (HFpEF) have a low functional status, which in turn is a risk factor for hospital admission and an important predictor of survival in HFpEF. HFpFE is a heterogeneous syndrome and recent studies have suggested an important role for careful, pathophysiological-based phenotyping to improve patient characterization. Cardiac rehabilitation has proven to be a useful tool in the framework of secondary prevention in patients with HFpEF. Facilitating decision-making and implementing cardiac rehabilitation programs is a challenge in public health systems for HFpEF management. The FUNNEL + study proposes to evaluate the efficacy of an exercise and education-based cardiac rehabilitation program on biomechanical, physiological, and imaging biomarkers in patients with HFpEF. METHODS: A randomised crossover clinical trial is presented among people older than 70 years with a diagnosis of HFpEF. The experimental group will receive a cardiac rehabilitation intervention for 12 weeks. Participants in the control group will receive one educational session per week for 12 weeks on HFpEF complications, functional decline, and healthy lifestyle habits. VO2peak is the primary outcome. Biomechanical, imaging and physiological biomarkers will be assessed as secondary outcomes. Outcomes will be assessed at baseline, 12 weeks, and 24 weeks. DISCUSSION: Identifying objective functional parameters indicative of HFpEF and the subsequent development of functional level stratification based on functional impairment ("biomechanical phenotypes") may help clinicians identify cardiac rehabilitation responders and non-responders and make future clinical decisions. In this way, future pharmacological and non-pharmacological interventions, such as exercise, could be improved and tailored to improve quality of life and prognosis and reducing patients' hospital readmissions, thereby reducing healthcare costs. TRIAL REGISTRATION: NCT05393362 (Clinicaltrials.gov).

Vitamin D and adolescent idiopathic scoliosis, should we stop the hype? A cross-sectional observational prospective study based on a geometric morphometrics approach.

PURPOSE: There is strong evidence supporting the presence of fluctuating asymmetry (FA) in Adolescents with Idiopathic Scoliosis (AIS). Additionally, recent research investigating the relationship between vitamin D and AIS found a relation between them. We hypothesize a negative correlation between FA and vitamin D. METHODS: We performed a surface scan of the torso of 53 AIS patients, a blood test to measure vitamin D and the radiographic Cobb angle. A correlation analysis between vitamin D and FA was carried out to test our hypothesis, and a regression of vitamin D on 3D shape was performed to observe shape differences between the vitamin D deficiency and insufficiency groups. RESULTS: There was no correlation between vitamin D and FA. We found a strong negative correlation between vitamin D and the Cobb angle only in the premenarche group (n = 7; r = - 0.92). Differences in shape were observed between the deficiency and insufficiency groups, and that differences were related to the width of the torso, but not the rotation or lateral flexion. CONCLUSIONS: Our results do not support the massive screening of vitamin D in AIS. Shape analysis revealed differences between the shape of the deficiency and insufficiency groups related to robustness. However, this finding had no relation with the scoliosis characteristics, it just reflected different body composition, and its importance should be explored in future.

Screening criteria for interstitial lung disease associated to rheumatoid arthritis: Expert proposal based on Delphi methodology.

OBJECTIVE: To develop a joint proposal for screening criteria of interstitial lung disease (ILD) in patients with rheumatoid arthritis (RA) and vice versa, which serves as a guidelines in patient referral between the Rheumatology and Pneumology departments to early detection of these patients. METHODS: A systematic literature review was carried out on the risk factors for the development of ILD in RA patients, and for the referral criteria to Rheumatology for suspected early RA. Based on the available evidence, screening criteria were agreed using the Delphi method by a panel of pneumologists and rheumatologists with expertise in these pathologies. RESULTS: Screening criteria for ILD in patients with RA and for the early detection of RA in cases with ILD of unknown etiology have been developed. In both cases, a detection strategy was based on clinical risk factors. Recommendations also included the complementary tests to be carried out in the different clinical scenarios and on the periodicity that screening should be repeated. CONCLUSION: A selective screening strategy is recommended for the first time in the early diagnosis of patients with ILD-RA. This multidisciplinary proposal aims to solve some common clinical questions and help decision-making, although its usefulness to identify these patients with good sensitivity must be confirmed in a validation study.

