Age-related changes of right atrial morphology and inflow pattern assessed using 4D flow cardiovascular magnetic resonance: results of a population-based study

Impaired venous return and right-heart function can be caused by a variety of pathologic conditions such as heart-failure, pulmonary hypertension, tricuspid valve disease, arrhythmogenic right ventricular (RV) cardiomyopathy and congenital heart disease [1‐3]. However, the likelihood of development of right heart failure is increased in elderly patients independent of the underlying disease [4]. The specific reasons for this age dependency remain unknown so far. The main diagnostic method used for monitoring right-heart pressures is the pulmonary floatation catheter [5]. However, this technique is an invasive procedure which requires a central venous access and can lead to complications such as pneumothorax and hemothorax, arterial laceration, cardiac arrhythmias, valvular damage, pulmonary artery perforation, false aneurysms, and catheter knotting in the case of right-heart catheterization [6]. A non-invasive alternative for assessment of morphological and functional aspects of the caval veins and right heart is 2D transthoracic echocardiography (TTE). Unfortunately, TTE accuracy is limited by the complex crescent shaped RV geometry and by its location behind the sternum [7]. While 3D-TTE can overcome some of these restraints, its applicability is often limited by suboptimal acoustic windows. This limitation can be overcome by using 3D imaging techniques such as 3D cardiovascular magnetic resonance (CMR) which can improve assessment of morphological features [8]. Furthermore, application of flow-sensitive 3D phase-contrast CMR (4D flow CMR) allows in-vivo visualization of blood flow from the caval veins through the right atrium (RA) into the RV [9]. 4D flow CMR was already used to highlight the role of vortex formation in healthy individuals as a driving force of RA filling [10]. Furthermore, it can be used to evaluate indices of RV systolic function from volume segmentation [11]. Despite its inherent potential to comprehensively assess right heart filling and associated pathologic conditions, most applications of cardiac 4D flow CMR, however, have focused on the left heart [12, 13] or the pulmonary arteries [11, 14].

One major reason for this may be the lack of age stratified reference data for 4D flow CMR, which hamper interpretation of hemodynamic findings. Therefore, it was our aim to assess age-related morphological and functional changes of the RV inflow tract using 4D flow CMR data obtained in an age-stratified population and to provide reference values for future clinical applications.

We performed 4D flow CMR of the RA inflow tract and the SVC and IVC in an age-stratified sample of 126 subjects of the population of a medium sized city in southern Germany. This is the first study investigating morphological and functional changes of the RA inflow tract in a large sample of the general population, systematically covering all age groups. Our results indicate that blood flow to the heart decreases with age. This effect may be a result of declining cardiac output which in turn leads to decreased venous return to the heart. One recent study quantified RA filling in 12 healthy subjects (8 male; 40 ± 13 years) using 4D flow CMR. They found similar combined stroke volumes of the RA inflow tract with a total stroke volume of 76.6 ± 21.4 ml (SVC 18.1 ± 7.1 ml; IVC 58.9 ± 19.6 ml) [10], compared to 75.9 ± 21.9 ml (SVC 24.5 ± 7.63 ml, IVC 51.3 ± 18.35 ml) in the group of 40–59 year old subjects in our study. The same was true for one study examining 10 healthy subjects (6 male; mean age 30 years) in which median flow at end inspiration was 31.0 ml in the SVC and 56.1 ml in the IVC [20], as compared to 24.2 ± 6.39 ml for the SVC and 57.2 ± 21.01 ml for the IVC in the group of 20–39 year old subjects in our study. A further study investigating SVC and IVC blood flow in atrio-pulmonary anastomosis did show higher stroke volumes in the SVC (70.0 ± 30.0 ml) and IVC (180.0 ± 40.0 ml) [21]. However, the SVC to IVC ratio (~ 1:2) was similar to our and the aforementioned studies [10, 21]. Interestingly, the ratio between SVC and IVC did not differ between different age groups in our study.

Our results indicate that morphological and functional changes of RA venous filling take place in the aging heart. Many studies have focussed on the effects of aging on left ventricular and left atrial morphology and the occurrence of cardiac hypertrophy and atrial fibrillation. However, our study is the first to systematically investigate morphological changes of the RA inflow tract during aging in a large sample of the general population. One recent study (13 healthy subjects [6 male, mean age 40 years] and 13 subjects [6 male, 40 years] with cryptogenic stroke and patent foramen ovale) also assessed the position of the caval veins by comparing the points at which the centerlines of the respective caval vein flows intersected with the orthogonal planes placed at the junction with the RA, and found positions of the caval veins to be constant in the antero-posterior direction but significantly variable in the right-left direction [22]. In the right-left plane the separation between the IVC and the SVC was greater in the group of subjects with patent foramen ovale compared to controls (10 ± 5 mm versus 3 ± 3 mm, p = 0.002) [22], as compared to 8.6 mm in the group of 60–80 year olds in our study.

