Skip to main content
NCBI home page
Structural Heart logoLink to Structural Heart
. 2022 Sep 15;6(5):100089. doi: 10.1016/j.shj.2022.100089

Left Ventricular Systolic Dysfunction in Aortic Stenosis: Pathophysiology, Diagnosis, Management, and Future Directions

Nikolaos Spilias 1, Trejeeve Martyn 1, Kara J Denby 1, Serge C Harb 1, Zoran B Popovic 1, Samir R Kapadia 1,∗
PMCID: PMC10242576  PMID: 37288060

Abstract

Degenerative calcific aortic stenosis (AS) is the most common valvular heart disease and often co-exists with left ventricular (LV) systolic dysfunction at the time of diagnosis. Impaired LV systolic function has been associated with worse outcomes in the setting of AS, even after successful aortic valve replacement (AVR). Myocyte apoptosis and myocardial fibrosis are the 2 key mechanisms responsible for the transition from the initial adaptation phase of LV hypertrophy to the phase of heart failure with reduced ejection fraction. Novel advanced imaging methods, based on echocardiography and cardiac magnetic resonance imaging, can detect LV dysfunction and remodeling at an early and reversible stage, with important implications for the optimal timing of AVR especially in patients with asymptomatic severe AS. Furthermore, the advent of transcatheter AVR as a first-line treatment for AS with excellent procedural outcomes, and evidence that even moderate AS portends worse prognosis in heart failure with reduced ejection fraction patients, has raised the question of early valve intervention in this patient population. With this review, we describe the pathophysiology and outcomes of LV systolic dysfunction in the setting of AS, present imaging predictors of LV recovery after AVR, and discuss future directions in the treatment of AS extending beyond the traditional indications defined in the current guidelines.

Keywords: Aortic stenosis, Aortic valve replacement, Late gadolinium enhancement, Strain echocardiography, Systolic dysfunction

Highlights

  • •

    Approximately one-third of patients with severe AS have reduced LV systolic function.

  • •

    LV systolic dysfunction portends worse prognosis even after valve replacement.

  • •

    Myocyte apoptosis and interstitial fibrosis are key pathophysiologic mechanisms of myocardial dysfunction.

  • •

    Advanced echocardiographic and CMR imaging methods can detect early LV dysfunction.

  • •

    Early valve intervention for certain AS patient groups is currently under investigation.

Introduction

Degenerative aortic stenosis (AS) affects 2% to 4% of patients older than 65 years.1,2 As the incidence of heart failure (HF) with reduced ejection fraction (HFrEF) increases with age, the AS often co-exists with left ventricular (LV) systolic dysfunction. Approximately one-third of patients who are diagnosed with severe AS have LV systolic dysfunction, defined as LV ejection fraction (LVEF) less than 50%.3, 4, 5

Aortic valve replacement (AVR), transcatheter or surgical, is the definitive treatment of severe AS; however, the presence of reduced LV systolic function at baseline may significantly affect prognosis and outcomes after the intervention. The most recent American College of Cardiology/American Heart Association guidelines for the management of valvular heart disease recommend AVR for symptomatic patients with severe AS and asymptomatic patients with severe AS and LVEF <50%.6

Although surgical AVR (SAVR) for severe AS is overall associated with survival benefit and morbidity reduction irrespective of baseline LV function, patients with systolic dysfunction have increased midterm and long-term mortality compared to patients with normal LV systolic function.7

In the recent years, transcatheter AVR (TAVR) has been established as an effective and less invasive first-line therapy for severe AS across all surgical risk categories.

In the high-risk surgical population of the Placement of Transcatheter Aortic Valves (PARTNER) trial (31.9% of the patients had LVEF <50%), all-cause mortality was similar between the groups of reduced and preserved LVEF at 30 days and 1 year after AVR. Approximately one-third of patients with baseline systolic LV dysfunction did not demonstrate improvement in LVEF (defined as absolute increase ≥10%) 30 days after TAVR.8,9 Absence of LVEF improvement was associated with 3-fold increase in 1-year mortality after TAVR.3 In contrast, in the intermediate-risk PARTNER 2 trial (28% had LVEF <50% at baseline), patients with reduced LVEF had a higher all-cause and cardiovascular mortality at 2 years than patients with normal baseline LV function. Baseline LVEF was an independent predictor of 2-year cardiovascular mortality after TAVR.4

Furthermore, retrospective data have shown that, even in patients with moderate AS, the presence of LV systolic dysfunction is associated with significant mortality and HF hospitalization rates.10 In a recent propensity-matched analysis, patients with LVEF <50% and moderate AS had higher all-cause mortality and HF hospitalization rates at 3 years than patients with LV dysfunction alone. A small subgroup of those patients who underwent AVR, and especially TAVR, had improved clinical outcomes and survival during follow-up.11

Overall, these findings suggest that baseline LV systolic dysfunction may adversely affect prognosis across the spectrum of AS severity. Detection of LV dysfunction at an early stage, followed by appropriate valve intervention, even in cases of nonsevere AS, may significantly improve patient outcomes.

Pathophysiology of LV Dysfunction in Aortic Stenosis

AS represents an increased afterload state for the LV. The increase in wall stress induces remodeling at the myocyte and extracellular matrix levels. This pressure overload state may remain clinically silent for years, until the AS becomes severe and the LV fails to compensate for the afterload mismatch and maintain adequate cardiac output, leading to development of symptoms. The LVEF reduction in patients with AS may be initially due to afterload/contractility mismatch. The increased afterload causes an increased stroke work and reduction in stroke volume despite preserved or even increased contractility during the early stages. As the disease progresses, irreversible myocardial damage and interstitial fibrosis occur, leading to LV systolic dysfunction and further decline in LVEF, if the AS is left untreated.12

Conversely, real-time pressure-volume loop analysis during TAVR has shown an acute increase in LVEF after valve replacement and LV unloading. A decrease in end-diastolic and end-systolic pressure results in reduced afterload and systolic work stress, which is reflected by decreased stroke work and total mechanical energy generated by the LV.13 These immediate changes may be attenuated by certain procedural steps, such as rapid ventricular pacing, which causes LV stunning and transient dilatation.14

The initial response to the development of AS and increased afterload at the cellular level is myocyte hypertrophy, leading to concentric LV remodeling and increase in wall thickness, in an effort to normalize the wall stress (according to Laplace’s Law) and maintain LV systolic function and cardiac output.15 While the concentric myocardial hypertrophy is adaptive, a clear association between increasing degrees of hypertrophy/myocardial mass and adverse cardiovascular events and mortality has been shown.16 As the AS progresses over time, the LV wall stress and end-diastolic pressure continue to increase, and eventually the LV contractile function declines. Ultimately, the patient transitions from the hypertrophy phase to HF with development of symptoms.

