Presence of mitral stenosis is a risk factor of new development of acute decompensated heart failure early after transcatheter aortic valve implantation

Study population

This single-centre prospective observational study included 156 consecutive patients with symptomatic severe AS who underwent TAVI at Osaka City University Hospital between January 2016 and February 2018 (figure 1). TAVI at our institution during the study period was indicated for patients at high risk for surgery. The inclusion criteria were as follows: (1) presence of symptoms, (2) presence of degenerative AS, (3) an estimated mean transaortic valve pressure gradient (mAVPG) of >40 mm Hg or a jet velocity of >4.0 m/s, and/or (4) an aortic valve area <1.0 cm² (or an effective orifice area index <0.6 cm²/m²) by transthoracic echocardiography (TTE), according to the guideline for valvular heart disease of the European Society of Cardiology and the European Association for Cardio-Thoracic Surgery.15 The indication and surgical risk for TAVI were determined based on the clinical consensus of a heart team comprised of cardiac surgeons, interventional cardiologists, anaesthesiologists and imaging specialists. For example, patients with a Society of Thoracic Surgery-Predicted Risk of Mortality (STS-PROM) score≧8, patients with frailty, and patients aged≧80 years were considered to be high surgical risk in the present study. Written informed consent was obtained from all patients. The authors had full access to the data and were responsible for its integrity. All authors have read and agreed to the manuscript as written.

Request permission

Standard procedure of TAVI

We chose the transfemoral approach as the first option when patients did not have an excessively narrow access route for insertion of the sheath or aortic arch atheroma. We performed TAVI under general anaesthesia in a hybrid operating room, except for two patients who underwent conscious sedation due to pulmonary dysfunction. Transcatheter heart valves were classified as balloon-expandable (Edwards Sapien XT or Sapien 3 Transcatheter Heart Valve; Edwards Lifesciences, Irvine, California, USA) or self-expandable (Medtronic classic CoreValve or CoreValve EvolutR; Medtronic, Minneapolis, Minnesota, USA). Balloon-expandable valves were the first choice, and self-expandable valves were reserved for patients with a narrow aortic annulus. We performed simultaneous catheter measurement to evaluate the invasive mAVPG as well as a measurement of left ventricular end-diastolic pressure before and after TAVI. After successful TAVI, patients were given a saline solution by intravenous infusion (1 mL/kg/hour) until the start of ingestion. The brachial blood pressure was maintained at less than 130 mm Hg using calcium channel blocker, if necessary.

Data collection

All data shown in the tables and figures were collected prospectively from patient records. Because this study aimed to generate hypothesis, preprocedural TTE evaluated AS-related indices as well as mitral stenosis (MS)-related findings such as the transmitral valve pressure gradient and presence or absence of mitral annular calcification (MAC). We defined significant MS as a mean mitral pressure gradient ≧5 mm Hg and defined MAC as a structure producing intense echocardiographic signals located at the junction of the atrioventricular groove and posterior mitral leaflet, although severe AS could result in low-flow, low-gradient MS with prolonged pressure half time which is related to impaired left ventricular relaxation.16–18 We also assessed the left ventricular diastolic function using transmitral E/A value with pulse-wave Doppler or the E/e’ value measured at the mitral annulus septum with tissue Doppler for reference. However, it is difficult to evaluate diastolic function with E/e' in the presence of MS, as stated in the American Society of Echocardiography guidelines.19 20 Multislice CT data were measured with the SYNAPSE VINCENT (Fujifilm, Japan). We defined areas with CT value of ≧600 Hounsfield units as calcification and individually measured the calcium volume of the aortic valve complex and that of the mitral valve apparatus (leaflet and annulus).21

Endpoint and statistical analysis

We set the primary endpoint as the new development of ADHF within 72 hours after the procedure and the objective of the present study was to investigate its risk factors. We defined the new development of ADHF after TAVI as worsening of HF symptoms, such as dyspnoea with objective signs of congestion like pulmonary oedema or hypoperfusion requiring treatments such as intravenous administration of diuretics, vasodilator, inotropes or respiratory supports based on recommendations by international guidelines.22

Continuous variables were summarised using medians and IQR (quartiles 1–3), and categorical variables were summarised using means of counts and percentages. We first divided our patients into two groups depending on the presence or absence of ADHF within 72 hours after TAVI and compared patient backgrounds because this is the hypothesis-generating study. Differences in continuous and categorical variables between groups were compared using the Wilcoxon rank-sum test and the χ² test, respectively. Then, the prespecified analysis included the evaluation of the risk factors of the new development of AHDF in the early phase after TAVI using univariable logistic regression analysis with its 95% CI. Since the absolute number of primary endpoint was estimated to be low, ad hoc adjustments of confounding factors by multivariable regression model was admitted only as a reference in the prespecified statistical protocol. In the multivariable model, we determined the confounders statistically based on the Akaike information criteria (AIC) and also performed conventional multivariable model employing variables, which showed statistical significance in the univariable logistic regression model. To avoid the problem of multicollinearity, New York Heart Association (NYHA) functional classification and urgency of the procedure were not used because these indices are included in the STS-PROM score, and invasive mAVPG improvement was selected as a representative value for preprocedural and postprocedural severity of AS in a multivariable model. In addition, we employed classification and regression tree (CART) analysis to reveal the most important risks among these variables.23 Furthermore, since AIC-based multivariable logistic regression and CART analyses revealed that the presence of MS was strongly associated with primary endpoint, we estimated and compared 2-year survival with its 95% CI after TAVI using the Kaplan-Meier method in patients with or without MS. The difference between groups was evaluated using the log-rank test. Statistical analyses were performed using R software packages (V.3.3; R Development Core Team). The significance level of a statistical hypothesis testing was set at 0.05 and the alternative hypothesis was two sided.

