Pressure Overload Of Aortic Stenosis Research Articles

220 Sex Differences in Cardiac Damage in Aortic Stenosis

OBJECTIVES/GOALS: Sex differences in aortic stenosis (AS) are vastly underestimated, contribute to disparities in treatment and worse outcomes for women including disproportionately higher mortality rates. This study aims to investigate sex differences in extent of cardiac damage (CD) from pressure overload in AS that may help account for the observed disparities. METHODS/STUDY POPULATION: CD in AS refers to a series of pathologic changes in the myocardium that occur due to chronic pressure overload imposed on the left ventricle by a progressively stenotic aortic valve (AV). These changes are associated with poor outcomes and lower survival in patients with AS. To acquire a deeper understanding of the factors and mechanisms affecting differences in the long-term survival and management of patients with AS, we are proposing to assess baseline stage of CD on echocardiography, and changes in transvalvular hemodynamics and CD stage (Δ CD) over time, in patients with moderate and severe AS at one of 2 large tertiary-care hospitals in MA. We also plan to assess time to and performance of aortic valve replacement (AVR), stratified by hemodynamic severity of stenosis and CD stage, and their interaction with sex. RESULTS/ANTICIPATED RESULTS: We hypothesize that women will have a higher stage of CD on their initial echocardiogram (TTE), demonstrating moderate or greater severity of AS, than men with the same hemodynamic severity of valvular stenosis. We additionally hypothesize that those with more advanced cardiac damage stage will likely have masking of transvalvular progression on echocardiogram. Finally, we anticipate that women will have AVR performed less frequently than men and will have minimal improvement in their Kansas City Cardiomyopathy Questionnaire (KCCQ) scores post-AVR indicative of more heart failure symptoms and a lower quality of life. DISCUSSION/SIGNIFICANCE: This study will seek to better understand sex-based differences in extent of cardiac damage to pressure overload in aortic stenosis (AS) to minimize treatment and outcome disparities for women and allow for more individualized and patient-centered care.

Abstract 13652: A Randomised Double-Blind Placebo-Controlled Study of Fenofibrate as a Metabolic Modulator to Augment Cardiac Physiology in Moderate-Severe Aortic Stenosis

Background: Pressure overload in aortic stenosis (AS) is associated with reduced cardiac fatty acid oxidation (FAO) and evidence of myocardial steatosis and impaired myocardial energetics. Here, we investigated whether modulating myocardial metabolism to increase FAO with a PPARα agonist, Fenofibrate in moderate-severe AS had effects on cardiac metabolism and physiology. Methods: 67 participants with asymptomatic moderate-severe AS were prospectively randomised (double-blinded) to receive either Fenofibrate 200mg once daily (N= 54) or placebo (N=13) for 6 months (180 ± 7 days duration). Follow-up data is available in 42 patients. Primary endpoint was reduction in myocardial triglyceride content (MTG) measured using proton magnetic resonance spectroscopy (MRS). Secondary endpoints included cardiac PCr/ATP measured by 31P-MRS and LV strain assessed using MR tagging. Results: There was significant reduction in MTG content (-0.40%, CI -0.74 to -0.06, p= 0.022), with a no significant reduction seen in placebo. (-0.46%, CI -1.1 to 0.17, p= 0.13). A significant increase in venous butyrate levels was seen in the fibrate group (+0.09 mmol/l, CI 0.006 to 0.17, p= 0.036) in line with increased fatty acid oxidation. No change in cardiac energetics was seen in either group. No change in cardiac function was seen in either group, global longitudinal strain (-0.07%, p 0.89 Fibrate vs -0.31%, p 0.67 Placebo), circumferential strain ( -0.15 %, p 0.80 Fibrate vs 1.71%, p 0.07 Placebo). Conclusions: Fenofibrate can potentially upregulate fatty acid oxidation in hypertrophied AS hearts reducing myocardial lipid content, but this did not have any measurable beneficial physiological effect in moderate-severe AS.