Two key processes driving LV decompensation and the transition from hypertrophy to HF are progressive myocyte apoptosis and reactive myocardial fibrosis.17,18 Apoptosis occurs as a direct response to biomechanical stress secondary to increased afterload and indirectly due to supply-demand ischemia of the myocardium as a result of hypertrophy, fibrosis, and diminished capillary density, leading to impaired coronary flow reserve.19 Increased circulating cytokine levels, such as tumor necrosis factor-A and its soluble receptors, have been described in animal and human models of cardiac pressure overload, with important implications in the process of myocyte apoptosis and LV decompensation.20,21

As a response to increased myocyte apoptosis and wall stress, myofibroblasts infiltrate the myocardium leading to increased expression of collagen type I, III, and IV genes and other transcripts involved in collagen synthesis.17 Additionally, increased expression of tissue matrix metalloproteinase inhibitors has been observed in patients with AS, compared to normal subjects.22 This imbalance in extracellular matrix synthesis and degradation ultimately leads to interstitial fibrosis, which is reflected in cardiac magnetic resonance (CMR) imaging findings. Extracellular volume (ECV) expansion (diffuse fibrosis), detected by T1, and mid-wall late gadolinium enhancement (LGE) (replacement fibrosis) are more pronounced in patients with AS. While ECV expansion has been described in the initial stages of this process, replacement fibrosis is considered the final and irreversible stage of LV remodeling in AS. These findings are associated with diastolic dysfunction and longitudinal systolic dysfunction, leading to LV decompensation and transition from adaptive hypertrophy to HF in patients with AS (Figure 1).23

Figure 1.

Figure 1

Open in a new tab

The progression from left ventricular hypertrophy to heart failure with reduced ejection fraction in patients with severe aortic stenosis.

Abbreviations: ANG-II, angiotensin II; AS, aortic stenosis; CM, cardiomyopathy; ECV, extracellular volume; GLS, global longitudinal strain; HFrEF, heart failure with reduced ejection fraction; LGE, late gadolinium enhancement; LV, left ventricle/ventricular; LVH, left ventricular hypertrophy; TNF-a, tumor necrosis factor-a.

LV Systolic Function Assessment and Predictors of Recovery After AVR

Echocardiography

LV function assessment is a key component in the evaluation of patients with severe AS and determining the timing of AVR. Echocardiography is the initial diagnostic test, as it enables assessment of LVEF, regional wall thickness, and LV mass, thus allowing classification of LV geometry into normal, concentric remodeling, concentric hypertrophy, and eccentric hypertrophy. Global longitudinal strain (GLS) is another marker of LV systolic function, which can detect LV dysfunction even in the presence of preserved LVEF and may be a better predictor of myocardial recovery after AVR.24,25 In a cohort of 395 patients with severe AS and preserved LVEF, about 75% of the patients were found to have depressed GLS.26

Several echocardiographic features may be predictive of LV recovery after AVR. Baseline LVEF ≤35% has been described as the strongest independent predictor of LV recovery after TAVR although associated with overall higher 1-year mortality.5 The presence of regional wall motion abnormalities consistent with a prior myocardial infarction are predictive of poor LV recovery.9

Baseline GLS greater than −13.3% was found to predict GLS normalization after TAVR. Expectedly, circumferential, rotational, and torsional mechanics were increased in severe AS with preserved ejection fraction (EF) and decreased in the low-EF group, with improvement after TAVR.27 In low-flow low-gradient (LFLG) AS patients, GLS improved but did not normalize, suggesting a degree of irreversible adverse remodeling and myocardial damage.26,28 In LFLG AS, GLS was a stronger predictor of LV recovery after TAVR than LVEF.22

Additionally, the role of LV mass index (LVMi) regression in LVEF recovery has been highlighted among patients in the PARTNER I, II, and S3 trials and registries. Despite no difference in baseline LVEF, patients with greater LVMi regression after AVR had higher LVEF at 1-year follow-up. Importantly, among patients with moderate or severe LV hypertrophy (LVH) treated with TAVR, greater LVMi regression at 1 year was also associated with lower mortality and hospitalization rates at 5 years, emphasizing the prognostic significance of LVMi.29

Other echocardiographic parameters, such as right ventricular dysfunction, bicuspid aortic valve (AV) anatomy, mean AV gradient, and postprocedural aortic regurgitation, have been linked to LV function recovery and are summarized in Table 1.9,27,30,31

Table 1.

Predictors of LV recovery after AVR

Modality Predicts recovery Predicts lack of recovery
ECG • Left ventricular hypertrophy • Left bundle brunch block
Echo • AV gradient ≥ 40 mm Hg
• GLS < 13.3%		 • LVEF < 35%
• Regional wall motion abnormalities suggesting prior myocardial infarction
• RV dysfunction
• Bicuspid valve morphology
• Moderate/severe AR or new mild AR
CMR • T2 relaxation time (highest quartile) • Late gadolinium enhancement
• T2 relaxation time (lowest quartile)
CT • Expanded extracellular volume
Nonimaging modalities • BNP reduction • Cytokines (hepatocyte growth factor)
Open in a new tab

AR, aortic regurgitation; AV, aortic valve; AVR, aortic valve replacement; BNP,B-type natriuretic peptide; CMR, cardiac magnetic resonance; CT, computed tomography; ECG, electrocardiography; GLS, global longitudinal strain; LV, left ventricle/ventricular; LVEF, left ventricular ejection fraction; RV, right ventricular.

