Frederik J. de Lange

Lineage and Morphogenetic Analysis of the Cardiac Valves

We used a genetic lineage-labeling system to establish the material contributions of the progeny of 3 specific cell types to the cardiac valves. Thus, we labeled irreversibly the myocardial (&agr;MHC-Cre+), endocardial (Tie2-Cre+), and neural crest (Wnt1-Cre+) cells during development and assessed their eventual contribution to the definitive valvar complexes. The leaflets and tendinous cords of the mitral and tricuspid valves, the atrioventricular fibrous continuity, and the leaflets of the outflow tract valves were all found to be generated from mesenchyme derived from the endocardium, with no substantial contribution from cells of the myocardial and neural crest lineages. Analysis of chicken-quail chimeras revealed absence of any substantial contribution from proepicardially derived cells. Molecular and morphogenetic analysis revealed several new aspects of atrioventricular valvar formation. Marked similarities are seen during the formation of the mural leaflets of the mitral and tricuspid valves. These leaflets form by protrusion and growth of a sheet of atrioventricular myocardium into the ventricular lumen, with subsequent formation of valvar mesenchyme on its surface rather than by delamination of lateral cushions from the ventricular myocardial wall. The myocardial layer is subsequently removed by the process of apoptosis. In contrast, the aortic leaflet of the mitral valve, the septal leaflet of the tricuspid valve, and the atrioventricular fibrous continuity between these valves develop from the mesenchyme of the inferior and superior atrioventricular cushions. The tricuspid septal leaflet then delaminates from the muscular ventricular septum late in development.

Two Distinct Pools of Mesenchyme Contribute to the Development of the Atrial Septum

Closure of the primary atrial foramen is achieved by fusion of the atrioventricular cushions with the mesenchymal cap on the leading edge of the muscular primary atrial septum. A fourth component involved is the vestibular spine, originally described by His in 1880 as an intra-cardiac continuation of the extra-cardiac mesenchyme of the dorsal mesocardium. The morphogenesis of this area is of great clinical interest, because of the high incidence of atrial and atrioventricular septal defects. Nonetheless, the origin of the participating components is largely unknown. Here we report that the primary atrial foramen is surrounded in its entirety by mesenchyme derived from endocardium. A second population of mesenchyme not derived from endocardium was observed at the caudal margin of the mesenchymal atrial cap, entirely embedded within the mesenchyme derived from endocardium and contiguous with the mesenchyme of the dorsal mesocardium. Our reconstructions show this second population does indeed take the form of a short spine, albeit that it is the right pulmonary ridge, rather than this spine, that protrudes into the atrial lumen. From the stance of morphological description, therefore, there is little thus far to substantiate the existence of an atrial spine.

Distinct Regulation of Developmental and Heart Disease–Induced Atrial Natriuretic Factor Expression by Two Separate Distal Sequences

Nppa, encoding atrial natriuretic factor, is expressed in fetal atrial and ventricular myocardium and is downregulated in the ventricles after birth. During hypertrophy and heart failure, Nppa expression is reactivated in the ventricles and serves as a highly conserved marker of heart disease. The Nppa promoter has become a frequently used model to study mechanisms of cardiac gene regulation. Nevertheless, the regulatory sequences that provide the correct developmental pattern and ventricular reactivation during cardiac disease remain to be defined. We found that proximal Nppa fragments ranging from 250 bp to 16 kbp provide robust reporter gene activity in the atria and correct repression in the atrioventricular canal and the nodes of the conduction system in vivo. However, depending on fragment size and site of integration into the genome of mice, the fetal ventricular activity was either absent or present in an incorrect pattern. Furthermore, these fragments did not provide ventricular reactivation in heart disease models. These results indicate that the proximal promoter does not provide a physiologically relevant model for ventricular gene activity. In contrast, 2 modified bacterial artificial chromosome clones with partially overlapping genomic Nppa sequences provided appropriate reactivation of the green fluorescent protein reporter during pressure overload–induced hypertrophy and heart failure in vivo. However, only 1 of these bacterial artificial chromosomes provided correct fetal ventricular green fluorescent protein activity. These results show that distinct distal regulatory sequences and divergent regulatory pathways control fetal ventricular activity and reactivation of Nppa during cardiac disease, respectively.