Cardiac magnetic resonance patterns of left ventricular hypertrophy in aortic stenosis patients

Abstract Background Left ventricular (LV) hypertrophy is a known compensatory mechanism to pressure overload in aortic stenosis (AS) patients. However, by cardiac magnetic resonance (CMR) different patterns of LV adaptation are seen in this group of patients. Aim To describe the patterns of LV adaptation (by CMR) and to analyze its structure and function indexes in AS patients referred for surgical aortic valve replacement (AVR). Methods We prospectively studied 134 consecutive patients (age: 73y [IQR 68–77y], 49% men) with severe symptomatic AS - mean transaortic pressure gradient (AVmean): 61±1.5 mmHg; mean aortic valve area: AVA): 0.7±0.1 cm2, referred for surgical AVR with no previous history of ischemic cardiomyopathy or other. All patients underwent electrocardiogram, 2D transthoracic echocardiogram (TTE) and cardiac magnetic resonance (CMR) before surgery for LV assessment and tissue characterization. Five patterns of LV structure were considered: normal ventricular structure (normal LV mass/volume ratio [M/V], normal LVMi and normal indexed LV end-diastolic volume (LVEDVi); concentric remodeling: increased M/V, normal LVMi; concentric hypertrophy: increased M/V and LVMi; eccentric hypertrophy: increased LVMi and LVEDVi, normal M/V and ejection fraction; and adverse remodeling: dilated left ventricle, increased LVMi and normal M/V in the context of an impaired ejection fraction. Echocardiogram and CMR structural and functional indexes were compared between these groups. Results At baseline study, at CMR: mean LV indexed mass [LVMi]: 80.3±26.5 g/m2; mean end-diastolic LV indexed volume [LVEDVi]: 84.4±24.5 mL/m2 and median geometric remodeling ratio [M/V]: 0.95 g/mL [IQR 0. 81–1.08 g/mL]. Overall, 22% patients had normal LV structure, 30% concentric remodeling ventricular geometry, and two patients had an adverse remodeling pattern. LV hypertrophy was the most prevalent pattern and occurred in 48% of subjects (concentric 43%; eccentric 4%). In our cohort, the severity of AS (AVmean (p<0.001), LV function (LV ejection fraction [p<0.001] and Global longitudinal strain [p<0.001]), LV loading conditions (indexed left atrial volume [p<0.001] and E/e' ratio [p<0.001]) and NT-proBNP (p<0.001) were related to the pattern of LV structure (Table 1). Conclusions In our cohort, AS patients presented several distinct patterns of LV remodeling. Disease severity, functional repercussion and loading conditions are distinct between them. Funding Acknowledgement Type of funding sources: None.

Correlation between Left Atrial Volume Index and Pulmonary Hypertension in Patient with Moderate to Severe Aortic Stenosis

Background: Left atrial dilatation is a response to pressure overload in aortic stenosis (AS). Objective: To study the correlation between left atrium volume index (LAVI) and the pulmonary hypertension in patients with moderate to severe AS. Materials and Methods: The authors retrospectively studied patients with moderate to severe AS (either one or all echocardiographic criteria of aortic valve area [AVA]) smaller than 1.5 cm², AV Vmax of more than 3 m/s, AV mean PG of more than 30 mmHg who underwent transthoracic echocardiography at Pranangklao Hospital between January 2015 and December 2019. Results: One hundred thirty-four patients (age 72.31±12.32 years, 46.3% male) were enrolled. In pulmonary hypertension group, proportion of atrial fibrillation (75%) were significantly higher Sinus Rhythm (26.3%). Right ventricular systolic pressure (RVSP) tended to increase when LAVI increased (r=0.695, p<0.001). The mean RVSP in four groups of LAVI (less than 35 ml/m², 35 to 41 ml/m², 42 to 48 ml/m², and more than 48 ml/m²) were 35.11±8.97, 38.22±11.71, 39.0±8.57, and 60.05±31 mmHg, respectively. RVSP in patients with LAVI of more than 48 ml/m² was significantly higher than those of the other group (p<0.001). LAVI in patients with RVSP of less than 50 and more than 50 mmHg were 35.13±6.86 and 65.22±11.55 ml/m², respectively (p<0.001). Conclusion: Moderate to severe AS, RVSP increase when LAVI increases. Keywords: Echocardiography, Left atrium volume index, Aortic stenosis, Pulmonary hypertension