The evolution, form and function of the human respiratory system.

This paper presents an updated view on the morphological and functional significance of the human respiratory system in the context of human evolutionary anatomy. While usually the respiratory system is treated either from a craniofacial perspective, mostly in the context of nasal evolution and air-conditioning, or from a postcranial perspective featuring on overall thoracic shape changes, here we pursue a holistic perspective on the form, function, integration, and evolutionary change of the entire organismal system in hominins. We first present a brief review of the most important morphological structures, their function, and its potential integration and interaction with the nasal cavity and thoracic skeleton. This is followed by an overview of the most important improvements in methods for the comparative study in recent humans and fossil hominins. We then overview and list a compendium of hominin fossil material currently available for the study. We propose four functional categories of hominin respiratory system configurations that differ potentially with respect to size, shape, biomechanics and/or bioenergetics. Finally, we discuss these and speculate on possible ways for future research into an anatomical system that, despite its under-investigated status, is central to the understanding of the form and functions of the hominin organism and its paleobiology.

Variation in human 3D trunk shape and its functional implications in hominin evolution.

This study investigates the contribution of external trunk morphology and posture to running performance in an evolutionary framework. It has been proposed that the evolution from primitive to derived features of torso shape involved changes from a mediolaterally wider into a narrower, and antero-posteriorly deeper into a shallower, more lightly built external trunk configuration, possibly in relation to habitat-related changes in locomotor and running behaviour. In this context we produced experimental data to address the hypothesis that medio-laterally narrow and antero-posteriorly shallow torso morphologies favour endurance running capacities. We used 3D geometric morphometrics to relate external 3D trunk shape of trained, young male volunteers (N = 27) to variation in running velocities during different workloads determined at 45-50%, 70% and 85% of heart rate reserve (HRR) and maximum velocity. Below 85% HRR no relationship existed between torso shape and running velocity. However, at 85% HRR and, more clearly, at maximum velocity, we found highly statistically significant relations between external torso shape and running performance. Among all trained subjects those with a relatively narrow, flat torso, a small thoracic kyphosis and a more pronounced lumbar lordosis achieved significantly higher running velocities. These results support the hypothesis that external trunk morphology relates to running performance. Low thoracic kyphosis with a flatter ribcage may affect positively respiratory biomechanics, while increased lordosis affects trunk posture and may be beneficial for lower limb biomechanics related to leg return. Assuming that running workload at 45-50% HRR occurs within aerobic metabolism, our results may imply that external torso shape is unrelated to the evolution of endurance running performance.

Preference for sublingual immunotherapy with tablets in a Spanish population with allergic rhinitis.

BACKGROUND: This study investigated patients' preference for allergy immunotherapy (AIT) administered as either sublingual immunotherapy-tablets versus monthly or weekly subcutaneous immunotherapy (SCIT) from a Spanish patient perspective. METHODS: A discrete choice experiment (DCE) consisting of two blocks with eight choice sets in each was constructed to elicit the preferences for AIT. Three attributes were included in the DCE for the mode of administration, including the frequency of administration, the risk of systemic reactions and the co-payment. Adults and caregivers of children with moderate to severe allergic rhinitis (AR) were included if they were not currently receiving or had not previously received AIT. RESULTS: In total, 587 adults and 613 caregivers started the survey. Of those, 579 adults and 611 caregivers completed the survey and were included in the study. Both adults and caregivers had a significant preference for tablets compared with both monthly and weekly injections (p ≤ 0.0001). Furthermore, the respondents showed a significant preference for reducing the risk of systemic reactions. Subgroup analyses showed that caregivers of polyallergic children and female caregivers were significantly less price sensitive when choosing their preferred treatment. CONCLUSION: Our study demonstrated that both adults with AR and caregivers of children with AR prefer daily SLIT-tablets to SCIT with either a weekly or monthly dose schedule.