Dobutamine Stress Echocardiography

Several studies have assessed the prognostic role of contractile/flow reserve in patients with LFLG severe AS by using dobutamine stress echocardiography. Although lack of contractile reserve was associated with higher operative mortality after SAVR in a small patient cohort, the presence or absence of contractile reserve did not predict LV recovery over time.32,33 In a larger patient cohort of LFLG severe AS and reduced EF, contractile flow reserve by dobutamine stress echocardiography was not predictive of survival. AVR (surgical or transcatheter) was associated with better survival independent of flow reserve.34

Cardiac Magnetic Resonance

CMR is the current gold standard for noninvasive assessment of systolic function and LV geometry, with the advantage of tissue characterization. T1-weighted images with LGE are helpful in detecting focal fibrosis (scar) that may represent irreversible myocardial damage,23,35 while T2-weighted images can detect increased water content within the myocardium, which represents inflammation or edema.36 The degree of myocardial fibrosis correlates with impaired longitudinal systolic function, increased LV cavity dimensions, and reduced LVEF. A dose-dependent relationship has been described between the amount of mid-wall LGE and adverse cardiovascular events and mortality.23 Additionally, CMR can facilitate the diagnosis of concomitant transthyretin amyloid cardiomyopathy, a treatable infiltrative disease that is common in older adults referred for severe AS evaluation.37,38 Further evaluation of myocardial tissue properties, through T2 relaxation time, may also provide prognostic information regarding LV recovery potential. In a study of patients with severe AS, T2 values above 70.2 ​milliseconds were associated with more pronounced reverse LV remodeling after TAVR, while patients with initial low T2 did not have significant improvement in LV end-diastolic volumes or LVEF.36

Computed Tomography

ECV derivation from computed tomography may predict early recovery of LV systolic function after AVR. Increased ECV has been associated with decreased LVEF recovery after TAVR in patients with impaired LV systolic function at baseline. With each percent increase in ECV over 30%, there was an 11% reduction in the likelihood of early LVEF recovery. Extracellular expansion and replacement fibrosis are considered to represent an advanced stage of LV dysfunction. An expanded ECV could also suggest cardiac amyloidosis which is associated with poor LV recovery.39

Electrocardiography

LVH, as detected on electrocardiography, has been associated with lower incidence of adverse clinical outcomes (all-cause death, major adverse cardiovascular events, and rehospitalization).40 Signs of hypertrophy represent viable myocardium and may be associated with greater reverse remodeling and LV function recovery after TAVR. Conversely, the absence of LVH could be related to extensive myocardial fibrosis or the presence of amyloidosis.40,41 Left bundle branch block before or after TAVR correlates with a lower rate of reverse LV remodeling, as is right ventricular pacing.42

Nonimaging Modalities

Reduction of B-type natriuretic peptide levels after TAVR has been associated with reverse LV remodeling, decrease in LV end-diastolic volume index, and improvement in GLS and LV contractility over time.43 Certain cytokines have also been linked to LV recovery after AVR although their clinical utility is limited. Elevated hepatocyte growth factor levels have been associated with reduced LV recovery.44 Table 1 summarizes the predictors of LV function recovery after AVR.

The Role of Medical Therapy in Degenerative Aortic Stenosis

The current paradigm of monitoring asymptomatic patients with progressive AS with serial echocardiograms, followed by AVR once severe AS is established and symptoms arise, does not delineate a specific role for HF medical therapy. As put forward in a recent viewpoint from Lindman and Lindenfeld, there has been no role for pharmacologic therapy to specifically treat or prevent AS and its known myocardial consequences.45

Observational data support a potential role for the renin-angiotensin system (RAS) blockade therapy in patients with AS before and after AVR, given its association with reverse LV remodeling, reduction of hypertrophy and fibrosis, and overall clinical and mortality benefit in the HF population.46, 47, 48, 49 Proposed mechanisms for increased survival associated with RAS blockade after AVR include cardioprotection (i.e., atherosclerotic plaque stabilization) and regression of myocardial fibrosis.50,51 Although increased angiotensin-converting enzyme 2 levels have been associated with increased valvular calcification, LV mass, LV end-diastolic volume, and higher mortality in patients with AS, data on the role of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ARBs) in slowing the progression of calcific AS have been inconclusive.52, 53, 54

Given that LV mass regression is associated with significantly lower rates of hospitalization after SAVR and TAVR, there has been growing interest in the role of RAS inhibition in facilitating reverse LV remodeling and improved outcomes. The Ramipril in Aortic Stenosis (RIAS) trial evaluated the use of ramipril in patients with asymptomatic moderate or severe AS and showed significant reduction in LV mass in the ramipril group compared to placebo; however, it was not powered to assess differences in clinical outcomes.55

Another randomized study evaluated the effect of the ARB candesartan on the LV mass of patients who underwent SAVR for severe AS. The study showed significantly lower LVMi in patients treated with candesartan, as well as lower rates of atrial fibrillation.56

Several large observational studies have demonstrated the association of angiotensin-converting enzyme inhibitors/ARB utilization with mortality benefit and reduced hospitalization rates in the TAVR population.57,58 These findings led to the design of a multicenter, open-label, randomized trial (RAS blockade After Transcatheter Aortic Valve Implantation [RASTAVI]) that is currently enrolling.59

With evolving treatment paradigms in HF across the LVEF spectrum, beyond the traditional RAS and beta blockade, there is growing interest in the extension of novel pharmacologic HF therapies to patients with AS. The potential benefits of newer agents, including sodium-glucose cotransporter 2 inhibitors, are currently under investigation. “Dapagliflozin after transcatheter aortic valve implantation” (DAPA TAVI; NCT04696185) is a prospective randomized trial, evaluating the effect of dapagliflozin on survival and HF hospitalization of patients with severe AS, LVEF ≤40%, and renal dysfunction undergoing TAVR.60 This study is currently enrolling with estimated completion in 2023.