Sex-Related Differences in the Extent of Myocardial Fibrosis in Patients With Aortic Valve Stenosis

ObjectivesThe aim of this study was to assess the effect of sex on myocardial fibrosis as assessed by using cardiac magnetic resonance (CMR) imaging in aortic stenosis (AS). BackgroundPrevious studies reported sex-related differences in the left ventricular (LV) remodeling response to pressure overload in AS. However, there are very few data regarding the effect of sex on myocardial fibrosis, a key marker of LV decompensation and adverse cardiac events in AS. MethodsA total of 249 patients (mean age 66 ± 13 years; 30% women) with at least mild AS were recruited from 2 prospective observational cohort studies and underwent comprehensive Doppler echocardiography and CMR examinations. On CMR, T1 mapping was used to quantify extracellular volume (ECV) fraction as a marker of diffuse fibrosis, and late gadolinium enhancement (LGE) was used to assess focal fibrosis. ResultsThere was no difference in age between women and men (age 66 ± 15 years vs 66 ± 12 years; p = 0.78). However, women presented with a better cardiovascular risk profile than men with less hypertension, dyslipidemia, diabetes, and coronary artery disease (all, p ≤ 0.10). As expected, LV mass index measured by CMR imaging was smaller in women than in men (p < 0.0001). Despite fewer comorbidities, women presented with larger ECV fraction (median: 29.0% [25th to 75th percentiles: 27.4% to 30.6%] vs. 26.8% [25th to 75th percentiles: 25.1% to 28.7%]; p < 0.0001) and similar LGE (median: 4.5% [25th–75th percentiles: 2.3% to 7.0%] vs. 2.8% [25th–75th percentiles: 0.6% to 6.8%]; p = 0.20) than men. In multivariable analysis, female sex remained an independent determinant of higher ECV fraction and LGE (all, p ≤ 0.05). ConclusionsWomen have greater diffuse and focal myocardial fibrosis independent of the degree of AS severity. These findings further emphasize the sex-related differences in LV remodeling response to pressure overload.

Time course of left ventricular remodelling and mechanics after aortic valve surgery: aortic stenosis vs. aortic regurgitation.

AimsPressure overload in aortic stenosis (AS) and both pressure and volume overload in aortic regurgitation (AR) induce concentric and eccentric hypertrophy, respectively. These structural changes influence left ventricular (LV) mechanics, but little is known about the time course of LV remodelling and mechanics after aortic valve surgery (AVR) and its differences in AS vs. AR. The present study aimed to characterize the time course of LV mass index (LVMI) and LV mechanics [by LV global longitudinal strain (LV GLS)] after AVR in AS vs. AR.Methods and resultsTwo hundred and eleven (61 ± 14 years, 61% male) patients with severe AS (63%) or AR (37%) undergoing surgical AVR with routine echocardiographic follow-up at 1, 2, and/or 5 years were evaluated. Before AVR, LVMI was larger in AR patients compared with AS. Both groups showed moderately impaired LV GLS, but preserved LV ejection fraction. After surgery, both groups showed LV mass regression, although a more pronounced decline was seen in AR patients. Improvement in LV GLS was observed in both groups, but characterized by an initial decline in AR patients while LV GLS in AS patients remained initially stable.ConclusionIn severe AS and AR patients undergoing AVR, LV mass regression and changes in LV GLS are similar despite different LV remodelling before AVR. In AR, relief of volume overload led to reduction in LVMI and an initial decline in LV GLS. In contrast, relief of pressure overload in AS was characterized by a stable LV GLS and more sustained LV mass regression.

