Determinants and treatments of heart failure after transcatheter aortic valve implantation: moving up a notch

Abstract Transcatheter aortic valve implantation (TAVI) has become an alternative to surgical aortic valve replacement for patients with symptomatic severe aortic stenosis in elderly and comorbid population. Significant improvement in heart function has been observed in patients undergoing TAVI, but numerous patients are readmitted to hospital for heart failure (HF). Moreover, repeat HF hospitalization is strongly associated with an adverse prognosis and increases the financial burden of health care. Although studies have identified pre‐existing and post‐procedural factors that contribute to HF hospitalization after TAVI, there is a paucity of data regarding optimal post‐procedural pharmacological treatments. This review aims to provide an overview of the current understanding of mechanisms, determinants, and potential treatments of HF following TAVI. We first review the pathophysiology of left ventricular (LV) remodelling, coronary microcirculation disorder, and endothelial dysfunction in patients with aortic stenosis and then examine the impact of TAVI on these conditions. We then present evidence of various factors and complications that may interplay with LV remodelling and contribute to HF events after TAVI. Next, we describe the triggers and predictors of early and late HF rehospitalizations following TAVI. Lastly, we discuss the potential of conventional pharmacological treatments, including renin–angiotensin blockers, beta‐blockers, and diuretics in TAVI patients. The paper explores the potential of newer drugs, including sodium–glucose co‐transporter 2 inhibitors, anti‐inflammatory drugs, and ion supplementation. Comprehensive knowledge in this field may aid in recognizing successful existing therapies, developing effective new treatments, and establishing dedicated patient care strategies during follow‐up after TAVI.


Introduction
Over the past decade, transcatheter aortic valve implantation (TAVI) has emerged as a minimally invasive approach for treating patients with severe aortic stenosis (AS). Given the results from large clinical trials, 1-3 TAVI has become the preferred treatment option for severe AS in older populations from any surgical risk category except certain challenging anatomies (e.g. bicuspid aortic valves, severe peripheral artery disease, and extensive vessel and aortic tortuosity). De-spite overwhelming evidence of acceptable clinical outcomes in TAVI patients, a considerable number of patients are readmitted to the hospital due to heart failure (HF) after TAVI. 4 The latter can be attributed to the persistence of ventricular hypertrophy and fibrosis, diastolic dysfunction (DD), and microvascular dysfunction. 5 In real-world registries, the rate of HF hospitalization at 1 year after TAVI ranges from 12% to 24%, 4,6,7 suggesting a long-term HF phenotype in post-TAVI patients. As expected, acute HF is strongly associated with higher mortality at follow-up. 8 In this review, we offer an integrated framework for learning the pathophysiology, predictors, and outcomes of HF in TAVI patients and discussing the current and potential pharmacological treatments for this population.

Pathophysiology of heart failure in patients with aortic stenosis and effects of transcatheter aortic valve implantation
Pathophysiology of heart failure in patients with severe aortic stenosis Aortic stenosis is a common valvular heart disease in the ageing population that is characterized by a variable asymptomatic period preceding the development of symptoms. The left ventricular (LV) pressure overload induces hypertrophy and fibrosis, resulting in impaired LV filling and progressive cardiac dysfunction (Figure 1). 9,10 At an advanced stage, long-standing persistent LV hypertrophy induces oxygen sup-ply demand mismatch, reduced capillary density, and chronic subendocardial ischaemia. Eventually, this process causes LV dilatation and reduced systolic function, pulmonary hypertension (PH), right ventricular (RV) dysfunction, and functional mitral regurgitation (MR) and tricuspid regurgitation (TR) (Figure 1). 11 Additionally, coronary microvascular dysfunction (CMD) may result from LV hypertrophy caused by increased afterload. A recent translational study indicates that pressure overload by AS induces major transcriptional and metabolic adaptations in cardiac microvascular endothelial cells, resulting in excess interstitial fibrosis, capillary rarefaction, and impaired angiogenesis. 12 The microvascular endothelial dysfunction blunts the protective effect exerted by endothelial cells on cardiomyocytes, causing LV dysfunction and increased oxidative stress. 13 Recent advances in AS pathophysiology have suggested that microparticles (MPs) shed by activated cells under flow disturbance represent an important mediator of endothelial dysfunction. 14 The increased platelet and endothelial-derived MPs levels are significantly associated with CMD in patients with cardiovascular (CV) disease. Consistently, our previous report has described the relevance of circulating MPs in the induction of endothelial dysfunction and senescence under atheroprone flow conditions. 15