How can directional and fluctuating asymmetry help in the prognosis of scoliosis along the course of the condition?

Fluctuating asymmetry (FA) is an indicator of developmental instability referred to random deviations from mean asymmetry. That average asymmetry is the directional asymmetry (DA), which, in the particular case of adolescent idiopathic scoliosis (AIS), corresponds to a right thoracic and left lumbar curves. Investigating the presence of FA and DA in AIS has never been done, and it is a key element of the pathophysiology of the scoliotic condition. Thirty-six X-rays of patients with AIS were digitized and analysed using Geometric Morphometric analyses to test for both statistical effects. The individual FA score for each patient was calculated using Procrustes ANOVA and a methodology based on the components of shape was used to estimate the individual DA score. DA is a stronger effect than FA (2.12 to 1), as it has been found in other clinical conditions. The individual DA score, with an effect size of 0.58, is a better predictor of the Cobb angle than FA score. The methodology presented in this paper to estimate DA score is a valid approach in the study of asymmetries in AIS. FA should be correlated in future studies with environmental covariates to serve as a variable in the medical prognosis, while DA will serve as a good predictor of the Cobb angle during the course of the condition, avoiding the abuse of X-rays. This potential use of DA should be tested on 3D shape due to the three-dimensional clinical presentation of AIS.

Endobronchial autologous bone marrow-mesenchymal stromal cells in idiopathic pulmonary fibrosis: a phase I trial.

RATIONALE: Idiopathic pulmonary fibrosis (IPF) has a dismal prognosis. Mesenchymal stromal cells (MSCs) have shown benefit in other inflammatory diseases. OBJECTIVES: To evaluate the safety and feasibility of endobronchial administration of bone marrow autologous MSCs (BM-MSC) in patients with mild-to-moderate IPF. METHODS: A phase I multicentre clinical trial (ClinicalTrials.gov NCT01919827) with a single endobronchial administration of autologous adult BM-MSCs in patients diagnosed with mild-to-moderate IPF. In a first escalating-dose phase, three patients were included sequentially in three dose cohorts (10×106, 50×106 and 100×106 cells). In a second phase, nine patients received the highest tolerated dose. Follow-up with pulmonary function testing, 6-min walk test and St George's Respiratory Questionnaire was done at 1, 2, 3, 6 and 12 months, and with computed tomography at 3, 6 and 12 months. RESULTS: 21 bone marrow samples were obtained from 17 patients. Three patients were excluded from treatment due to chromosome aberrations detected in MSCs after culture, and one patient died before treatment. Finally, 13 patients received the BM-MSC infusion. No treatment-related severe adverse events were observed during follow-up. Compared to baseline, the mean forced vital capacity showed an initial decline of 8.1% at 3 months. The number of patients without functional progression was six (46%) at 3 months and three (23%) at 12 months. CONCLUSIONS: The endobronchial infusion of BM-MSCs did not cause immediate serious adverse events in IPF patients, but a relevant proportion of patients suffered clinical and/or functional progression. Genomic instability of BM-MSCs during culture found in three patients may be troublesome for the use of autologous MSCs in IPF patients.

Geometric morphometrics of adolescent idiopathic scoliosis: a prospective observational study.

OBJECTIVE: Adolescent idiopathic scoliosis is the most prevalent type of scoliosis, and its consequences on the human torso have not been deeply studied. In spite of being a 3D condition, clinical management is circumscribed to 2D images among health-care professionals. GMM is a well-recognized tool in the study of 3D shape and symmetry. METHODS: Twenty-four subjects with AIS and 24 controls were subjected to surface scan. Digitization and shape data were extracted and submitted to GMM analysis. 3D shape and asymmetry were correlated with Cobb angle in subjects with X-ray availability. Comparisons of mean shapes were done between each group and its symmetric average shape and between each group at two states: initial and 6 months after. RESULTS: AIS and controls show similar areas of asymmetry, being significantly higher in quantity in AIS (PD = 0.045; PD 0.037; p < 0.001). Significant correlation was observed between Cobb angle and Procrustes asymmetry (r = 0.38; p = 0.01) as happened with 3D shape (r = 0.11; p < 0.001). No significant changes were observed in the 3D shape of both groups 6 months after (AIS, p = 0.51; control, p = 0.304). CONCLUSION: The greater asymmetry observed in AIS was expectable, but the similarity of areas of asymmetry in both groups made us suspect of directional asymmetry in the human torso that could explain the high prevalence of right scoliosis observed in nature. The shape of the torso and the asymmetry should be considered as variables to study in AIS due to its correlation with Cobb angle. Progression of the deformities was not observed in our study, maybe due to short-term follow-up.