SEX-RELATED DIFFERENCES IN THE EXTENT OF MYOCARDIAL FIBROSIS IN PATIENTS WITH AORTIC VALVE STENOSIS

Abstract Objectives The aim of this study was to assess the effect of sex on myocardial fibrosis as assessed by using cardiac magnetic resonance (CMR) imaging in aortic stenosis (AS). Background Previous studies reported sex-related differences in the left ventricular (LV) remodeling response to pressure overload in AS. However, there are very few data regarding the effect of sex on myocardial fibrosis, a key marker of LV decompensation and adverse cardiac events in AS. Methods A total of 249 patients (mean age 66 ± 13 years; 30% women) with at least mild AS were recruited from 2 prospective observational cohort studies and underwent comprehensive Doppler echocardiography and CMR examinations. On CMR, T1 mapping was used to quantify extracellular volume (ECV) fraction as a marker of diffuse fibrosis, and late gadolinium enhancement (LGE) was used to assess focal fibrosis. Results There was no difference in age between women and men (age 66 ± 15 years vs 66 ± 12 years; p = 0.78). However, women presented with a better cardiovascular risk profile than men with less hypertension, dyslipidemia, diabetes, and coronary artery disease (all, p ≤ 0.10). As expected, LV mass index measured by CMR imaging was smaller in women than in men (p Conclusions Women have greater diffuse and focal myocardial fibrosis independent of the degree of AS severity. These findings further emphasize the sex-related differences in LV remodeling response to pressure overload.

Cardiac Mechanics in Isolated Bicuspid Aortic Valve Disease With Normal Ejection Fraction: A Study of Various Valvular Lesion Types.

Aortic stenosis (AS) and aortic regurgitation (AR) are associated with congenital isolated bicuspid aortic valve (BAV) disease. The chronic pressure overload of AS and the volume overload of AR are known to impair the left ventricular function. This study assessed whether two-dimensional speckle tracking echocardiography (2D-STE) is capable of detecting the myocardial dysfunction associated with BAV caused by various aortic valve lesions in patients retaining normal ejection fraction (EF).Thirty-two isolated BAV patients and 20 healthy tricuspid aortic valve (TAV) volunteers were recruited. BAV patients were divided into 4 subgroups based on aortic valvular lesion types: normal function (NF) group, isolated AS group, isolated AR group, and a group who had both AS&AR. Myocardial strain and degree of twist were analyzed and compared between the BAV and TAV groups, as well as between valvular lesion groups and the NF group.Compared with healthy TAV controls, global radial strain (GRS), global circumferential strain (GCS), global longitudinal strain (GLS), and twist angle absolute values were lower in the BAV group (P < 0.05). The AS, AR, and AS&AR groups all demonstrated a significant decrease in GRS and GCS when compared with the TAV group. The AS and AS&AR groups demonstrated lower GLS than the TAV group, and the smallest degree of twist was detected in the AR group. There were no significant differences between the NF and TAV groups. The AR and AS&AR groups demonstrated significant differences in multiple parameters of cardiac mechanics compared with the NF group.2D-STE is able to detect altered cardiac mechanics associated with aortic lesion types in BAV patients with normal EF compared with normal TAV controls, and so can provide valuable information for clinical decision-making.

Gender influences left ventricular remodelling in the setting of aortic stenosis but does not appear to impact on reverse remodelling following transcatheter aortic valve implantation

Background Left ventricular (LV) remodelling in the setting of the chronic pressure overload of aortic stenosis (AS) appears to differ according to gender. Women appear to have an improved survival compared to men following transcatheter aortic valve implantation (TAVI) but the reasons for this are yet to be established. Potential mechanisms include differing patterns of LV reverse remodelling, LV fibrosis regression and reduced aortic regurgitation in females. We sought to establish using cardiac magnetic resonance (CMR) imaging, the reference standard noninvasive technique for LV mass and scar quantification, whether there were any gender differences in these parameters before and after TAVI.