RA volume was larger in older patients in our study and may explain the phenomena reported in our study in particular given the fact, that the occurrence of turbulences and the lateral axis shift was associated with changes in atrial volume. Our results regarding RAVI are lower than reported in the literature (54 mL/m2 [95% CI: 34, 75]) [18]. All diameters and areas derived from 2D images in the literature [18] and in our study were measured in the phase at which the RA size and volume measurements were at a maximum, i.e. ventricular systole. In the literature, measurements of RA volumes [18] were performed using retrospectively ECG triggered balanced steady-state free precession imaging end-expiratory breath-hold cines which were acquired in the two (left and right chambers) and four chamber views, with subsequent contiguous short-axis cines from the atrioventricular ring to the base of the atria. This sequence was not included in our current study protocol and our measurements were based on a combination of the extracted vessel surface based on 3D phase contrast CMR datasets and a volume rendering of the magnitude image. This may have resulted in underestimation of the absolute RA volumes, however as this effect applies to all our study subjects it should not have influence on the association of RA volumes and the flow phenomena reported in this study.

Cardiac looping during embryonic development leads to asymmetries and curvatures which have potential fluidic and dynamic advantages [23]. This is expressed by the uniform clockwise rotating helix of blood flow in healthy subjects comprising 80% of ventricular inflow volume as shown in a previous study [10]. This mechanism allows the momentum of inflowing streams to be redirected towards atrio-ventricular valves. Interference with ventricular ejection flow may be minimized by the change in direction at the ventricular level which can enhance ventriculo-atrial coupling and may minimize dissipative interaction between entering, recirculating and outflowing streams [23]. These factors might combine to improve hemodynamics when heart rate and output increase during exercise. However, this mechanism may be weakened by morphological changes of the aging heart such as divergence of the frontal axis of the caval veins and convergence of the lateral axis. As a result, the convergence of inflowing streams of blood from the IVC and SVC occurs at a different angle, which impedes formation of a clockwise rotating helix and makes room for turbulences to occur. These turbulences and the loss of fluidic and dynamic advantages lead to diminished inflow and may further increase susceptibility for right heart failure in elderly patients. Furthermore, one recent study showed that absence of the ‘standard’ vortex during systole and diastole was more common in 13 subjects with patent foramen ovale and cryptogenic stroke compared to age-matched controls [22]. Hence, future large scale studies on cryptogenic stroke may be a potential application of vortex analysis using 4D flow CMR in the RA.

Respiratory activity affects venous return through changes in RA pressure and changes of the volume of the caval veins (e.g. vena cava compression) and cardiac chambers (e.g. changing cardiac preload). During expiration the chest wall collapses and the diaphragm ascends which makes the intrapleural pressure become more positive resulting in reduction of cardiac chamber and caval vein size. All datasets were acquired in end-expiration in this study. Accordingly, absolute flow values and volumes presented here may be smaller compared with data acquisition in end-inspiration. However, as all datasets were acquired similarly this has no influence on the analysis of age-related changes of RA morphology and filling.

Potential limitations of our study were the relative small sample size and the amount of initial nonresponse to our study invitation. When compared with registry data [24] and data from another German population-based study [25] the subjects under investigation less often had hypertension, hypercholesterolemia, diabetes, were less often smokers, obese, and only few patients suffered from a cardiovascular disease. This was probably due to the recruitment modality which required participants to actively contact the study team and to visit the University Medical Center without receiving a reimbursement. Accordingly, particularly healthier or health-conscious residents were probably interested in collaborating in this study. Inclusion of sufficient number of young (20–29 years of age) males is a common problem in cohorts like ours. Accordingly, 14 included subjects were recruited from the personnel of our institution (n = 922 male 20–29 years of age) on the basis of first-come, first-served to minimize bias.

In conclusion, we have shown that 4D flow CMR can be used to visualize and assess flow in the caval veins and in the RA inflow tract. Furthermore, we provided reference values for 4D flow CMR based flow quantification in the caval veins. We demonstrated that age has a significant impact on caval blood flow and RV hemodynamics. This effect of aging should be taken into account when assessing pathologic conditions of the heart in future studies using 4D flow CMR. Findings of this population-based study are highly valuable for comparison with those in patients with manifest cardiac diseases.