History taking as a diagnostic test in patients with syncope: developing expertise in syncope

Transient loss of consciousness (T-LOC) is very common and caused by many disorders spanning multiple specialties with consequences varying from benign to lethal, necessitating an accurate, efficient diagnostic work-up. The European Society of Cardiology Guidelines on Syncope recommends that the initial work-up of suspected syncope consists of history taking, a physical examination, and ECG. The emphasis on taking a history is justified by its high diagnostic yield.1,2 Surprisingly, there is relatively little research on how data from the medical history are collected and analysed in syncope patients. While a few studies have described evidence-based point scores for diagnosing patients with syncope, the added value of expert history taking in syncope has received less attention.2 The diagnostic yield of the initial work-up by non-expert physicians in patients with T-LOC according to the ESC guidelines is reported to be 60–70% with history taking as the main factor,3 while after standardized evaluation in dedicated units (syncope units) ∼85% of patients are reported to be diagnosed.4,5 The diagnostic yield of expert history taking in patients who remain undiagnosed after standardized approaches according to the management model proposed by the ESC is unknown. The focus of this current opinion is on the roles of evidence-based point scores and expert history taking in diagnosing suspected syncope. An effective diagnostic strategy for syncope requires knowledge of other causes of T-LOC and hence requires training or experience in relevant aspects of cardiology, neurology, internal medicine, emergency medicine, paediatrics, geriatrics, and psychiatry. These specialties are all within general internal medicine, which has become fragmented leading to decrease in the broad skills of history taking and physical examination. The majority of patients with suspected syncope have vasovagal or other types of reflex syncope like situational or carotid sinus syncope. In the emergency …