Myocardial and circulating levels of microRNA-21 reflect left ventricular fibrosis in aortic stenosis patients

BackgroundVarious human cardiovascular pathophysiological conditions associate aberrant expression of microRNAs (miRNAs) and circulating miRNAs are emerging as promising biomarkers. In mice, myocardial miR-21 overexpression is related to cardiac fibrosis elicited by pressure overload. This study was designed to determine the role of myocardial and plasmatic miR-21 in the maladaptive remodeling of the extracellular matrix induced by pressure overload in aortic stenosis (AS) patients and the clinical value of miR-21 as a biomarker for pathological myocardial fibrosis. MethodsIn left ventricular biopsies from 75 AS patients and 32 surgical controls, we quantified the myocardial transcript levels of miR-21, miR-21-targets and ECM- and TGF-β-signaling-related elements. miR-21 plasma levels were determined in 25 healthy volunteers and in AS patients. In situ hybridization of miR-21 was performed in myocardial sections. ResultsThe myocardial and plasma levels of miR-21 were significantly higher in the AS patients compared with the controls and correlated directly with the echocardiographic mean transvalvular gradients. miR-21 overexpression was confined to interstitial cells and absent in cardiomyocytes. Using bootstrap validated multiple linear regression, the variance in myocardial collagen expression was predicted by myocardial miR-21 (70% of collagen variance) or plasma miR-21 (52% of collagen variance), together with the miR-21 targets RECK and PDCD4, and effectors of TGF-ß signaling. ConclusionsOur results support the role of miR-21 as a regulator of the fibrotic process that occurs in response to pressure overload in AS patients and underscore the value of circulating miR-21 as a biomarker for myocardial fibrosis.

Assessment of left ventricular function in aortic stenosis

Degenerative aortic stenosis (AS) has become the most common valvular heart disease and the definitive treatment of symptomatic, severe AS is surgical valve replacement. In the absence of symptoms, the presence of left ventricular (LV) systolic dysfunction is pivotal in making treatment decisions for patients with AS. However, the LV ejection fraction is not a sensitive marker of global LV systolic function in the presence of LV hypertrophy, implying that asymptomatic patients with AS can have myocardial dysfunction with preserved LV ejection fraction. Abnormal myocardial mechanics might explain the pathophysiological processes underlying chronic pressure overload in AS. In this article, we review how new echocardiographic deformation parameters--such as myocardial strain, strain rate, and twist measurements--offer the potential for clinicians to monitor the course of LV dysfunction in patients with AS. Quantifying disturbances in LV function might provide insight into the timing of aortic valve replacement and into the improvement of LV systolic and diastolic properties through regression of LV hypertrophy and fibrosis after valve implantation.

Preoperative, Postoperative and One-Year Follow-Up of N-Terminal Pro-B-Type Natriuretic Peptide Levels in Volume Overload of Aortic Regurgitation: Comparison with Pressure Overload of Aortic Stenosis

Objectives: Limited data are available regarding the impact of pressure or volume overload on the clinical or echocardiographic parameters and the levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients with chronic severe aortic valve diseases. We aimed to investigate and compare the relationships between these parameters in such patients. Methods: One hundred twenty-four consecutive patients who underwent aortic valve replacement for chronic severe aortic valve diseases were enrolled. Plasma NT- proBNP was measured and echocardiographic parameters were recorded before surgery, before discharge and 12 months after surgery. Results: NT-proBNP levels were significantly higher in patients with aortic regurgitation (AR) (n = 63) than in those with aortic stenosis (n = 61) (1,836.0 ± 376.1 vs. 508.4 ± 74.5 pg/ml, p = 0.001). There was a significant relationship between NT-proBNP levels and left ventricular mass index (LVMI) in AR (r = 0.436, p = 0.002) and a weaker, but significant, relationship between NT-proBNP levels and LVMI in aortic stenosis patients (r = 0.290, p = 0.046). In the AR group, preoperative NT-proBNP levels positively correlated with LVMI regression during the 12 months after surgery (r = 0.488, p = 0.001). Conclusion: NT-proBNP levels may reflect LVMI changes that are caused by volume overload rather than pressure overload in chronic aortic valve diseases. Higher preoperative NT-proBNP levels may predict left ventricular reverse remodeling early after surgery for chronic severe AR.