Future Directions

Staging of AS Severity Based on Cardiac Damage

Recognizing the prognostic significance of LV dysfunction in patients with AS undergoing AVR, Généreux et al.61 suggested a new staging system for AS based on the extent of upstream cardiac changes and damage, utilizing data from the PARTNER 2A and 2B trials (1661 patients). More specifically, patients were categorized into 5 stages depending on the presence or absence of cardiac damage or dysfunction (myocardial and valvular), as detected by echocardiography prior to AVR (Figure 2). The study showed a consistent association between the extent of upstream cardiac damage prior to AVR and all-cause and cardiac mortality at 1 year after AVR (Figure 2).61 Although this staging system requires further validation, its integration as a risk-stratification tool for patients with severe AS may facilitate an earlier intervention and help improve prognosis after AVR.

Figure 2.

Figure 2

Open in a new tab

Staging of aortic stenosis based on the extent of upstream cardiac damage (top). One-year all-cause mortality after AVR among the different stages of cardiac damage (bottom). P. Généreux, et al., Staging classification of aortic stenosis based on the extent of cardiac damage, European Heart Journal, 2017. 38 (45); 3351-3358, by permission of Oxford University Press on behalf of the European Society of Cardiology.

Abbreviations: AVR, aortic valve replacement; LA, left atrium; LV, left ventricle/ventricular; RV, right ventricular.

Moderate AS and LV Systolic Dysfunction

The observation that moderate AS is associated with significant mortality, HF hospitalization rates, and need for AVR in patients with HFrEF10 supports the utility of an early AV intervention in this patient population.

In a retrospective study of patients with HFrEF and moderate AS, moderate AS was independently associated with almost a 3-fold increase in all-cause mortality compared to patients with HFrEF without AS. TAVR was associated with improved survival in this patient population compared to medical therapy and expectant management.11 Furthermore, a retrospective analysis of a large patient cohort from the Duke Echocardiographic Database showed mortality benefits from AVR (with or without concomitant coronary artery bypass grafting) in patients with moderate AS and LV systolic dysfunction.62 These findings suggest that the increased afterload imposed on the LV by moderate AS may negatively affect prognosis and outcomes in the HFrEF population, supporting the hypothesis for an early AV intervention.

This hypothesis led to the design of the “Transcatheter Aortic Valve Replacement to Unload the Left Ventricle in Patients with Advanced Heart Failure” (TAVR UNLOAD; NCT02661451), which is an international randomized-controlled trial aiming to evaluate the safety and efficacy of transfemoral TAVR plus optimal HF therapy compared with optimal HF therapy alone in patients with moderate AS and LVEF <50%. This study is based on the rationale that TAVR may provide additional afterload reduction and thus improve prognosis and clinical outcomes in patients with moderate AS and LV dysfunction.63

Asymptomatic Patients With Severe AS

Close monitoring and expectant management of asymptomatic patients with severe AS and preserved LVEF (defined currently as >50%) has been historically considered as a safe strategy without adverse effects on prognosis.

However, observational data suggest that the natural history of asymptomatic severe AS is not as benign as originally thought. Early SAVR has been associated with improved survival in this patient population compared to conservative/expectant management.64,65

Advancements in cardiac imaging leading to early detection of LV remodeling and dysfunction, that precede the reduction in LVEF and development of symptoms, have raised the question about possible early intervention in asymptomatic patients with severe AS and signs of early, and thus reversible, LV dysfunction.

As mentioned above, reduced LV GLS is an early and more sensitive marker of impaired contractile function, when LVEF is still preserved, that corresponds to the development of interstitial fibrosis. A recent individual participant data meta-analysis of asymptomatic patients with severe AS showed that GLS <14.7% was associated with a 2.5-fold increase in mortality.66 Impaired GLS is also frequently detected among patients with moderate AS and has been associated with worse prognosis and higher mortality even after subsequent AVR.67

In the same context, the development of high-sensitivity assays for the detection of cardiac biomarkers of myocyte injury and death, such as high-sensitivity troponin I (hsTnI), has led to studies investigating the role of such biomarkers in prognosis of asymptomatic patients with severe AS. Plasma hsTnI concentrations have been shown to correlate with an advanced hypertrophic response (LV mass) and replacement fibrosis (mid-wall LGE) and are associated with higher cardiovascular mortality and AVR, independent of the burden of coronary artery disease.68

The accumulating evidence that subclinical LV dysfunction, myocyte apoptosis, and interstitial fibrosis in asymptomatic patients with severe AS are associated with adverse outcomes and increased mortality, the challenges in accurate determination of symptom status particularly in sedentary elderly patients, along with the low periprocedural morbidity and mortality of AVR in contemporary practice (especially TAVR), led to the design of 2 clinical trials that focus on early intervention.

The “Early Valve Replacement Guided by Biomarkers of LV Decompensation in Asymptomatic Patients With Severe AS” (EVOLVED; NCT03094143) trial is a multicenter randomized-controlled trial investigating whether objective markers of early LV decompensation can be used to optimize the timing of AVR. Asymptomatic patients with severe AS, normal LVEF, elevated hsTnI levels, and evidence of mid-wall myocardial fibrosis by CMR will be randomized to early AVR (TAVR or SAVR) or the standard watchful waiting approach. The primary endpoint will be the composite of all-cause mortality or unplanned hospitalization related to AS during the follow-up period.69

A more broadly inclusive trial is the “Evaluation of Transcatheter Aortic Valve Replacement Compared to Surveillance for Patients With Asymptomatic Severe Aortic Stenosis” (EARLY TAVR; NCT03042104). This is a prospective, randomized-controlled, multicenter study that aims to investigate the role of TAVR in asymptomatic patients with severe AS and preserved LV function, without requiring objective data of structural or functional LV decompensation. The trial protocol mandates the use of exercise testing in most patients, which should be normal before randomization. The primary endpoint will be the composite of all-cause mortality, stroke, and unplanned cardiovascular hospitalization at 2 years.70

LVEF Threshold

The threshold that has been traditionally used for the definition of systolic LV dysfunction and indication for intervention in patients with severe AS is 50%. Data from the Heart Valve Clinic International Database (HAVEC registry) showed that asymptomatic patients with severe AS and LVEF between 50% and 59% had worse outcomes and experienced more HF-related deaths than those with LVEF >60%, even after successful AVR.71 This finding may support the re-evaluation and possible adjustment of the optimal LVEF cutoff to define dysfunction and consider AVR in patients with asymptomatic severe AS.