Impact of transcatheter aortic valve implantation in patients with severe aortic stenosis
Transcatheter aortic valve implantation immediately improves cardiac loading conditions, enabling the recovery of LV function, regression of LV mass, and consequent improvement of RV function and functional MR and TR following TAVI (Figure 2). [16][17][18][19][20][21] In biopsy-based studies, the regression of cellular hypertrophy and interstitial fibrosis content can be evidenced after aortic valve replacement. 22,23 A recent meta-analysis of 305 patients who completed preand post-TAVI cardiac magnetic resonance (CMR) demonstrated that LV reverse remodelling occurs within 6-15 months after TAVI. 24 Likewise, an improvement of microvascular function can be observed in TAVI patients. 25 This could be explained by the increased aortic flow, the reduced intraventricular pressure, and the progressive regression of LV mass, which is responsible for the fixed compression of the coronary microcirculation and impedes its ability to vasodilate in response to hyperaemic agents in AS patients. 26 Moreover, a reduction of MPs following TAVI was reported in another research, suggesting the improvement of endothelial function after valve implantation. 27 Our prior study identified that a rapid decrease in oxidative stress after TAVI potentially reflects the recovery of endothelial function and partially explaining the mechanism of the LV recovery. 28 Overall, TAVI decreases LV afterload and ameliorates coronary microcirculation and endothelial function while decreasing oxidative stress. These conditions lead to improved heart function and LV reverse remodelling in patients with severe AS.

Clinical factors associated with heart failure hospitalization after transcatheter aortic valve implantation
Despite the improvement in heart function following TAVI, numerous TAVI patients continue to experience LV dysfunction and require readmission to the hospital. 4 This chapter describes the factors that are associated with LV dysfunction and HF hospitalization following TAVI ( Figure 3).

Left ventricular systolic dysfunction
The incidence of impaired LV ejection fraction (LVEF < 50%) in patients undergoing TAVI ranges from 26% to 34% in real-world registries, 29,30 suggesting that baseline LVEF is preserved in a large proportion of TAVI patients. In the PARTNER I trial, which enrolled 332 patients, the incidence of repeat hospitalization within 1 year after TAVI was higher in patients with baseline LVEF < 50%. 18 Likewise, the TVT registry that included 11 292 patients reported increased mortality and recurrent HF in patients with severe baseline LV dysfunction. 31 By 1 year follow-up, 54% of the patients with impaired LVEF normalized their LV function (reached LVEF ≥ 50%) after TAVI. 18 As expected, poor improvement of LVEF was associated with mortality and HF hospitalization. 18

Impaired global longitudinal strain
Global longitudinal strain (GLS) is an imaging marker of LV systolic function that has additional prognostic value to LVEF in AS and TAVI patients. Left ventricular dysfunction detected by GLS in AS patients has been correlated with myocardial fibrosis on endomyocardial biopsies. 32 An inverse correlation has been observed between the level of fibrosis and GLS recovery. Indeed, GLS has been found to improve in patients who have less myocardial fibrosis, compared with those with extensive fibrosis who do not exhibit any enhancement in GLS. 33 In an observational study of 431 TAVI patients, the absence of GLS improvement assessed by computed tomography was associated with increased all-cause death or HF hospitalization. 34 A prospective study of 121 TAVI patients demonstrated that elevated inflammatory mediators, including interleukin (IL)-21, IL-1A, and macrophage inflammatory protein-1A, were significantly related to less improvement in GLS at 1 year follow-up after TAVI. 35 These results indicated the noxious impact of continuous inflammation on LV recovery following TAVI. Most recently, Stassen et al. illustrated that reduced GLS is associated with an increased risk of all-cause mortality in patients with moderate AS regardless of LVEF, suggesting that this marker could provide further risk stratification in patients with moderate AS and identify patients who would benefit from closer follow-up and early intervention. 36

