Sex-related differences in the clinical course of aortic root and ascending aortic aneurysms: the DisSEXion Study.

BACKGROUND AND AIMS: To explore male-female differences in aneurysm growth and clinical outcomes in a two-centre retrospective Dutch cohort study of adult patients with ascending aortic aneurysm (AscAA). METHODS: Adult patients in whom imaging of an AscAA (root and/or ascending: ≥40 mm) was performed between 2007 and 2022 were included. Aneurysm growth was analysed using repeated measurements at the sinuses of Valsalva (SoV) and tubular ascending aorta. Male-female differences were explored in presentation, aneurysm characteristics, treatment strategy, survival, and clinical outcomes. RESULTS: One thousand eight hundred and fifty-eight patients were included (31.6% female). Median age at diagnosis was 65.4 years (interquartile range: 53.4-71.7) for females and 59.0 years (interquartile range: 49.3-68.0) for males (P < .001). At diagnosis, females more often had tubular ascending aortic involvement (75.5% vs. 70.2%; P = .030) while males more often had SoV involvement (42.8% vs. 21.6%; P < .001). Maximum absolute aortic diameter, at any location, at diagnosis did not differ between females (45.0 mm) and males (46.5 mm; P = .388). In females, tubular ascending growth was faster (P < .001), whereas in males, SoV growth was faster (P = .005), corrected for covariates. Unadjusted 10-year survival was 72.5% [95% confidence interval (CI) 67.8%-77.6%] for females and 78.3% (95% CI 75.3%-81.3%) for males (P = .010). Twenty-three type A dissections occurred, with an incidence rate of 8.2/1000 patient-years (95% CI 4.4-14.1) in females and 2.4/1000 patient-years (95% CI 1.2-4.5) in males [incidence rate ratio females/males: 3.4 (95% CI 1.5-8.0; P = .004)]. CONCLUSIONS: In patients having entered a diagnostic programme, involvement of aortic segments and age- and segment-related growth patterns differ between women and men with AscAA, particularly at an older age. Unravelling of these intertwined observations will provide a deeper understanding of AscAA progression and outcome in women and men and can be used as an evidence base for patient-tailored clinical guideline development.

Surgical Heritage: You Had to Be There, Ross: The Comeback Kid.

Half a century after the first pulmonary autograft operation (Ross operation), performed in 1967 by Donald Ross in central London, there is a very strong conviction that the Ross operation is the best available valve substitute today, not only for children, but also for younger and older adults. The Ross operation has stimulated a lot of science to do with tissue-engineering and biology of heart valves, which is a promising avenue for the future. For one of us (M.Y.), it has certainly been a privilege to be associated with the comeback of the Ross operation.

Paediatric aortic valve replacement: a meta-analysis and microsimulation study.

AIMS: To support decision-making in children undergoing aortic valve replacement (AVR), by providing a comprehensive overview of published outcomes after paediatric AVR, and microsimulation-based age-specific estimates of outcome with different valve substitutes. METHODS AND RESULTS: A systematic review of published literature reporting clinical outcome after paediatric AVR (mean age <18 years) published between 1/1/1990 and 11/08/2021 was conducted. Publications reporting outcome after paediatric Ross procedure, mechanical AVR (mAVR), homograft AVR (hAVR), and/or bioprosthetic AVR were considered for inclusion. Early risks (<30d), late event rates (>30d) and time-to-event data were pooled and entered into a microsimulation model. Sixty-eight studies, of which one prospective and 67 retrospective cohort studies, were included, encompassing a total of 5259 patients (37 435 patient-years; median follow-up: 5.9 years; range 1-21 years). Pooled mean age for the Ross procedure, mAVR, and hAVR was 9.2 ± 5.6, 13.0 ± 3.4, and 8.4 ± 5.4 years, respectively. Pooled early mortality for the Ross procedure, mAVR, and hAVR was 3.7% (95% CI, 3.0%-4.7%), 7.0% (5.1%-9.6%), and 10.6% (6.6%-17.0%), respectively, and late mortality rate was 0.5%/year (0.4%-0.7%/year), 1.0%/year (0.6%-1.5%/year), and 1.4%/year (0.8%-2.5%/year), respectively. Microsimulation-based mean life-expectancy in the first 20 years was 18.9 years (18.6-19.1 years) after Ross (relative life-expectancy: 94.8%) and 17.0 years (16.5-17.6 years) after mAVR (relative life-expectancy: 86.3%). Microsimulation-based 20-year risk of aortic valve reintervention was 42.0% (95% CI: 39.6%-44.6%) after Ross and 17.8% (95% CI: 17.0%-19.4%) after mAVR. CONCLUSION: Results of paediatric AVR are currently suboptimal with substantial mortality especially in the very young with considerable reintervention hazards for all valve substitutes, but the Ross procedure provides a survival benefit over mAVR. Pros and cons of substitutes should be carefully weighed during paediatric valve selection.