Conclusion

LV systolic dysfunction is associated with worse outcomes in patients with AS, even after successful AVR. Advanced methods of assessing myocardial function and structure, such as echocardiographic GLS, CMR assessment of the extracellular matrix, measurement of high-sensitivity biomarkers of myocyte injury and apoptosis, and the addition of the stage of cardiac damage as a covariable, may lead to better risk stratification, optimization of the timing of AVR, and improvement in patient outcomes. The optimal timing of AVR in asymptomatic patients with severe AS and the potential benefit of treating moderate AS in HFrEF are currently under investigation in randomized trials.

Funding

The authors have no funding to report.

Disclosure statement

Dr Trejeeve Martyn receives research support from Ionis Therapeutics and is an advisor to Recora Health. The other authors have no conflicts to declare.

References

  • 1.Carabello B.A. Evaluation and management of patients with aortic stenosis. Circulation. 2002;105(15):1746–1750. doi: 10.1161/01.cir.0000015343.76143.13. [DOI] [PubMed] [Google Scholar]
  • 2.Supino P.G., Borer J.S., Preibisz J., Bornstein A. The epidemiology of valvular heart disease: a growing public health problem. Heart Fail Clin. 2006;2(4):379–393. doi: 10.1016/j.hfc.2006.09.010. [DOI] [PubMed] [Google Scholar]
  • 3.Elmariah S., Palacios I.F., McAndrew T., et al. Outcomes of transcatheter and surgical aortic valve replacement in high-risk patients with aortic stenosis and left ventricular dysfunction: results from the placement of aortic transcatheter valves (PARTNER) trial (cohort A) Circ Cardiovasc Interv. 2013;6(6):604–614. doi: 10.1161/CIRCINTERVENTIONS.113.000650. [DOI] [PubMed] [Google Scholar]
  • 4.Furer A., Chen S., Redfors B., et al. Effect of baseline left ventricular ejection fraction on 2-year outcomes after transcatheter aortic valve replacement: analysis of the PARTNER 2 trials. Circ Heart Fail. 2019;12(8) doi: 10.1161/CIRCHEARTFAILURE.118.005809. [DOI] [PubMed] [Google Scholar]
  • 5.Elhmidi Y., Bleiziffer S., Deutsch M.A., et al. Transcatheter aortic valve implantation in patients with LV dysfunction: impact on mortality and predictors of LV function recovery. J Invasive Cardiol. 2014;26(3):132–138. [PubMed] [Google Scholar]
  • 6.Writing Committee Members. Otto C.M., Nishimura R.A., et al. 2020 ACC/AHA guideline for the management of patients with valvular heart disease: executive summary: a report of the American College of Cardiology/American Heart Association Joint Committee on clinical practice guidelines. J Am Coll Cardiol. 2021;77(4):450–500. doi: 10.1016/j.jacc.2020.11.035. [DOI] [PubMed] [Google Scholar]
  • 7.Halkos M.E., Chen E.P., Sarin E.L., et al. Aortic valve replacement for aortic stenosis in patients with left ventricular dysfunction. Ann Thorac Surg. 2009;88(3):746–751. doi: 10.1016/j.athoracsur.2009.05.078. [DOI] [PubMed] [Google Scholar]
  • 8.Passeri J.J., Elmariah S., Xu K., et al. Transcatheter aortic valve replacement and standard therapy in inoperable patients with aortic stenosis and low EF. Heart. 2015;101(6):463–471. doi: 10.1136/heartjnl-2014-306737. [DOI] [PubMed] [Google Scholar]
  • 9.Dauerman H.L., Reardon M.J., Popma J.J., et al. Early recovery of left ventricular systolic function after CoreValve transcatheter aortic valve replacement. Circ Cardiovasc Interv. 2016;9(6) doi: 10.1161/CIRCINTERVENTIONS.115.003425. [DOI] [PubMed] [Google Scholar]
  • 10.van Gils L., Clavel M.A., Vollema E.M., et al. Prognostic implications of moderate aortic stenosis in patients with left ventricular systolic dysfunction. J Am Coll Cardiol. 2017;69(19):2383–2392. doi: 10.1016/j.jacc.2017.03.023. [DOI] [PubMed] [Google Scholar]
  • 11.Jean G., Van Mieghem N.M., Gegenava T., et al. Moderate aortic stenosis in patients with heart failure and reduced ejection fraction. J Am Coll Cardiol. 2021;77(22):2796–2803. doi: 10.1016/j.jacc.2021.04.014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Mohamed Ali A., Wasim D., Løland K.H., Rotevatn S., Bleie Ø., Saeed S. Impact of transcatheter aortic valve implantation on left ventricular function recovery, mass regression and outcome in patients with aortic stenosis: protocol of the TAVI-NOR prospective study. BMJ Open. 2021;11(1) doi: 10.1136/bmjopen-2020-039961. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Yin M.Y., Tandar A., Sharma V., et al. Left ventricular hemodynamic changes during transcatheter aortic valve replacement assessed by real-time pressure-volume loops. JACC Cardiovasc Interv. 2020;13(18):2190–2192. doi: 10.1016/j.jcin.2020.04.008. [DOI] [PubMed] [Google Scholar]
  • 14.Sarraf M., Burkhoff D., Brener M.I. First-in-Man 4-Chamber pressure-volume analysis during transcatheter aortic valve replacement for bicuspid aortic valve disease. JACC Case Rep. 2021;3(1):77–81. doi: 10.1016/j.jaccas.2020.11.041. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Ozkan A., Kapadia S., Tuzcu M., Marwick T.H. Assessment of left ventricular function in aortic stenosis. Nat Rev Cardiol. 2011;8(9):494–501. doi: 10.1038/nrcardio.2011.80. [DOI] [PubMed] [Google Scholar]