Left ventricular diastolic dysfunction
Given the high incidence of HF with preserved LVEF (HFpEF) in TAVI patients, 30 these patients are likely to have persistent LV hypertrophy with DD, a marker of LV adverse remodelling and fibrosis. Recent investigations have identified preoperative DD as a determinant of post-operative outcomes in patients undergoing surgical aortic valve replacement (SAVR) and TAVI. 19,37 In the PARTNER 2 registry of 1750 TAVI patients, 19 increasing baseline grades of DD was associated with adverse outcomes particularly with 1 year rehospitalization. These patients were divided according to the American Society of Echocardiography (ASE)/European Association of Cardiovascular Imaging (EACVI) DD classification into four groups: Grade 1 DD, intermediate, Grade 2 DD, and Grade 3 DD, demonstrating that patients with baseline Grade 3 DD had higher 1 year CV death or rehospitalization than those with baseline Grade 1 DD [hazard ratio: 2.24 (95% confidence interval: 1.34-3.76); P = 0.002]. Lack of improvement in diastolic function at 30 days was found in 30% of patients and was characterized by a higher Society of Thoracic Surgeons (STS) risk score at baseline, a larger LV end-diastolic diameter, a higher systolic pulmonary artery pressure (sPAP), and a higher proportion of patients with greater than or equal to moderate MR and TR. Notably, improvement by ≥1 grade in DD at 30 days was associated with 2.6-fold reduction in 1 year CV death or rehospitalization.

Left ventricular fibrosis
A recent investigation of 41 AS patients who underwent CMR before and 4 months after TAVI clarified that circulatory efficacy, a marker of myocardial performance, remained abnormal in 24% of patients. 38 The absence of improvement in circulatory effect was associated with less regression of myocardial fibrosis after TAVI. It is important to note that the prognosis of patients with AS after valve replacement may not solely depend on improved flow dynamics but rather on the extent of irreversible myocardial fibrosis during the remodelling phase that occurs before the intervention. 39 Myocardial fibrosis can be divided in two categories: diffuse fibrosis occurs in the early phase of the disease, is potentially reversible, and can be quantified as extracellular volume (ECV) with CMR T1 mapping techniques, whereas replacement fibrosis is irreversible and can be identified using late gadolinium enhancement (LGE) on CMR. 39-41 Consistent with these findings, a multicentre, observational, outcome study with imaging core-lab analysis of 674 patients with severe AS, LGE on CMR before SAVR or TAVI was independently associated with all-cause mortality. 42 On the other hand, ECV is associated with myocardial functional recovery from HF following TAVI. 41 Additionally, electrocardiographic strain pattern (ESP) is a relevant marker of myocardial fibrosis that is associated with an increased risk of CV morbidity and mortality in asymptomatic AS and SAVR patients. The incidence of ESP in TAVI patients ranged from 12% to 31% and was evidenced as a strong predictor of HF recurrence regardless of the extent of LV hypertrophy. 9 Similarly, Puls et al. investigated 100 patients who had undergone TAVI and LV biopsy, highlighting the link between a large burden of histological LV fibrosis and increased CV mortality. 32

Coronary microvascular dysfunction
A recent observation demonstrated an elevated risk of adverse CV events in AS patients with reduced myocardial flow reserve evaluated by positron emission computed tomography. 43 The serial change in coronary circulation fol-lowing TAVI was recently described by Vendrik et al., indicating that the median coronary flow reserve (CFR) values had increased from 1.28 at baseline to 1.94 six months after TAVI. 25 Despite the limited sample size (13 patients), the data indicated that certain patients may continuously suffer from CMD following TAVI. According to a new paradigm for HFpEF, coronary microvascular endothelial dysfunction induced by systemic inflammation alters paracrine signalling between endothelial cells and cardiomyocytes and allows leucocytes to infiltrate the myocardium. 13 Nitroxide (NO) released by endothelial cells has antihypertrophic and antifibrotic effects and regulates cardiomyocyte contraction and relaxation, and this effect is blunted in the context of CMD. 13 Thus, persisting CMD following TAVI may cause continuous LV hypertrophy and fibrosis, resulting in continuous LV dysfunction. In line with these findings, worse outcomes after TAVI have been observed in patients with systemic inflammation, 44 which adversely affects the LV reverse remodelling after TAVI. Therefore, future studies are crucial to clarify the incidence of CMD following TAVI and its impact on LV recovery and HF events.