Remote Health Monitoring in the Workplace for Early Detection of COVID-19 Cases during the COVID-19 Pandemic Using a Mobile Health Application: COVIDApp.

Background: COVIDApp is a platform created for management of COVID-19 in the workplace. Methods: COVIDApp was designed and implemented for the follow-up of 253 workers from seven companies in Catalonia. The assessment was based on two actions: first, the early detection and management of close contacts and potential cases of COVID-19, and second, the rapid remote activation of protocols. The main objectives of this strategy were to minimize the risk of transmission of COVID-19 infection in the work area through a new real-time communication channel and to avoid unnecessary sick leave. The parameters reported daily by workers were close contact with COVID cases and signs and/or symptoms of COVID-19. Results: Data were recorded between 1 May and 30 November 2020. A total of 765 alerts were activated by 76 workers: 127 green alarms (16.6%), 301 orange alarms (39.3%), and 337 red alarms (44.1%). Of all the red alarms activated, 274 (81.3%) were activated for symptoms potentially associated with COVID-19, and 63 (18.7%) for reporting close contact with COVID-19 cases. Only eight workers (3.1%) presented symptoms associated with COVID-19 infection. All of these workers underwent RT-PCR tests, which yielded negative results for SARS-CoV2. Three workers were considered to have had a risk contact with COVID-19 cases; only 1 (0.4%) asymptomatic worker had a positive RT-PCR test result, requiring the activation of protocols, isolation, and contact tracing. Conclusions: COVIDApp contributes to the early detection and rapid activation of protocols in the workplace, thus limiting the risk of spreading the virus and reducing the economic impact caused by COVID-19 in the productive sector. The platform shows the progression of infection in real time and can help design new strategies.

COVIDApp as an Innovative Strategy for the Management and Follow-Up of COVID-19 Cases in Long-Term Care Facilities in Catalonia: Implementation Study.

BACKGROUND: The coronavirus disease (COVID-19) pandemic has caused an unprecedented worldwide public health crisis that requires new management approaches. COVIDApp is a mobile app that was adapted for the management of institutionalized individuals in long-term care facilities. OBJECTIVE: The aim of this paper is to report the implementation of this innovative tool for the management of long-term care facility residents as a high-risk population, specifically for early identification and self-isolation of suspected cases, remote monitoring of mild cases, and real-time monitoring of the progression of the infection. METHODS: COVIDApp was implemented in 196 care centers in collaboration with 64 primary care teams. The following parameters of COVID-19 were reported daily: signs/symptoms; diagnosis by reverse transcriptase-polymerase chain reaction; absence of symptoms for ≥14 days; total deaths; and number of health care workers isolated with suspected COVID-19. The number of at-risk centers was also described. RESULTS: Data were recorded from 10,347 institutionalized individuals and up to 4000 health care workers between April 1 and 30, 2020. A rapid increase in suspected cases was seen until day 6 but decreased during the last two weeks (from 1084 to 282 cases). The number of confirmed cases increased from 419 (day 6) to 1293 (day 22) and remained stable during the last week. Of the 10,347 institutionalized individuals, 5,090 (49,2%) remained asymptomatic for ≥14 days. A total of 854/10,347 deaths (8.3%) were reported; 383 of these deaths (44.8%) were suspected/confirmed cases. The number of isolated health care workers remained high over the 30 days, while the number of suspected cases decreased during the last 2 weeks. The number of high-risk long-term care facilities decreased from 19/196 (9.5%) to 3/196 (1.5%). CONCLUSIONS: COVIDApp can help clinicians rapidly detect and remotely monitor suspected and confirmed cases of COVID-19 among institutionalized individuals, thus limiting the risk of spreading the virus. The platform shows the progression of infection in real time and can aid in designing new monitoring strategies.