Long Term Health Related Quality of Life After Acute Type B Aortic Dissection: a Cross Sectional Survey Study.

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.

Uncertainties and challenges in surgical and transcatheter tricuspid valve therapy: a state-of-the-art expert review.

Tricuspid regurgitation (TR) is a frequent and complex problem, commonly combined with left-sided heart disease, such as mitral regurgitation. Significant TR is associated with increased mortality if left untreated or recurrent after therapy. Tricuspid regurgitation was historically often disregarded and remained undertreated. Surgery is currently the only Class I Guideline recommended therapy for TR, in the form of annuloplasty, leaflet repair, or valve replacement. As growing experience of transcatheter therapy in structural heart disease, many dedicated transcatheter tricuspid repair or replacement devices, which mimic well-established surgical techniques, are currently under development. Nevertheless, many aspects of TR are little understood, including the disease process, surgical or interventional risk stratification, and predictors of successful therapy. The optimal treatment timing and the choice of proper surgical or interventional technique for significant TR remain to be elucidated. In this context, we aim to highlight the current evidence, underline major controversial issues in this field and present a future roadmap for TR therapy.

Male-female differences in quality of life and coping style in patients with Marfan syndrome and hereditary thoracic aortic diseases.

Hereditary thoracic aortic diseases (HTAD) such as Marfan syndrome (MFS) affect multiple organ systems and provide a risk of acute aortic dissection, which causes lifelong uncertainties. Although health-related quality of life (HRQOL) was found to be reduced in HTAD patients, no studies have evaluated male-female-specific aspects of HRQOL and coping in this population. This study aims to evaluate HRQOL in HTAD patients compared to the general population; assess male-female differences in HRQOL and factors associated with HRQOL; evaluate coping styles in male and female HTAD patients and identify factors associated with acceptance. All consecutive adult patients who visited the specialized HTAD outpatient clinic between 2013 and 2018 were asked to complete three HRQOL questionnaires: the Short Form 36 (SF-36), the Hospital Anxiety and Depression Scale (HADS), and the Nijmegen Clinical Screening Instrument (NCSI). In total, 142 patients were included (mean age 42.1 years, 65 females, 123 MFS). Compared to the general population, HTAD patients scored significantly lower on multiple SF-36 sub-domains (males: General Health 54.5 ± 18.8 vs. 71.6 ± 20.6, p < .001; Vitality 58.3 ± 20.4 vs. 71.9 ± 18.3, p < .001; females: Physical Functioning 67.5 ± 23.8 vs. 80.4 ± 24.2, p = .003; Role Physical 58.3 ± 45.1 vs. 73.8 ± 38.5, p = .047; General Health 49.4 ± 24.3 vs. 69.9 ± 20.6, p < .001; Social Functioning 73.5 ± 22.0 vs. 82.0 ± 23.5, p = .027). Females scored significantly lower than males on the SF-36 physical component score (41.6 [IQR 35.5-53.1] vs. 49.3 [IQR 42.3-54.6], p = .035). Males scored significantly higher on the coping style denial than females (2.75 [IQR 2.00-3.25] vs. 2.25 [IQR 1.75-3.25], p = .018). High scores on acceptance were found in 38 (26.8%) of HTAD patients, and these patients showed significantly better scores on the NCSI, SF-36, and HADS, except on NCSI Satisfaction Relationships and SF-36 Physical Functioning and Mental Health. Acceptance was associated with more medication use (beta blocker use, p = .008; angiotensin receptor blocker use, p = .003) and less hypertension (p = .001). In patients with MFS, employment was strongly associated with better scores on the NCSI. In conclusion, HTAD patients showed subnormal HRQOL, especially females. Interestingly, in both males and females factors such as employment, coping style, and disease acceptance seem more important for HRQOL than disease-related factors. This highlights the importance of genetic counseling and guidance for HTAD patients, and offers valuable leads for HRQOL improvement.