Atrial fibrillation
The prevalence of atrial fibrillation (AF) in TAVI patients is 50% when combining both pre-procedural and new-onset AF. 45 Recent analyses have shown an increased risk of cardiac events in AF patients. 45 Notably, new-onset AF occurred in 7-8% of TAVI patients 45,46 and was associated with higher risk of all-cause mortality and HF hospitalization compared with pre-existing AF. 47 Volume overload could cause stretching of the atria and lead to atrial remodelling, potentially creating a substrate of AF. 47 Although prior reports have suggested that preload may be improved after TAVI, 48 volume overload at baseline is strongly associated with HF hospitalization and all-cause death, 49 suggesting that fluid overload may be persistent in some patients even after valve replacement. Nevertheless, further investigation is needed to explore whether decongestive treatments in overhydrated AS patients could prevent new-onset AF and further improve outcomes beyond TAVI. Other potential mechanisms of new-onset AF include systemic inflammatory response, oxidative atrial stress, local inflammation, and pain following TAVI. 50 The relationship between increased HF hospitalization and AF is multifactorial, but haemodynamic and functional impairment, renal failure, and the coexistence of MR are crucial. 50

Mitral regurgitation
The prevalence of baseline moderate to severe MR ranges between 9.1% and 33.4% in patients undergoing TAVI. [51][52][53] Heart failure following TAVI One year after TAVI, the improvement in MR was observed in 38-55% of patients, 52,53 suggesting that the reduction in afterload and LV reverse remodelling could help improve the coaptation of leaflets in secondary MR. Moreover, a registry of 1587 patients indicated that among patients with significant MR before TAVI, unchanged or worsened MR after TAVI was related to HF hospitalization. 51 Given the high mortality rate in patients with residual MR, transcatheter mitral valve repair after TAVI may be a considerable option. The latest European Society of Cardiology (ESC) guidelines suggest that transcatheter edge-to-edge repair for severe primary MR could be a safe alternative to surgery in patients with contraindications for surgery or high operative risk. 54 On the other hand, the guidelines propose reconsidering the severity of secondary MR after coronary revascularization and/or TAVI, as those procedures have the potential to ameliorate LV function and secondary MR. Thus, it is noteworthy that a different form of follow-up and treatment strategy is required between primary and secondary MR due to their distinct causes and pathophysiologies. An ongoing MITAVI trial aims to evaluate whether TAVI patients with concomitant moderate to severe MR benefit from an additional treatment by MitraClip [National Clinical Trial (NCT) 04009434].

Pulmonary hypertension
Coexisting PH with severe AS confers an increased risk of HF hospitalization and mortality in TAVI patients. 4, 7 Weber et al. studied 503 patients prior to aortic valve replacement, finding that 48% of the patients had PH. 55 In this study, patients with combined pre-and post-capillary PH (Cpc-PH) [mean pulmonary artery wedge pressure (mPAWP) >15 mmHg, pulmonary vascular resistance (PVR) >3 Wood units] had higher mortality than those with isolated post-capillary PH (Ipc-PH) and pre-capillary PH and without PH. Cpc-PH reflects the chronicity of backwards transmission of increased left-sided filling pressures, which induces pulmonary vascular remodelling and RV dysfunction. Improvement in LV diastolic function after TAVI may decrease the burden of secondary PH leading to better outcomes, but patients with persistent PH generally do worse. Persistent PH (sPAP > 60 mmHg) was observed in 6% of TAVI patients and significantly associated with HF hospitalization and mortality. 7,56 A retrospective study examining 1400 TAVI patients suggested that persistent PH after TAVI was more frequent in Cpc-PH than in Ipc-PH, pre-capillary PH, and no PH subgroups. 57 Nevertheless, given the updated threshold of PVR to classify pre-and post-capillaryPH (2 Wood units) in the latest ESC/European Respiratory Society (ERS) guidelines, 58 further investigation is needed on the relationship between different types of PH based on the new threshold and clinical outcomes following TAVI.