Adult congenital heart disease in Spain: health care structure and activity, and clinical characteristics.

INTRODUCTION AND OBJECTIVES: To assess the structure of health care delivery and the clinical characteristics of adults with congenital heart disease (ACHD) attending specialized centers in Spain. METHODS: A survey was conducted among 32 Spanish centers in 2014. The centers were classified into 2 levels based on their resources. In 2017, a clinical dataset was collected of all consecutive patients attended for a 2-month period at these centers. RESULTS: A total of 31 centers (97%) completed the survey. Seven centers without specialized ACHD clinics were excluded from the analysis. In 2005, only 5 centers met the requirements for specific care. In 2014, there were 10 level 1 and 14 level 2 centers, with a total of 19 373 patients under follow-up. Health care structure was complete in most centers but only 33% had ACHD nurse specialists on staff and 29% had structured transition programs. Therapeutic procedures accounted for 99% and 91% of those reported by National Registries of Cardiac Surgery and Cardiac Catheterization, respectively. Among attended patients, 48% had moderately complex lesions and 24% had highly complex lesions. Although 46% of patients attending level 2 centers had simple lesions, 17% had complex lesions. CONCLUSIONS: The structure for ACHD health care delivery in Spain complies with international recommendations and is similar to that of other developed countries. Congenital heart diseases under specialized care consist mostly of moderately and highly complex lesions, even in level 2 centers. It would be desirable to reorganize patient follow-up according to international recommendations in clinical practice.

Case report of asymptomatic very late presentation of ALCAPA syndrome: review of the literature since pathophysiology until treatment.

BACKGROUND: Anomalous origin of the left coronary artery (LCA) from the pulmonary artery (ALCAPA) is an unusual congenital heart defect which affects approximately 1 in 300 000 live births and accounts for 0.5% of all congenital heart disease. Without surgical intervention, most patients die in infancy (nearly 90%). CASE SUMMARY: We present a rare case of an asymptomatic 67-year-old female. Transthoracic echocardiography demonstrated a dilated right coronary artery (RCA) and multiple collaterals. ALCAPA was confirmed by multidetector computed tomography. The left main artery was seen originating from the pulmonary artery and well-developed collaterals were visualized between the RCA and LCA. No areas of myocardial infarction were identified on cardiac magnetic resonance. Stress studies showed no inducible ischaemia. DISCUSSION: Our clinical case of an ALCAPA patient who survived and remained asymptomatic to their late 60's, highlights the importance of well-collateralized and pressurized coronary system to maintain adequate myocardial perfusion. Physicians should be aware of this congenital anomaly as appropriate early diagnosis is crucial to prevent irreversible myocardial damage, acute ischaemia, and arrhythmias, and can improve patient outcomes. Surgical treatment is suggested irrespective of symptomatology or the presence of inducible myocardial ischaemia.

Hyperkalemia in heart failure patients in Spain and its impact on guidelines and recommendations: ESC-EORP-HFA Heart Failure Long-Term Registry.