The heart cannot pump blood that it does not receive

Orthostatic gravitational stress results in a decrease in venous return. Because the heart cannot pump blood that it does not receive, ventricular stroke volume and cardiac output decline, but until the point of presyncope, there is little change in arterial pressure. There is little doubt that the vasomotor outflow to the resistance vessels and presumably the splanchnic capacitance vessels are of fundamental importance in the prevention of hypotension (Rowell, 1993; Wieling and van Lieshout, 2008), but there is also a concomitant increase in heart rate and the significance of this is much less clear (Hainsworth, 2000). In a recent issue of Frontiers in Physiology, Convertino focussed on the physiology of maximal compensation to orthostasis studying high and low tolerant healthy subjects. Exposure to a maximal lower body negative pressure (LBNP) test was used to quantify orthostatic tolerance. The author argues that this stressor is equivalent to actual orthostasis. However, recent studies suggest that pooling in the splanchnic area during actual orthostasis (standing/head-up tilting) is more important than previously reported in studies using simulated orthostasis by applying lower-body negative pressure up to the levels of the iliac crest (Taneja et al., 2007). More pronounced splanchnic pooling during orthostasis may result in more stimulation of vascular subdiaphramatic receptors that are postulated to play a role in orthostatic adjustment by causing vasoconstriction and augmentation of the carotid baroreflex (Doe et al., 1996). Other obvious differences with LBNP are that during free standing the carotid baroreceptors are always above the heart and the static increase in skeletal muscle tone during active standing opposes pooling of blood in limb veins (Wieling and van Lieshout, 2008; Wieling et al., 2014). Increases in skeletal muscle tone are a key factor in orthostatic adjustment. Accordingly, a static increase in skeletal muscle tone by leg-crossing during a maximal LBNP test increases time to presyncope considerably (Krediet et al., 2006). Therefore, a device which combines head-up tilting with negative pressure to the lower part of the body (Hainsworth, 2000) seems a more physiological approach to quantify orthostatic tolerance in a reproducible way. Although LBNP (in the horizontal position) is a deficient model for studying orthostasis, it can be used to simulate loss of central blood volume (hemorrhage) (Johnson et al., 2014). As far as the physiology of maximal hemodynamic compensation in high and low tolerant healthy subjects, the author reaffirms the concept that the heart rate response contributes significantly to orthostatic tolerance (Convertino, 2014). The observations of Convertino are of considerable interest, but it important to realize that they are based on studies in young adult healthy subjects exposed to a maximal LBNP stress. The observations cannot be generalized to the adjustment to the upright posture during free standing. Based on clinical observations the following data indicate that neural heart rate control is not important for orthostatic tolerance. Weissler studied the effects of posture and atropine on the cardiac output in six young adult male subjects. He documented that atropine administered in the supine position increased heart rate on average by 44 beats/min. The heart rate increase was accompanied by a cardiac output rise of about a factor 2 with an increase in mean arterial pressure. After administration of atropine in the upright posture heart rate increase by 65 beats/min, but no effect on cardiac output and blood posture were observed. When pooling of blood in the upright posture was prevented by sustained inflation of an anti-gravity suite, the cardiac responsiveness to atropine in tilted subjects was restored, in part (Weissler et al., 1957a). In another study it was documented that administration of atropine could not prevent an impending vasovagal faint (Weissler et al., 1957b). Patients with a cardiac transplants have no increase in heart rate on standing, but intact orthostatic blood pressure control (Figure ​(Figure1,1, left panel) (Van Lieshout et al., 1989; Wieling and Karemaker, 2013). Figure 1 Blood pressure and heart rate responses induced by active standing in a 38 year-old fit patient with a cardiac transplant (left panel) and a 23-year-old female patient with orthostatic hypotension (hypoadrenergic) with intact heart rate control (right ... In patients with sympathetic vasomotor lesions, but intact vagal heart rate control pronounced orthostatic hypotension occurs despite an impressive postural tachycardia (Figure ​(Figure1,1, right panel) (Wieling and Karemaker, 2013). Atrial tachypacing at best has marginal effects on hypotension in patients with severe orthostatic hypotension due to autonomic failure (Sahul et al., 2004) and cardiac pacing does not improve orthostatic tolerance in patients with vasovagal syncope (El-Bedawi et al., 1994). However, benefit from rate-drop pacing in older patients with documented prolonged asystolic syncope has been reported (Brignole et al., 2012). Another example of the disconnect between the heart rate responses and orthostatic tolerance are patients with the postural orthostatic tachycardia syndrome in whom very high orthostatic heart rates are associated with orthostatic presyncope. The treatment in these patients is aimed at decreasing postural complaints by decreasing the postural tachycardia (Joyner, 2011). These data strongly support the view that the central venous reservoir is an important determinant of cardiac responsiveness to changes in heart rate i.e., a heart cannot pump blood that it does not receive. In fact, very high heart rates would decrease cardiac filling time and during conditions of impaired venous return such as orthostatic stress, could actually impair cardiac output (Hainsworth, 2000). The positive correlation between orthostatic tolerance and the maximal sympathetically mediated heart rate before syncope in high and low tolerant healthy subjects observed by Convertino may have been because in this situation heart rate is a marker for enhanced sympathetic drive to resistance vessels, which provide the main defense against hypotension (Rowell, 1993; Hainsworth, 2000). In conclusion, The arterial (and especially carotid) baroreceptor control of sympathetic motor tone of resistance and splanchnic capacitance vessels in combination with the central blood volume are the most important components in the maintenance of postural normotension in humans (Rowell, 1993; Wieling and van Lieshout, 2008). Activation of the skeletal muscle pump in the lower body can compensate in part for defects in control of vasomotor tone and a reduction of central blood volume. Cardiac effector mechanisms appear not to be important for the adjustment of arterial pressure to the upright posture.