Right ventricular dysfunction and tricuspid regurgitation
Right ventricular dysfunction and TR are mainly associated with impaired LVEF, increased LV mass, and increased left atrial volume in patients undergoing TAVI, reflecting the long-standing elevated LV pressure due to severe AS. 11,59 The presence of RV systolic dysfunction (RVSD) and moderate to severe TR are~35% and 20% in patients undergoing TAVI, 60,61 respectively. Reports from the Swiss TAVI registry have demonstrated that normalized RV function and reduced TR were found in more than half of the patients who underwent TAVI. 60,62 In a meta-analysis of 3166 patients, RVSD, RV dilatation, and severe TR at baseline were independent risk factors of 1 year mortality after TAVI. 61 Although TAVI is likely to improve RV function and TR, worsening RV function and residual TR appeared in a small proportion of post-TAVI patients and were associated with mortality and HF symptoms. 60,63 Thus, a stepwise approach from aortic to tricuspid valves could be considered with TAVI, mitral transcatheter edge-to-edge repair, and transcatheter tricuspid intervention in high-risk patients with mixed valvular heart disease, 64 reassessing cardiac remodelling and the improvement of valve dysfunction after each intervention, given the complex nature of their condition. It is noteworthy that 3% of TAVI patients were deemed potential candidates for transcatheter tricuspid valve procedure, 60 suggesting the importance of future studies to clarify the utility of aggressive intervention in those patients.

Cardiac damage
Pooled analyses from the PARTNER 2 and 3 trials have demonstrated that the extent of extravalvular cardiac damage was associated with worse health status at 1 year and 1 and 2 year mortality rates. 11,65,66 Classification of cardiac damage was classified by echocardiography (Stage 0, no damage; Stage 1, LV damage; Stage 2, left atrial or mitral valve damage; Stage 3, pulmonary vasculature or tricuspid valve damage; and Stage 4, RV damage) and showed a stepwise increase in all-cause death, cardiac death, and rehospitalization. 66 Moreover, cardiac damage ameliorated in~15% of patients, remained unchanged in~60% of patients, and worsened in~25% of patients at 1 year, suggesting that the majority of severe AS patients undergoing TAVI have persistent cardiac damage even after valve replacement. As expected, worsening cardiac damage was independently associated with mortality and a composite of death or HF hospitalization at 2 years. 65 These data indicate that continuous HF therapy is of paramount importance and that earlier detection of AS and intervention before the development of irreversible cardiac damage could improve the cardiac function and prognosis of patients with AS.

Cardiac amyloidosis
Cardiac amyloidosis is an infiltrative process resulting from the myocardial deposition of amyloid fibrils. Recent studies have indicated that the prevalence of coexisting AS and cardiac amyloidosis ranges from 12% to 16%. 67-69 The echocardiographic phenotype of cardiac amyloidosis is characterized by low flow-low gradient with reduced LVEF and severe DD. 67 Cardiac amyloidosis does not affect mortality in AS patients undergoing TAVI but increases 1 year recurrent HF hospitalization by 2.7-fold compared with those without cardiac amyloidosis. 68 Importantly, treatment with tafamidis, a pharmacological chaperone, which stabilizes the correctly folded tetrameric form of the transthyretin protein, reduces all-cause mortality and CV hospitalization in transthyretin cardiac amyloidosis patients with the New York Heart Association (NYHA) Class I-II symptoms but not in those with NYHA Class III. These results suggest the importance of early pharmacological intervention. 70 Complications associated with heart failure hospitalization after transcatheter aortic valve implantation

Paravalvular leakage
A recent pooled analysis of aortograms from 2258 patients described the proportion of paravalvular leakage (PVL) evaluated by an academic core laboratory. Significant PVL (moderate or severe regurgitation) was found in 30.1% in CoreValve, 8.8% in Evolut R, 5.3% in Evolut PRO, 10.9% in SAPIEN XT, 8.3% in SAPIEN 3, 11.3% in ACURATE, and 2.2% in Lotus valve. 71 Numbers of studies, including ours, have reinforced that significant PVL is associated with mortality, bleeding events, and HF rehospitalization. 4,72-76 A favourable LV remodelling occurred in most TAVI patients, whereas significant PVL hampered LV structural and functional reverse remodelling and worsened diastolic function. [77][78][79] Given this evidence, the incidence of significant PVL has been significantly reduced due to the development of prosthetic valve technology. However, recent reports have suggested that even mild PVL could be a determinant of worse midterm and long-term outcomes following TAVI. [80][81][82] It is noteworthy that newer generation valves with a taller skirt could seal the bioprosthesis and reduce the severity of PVL. 83 Moreover, a recent report by Akodad et al. demonstrated that late dilatation (a median of 4.6 months) for symptomatic transcatheter heart valve dysfunction reduced the transvalvular gradient and the PVL to less than or equal to mild in all cases with greater than mild PVL without inducing any complications. These results indicated that late post-dilatation of TAVI valves could be an attractive option especially in cases of underexpansion. 84