Individualized dynamic prediction of survival with the presence of intermediate events.

Often, in follow-up studies, patients experience intermediate events, such as reinterventions or adverse events, which directly affect the shapes of their longitudinal profiles. Our work is motivated by two studies in which such intermediate events have been recorded during follow-up. In both studies, we are interested in the change of the longitudinal evolutions after the occurrence of the intermediate event and in utilizing this information to improve the accuracy of dynamic prediction of their risk. To achieve so, we propose a flexible joint modeling framework for longitudinal and time-to-event data, which includes features of the intermediate event as time-varying covariates in both the longitudinal and survival submodels. We consider a set of joint models that postulate different effects of the intermediate event in the longitudinal profile and the risk of the clinical endpoint, with different formulations for the association structure while allowing its functional form to change after the occurrence of the intermediate event. Based on these models, we derive dynamic predictions of conditional survival probabilities which are adaptive to different scenarios with respect to the occurrence of the intermediate event. We evaluate the predictive accuracy of these predictions with a simulation study using the time-dependent area under the receiver operating characteristic curve and the expected prediction error adjusted to our setting. The results suggest that accounting for the changes in the longitudinal profiles and the instantaneous risk for the clinical endpoint is important, and improves the accuracy of the dynamic predictions.

Improved dynamic predictions from joint models of longitudinal and survival data with time-varying effects using P-splines.

In the field of cardio-thoracic surgery, valve function is monitored over time after surgery. The motivation for our research comes from a study which includes patients who received a human tissue valve in the aortic position. These patients are followed prospectively over time by standardized echocardiographic assessment of valve function. Loss of follow-up could be caused by valve intervention or the death of the patient. One of the main characteristics of the human valve is that its durability is limited. Therefore, it is of interest to obtain a prognostic model in order for the physicians to scan trends in valve function over time and plan their next intervention, accounting for the characteristics of the data. Several authors have focused on deriving predictions under the standard joint modeling of longitudinal and survival data framework that assumes a constant effect for the coefficient that links the longitudinal and survival outcomes. However, in our case, this may be a restrictive assumption. Since the valve degenerates, the association between the biomarker with survival may change over time. To improve dynamic predictions, we propose a Bayesian joint model that allows a time-varying coefficient to link the longitudinal and the survival processes, using P-splines. We evaluate the performance of the model in terms of discrimination and calibration, while accounting for censoring.

Mechanical aortic valve replacement in non-elderly adults: meta-analysis and microsimulation.

AIMS: To support decision-making regarding prosthetic valve selection in non-elderly adults, we aim to provide a detailed overview of outcome after contemporary mechanical aortic valve replacement (AVR). METHODS AND RESULTS: A systematic review was conducted for papers reporting clinical outcome after AVR with bileaflet mechanical valves with a mean patient age ≥18 and ≤55 years, published between 1 January 1995 and 31 December 2015. Through meta-analysis outcomes were pooled and entered into a microsimulation model to calculate (event-free) life expectancy and lifetime event risk. Twenty-nine publications, encompassing a total of 5728 patients with 32 515 patient-years of follow-up (pooled mean follow-up: 5.7 years), were included. Pooled mean age at surgery was 48.0 years. Pooled early mortality risk was 3.15% (95% confidence interval (CI):2.37-4.23), late mortality rate was 1.55%/year (95%CI:1.25-1.92); 38.7% of late deaths were valve-related. Pooled thromboembolism rate was 0.90%/year (95%CI:0.68-1.21), major bleeding 0.85%/year (95%CI:0.65-1.12), nonstructural valve dysfunction 0.39%/year (95%CI:0.21-0.76), endocarditis 0.41%/year (95%CI:0.29-0.57), valve thrombosis 0.14%/year (95%CI:0.08-0.25), structural valve deterioration 0.00%/year (zero events observed), and reintervention 0.51%/year (95%CI:0.37-0.71), mostly due to nonstructural valve dysfunction and endocarditis. For a 45-year-old, for example, this translated to an estimated life expectancy of 19 years (general population: 34 years) and lifetime risks of thromboembolism, bleeding and reintervention of 18%, 15%, and 10%, respectively. CONCLUSION: This study demonstrates that outcome after mechanical AVR in non-elderly adults is characterized by suboptimal survival and considerable lifetime risk of anticoagulation-related complications, but also reoperation. Non-elderly adult patients who are facing prosthetic valve selection are entitled to conveyance of evidence-based estimates of the risks and benefits of both mechanical and biological valve options in a shared decision-making process.