INTRODUCTION AND OBJECTIVES: Hyperkalemia is a growing concern in the treatment of patients with heart failure and reduced ejection fraction because it limits the use of effective drugs. We report estimates of the magnitude of this problem in routine clinical practice in Spain, as well as changes in potassium levels during follow-up and associated factors. METHODS: This study included patients with acute (n=881) or chronic (n=3587) heart failure recruited in 28 Spanish hospitals of the European heart failure registry of the European Society of Cardiology and followed up for 1 year. Various outcomes were analyzed, including changes in serum potassium levels and their impact on treatment. RESULTS: Hyperkalemia (K+> 5.4 mEq/L) was identified in 4.3% (95%CI, 3.7%-5.0%) and 8.2% (6.5%-10.2%) of patients with chronic and acute heart failure, respectively, and was responsible for 28.9% of all cases of contraindication to mineralocorticoid receptor antagonist use and for 10.8% of all cases of failure to reach the target dose. Serum potassium levels were not recorded in 291 (10.8%) of the 2693 chronic heart failure patients with reduced ejection fraction. During follow-up, potassium levels increased in 179 of 1431 patients (12.5%, 95%CI, 10.8%-14.3%). This increase was directly related to age, diabetes, and history of stroke and was inversely related to history of hyperkalemia. CONCLUSIONS: This study highlights the magnitude of the problem of hyperkalemia in patients with heart failure in everyday clinical practice and the need to improve monitoring of this factor in these patients due to its interference with the possibility of receiving optimal treatment.

Comparative survival analysis between idiopathic pulmonary fibrosis and chronic hypersensitivity pneumonitis.

INTRODUCTION: Chronic hypersensitivity pneumonitis (CHP) is an interstitial lung disease with limited treatment response and bad prognosis. Sometimes it is indistinguishable from idiopathic pulmonary fibrosis (IPF) becoming one of the main differential diagnosis. The aim of our study is to compare survival and functional decline between these two entities. METHODS: Survival and functional decline more than 10% in FVC were compared using Kaplan Meier (KM) method between patients with CHP and IPF. Cox proportional hazard analysis was used to identify independent predictors of survival and functional decline. RESULTS: 146 patients were included, 54 with CHP and 92 with IPF. KM rate for 2 years survival was 0.71 (CI 95% 0,6-0,8) for CHP group and 0,83 (CI 95% 0,66 - 0,92) for IPF (p=0,027). Nevertheless this difference disappeared using Cox proportional hazard analysis, the adjusted HR for survival among CHP patients was 0,53 (CI 95% 0,25-1,15) (p=0,11). There was no difference in functional evolution between the two groups. KM rate for a decline more than or equal to 10% was 0,64 for CHP (CI 95% 0,43-0,79) and 0,78 for IPF (IC 95% 0,6-0,88) (p=0,22). This observation did not change after using Cox proportional hazard analysis. CONCLUSIONS: Our study shows that both IPF and CHP are fibrosing interstitial diseases with a similar evolution and survival. It might be possible that therapeutic approach in patients with CHP should change in the light of these observations.

Porcine Breed, Sex, and Production Stage Influence the Levels of Health Status Biomarkers in Saliva Samples.

In this study, the influence of several factors such as breed, sex, and production stage over the normal range values of salivary biomarkers of health status was evaluated in pigs. A total of 409 pigs of 2 different breeds (conventional Large White × Duroc and Iberian pigs) were included in the study. Animals were divided into different groups according to their sex (male or female) and the stage of the production cycle they were in (post-weaning, nursery, fattening, and finishing). The levels of an inflammatory marker, adenosine deaminase (ADA), and two acute phase proteins, C-reactive protein (CRP) and haptoglobin (Hp) were measured in saliva samples. Moreover, the total antioxidant capacity level (TAC) was quantified for the first time in porcine saliva; therefore, an analytical validation and stability analysis during storage at -80°C were also performed. Differences according to breed were observed for all the markers studied; thus, the influence of age and sex on the normal range values were studied separately for conventional and Iberian pigs. In Large White × Duroc pigs the overall median values of ADA, CRP, Hp and TAC were 282 U/L, 10.49 ng/mL, 0.88 µg/mL, and 21.73 µM Trolox equivalents, respectively. However, higher values of inflammatory marker and acute phase proteins were observed in males at the initial stages of the production cycle, while females presented higher values when they had reached sexual maturity. In Iberian pigs the overall median values observed were 585 U/L, 4.81 ng/mL, 0.63 µg/mL, and 21.21 µM Trolox equivalents for ADA, CRP, Hp, and TAC respectively with slight differences in the influence of the studied factors. Sex differences were not observed in the levels of acute phase proteins in Iberian pigs, probably due to the castration of males during the first days of life; however, ADA levels were found to be higher in male pigs at the end of the production cycle. It could be concluded that breed, sex, and production stage influence the range values of salivary markers of health status in pigs and should be taken into account to further establish reference intervals.