Conduction disturbance and permanent pacemaker implantation
The most frequent complications after TAVI are conduction disturbance such as high-degree atrioventricular block leading to new-onset left bundle branch block (LBBB) and permanent pacemaker implantation (PPI). 85,86 A large meta-analysis of 30 studies demonstrated that the incidence of new-onset LBBB ranged from 10.5% to 52.3%, whereas PPI at discharge ranged from 5.9% to 32.0%. 85 Importantly, new-onset LBBB and PPI were associated with mortality and HF hospitalization. Our prior study consistently showed that new-onset LBBB and/or PPI led to a two-fold higher major adverse clinical events at 3 year follow-up. 86 In a recent meta-analysis of 50 282 TAVI patients, 7232 patients underwent PPI after TAVI and had an increased mortality rate [hazard ratio: 1.21 (95% confidence interval: 1.14-1.28); P < 0.001] and HF rehospitalization [hazard ratio: 1.30 (95% confidence interval: 1.17-1.45); P < 0.001]. 87 The noxious impact of conduction disturbance and/or PPI on LV reverse remodelling may be caused by the deleterious effect of dyssynchronization induced by new-onset LBBB or pacing.

Prosthesis-patient mismatch
The adverse impact of prosthesis-patient mismatch (PPM) following SAVR has been described in many studies, indicating a worse post-operative functional status, smaller regression of LV mass, and higher mortality. 88,89 In a large meta-analysis including 108 182 patients who underwent SAVR, moderate/severe PPM occurred in 54% and was associated with perioperative mortality and 1, 5, and 10 year mortality. 90 Certain surgical techniques such as aortic annulus/root enlargement may avoid PPM after SAVR and improve survival after SAVR. 91,92 It is likely that severe PPM is more common in SAVR patients than in TAVI patients, particularly when small-sized prosthesis is implanted. 93 A meta-analysis of 81 969 TAVI patients indicated that moderate or severe PPM appeared in 24% of patients and was associated with increased mortality risk at 5 year follow-up. 94 The sensitivity analysis revealed that severe PPM was significantly associated with a higher risk of mortality, whereas moderate PPM no longer had an impact on mortality. As expected, PPM was associated with incomplete regression of LV hypertrophy following TAVI. 95 Given that valve-in-valve (ViV) TAVI in bioprosthetic surgical structural valve degeneration is less invasive than redo SAVR, ViV TAVI has become a feasible treatment option particularly for the elderly population. However, the rate of severe PPM is likely to be higher in patients under-Heart failure following TAVI going ViV TAVI than in those undergoing redo SAVR, whereas the rates of early mortality and major bleeding events were lower in ViV TAVI. 96 These results could occur because the restoration of the native aortic valve annular size in patients with failed bioprosthesis is not an option during ViV TAVI. A recent meta-analysis of observational studies, including 3345 patients who underwent either ViV TAVI or redo SAVR, demonstrated that the early advantage of ViV TAVI reverses over time and that redo SAVR was eventually a protective factor for all-cause mortality at 6 months. 97 The significant association of PPM with increased mortality in the ViV arm may have partially accounted for this observation. 97 Nonetheless, future randomized trials that compare ViV TAVI and redo SAVR are warranted to confirm these findings.