Personalized screening intervals for biomarkers using joint models for longitudinal and survival data.

Screening and surveillance are routinely used in medicine for early detection of disease and close monitoring of progression. Motivated by a study of patients who received a human tissue valve in the aortic position, in this work we are interested in personalizing screening intervals for longitudinal biomarker measurements. Our aim in this paper is 2-fold: First, to appropriately select the model to use at the time point the patient was still event-free, and second, based on this model to select the optimal time point to plan the next measurement. To achieve these two goals, we combine information theory measures with optimal design concepts for the posterior predictive distribution of the survival process given the longitudinal history of the subject.

Systematic review and meta-analysis of music interventions in hypertension treatment: a quest for answers.

BACKGROUND: Adverse effects, treatment resistance and high costs associated with pharmacological treatment of hypertension have led to growing interest in non-pharmacological complementary therapies such as music interventions. This meta-analysis aims to provide an overview of reported evidence on the efficacy of music interventions in the treatment of hypertension. METHODS: A systematic literature search was conducted for publications on the effect of music interventions on blood pressure in adult hypertensive subjects published between January 1990-June 2014. Randomized controlled trials with a follow-up duration ≥28 days were included. Blood pressure measures were pooled using inverse variance weighting. RESULTS: Of the 1689 abstracts reviewed, 10 randomized controlled trials were included. Random-effects pooling of the music intervention groups showed a trend toward a decrease in mean systolic blood pressure (SBP) from 144 mmHg(95 % CI:137-152) to 134 mmHg(95 % CI:124-144), and in mean diastolic blood pressure (DBP) from 84 mmHg(95 % CI:78-89) to 78 mmHg(95 % CI:73-84). Fixed-effect analysis of a subgroup of 3 trials with valid control groups showed a significant decrease in pooled mean SBP and DBP in both intervention and control groups. A comparison between music intervention groups and control groups was not possible due to unavailable measures of dispersion. CONCLUSIONS: This systematic review and meta-analysis revealed a trend towards a decrease in blood pressure in hypertensive patients who received music interventions, but failed to establish a cause-effect relationship between music interventions and blood pressure reduction. Considering the potential value of this safe, low-cost intervention, well-designed, high quality and sufficiently powered randomized studies assessing the efficacy of music interventions in the treatment of hypertension are warranted.

Drug therapy in the prevention of failure of the Fontan circulation: a systematic review.

BACKGROUND: The Fontan circulation is the optimal treatment for patients with univentricular hearts. These patients are at high risk of circulatory failure. There is no consensus on the optimal drug treatment for the prevention of failure of the Fontan circulation. The aim of this systematic review was to provide an overview of evidence for drug therapy used in the prevention of Fontan circulatory failure. METHODS: We searched the Embase database for articles that reported drug therapy in Fontan patients. Studies published between 1997 and 2014 were included if efficacy or safety of medication was assessed, drug therapy aimed to prevent or treat failure of the Fontan circulation, and if the full text was available. Case reports were excluded. RESULTS: A total of nine studies were included with a total of 267 Fontan patients; four studies evaluated the medication sildenafil, one iloprost, three bosentan, and one enalapril. Among all, two sildenafil studies reported improvement in exercise capacity, one in exercise haemodynamics, and one in ventricular performance. In the largest study of bosentan, an increase in exercise capacity was found. Enalapril did not result in improvements. CONCLUSION: The studies analysed in this review suggest that bosentan, sildenafil, and iloprost may improve exercise capacity at the short term. Given the limitations of the studies, more, larger, placebo-controlled studies with longer follow-up periods are needed to better understand which drug therapies are effective in the prevention of failure of the Fontan circulation.