  • 16.Cioffi G., Faggiano P., Vizzardi E., et al. Prognostic effect of inappropriately high left ventricular mass in asymptomatic severe aortic stenosis. Heart. 2011;97(4):301–307. doi: 10.1136/hrt.2010.192997. [DOI] [PubMed] [Google Scholar]
  • 17.Dweck M.R., Boon N.A., Newby D.E. Calcific aortic stenosis: a disease of the valve and the myocardium. J Am Coll Cardiol. 2012;60(19):1854–1863. doi: 10.1016/j.jacc.2012.02.093. [DOI] [PubMed] [Google Scholar]
  • 18.Hein S., Arnon E., Kostin S., et al. Progression from compensated hypertrophy to failure in the pressure-overloaded human heart: structural deterioration and compensatory mechanisms. Circulation. 2003;107(7):984–991. doi: 10.1161/01.cir.0000051865.66123.b7. [DOI] [PubMed] [Google Scholar]
  • 19.Galiuto L., Lotrionte M., Crea F., et al. Impaired coronary and myocardial flow in severe aortic stenosis is associated with increased apoptosis: a transthoracic Doppler and myocardial contrast echocardiography study. Heart. 2006;92(2):208–212. doi: 10.1136/hrt.2005.062422. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Kapadia S.R., Oral H., Lee J., Nakano M., Taffet G.E., Mann D.L. Hemodynamic regulation of tumor necrosis factor-alpha gene and protein expression in adult feline myocardium. Circ Res. 1997;81(2):187–195. doi: 10.1161/01.res.81.2.187. [DOI] [PubMed] [Google Scholar]
  • 21.Kapadia S.R., Yakoob K., Nader S., Thomas J.D., Mann D.L., Griffin B.P. Elevated circulating levels of serum tumor necrosis factor-alpha in patients with hemodynamically significant pressure and volume overload. J Am Coll Cardiol. 2000;36(1):208–212. doi: 10.1016/s0735-1097(00)00721-x. [DOI] [PubMed] [Google Scholar]
  • 22.Heymans S., Schroen B., Vermeersch P., et al. Increased cardiac expression of tissue inhibitor of metalloproteinase-1 and tissue inhibitor of metalloproteinase-2 is related to cardiac fibrosis and dysfunction in the chronic pressure-overloaded human heart. Circulation. 2005;112(8):1136–1144. doi: 10.1161/CIRCULATIONAHA.104.516963. [DOI] [PubMed] [Google Scholar]
  • 23.Chin C.W.L., Everett R.J., Kwiecinski J., et al. Myocardial fibrosis and cardiac decompensation in aortic stenosis. JACC Cardiovasc Imaging. 2017;10(11):1320–1333. doi: 10.1016/j.jcmg.2016.10.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Treibel T.A., Badiani S., Lloyd G., Moon J.C. Multimodality imaging markers of adverse myocardial remodeling in aortic stenosis. JACC Cardiovasc Imaging. 2019;12(8 Pt 1):1532–1548. doi: 10.1016/j.jcmg.2019.02.034. [DOI] [PubMed] [Google Scholar]
  • 25.Kempny A., Diller G.P., Kaleschke G., et al. Longitudinal left ventricular 2D strain is superior to ejection fraction in predicting myocardial recovery and symptomatic improvement after aortic valve implantation. Int J Cardiol. 2013;167(5):2239–2243. doi: 10.1016/j.ijcard.2012.06.012. [DOI] [PubMed] [Google Scholar]
  • 26.Kusunose K., Goodman A., Parikh R., et al. Incremental prognostic value of left ventricular global longitudinal strain in patients with aortic stenosis and preserved ejection fraction. Circ Cardiovasc Imaging. 2014;7(6):938–945. doi: 10.1161/CIRCIMAGING.114.002041. [DOI] [PubMed] [Google Scholar]
  • 27.Poulin F., Carasso S., Horlick E.M., et al. Recovery of left ventricular mechanics after transcatheter aortic valve implantation: effects of baseline ventricular function and postprocedural aortic regurgitation. J Am Soc Echocardiogr. 2014;27(11):1133–1142. doi: 10.1016/j.echo.2014.07.001. [DOI] [PubMed] [Google Scholar]
  • 28.Wani A., Harland D.R., Bajwa T.K., et al. Left ventricular mechanics differ in subtypes of aortic stenosis following transcatheter aortic valve replacement. Front Cardiovasc Med. 2022;8 doi: 10.3389/fcvm.2021.777206. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Chau K.H., Douglas P.S., Pibarot P., et al. Regression of left ventricular mass after transcatheter aortic valve replacement: the PARTNER trials and registries. J Am Coll Cardiol. 2020;75(19):2446–2458. doi: 10.1016/j.jacc.2020.03.042. [DOI] [PubMed] [Google Scholar]
  • 30.Aventin B.P., Ruberte E.G., Paracuellos T.S., et al. Predictors of left ventricular ejection fraction recovery after transcatheter aortic valve replacement (TAVR) Eur Heart J. 2021;42(Suppl 1):847. [Google Scholar]
  • 31.Xiong T.Y., Wang X., Li Y.J., et al. Less pronounced reverse left ventricular remodeling in patients with bicuspid aortic stenosis treated with transcatheter aortic valve replacement compared to tricuspid aortic stenosis. Int J Cardiovasc Imaging. 2018;34(11):1761–1767. doi: 10.1007/s10554-018-1401-6. [DOI] [PubMed] [Google Scholar]
  • 32.Quere J.P., Monin J.L., Levy F., et al. Influence of preoperative left ventricular contractile reserve on postoperative ejection fraction in low-gradient aortic stenosis. Circulation. 2006;113(14):1738–1744. doi: 10.1161/CIRCULATIONAHA.105.568824. [DOI] [PubMed] [Google Scholar]
  • 33.Ribeiro H.B., Lerakis S., Gilard M., et al. Transcatheter aortic valve replacement in patients with low-flow, low-gradient aortic stenosis: the TOPAS-TAVI registry. J Am Coll Cardiol. 2018;71(12):1297–1308. doi: 10.1016/j.jacc.2018.01.054. [DOI] [PubMed] [Google Scholar]