Practical Instructions for the 2018 ESC Guidelines for the diagnosis and management of syncope

The content of these European Society of Cardiology (ESC) Guidelines has been published for personal and educational use only. No commercial use is authorized. No part of the ESC Guidelines may be translated or reproduced in any form without written permission from the ESC. Permission can be obtained upon submission of a written request to Oxford University Press, the publisher of the European Heart Journal and the party authorized to handle such permissions on behalf of the ESC (journals.permissions@oxfordjournals.org).

To the Editor : History taking as a diagnostic test in patients with vasovagal syncope

The 2015 Heart Rhythm Society Expert Consensus Statement on Diagnosis and treatment of Postural Tachycardia Syndrome, Inappropriate Sinus Tachycardia, and Vasovagal Syncope (of which one of us [RS] was a co-author) is an evidence-based document intended to help front-line cardiologists. As far as the diagnosis of vasovagal syncope is concerned, there is some emphasis on history taking, but a crucial point not addressed in the HRS Consensus is that collecting information on what has happened is not as straightforward as it seems. History taking as a diagnostic test is not a simple issue. It makes a great difference whether the data are collected by checklists or questionnaires vs an interview by an experienced syncope doctor. The medical history is an operatordependent test. A highly likely diagnosis can be made by a nonexpert in 60% to 70%, and with expert history taking the yield rises to 90%. The initial one-on-one encounter between patient and clinician occurs before application of diagnostic scores. The 80% to 100% positive diagnostic probability from history building with a patient (ie, the patient’s narrative) is very different from the 80% to 100% test positive probability based on a diagnostic procedure. What level of diagnostic certainty is needed in patients with suspected syncope before management can commence? If cardiac syncope is unlikely, given the medical history, a 60% to 80% subjective probability based on the history is sufficient to reassure and advise the patient. The aim of the diagnosis is to reduce recurrences and improve quality of life. It is not to obtain a rigorously defined 100% diagnostic certainty. Application of evidence-based medicine is important in the evaluation of patients with suspected syncope, but building a narrative with a patient comes first and may be all that is required.

Syncopedia: training a new generation of syncope specialists

Syncopedia is a free-access educational website targeted at students, residents and physicians who want to learn about syncope (Fig. 1). The website is an initiative of the Syncopedia Foundation, a nonprofit organization founded in 2014. The goal of the Syncopedia Foundation is: “improving medical knowledge, especially in the field of syncope, and providing access to this knowledge by facilitating publications in digital or other forms, for example by building and maintaining websites.” The goal of the Syncopedia website is to enhance physicians’ knowledge of (suspected) syncope and reduce misdiagnosis, unnecessary testing, and excessive specialist consultations. Syncope is a symptom with many possible causes, requiring all-round rather than organ-specific knowledge. Unfortunately, thorough history taking and a knowledge of cardiovascular physiology are no longer included in the core medical curricula [1, 2]. In this editorial, we address the importance of history taking in patients with suspected syncope and emphasize that, while a knowledge of cardiovascular physiology is important, a deep understanding is better for optimal syncope care. Initial evaluation of patients with transient loss of consciousness

Effectiveness of a Cardiovascular Evaluation and Intervention in Older Fallers: A Pilot Study