Survival and treatment of non-small cell lung cancer stage I-II treated surgically or with stereotactic body radiotherapy: patient and tumor-specific factors affect the prognosis.

BACKGROUND: This study was designed to define clinical baseline parameters associated with impaired survival of patients with stage I or II non-small cell lung cancer (NSCLC) who underwent surgery or stereotactic body radiotherapy (SBRT). METHODS: From January 2001 to January 2011, 425 patients (216 surgery, 209 SBRT) were identified with clinical stage I or II NSCLC. Cox proportional-hazards regression analyses were used to investigate risk factors for mortality. RESULTS: Median age of patients in the surgery and SBRT groups was 65 and 74 years, respectively. A smaller proportion of the surgical group had Charlson Comorbidity Index (CCI) score ≥1 compared with the SBRT group: 52 and 72 % (p < 0.001), respectively. Overall survival in the surgical group at 2 and 4 years was 79 and 65 %, respectively. In the SBRT group, this was 65 % at 2 years and 44 % at 4 years. In the surgical group older age, CCI score = 4 and clinical stage = IIB were associated with long-term mortality. In the SBRT group, this was CCI score ≥5 and clinical stage >IA. The area under the curve was calculated for the model with clinical and tumor factors: 0.77 for the surgery and 0.85 for the SBRT group. CONCLUSIONS: Both patient characteristics and survival of NSCLC I-II patients undergoing surgical treatment or SBRT differ considerably. Long-term survival as a result of treatment strategy of NSCLC patients might be optimized by focusing on patient and tumor specific factors. In addition to TNM staging, the consideration of patient age and CCI can be useful for prognostication of NSCLC patients.

Is the patient with mesothelioma without hope?

Hope is a very important mindset for malignant pleural mesothelioma patients as their cancer has a grim prognosis and limited therapeutic options. In this paper, we briefly discuss what hope means for a patient and how hope can help to cope with this disease. In addition, we discuss false hope. We also briefly touch on a few of the new therapies currently under development.

Dynamic prediction of outcome for patients with severe aortic stenosis: application of joint models for longitudinal and time-to-event data.

BACKGROUND: Physicians utilize different types of information to predict patient prognosis. For example: confronted with a new patient suffering from severe aortic stenosis (AS), the cardiologist considers not only the severity of the AS but also patient characteristics, medical history, and markers such as BNP. Intuitively, doctors adjust their prediction of prognosis over time, with the change in clinical status, aortic valve area and BNP at each outpatient clinic visit. With the help of novel statistical approaches to model outcomes, it is now possible to construct dynamic event prediction models, employing longitudinal data such as AVA and BNP, and mimicking the dynamic adjustment of prognosis as employed intuitively by cardiologists. We illustrate dynamic prediction of patient survival and freedom from intervention, using baseline patient characteristics and longitudinal BNP data that are becoming available over time, from a cohort of patients with severe aortic stenosis. METHODS: A 3-step approach was employed: (1) construction of a mixed-effects model to describe temporal BNP progression, (2) jointly modeling the mixed-effects model with time-to-event data (death and freedom from intervention), and (3) using the joint model to build subject-specific prediction risk models. The dataset used for this purpose includes 191 patients with severe aortic stenosis who were followed over a 3-year time period. RESULTS: In the mixed-effects model BNP was significantly influenced by time, baseline patient age, gender, LV fractional ejection fraction and creatinine. Additionally, the joint model showed that an increasing BNP trend over time was found to be a significant predictor of death. CONCLUSIONS: By jointly modeling longitudinal data with time-to-event outcomes it is possible to construct individualized dynamic event prediction models that renew over time with accumulating evidence. It provides a potentially valuable evidence-based tool for everyday use in medical practice.