  • 34.Sato K., Sankaramangalam K., Kandregula K., et al. Contemporary outcomes in low-gradient aortic stenosis patients who underwent dobutamine stress echocardiography. J Am Heart Assoc. 2019;8(6) doi: 10.1161/JAHA.118.011168. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Kockova R., Kacer P., Pirk J., et al. Native T1 relaxation time and extracellular volume fraction as accurate markers of diffuse myocardial fibrosis in heart valve disease - comparison with targeted left ventricular myocardial biopsy. Circ J. 2016;80(5):1202–1209. doi: 10.1253/circj.CJ-15-1309. [DOI] [PubMed] [Google Scholar]
  • 36.Gastl M., Behm P., Haberkorn S., et al. Role of T2 mapping in left ventricular reverse remodeling after TAVR. Int J Cardiol. 2018;266:262–268. doi: 10.1016/j.ijcard.2018.02.029. [DOI] [PubMed] [Google Scholar]
  • 37.Nitsche C., Scully P.R., Patel K.P., et al. Prevalence and outcomes of concomitant aortic stenosis and cardiac amyloidosis. J Am Coll Cardiol. 2021;77(2):128–139. doi: 10.1016/j.jacc.2020.11.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Castaño A., Narotsky D.L., Hamid N., et al. Unveiling transthyretin cardiac amyloidosis and its predictors among elderly patients with severe aortic stenosis undergoing transcatheter aortic valve replacement. Eur Heart J. 2017;38(38):2879–2887. doi: 10.1093/eurheartj/ehx350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Han D., Tamarappoo B., Klein E., et al. Computed tomography angiography-derived extracellular volume fraction predicts early recovery of left ventricular systolic function after transcatheter aortic valve replacement. Eur Heart J Cardiovasc Imaging. 2021;22(2):179–185. doi: 10.1093/ehjci/jeaa310. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Tanaka T., Yahagi K., Asami M., et al. Prognostic impact of electrocardiographic left ventricular hypertrophy following transcatheter aortic valve replacement. J Cardiol. 2021;77(4):346–352. doi: 10.1016/j.jjcc.2020.12.017. [DOI] [PubMed] [Google Scholar]
  • 41.Yang Y., Ahn J.M., Kang D.Y., et al. Implication of different ECG left ventricular hypertrophy in patients undergoing transcatheter aortic valve replacement. J Am Heart Assoc. 2022;11(4) doi: 10.1161/JAHA.121.023647. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Carrabba N., Valenti R., Migliorini A., et al. Impact on left ventricular function and remodeling and on 1-year outcome in patients with left bundle branch block after transcatheter aortic valve implantation. Am J Cardiol. 2015;116(1):125–131. doi: 10.1016/j.amjcard.2015.03.054. [DOI] [PubMed] [Google Scholar]
  • 43.Sato K., Kumar A., Krishnaswamy A., et al. B-type natriuretic peptide is associated with remodeling and exercise capacity after transcatheter aortic valve replacement for aortic stenosis. Clin Cardiol. 2019;42(2):270–276. doi: 10.1002/clc.23138. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Kim J.B., Kobayashi Y., Kuznetsova T., et al. Cytokines profile of reverse cardiac remodeling following transcatheter aortic valve replacement. Int J Cardiol. 2018;270:83–88. doi: 10.1016/j.ijcard.2018.05.020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Lindman B.R., Lindenfeld J. Prevention and mitigation of heart failure in the treatment of calcific aortic stenosis: a unifying therapeutic principle. JAMA Cardiol. 2021;6(9):993–994. doi: 10.1001/jamacardio.2021.2082. [DOI] [PubMed] [Google Scholar]
  • 46.Yusuf S., Pfeffer M.A., Swedberg K., et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-preserved trial. Lancet. 2003;362(9386):777–781. doi: 10.1016/S0140-6736(03)14285-7. [DOI] [PubMed] [Google Scholar]
  • 47.SOLVD Investigators. Yusuf S., Pitt B., Davis C.E., Hood W.B., Cohn J.N. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991;325(5):293–302. doi: 10.1056/NEJM199108013250501. [DOI] [PubMed] [Google Scholar]
  • 48.CONSENSUS Trial Study Group Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) N Engl J Med. 1987;316(23):1429–1435. doi: 10.1056/NEJM198706043162301. [DOI] [PubMed] [Google Scholar]
  • 49.Goel S.S., Kleiman N.S., Zoghbi W.A., Reardon M.J., Kapadia S.R. Renin-angiotensin system blockade in aortic stenosis: implications before and after aortic valve replacement. J Am Heart Assoc. 2020;9(18) doi: 10.1161/JAHA.120.016911. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Treibel T.A., Kozor R., Schofield R., et al. Reverse myocardial remodeling following valve replacement in patients with aortic stenosis. J Am Coll Cardiol. 2018;71(8):860–871. doi: 10.1016/j.jacc.2017.12.035. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Dahl J.S., Videbaek L., Poulsen M.K., et al. Effect of candesartan treatment on left ventricular remodeling after aortic valve replacement for aortic stenosis. Am J Cardiol. 2010;106(5):713–719. doi: 10.1016/j.amjcard.2010.04.028. [DOI] [PubMed] [Google Scholar]
  • 52.Ramchand J., Patel S.K., Kearney L.G., et al. Plasma ACE2 activity predicts mortality in aortic stenosis and is associated with severe myocardial fibrosis. JACC Cardiovasc Imaging. 2020;13(3):655–664. doi: 10.1016/j.jcmg.2019.09.005. [DOI] [PubMed] [Google Scholar]
  • 53.Epelman S., Shrestha K., Troughton R.W., et al. Soluble angiotensin-converting enzyme 2 in human heart failure: relation with myocardial function and clinical outcomes. J Card Fail. 2009;15(7):565–571. doi: 10.1016/j.cardfail.2009.01.014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.O'Brien K.D., Probstfield J.L., Caulfield M.T., et al. Angiotensin-converting enzyme inhibitors and change in aortic valve calcium. Arch Intern Med. 2005;165(8):858–862. doi: 10.1001/archinte.165.8.858. [DOI] [PubMed] [Google Scholar]