To the Editor: Cardiovascular abnormalities are increasingly being recognized as important fall-risk factors in older persons because syncope in older persons is often mistaken for falls because they have retrograde amnesia. Despite recommendations of falls guidelines, cardiovascular examinations are still not routinely performed in the evaluation of older fallers. Furthermore, the effectiveness of treating these abnormalities on fall incidence is uncertain. The efficacy and feasibility of a comprehensive cardiovascular evaluation and intervention were therefore studied in a prospective pilot study of individuals aged 65 and older with one or more falls in the past year referred to a falls clinic. In addition to the routine multidisciplinary falls assessment, in which “traditional” modifiable fall-risk factors were identified, a comprehensive cardiovascular assessment was performed, including structured history taking, echocardiography, electrocardiography, and tilt-table testing with continuous blood pressure (BP) recording. A multidisciplinary evaluation followed this, and treatment advice (cardiologist and geriatrician) was provided. Main cardiovascular fall-risk factors under consideration were orthostatic hypotension (OH), carotid sinus syndrome (CSS), vasovagal syncope, structural cardiac abnormalities (ventricular dysfunction, heart valve abnormalities), and cardiac arrhythmia, diagnosed according to syncope guidelines. The intervention was aimed at optimizing cardiovascular function (drug interventions, specific advice, invasive diagnostics and treatment) to improve the effectiveness of the multifactorial intervention. The primary outcome measure was diagnosis of one or more additional cardiovascular conditions that contributed to the fall incident, followed by subsequent treatment. Secondary outcome measures included feasibility of the multidisciplinary intervention, fall incidents, and related injuries during 6 months of follow-up. Fifteen participants were included (mean age 75 7, 67% female). In 10 participants, a diagnosis was made upon comprehensive cardiovascular examination. These abnormalities were considered a cause or contributing factor to the fall incident in seven participants (47%): initial OH in four, delayed OH in one, CSS in one, and drug-induced hypotension in one (Table 1). Five participants (33%) fell during follow-up; one fall was injurious. The evaluation and intervention appeared to be feasible in current clinical practice. Cardiovascular conditions can lead to near-syncope, and thus falls, in those who already have other fall-risk factors, such as unstable gait, poor vision, or use of sedative medications, whereas this is not necessarily the case for younger and healthier individuals. The results of the pilot study show that, even in participants in whom falls were considered explained after multifactorial falls assessment, cardiovascular abnormalities that contributed to their fall incidents were found. For diagnosis of initial OH and CSS, continuous noninvasive BP measurement is required, which is not yet routinely performed in most fall clinics. Therefore, two important modifiable risk factors (CSS and initial OH) may be overlooked in current fall-prevention care, because important BP drops may be missed using intermittent measurements. Echocardiographic and electrocardiographic abnormalities were found in half of participants, none of which were considered a contribution to the fall in this sample, but recent studies have linked atrial fibrillation, poor left ventricular function, and valve abnormalities to falls. This suggests that greater awareness of atrial fibrillation and structural cardiac abnormalities may be necessary in older fallers, but this requires further study. These results confirm the multifactorial nature of fall incidents and emphasized the need for a broad assessment of fallers, including cardiovascular risk factors. This contrasts with current syncope guidelines, in which detailed history taking is considered the cornerstone of syncope assessment. In six participants in whom a cardiovascular cause of or contribution to their fall was found, the Table 1. Findings of a Comprehensive Cardiovascular Evaluation in Older Fallers (N = 15)

Decreased left ventricular (LV) function is associated with hip-fractures

BACKGROUND Several risk factors for falls and hip-fractures have been recognized, but controversy still exists toward the importance of structural cardiac abnormalities as a potentially modifiable risk factor for recurrent falls. Aim of this study was to determine the association between echocardiographic abnormalities and hip-fractures. METHODS Design case-control study within consecutive patients undergoing hip-surgery in an academic hospital. CASES patients with traumatic hip-fractures. CONTROLS patients undergoing planned hip surgery (non-traumatic). INCLUSION CRITERIA age≥50 years, presence of pre-operative echocardiogram. EXCLUSION CRITERIA high energy trauma, pathological and/or previous hip-fracture. OUTCOME echocardiographic abnormalities (ventricular function, atrial enlargement, valve stenosis and/or regurgitation, pulmonary hypertension (pulmonary artery pressure (PAP) ≥35mmHg)). Multivariate logistic regression was performed to calculate odds ratios (OR) and to correct for confounders. RESULTS We included 197 patients (141 cases). Mean age was 77 years (SD), 65% female. After adjustment for potential confounders, decreased LV systolic function was associated with hip-fractures (OR 3.2 [95%CI 1.1-9.1]). Increasing severity of LV dysfunction was also associated with hip-fractures (p for trend=0.012). DISCUSSION In conclusion, patients with traumatic hip-fracture had greater risk of decreased LV function than patients who underwent planned hip-surgery. Possibly, decreased LV function is an underestimated risk factor for injurious falls.