Surgical outcome of discrete subaortic stenosis in adults: a multicenter study.

BACKGROUND: Discrete subaortic stenosis is notable for its unpredictable hemodynamic progression in childhood and high reoperation rate; however, data about adulthood are scarce. METHODS AND RESULTS: Adult patients who previously underwent surgery for discrete subaortic stenosis were included in this retrospective multicenter cohort study. Mixed-effects and joint models were used to assess the postoperative progression of discrete subaortic stenosis and aortic regurgitation, as well as reoperation. A total of 313 patients at 4 centers were included (age at baseline, 20.2 years [25th-75th percentile, 18.4-31.0 years]; 52% male). Median follow-up duration was 12.9 years (25th-75th percentile, 6.2-20.1 years), yielding 5617 patient-years. The peak instantaneous left ventricular outflow tract gradient decreased from 75.7±28.0 mm Hg preoperatively to 15.1±14.1 mm Hg postoperatively (P<0.001) and thereafter increased over time at a rate of 1.31±0.16 mm Hg/y (P=0.001). Mild aortic regurgitation was present in 68% but generally did not progress over time (P=0.76). A preoperative left ventricular outflow tract gradient ≥80 mm Hg was a predictor for progression to moderate aortic regurgitation postoperatively. Eighty patients required at least 1 reoperation (1.8% per patient-year). Predictors for reoperation included female sex (hazard ratio, 1.53; 95% confidence interval, 1.02-2.30) and left ventricular outflow tract gradient progression (hazard ratio, 1.45; 95% confidence interval, 1.31-1.62). Additional myectomy did not reduce the risk for reoperation (P=0.92) but significantly increased the risk of a complete heart block requiring pacemaker implantation (8.1% versus 1.7%; P=0.005). CONCLUSIONS: Survival is excellent after surgery for discrete subaortic stenosis; however, reoperation for recurrent discrete subaortic stenosis is not uncommon. Over time, the left ventricular outflow tract gradient slowly increases and mild aortic regurgitation is common, although generally nonprogressive over time. Myectomy does not show additional advantages, and because it is associated with an increased risk of complete heart block, it should not be performed routinely.

Joint modeling of two longitudinal outcomes and competing risk data.

Aortic gradient and aortic regurgitation are echocardiographic markers of aortic valve function. Both are biomarkers repeatedly measured in patients with valve abnormalities, and thus, it is expected that they are biologically interrelated. Loss of follow-up could be caused by multiple reasons, including valve progression related, such as an intervention or even the death of the patient. In that case, it would be of interest and appropriate to analyze these outcomes jointly. Joint models have recently received much attention because they cover a wide range of clinical applications and have promising results. We propose a joint model consisting of two longitudinal outcomes, one continuous (aortic gradient) and one ordinal (aortic regurgitation), and two time-to-events (death and reoperation). Moreover, we allow for more flexibility for the average evolution and the subject-specific profiles of the continuous repeated outcome by using B-splines. A disadvantage, however, is that when adopting a non-linear structure for the model, we may have difficulties when interpreting the results. To overcome this problem, we propose a graphical approach. In this paper, we apply the proposed joint models under the Bayesian framework, using a data set including serial echocardiographic measurements of aortic gradient and aortic regurgitation and measurements of the occurrence of death and reoperation in patients who received a human tissue valve in the aortic position. The interpretation of the results will be discussed.

Natural history of discrete subaortic stenosisin adults: a multicentre study.