  • 55.Bull S., Loudon M., Francis J.M., et al. A prospective, double-blind, randomized controlled trial of the angiotensin-converting enzyme inhibitor ramipril in aortic stenosis (RIAS trial) Eur Heart J Cardiovasc Imaging. 2015;16(8):834–841. doi: 10.1093/ehjci/jev043. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Ochiai T., Saito S., Yamanaka F., et al. Renin-angiotensin system blockade therapy after transcatheter aortic valve implantation. Heart. 2018;104(8):644–651. doi: 10.1136/heartjnl-2017-311738. [DOI] [PubMed] [Google Scholar]
  • 57.Rodriguez-Gabella T., Catalá P., Muñoz-García A.J., et al. Renin-angiotensin system inhibition following transcatheter aortic valve replacement. J Am Coll Cardiol. 2019;74(5):631–641. doi: 10.1016/j.jacc.2019.05.055. [DOI] [PubMed] [Google Scholar]
  • 58.Inohara T., Manandhar P., Kosinski A.S., et al. Association of renin-angiotensin inhibitor treatment with mortality and heart failure readmission in patients with transcatheter aortic valve replacement. JAMA. 2018;320(21):2231–2241. doi: 10.1001/jama.2018.18077. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59.Amat-Santos I.J., Catalá P., Diez Del Hoyo F., et al. Impact of renin-angiotensin system inhibitors on clinical outcomes and ventricular remodelling after transcatheter aortic valve implantation: rationale and design of the RASTAVI randomised multicentre study. BMJ Open. 2018;8(2) doi: 10.1136/bmjopen-2017-020255. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.Amat-Santos I.J., Sánchez-Luna J.P., Abu-Assi E., et al. Dapagliflozin after transcatheter aortic valve implantation (DapaTAVI) Investigators. Rationale and design of the dapagliflozin after transcatheter aortic valve implantation (DapaTAVI) randomized trial. Eur J Heart Fail. 2022;24(3):581–588. doi: 10.1002/ejhf.2370. [DOI] [PubMed] [Google Scholar]
  • 61.Généreux P., Pibarot P., Redfors B., et al. Staging classification of aortic stenosis based on the extent of cardiac damage. Eur Heart J. 2017;38(45):3351–3358. doi: 10.1093/eurheartj/ehx381. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62.Samad Z., Vora A.N., Dunning A., et al. Aortic valve surgery and survival in patients with moderate or severe aortic stenosis and left ventricular dysfunction. Eur Heart J. 2016;37(28):2276–2286. doi: 10.1093/eurheartj/ehv701. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Spitzer E., Van Mieghem N.M., Pibarot P., et al. Rationale and design of the Transcatheter Aortic Valve Replacement to UNload the Left ventricle in patients with ADvanced heart failure (TAVR UNLOAD) trial. Am Heart J. 2016;182:80–88. doi: 10.1016/j.ahj.2016.08.009. [DOI] [PubMed] [Google Scholar]
  • 64.Pai R.G., Kapoor N., Bansal R.C., Varadarajan P. Malignant natural history of asymptomatic severe aortic stenosis: benefit of aortic valve replacement. Ann Thorac Surg. 2006;82(6):2116–2122. doi: 10.1016/j.athoracsur.2006.07.043. [DOI] [PubMed] [Google Scholar]
  • 65.Taniguchi T., Morimoto T., Shiomi H., et al. Initial surgical versus conservative strategies in patients with asymptomatic severe aortic stenosis. J Am Coll Cardiol. 2015;66(25):2827–2838. doi: 10.1016/j.jacc.2015.10.001. [DOI] [PubMed] [Google Scholar]
  • 66.Magne J., Cosyns B., Popescu B.A., et al. Distribution and prognostic significance of left ventricular global longitudinal strain in asymptomatic significant aortic stenosis: an individual participant data meta-analysis. JACC Cardiovasc Imaging. 2019;12(1):84–92. doi: 10.1016/j.jcmg.2018.11.005. [DOI] [PubMed] [Google Scholar]
  • 67.Zhu D., Ito S., Miranda W.R., et al. Left ventricular global longitudinal strain is associated with long-term outcomes in moderate aortic stenosis. Circ Cardiovasc Imaging. 2020;13(4) doi: 10.1161/CIRCIMAGING.119.009958. [DOI] [PubMed] [Google Scholar]
  • 68.Chin C.W., Shah A.S., McAllister D.A., et al. High-sensitivity troponin I concentrations are a marker of an advanced hypertrophic response and adverse outcomes in patients with aortic stenosis. Eur Heart J. 2014;35(34):2312–2321. doi: 10.1093/eurheartj/ehu189. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69.Bing R., Everett R.J., Tuck C., et al. Rationale and design of the randomized, controlled early valve replacement guided by biomarkers of left ventricular decompensation in asymptomatic patients with severe aortic stenosis (EVOLVED) trial. Am Heart J. 2019;212:91–100. doi: 10.1016/j.ahj.2019.02.018. [DOI] [PubMed] [Google Scholar]
  • 70.Lindman B.R., Dweck M.R., Lancellotti P., et al. Management of asymptomatic severe aortic stenosis: evolving concepts in timing of valve replacement. JACC Cardiovasc Imaging. 2020;13(2 Pt 1):481–493. doi: 10.1016/j.jcmg.2019.01.036. [DOI] [PubMed] [Google Scholar]
  • 71.Lancellotti P., Magne J., Dulgheru R., et al. Outcomes of patients with asymptomatic aortic stenosis followed up in heart valve clinics. JAMA Cardiol. 2018;3(11):1060–1068. doi: 10.1001/jamacardio.2018.3152. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Structural Heart are provided here courtesy of Elsevier

RESOURCES