Mechanism of developing ADHF after TAVI

In general, the pathophysiology of developing HF is considered multifactorial, and numerous disparate aetiologies are indicated in previous reports such as left ventricular dysfunction, coronary artery diseases and valvular diseases.22 Furthermore, alternative access, such as transapical TAVI, could lead to the development of HF due to its invasiveness compared with the transfemoral approach.25 However, the risk factors or mechanisms of ADHF early after TAVI has yet to be fully elucidated although in-hospital ADHF after TAVI is sometimes encountered in the clinical setting.3–5 8–14 Based on the results of the present study, we hypothesised that rapid worsening of haemodynamics associated with increased cardiac output after TAVI and resultant increase of left atrial pressure due to severe MS play an important role in the development of ADHF early after TAVI. That is, in the first step, TAVI could immediately release the left ventricular outflow obstruction, which then leads to a drastic increase in cardiac output.26 Actually, it is reported that cardiac index increase from 2.0±0.6 L/min/m² to 3.1±0.7 after TAVI.26 We also hypothesised that a greater decrease in mAVPG, namely greater improvement of mAVPG through greater release of the left ventricular outflow obstruction, can be associated with higher cardiac output and resulting high-output HF. However, in the next step, the left atria with significant MS could not sufficiently handle the increased left atrial volume overload from the pulmonary vein. This also led to severe left atrial volume overload, increased the left atrial and pulmonary artery wedge pressures, and led to rapid progression of pulmonary oedema. Considering these, it is intuitively understandable that both MS and improvement of mAVPG were associated with the new development of ADHF early after TAVI in the present study. Thus, we hypothesised that ADHF after TAVI is categorised as so-called high-output HF, which easily emerges when complicated with MS.

Clinical implication

We believe that our results remind us one important and two possible clinical implications. First, it is noteworthy that the OR of significant MS was much greater than those of other variables and that CART analysis suggested that the most predictive index of new development of ADHF early after TAVI was significant MS. Since the high incidence of comorbid MS (>10%) due to degenerative MAC (>45%) in patients who undergo TAVI, it is important to know the potential risk of MS.13 27 28 Preprocedural risk stratification and risk assessment such as in-hospital ADHF early after TAVI may contribute to the improvements of outcomes in AS patients who undergo TAVI. Actually, Joseph et al reported that severe MS was an independent predictor of in-hospital death and indicated that severe MS was an independent predictor of 1-year mortality and HF-related hospitalisation.13 Furthermore, Asami et al reported that patients with MS had an increased risk of cardiovascular death both at 30 days (adjusted HR 4.05: 95% CI 2.10 to 7.82) and 1 year (adjusted HR 3.64: 95% CI 2.38 to 5.56).29 Considering the above-mentioned possible mechanisms of developing ADHF early after TAVI, it is intuitively understandable that MS may affect not only the development of in-hospital ADHF but also long-term prognosis after TAVI in the same mechanisms through high-output type haemodynamic impairment. Actually, this is consistent with our results demonstrating higher 2-year mortality in patients with significant MS than those without MS (figure 3). Second, we speculated that measurements of cardiac output, transmitral valve pressure gradient, left atrial pressure using pulmonary artery wedge pressure, especially after TAVI, may be recommended in assessing the risk of ADHF when treating patients with severe AS complicated with significant MS. Finally, risks and benefits of concomitant management of significant MS can be next objectives when external validity of the risk of significant MS after TAVI was established although definite management choices are unknown for the management of significant MS at present.

Study limitations

This study has several limitations due to the nature of single-centre design. First, the small study population (n=156) and low incidence of primary endpoint underpowered the statistical analysis, and there are some differences regarding baseline characteristics, such as AS severity and HF condition, between study groups even though we tried to minimise these differences using multivariable models. The management of perioperative HF in the ADHF group was insufficient partly because we could not help but manage AS patients complicated with MS in a wet volume condition, in order to avoid low-output HF associated with AS and MS. Second, although we defined significant MS as a mean mitral pressure gradient ≧5 mm Hg according to the guidelines of the American and European Society of Echocardiography, severe AS could underestimate the mitral valve pressure gradient.18

Also, the planimetry data using three-dimensional transoesophageal echocardiography were not available although it is prioritised for the diagnosis of MS complicated with AS in the current guidelines, because we were unaware of the guidelines when we planned the study in 2016.18 Third, external validity cannot be secured and should be evaluated in future studies. Lastly, we did not perform direct measurements of cardiac output and pulmonary artery wedge pressure, although these two factors may be important to verify our above-mentioned hypothesis that rapid worsening of haemodynamics is associated with increased cardiac output after TAVI and resultant increase of left atrial pressure due to severe MS. Hence, readers should keep in mind these limitations when interpreting these results, especially considering the critical limitation of low incidence of the primary endpoint, although that we employed two kinds of analyses in order to validate a robustness of our results.

In conclusion, MS and drastic improvement of mAVPG were associated with the new development of ADHF within 72 hours after TAVI.

In-out balance was calculated as a volume of infusion and blood transfusion minus urine output.