AIMS: Discrete subaortic stenosis (DSS) is often diagnosed early in life and known for its sometimes rapid haemodynamic progression in childhood and strong association with aortic regurgitation (AR). However, data about the evolution of DSS in adulthood are scarce. Therefore, we aimed to evaluate the natural history of DSS, and identify risk factors for the progression of DSS, AR, and intervention-free survival. METHODS AND RESULTS: Conservatively managed adult DSS patients were included in this retrospective multicentre cohort study. Mixed-effects and joint models were used to assess the progression of DSS and AR, and intervention-free survival. Longitudinal natural history data were available for 149 patients [age 20 (IQR: 18-34) years, 48% male]. Sixty patients (40.3%) had associated congenital heart defects (CHDs). The median follow-up duration was 6.3 (IQR: 3.0-12.4) years. The baseline peak left ventricular outflow tract (LVOT) gradient was 32.3 ± 17.0 mmHg and increased by 0.8 ± 0.1 mmHg/year. While the baseline LVOT gradient (P = 0.891) or age (P = 0.421) did not influence the progression rate, the presence of associated CHD was associated with faster progression (P = 0.005). Mild AR was common (58%), but did not significantly progress over time (P = 0.701). The median intervention-free survival was 16 years and associated with the baseline LVOT gradient [hazard ratio (HR) = 3.9 (95% CI: 2.0-7.6)], DSS progression [HR = 2.6 (95% CI: 2.0-3.5)], and AR [HR = 6.4 (95% CI 2.6-15.6)]. CONCLUSION: In contrast to children, DSS progresses slowly in adulthood. In particular, patients with associated CHD are at risk for faster progression and should be monitored cautiously. Discrete subaortic stenosis progression is not influenced by the baseline LVOT gradient or age. Mild AR is common, but non-progressive over time.

Aortic Valve Embryology, Mechanobiology, and Second Messenger Pathways: Implications for Clinical Practice.

During the Renaissance, Leonardo Da Vinci was the first person to successfully detail the anatomy of the aortic root and its adjacent structures. Ever since, novel insights into morphology, function, and their interplay have accumulated, resulting in advanced knowledge on the complex functional characteristics of the aortic valve (AV) and root. This has shifted our vision from the AV as being a static structure towards that of a dynamic interconnected apparatus within the aortic root as a functional unit, exhibiting a complex interplay with adjacent structures via both humoral and mechanical stimuli. This paradigm shift has stimulated surgical treatment strategies of valvular disease that seek to recapitulate healthy AV function, whereby AV disease can no longer be seen as an isolated morphological pathology which needs to be replaced. As prostheses still cannot reproduce the complexity of human nature, treatment of diseased AVs, whether stenotic or insufficient, has tremendously evolved, with a similar shift towards treatments options that are more hemodynamically centered, such as the Ross procedure and valve-conserving surgery. Native AV and root components allow for an efficient Venturi effect over the valve to allow for optimal opening during the cardiac cycle, while also alleviating the left ventricle. Next to that, several receptors are present on native AV leaflets, enabling messenger pathways based on their interaction with blood and other shear-stress-related stimuli. Many of these physiological and hemodynamical processes are under-acknowledged but may hold important clues for innovative treatment strategies, or as potential novel targets for therapeutic agents that halt or reverse the process of valve degeneration. A structured overview of these pathways and their implications for cardiothoracic surgeons and cardiologists is lacking. As such, we provide an overview on embryology, hemodynamics, and messenger pathways of the healthy and diseased AV and its implications for clinical practice, by relating this knowledge to current treatment alternatives and clinical decision making.

How microsimulation translates outcome estimates to patient lifetime event occurrence in the setting of heart valve disease.

Treatment decisions in healthcare often carry lifelong consequences that can be challenging to foresee. As such, tools that visualize and estimate outcome after different lifetime treatment strategies are lacking and urgently needed to support clinical decision-making in the setting of rapidly evolving healthcare systems, with increasingly numerous potential treatments. In this regard, microsimulation models may prove to be valuable additions to current risk-prediction models. Notable advantages of microsimulation encompass input from multiple data sources, the ability to move beyond time-to-first-event analysis, accounting for multiple types of events and generating projections of lifelong outcomes. This review aims to clarify the concept of microsimulation, also known as individualized state-transition models, and help clinicians better understand its potential in clinical decision-making. A practical example of a patient with heart valve disease is used to illustrate key components of microsimulation models, such as health states, transition probabilities, input parameters (e.g. evidence-based risks of events) and various aspects of mortality. Finally, this review focuses on future efforts needed in microsimulation to allow for increasing patient-tailoring of the models by extending the general structure with patient-specific prediction models and translating them to meaningful, user-friendly tools that may be used by both clinician and patient to support clinical decision-making.