Adherence to Long-Term Oxygen Therapy. Influence of Tobacco Use. / Cumplimiento de la oxigenoterapia crónica domiciliaria. Influencia del consumo de tabaco.

INTRODUCTION: Domiciliary oxygen therapy (DOT) is a treatment that requires a high level of cooperation from patients due to the time it takes every day. A high level of non-compliance has been determined among patients receiving DOT. The aim of our study was to assess the level of non-compliance and the influence of active tobacco consumption on compliance. MATERIAL AND METHODS: Patients were monitored in the home using direct and indirect methods, to assess both compliance and tobacco consumption. RESULTS: The level of non-compliance detected by indirect methods was 22.6%, and 66.3% by direct methods. Tobacco consumption determined by indirect methods was 5.8%-8%, depending on the method used, and 16.2% when CO in exhaled air ≥10ppm was established as an indicator of tobacco use. The group of smokers complied with oxygen therapy for a significantly fewer number of hours per day (P<.001) than non-smokers. CONCLUSIONS: There is a high level of therapeutic non-compliance and a significant percentage of patients receiving DOT continue to smoke. Compliance must be monitored, and the correct use of DOT must be emphasized. Additional efforts should also be made to help smokers with DOT to stop smoking, since continued smoking impacts negatively on therapeutic non-compliance.

Formin Homology 2 Domain Containing 3 (FHOD3) Is a Genetic Basis for Hypertrophic Cardiomyopathy.

BACKGROUND: The genetic cause of hypertrophic cardiomyopathy remains unexplained in a substantial proportion of cases. Formin homology 2 domain containing 3 (FHOD3) may have a role in the pathogenesis of cardiac hypertrophy but has not been implicated in hypertrophic cardiomyopathy. OBJECTIVES: This study sought to investigate the relation between FHOD3 mutations and the development of hypertrophic cardiomyopathy. METHODS: FHOD3 was sequenced by massive parallel sequencing in 3,189 hypertrophic cardiomyopathy unrelated probands and 2,777 patients with no evidence of cardiomyopathy (disease control subjects). The authors evaluated protein-altering candidate variants in FHOD3 for cosegregation, clinical characteristics, and outcomes. RESULTS: The authors identified 94 candidate variants in 132 probands. The variants' frequencies were significantly higher in patients with hypertrophic cardiomyopathy (74 of 3,189 [2.32%]) than in disease control subjects (18 of 2,777 [0.65%]; p < 0.001) or in the gnomAD database (1,049 of 138,606 [0.76%]; p < 0.001). FHOD3 mutations cosegregated with hypertrophic cardiomyopathy in 17 families, with a combined logarithm of the odds score of 7.92, indicative of very strong segregation. One-half of the disease-causing variants were clustered in a small conserved coiled-coil domain (amino acids 622 to 655); odds ratio for hypertrophic cardiomyopathy was 21.8 versus disease control subjects (95% confidence interval: 1.3 to 37.9; p < 0.001) and 14.1 against gnomAD (95% confidence interval: 6.9 to 28.7; p < 0.001). Hypertrophic cardiomyopathy patients carrying (likely) pathogenic mutations in FHOD3 (n = 70) were diagnosed after age 30 years (mean 46.1 ± 18.7 years), and two-thirds (66%) were males. Of the patients, 82% had asymmetric septal hypertrophy (mean 18.8 ± 5 mm); left ventricular ejection fraction <50% was present in 14% and hypertrabeculation in 16%. Events were rare before age 30 years, with an annual cardiovascular death incidence of 1% during follow-up. CONCLUSIONS: FHOD3 is a novel disease gene in hypertrophic cardiomyopathy, accounting for approximately 1% to 2% of cases. The phenotype and the rate of cardiovascular events are similar to those reported in unselected cohorts. The FHOD3 gene should be routinely included in hypertrophic cardiomyopathy genetic testing panels.