Triggers and predictors of early and late heart failure hospitalization after transcatheter aortic valve implantation
In a single-centre retrospective study of 750 patients, 4 the incidence of early (≤30 days) HF readmission and late (>30 days) HF readmission was 6.6% and 7.1%, respectively. The predominant triggers of early readmission were medication or nonadherence (21%), supraventricular arrhythmia (14%), and anaemia (9%). On the other hand, the most frequent causes of late readmissions were medication or nonadherence (21%), supraventricular arrhythmia (14%), and non-CV causes (8%). The authors failed to identify the trigger of HF readmission in~30% of TAVI patients, potentially due to the persistent LV hypertrophy and diffuse fibrosis in post-TAVI patients. 98 Notably, patients with late and multiple HF hospitalizations were associated with a two-fold increase in all-cause mortality, suggesting that the evolved heart disease is likely to be the major determinant of adverse clinical outcomes. Given these results, optimizing HF therapy and correcting anaemia may reduce the burden of HF hospitalization. Although supraventricular arrhythmia may simply mirror more advanced myocardial structural remodelling and fibrosis, 4,50 further investigation is warranted to clarify the utility of maintaining sinus rhythm following TAVI.

Current therapeutic options
Due to the improvements in device technology and the maturation of procedures, procedural complications such as PVL and conduction disturbance have been progressively mitigated. 2,3,99 Additionally, PPM may be avoided by employing supra-annular self-expanding valves in patients with a small aortic annulus. 100,101 Although procedural complications have decreased and indications have expanded to

Conventional heart failure drugs
Among conventional HF drugs, renin-angiotensin system (RAS) inhibitors have shown favourable results in TAVI patients. In a cohort of 3979 patients from the PARTNER 2 trial and registries, RAS inhibitors at baseline were independently associated with a lower risk of 2 year all-cause and CV mortality. 102 Consistently, a multicentre registry of 2785 TAVI patients revealed that RAS inhibitors helped lower 3 year cardiac mortality and reduction of LV volumes and hypertrophy. 103 Interestingly, LV reverse remodelling was related to reductions in AF, cerebrovascular events, and rehospitalization. A randomized trial is in progress to confirm the effects of RAS blockage in TAVI patients (NCT 03201185) ( Table 1).
In contrast, the OCEAN-TAVI registry including 2563 TAVI patients failed to show the cardioprotective effects of beta-blocker. 104 However, its beneficial effects were specifically found in patients with a history of coronary artery bypass surgery, peripheral artery disease, and post-procedural LVEF < 50%, suggesting that the benefits of beta-blockers could be limited to certain high-risk subgroups.
Increased dosage of diuretics has been observed in patients with HF rehospitalization following TAVI. 4 A small registry including 85 patients recently described an elevation of pulmonary capillary wedge pressure following TAVI as associated with an increased risk of 2 year CV death or HF hospitalization. 63 Among patients with high wedge pressure, uptitration of diuretics was found in patients who did not experience CV events, suggesting that aggressive cardiac unloading may benefit certain patients with mild cardiac congestion ( Figure 4).

Sodium-glucose co-transporter 2 inhibitors
Sodium-glucose co-transporter 2 (SGLT2) inhibitors have demonstrated a beneficial metabolic profile and have significantly reduced HF hospitalization, CV mortality, and chronic kidney disease (CKD) progression. [105][106][107][108] Most recently, clinical trials have highlighted that SGLT2 inhibitors reduce the risk of HF hospitalization in both HF with reduced ejection fraction (HFrEF) and HFpEF patients regardless of diabetic status. [109][110][111] These findings represent the first clinical trial demonstrating a noteworthy advantage of any medication in terms of major clinical outcomes among patients diagnosed with HFpEF. Although the underlying mechanisms are still under investigation, clinical and preclinical studies, including ours, have indicated cardioprotective effects of SGLT2 inhibitors on LV hypertrophy and fibrosis, LV DD, pulmonary artery remodelling, CMD, endothelial dysfunction, inflammation, and oxidative stress. [112][113][114][115][116][117][118] All the effects likely contribute to the persistent cardiac dysfunction in TAVI patients. The mechanistic pathways were partly clarified in our latest experiments, showing the cardioprotective effects of SGLT2 inhibitors on endothelial function through the angiotensin II type 1 receptor (AT1R)/NADPH oxidase/sodium-glucose cotransporter 1 (SGLT1) and SGLT2 pathways. 112 In this report, preserved NO expression, decreased oxidative stress, reduced pro-inflammatory, pro-adhesive and pro-thrombotic phenotypes, and prevention of local RAS activation were evidenced after treatment with empagliflozin. Additionally, the noxious effects of MPs on endothelial function were also blunted by empagliflozin. Direct cardiac effects of SGLT2 inhibitors have also been described in recent reports. Although the heart metabolism relies more on free fatty acids and ketones than on glucose under HF condition, SGLT2 inhibitors switch fuel consumption from glucose towards fatty acids and ketone bodies. 119 Moreover, a recent meta-analysis of 52 115 patients found that SGLT2 inhibitors reduce the risk of AF and ventricular tachycardia in patients with diabetes, CKD, and HF. 120 Furthermore, the preservation of kidney function by SGLT2 inhibitors may indirectly protect TAVI patients from adverse CV events. 106 In sum, SGLT2 inhibitors appear to be a promising HF therapy for TAVI patients by providing multiple favourable cardiorenal effects (Figure 4). To date, the Dapagliflozin after Transcatheter Aortic Valve Implantation (DapaTAVI) trial (NCT 04696185) is the only ongoing randomized trial designed to assess the clinical benefit of SGLT2 inhibitors in TAVI patients ( Table 1). 121

