The outcome of patients treated with TIPS is often unpredictable, because the favourable effects of stenting on bleeding and ascites can be negated by the risk of progressive liver failure that leads to death within a few months or even weeks. The most likely cause of this negative event is a reduction in portal vein liver perfusion not compensated for by an increase in arterial perfusion. This makes it plausible that cardiac and haemodynamic dysfunction and their features can be related to the probability of post‐TIPS survival.
The present study shows that a post‐TIPS E/A ratio
1, a feature of diastolic dysfunction, is significantly related to the death of patients with cirrhosis treated with TIPS. The only other variable associated with death in the univariate analysis was a high baseline MELD, a score originally obtained as a predictor of the outcome of patients with cirrhosis treated with TIPS,16
and recently validated in other clinical contects of liver cirrhosis.17,18,19
Cox's regression analysis showed that the post‐TIPS E/A ratio was independently related to death. However, owing to the low number of patients and end points, the confidence of this result, as suggested by the wide confidence interval, is limited.
It is worth mentioning that no patients with a post‐TIPS E/A ratio >1 died during the first year of follow‐up, whereas 6 of 10 patients with E/A
1 died during the same period (fig 2). This could mean that the E/A ratio might be a useful predictor in patients who receive TIPS as a bridge to liver transplantation, because patients with a post‐TIPS E/A ratio
1 should be transplanted sooner than those with a normal E/A ratio. However, any potential clinical application of E/A ratio in this setting should be preceded by confirmation of the present results in an independent cohort of patients with cirrhosis.
As no patient participating in this study died of cardiac failure, the reason why the presence of post‐TIPS diastolic dysfunction was related to shorter survival is uncertain. The most favoured hypothesis is that diastolic dysfunction can simply identify patients with more advanced liver disease, who have a high risk of dying after TIPS because of progressive liver failure caused by the reduction of hepatic blood perfusion, or who have a high risk of developing classic cirrhotic complications. This hypothesis is supported by the association found between a low post‐TIPS E/A value and a baseline elevated MELD score, which encompasses variables estimating both liver and kidney functions. A strict relationship between cardiac diastolic dysfunction and liver function is also supported by the evidence that the E/A ratio is lower in patients with ascitis than in those with compensated cirrhosis,8
and by the recent demonstration that diastolic dysfunction can be completely reversed after liver transplantation.20
However, a different explanation is possible, involving the concept that, although patients with diastolic dysfunction do not show overt cardiac failure, they have a substantial limitation in exercise tolerance, owing to a limited ability to use the Frank–Starling mechanism.21
Indeed, impaired cardiac response and a reduction in anaerobic capacity in patients with cirrhosis during physical exercise were demonstrated by Wong et al
Accordingly, patients with cirrhosis with diastolic dysfunction might have a subtle cardiac dysfunction that makes them more fragile when they develop serious complications such as renal failure or sepsis. This hypothesis is supported by our finding that six out of the nine patients who died because of hepatorenal syndrome had a post‐TIPS E/A ratio
1. A role played by the heart in the occurrence and outcome of hepatorenal syndrome was also suggested by Ruiz del Arbol et al
who found that, in patients with cirrhosis with spontaneous bacterial peritonitis, the risk of hepatorenal syndrome and death was inversely related to the cardiac output.
The origin of diastolic dysfunction in patients with cirrhosis is also a topic of debate.24
The study presented here found no relationship between the presence of diastolic dysfunction and the alcoholic or viral aetiology of liver disease, thus confirming that cirrhotic cardiomyopathy is independent of alcohol aetiology. As the prevalence of diastolic dysfunction varies directly with the mean age of the population,21
it cannot be excluded that older age adversely affected the E/A ratio of some patients, considering that there was a slight but insignificant correlation of E/A ratio with age (p
0.1) in the study.
Conceptually, diastolic dysfunction occurs when the process of ventricular relaxation is prolonged, slowed or incomplete.21
This abnormality can be caused by increased stiffness in the ventricle,25
and also by any event that reduces the left atrial pressure, including low blood volume and low preload.5,12
Some investigators suggested that the increased stiffness of the myocardium, which causes diastolic dysfunction in cirrhosis, is due to thickening of the ventricular walls and of the interventricular septum,4,26,27
but others did not find any modification in the width of the ventricular walls.2
However, the structural characteristics of the hearts of the patients in this study were not investigated. Hyperaldosteronism is a common finding in patients with decompensated cirrhosis and has been shown to have a direct effect on the heart by way of causing fibrosis, stiffness and diastolic dysfunction,28
but a significant relationship between plasma aldosterone levels and the E/A ratio was not found in this study. Recently, Pozzi et al29
showed that a 6‐month administration of an aldosterone receptor antagonist to patients with Child A cirrhosis did not improve the low E/A ratio but reduced the end LVEDV and the left ventricular wall thickness. However, the inefficacy of the E/A ratio could have been due to the inadequate period of treatment.
In the study presented here, the changes in E/A ratio after TIPS were directly correlated with the changes in ANP concentrations and inversely correlated with the changes of PRA. Taking into account the relationships of these hormones with the effective blood volume, it is conceivable that, at least in patients in whom TIPS insertion normalised the E/A ratio, the low pre‐TIPS E/A ratio was partly due to central hypovolaemia and low atrial pressure, which were corrected after TIPS. An increase in central blood volume was also suggested by the observation that, after TIPS cardiac output, LVEDV and LVESV significantly increased but the blood pressure did not change. Conversely, in patients in whom TIPS did not normalise the E/A ratio, diastolic dysfunction might have been caused by structural alterations of the myocardium, involving a limited ability to use the Frank–Starling mechanism to increase SV.30
Indeed, unlike their counterparts with a normal E/A ratio, patients with a post‐TIPS E/A ratio
1 showed a reduction in SV and a failure in ANP increase after TIPS insertion (table 4). This interpretation could also explain why the post‐TIPS E/A ratio, but not the pre‐TIPS E/A ratio, was able to predict patient outcome in this study.
The main limitation of the present study is the relatively small number of patients; hence, the possibility of type 2 error cannot be excluded. In this case, the statistical analysis could have overlooked evidence for other predictive factors and differences. These limitations mean that further evaluation of the E/A ratio in a larger and independent cohort of patients is necessary before it can be adjudged a useful predictor in patients with TIPS.
In conclusion, a low E/A ratio, a feature of diastolic dysfunction that may be easily measured by pulsed Doppler during echocardiography, is shown to independently predict death in patients with TIPS. Measuring the E/A ratio is a simple, non‐invasive and cheap investigative technique that can be repeated as often as necessary and is a good prerequisite for a predictive test. Moreover, this result corroborates the hypothesis that cirrhotic cardiomyopathy is actively involved in the clinical outcome of patients with cirrhosis and deserves to be studied in other complications of portal hypertension.