Anti-inflammatory drugs
The development and progression of HFpEF are underpinned by CMD, which is promoted or aggravated by low-grade systemic inflammation. 13 Given the increased risks in TAVI pa-tients with systemic inflammation, targeting inflammation may prevent CMD and the progression of HFpEF. The Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) trial randomized 10 061 patients with prior myocardial infarction and high-sensitivity C-reactive protein ≥2 mg/L to canakinumab, a monoclonal IL-1β selective antibody, or placebo. 122 A dose-dependent reduction in HF hospitalization and HF-related death was found in the canakinumab group, reinforcing the role of the innate immune system to cardiac remodelling and HF. Colchicine is another anti-inflammatory drug that targets microtubule function, 123 and its cardioprotective effects have been evidenced in patients with ischaemic heart disease. 124 The effects of colchicine on TAVI patients are being investigated in a trial focusing on the occurrence of AF and conduction disturbance following TAVI (NCT 04870424) ( Table 1).

Iron supplementation
Anaemia is highly prevalent among patients undergoing TAVI and is associated with a poor prognosis. 125 In a single-centre study of 549 TAVI patients, anaemia was present in 45% and identified as a determinant of death or HF hospitalization. 126 In those patients, iron deficiency was found in 79% of patients. Iron deficiency in patients with HF is associated with reduced exercise capacity, impaired quality of life, and a poor prognosis independently of LVEF. 127 In HF, iron deficiency can be due to an absolute decrease in total body iron or an inadequate distribution because of iron sequestration in the storage pool. 127 Although early studies provided the potential role of intravenous iron therapy in patients with HFrEF and HFpEF, 128,129 the role of iron supplementation in TAVI patients remains unconfirmed. One randomized trial is ongoing to explore the potential of intravenous iron therapy in TAVI patients (NCT 04797832) ( Table 1).

Early intervention in patients with moderate aortic stenosis
Recent evidence has indicated that moderate AS was associated with a mortality risk higher than that caused by no or mild AS. 130 Nonetheless, the current guidelines do not recommend aortic valve replacement when AS severity is moderate at rest and/or on low-dose dobutamine stress echocardiogram. 54 It has been suggested that relieving AS at an earlier stage of the disease might be beneficial, particularly in patients with HFrEF, because each progressive increase in AS severity imposes a certain amount of pressure on the LV. 131,132 Several ongoing trials are assessing the use of TAVI in patients with moderate AS. The Transcatheter Aortic Valve Replacement to UNload the Left Ventricle in Patients With ADvanced Heart Failure (TAVR-UNLOAD) trial is assessing the efficacy and safety of transfemoral TAVI in patients with moderate AS, HF, and impaired LVEF (NCT 02661451). Additionally, the PROGRESS trial is evaluating the utility of TAVI in patients with moderate AS and HF symptoms (NCT 04889872).

Conclusions
A non-negligible proportion of patients develop HF hospitalization following TAVI. Although various causes have been reported, evidence of HF therapy following TAVI scarcely exists. Given the recent cumulative evidence regarding HF, SGLT2 inhibitors may produce favourable cardiorenal effects that could prevent HF events after TAVI.