Is there an innate sex-based difference in the manner in which the left ventricle responds to the pressure overload of aortic stenosis?

Numerous investigators have suggested that women are particularly prone to develop an exaggerated LV hypertrophy (LVH) response to increased developed pressure as compared to men. This has been best exemplified in both HTN and aortic stenosis (AS) states and has been proposed euphemistically as 'exuberant hypertrophy'. This reference implies that there is an inappropriate physiologic amplification to the typical and necessary hypertrophic response for any given blood pressure/afterload experienced by the LV. Furthermore, it suggests that there is a divergent response at the gene level to explain this phenomenon. The implications for this are vast, potentially calling for distinct sex-based clinical treatment programs. The societal ramifications for differential therapy are immense as our resources are limited. On the other hand, the majority of the inferences of this dichotomized observation have stemmed from 2D echocardiography and consequently may be artifactual if evaluated in a 3D CMR manner.

Mo-P4:245 Osteoprotegerin is increased in heart failure due to left ventricular pressure overload in aortic stenosis

Mo-P4:245 Osteoprotegerin is increased in heart failure due to left ventricular pressure overload in aortic stenosis

Vasodilators in Aortic Regurgitation — Where Is the Evidence of Their Effectiveness?

Although aortic regurgitation imposes a volume load on the left ventricle, it became clear more than two decades ago that the resulting large stroke volume and wide pulse pressure also lead to systolic hypertension and concomitant left ventricular pressure overload.1,2 In fact, afterload is much higher in aortic regurgitation than in mitral regurgitation and may be as high as that in the more typically recognized pressure overload of aortic stenosis.3 The excess afterload in aortic regurgitation, in turn, forms the basis for the idea that afterload-reducing agents, such as vasodilators, might be beneficial in the medical treatment of this . . .

Heterogeneity of response to pressure overload in aortic stenosis

Heterogeneity of response to pressure overload in aortic stenosis

Prevalence of late potentials in adult aortic stenosis

Sudden death and syncope are well-recognized clinical manifestations of valvular aortic stenosis (AS). Furthermore, patients with left ventricular hypertrophy due to hypertension have a greater prevalence of late potentials (LP) compared with normal subjects. Chronic pressure overload in AS is frequently characterized by development of left ventricular hypertrophy. The aims of this study were (1) to determine the prevalence of LP in patients with moderate to severe AS, and (2) to investigate the relationship between LP and left ventricular hypertrophy. Signal-averaged electrocardiograms (SAECG) were recorded using a 40 Hz high pass filter in 32 patients (19 M and 13 F), aged 69 ± 11 years with AS, and in 25 age- and sex-matched controls. QRS duration (QRSD) <114 ms, low amplitude signal of last 40 ms (LAS40) <38 ms and root mean square voltage of last 40 ms (RMS40) > 20 μV were considered normal. LP were considered to be present if at least two of the above criteria were abnormal. Each patient underwent a complete echo-Doppler examination and the following parameters were measured: aortic valve area, fractional shortening, left ventricular end-diastolic diameter and mass index. Coronary arteriography was performed in 17 (53%) patients. LP were present in 8 out of 32 (25%) AS patients and in 1 out of 25 controls (4%); this difference was statistically significant ( P < 0.006). No difference with regard to age, sex, presence of congestive heart failure, angina, syncope, complex ventricular arrhythmias and coronary artery disease was found in AS patients with and without LP. No correlation was found between indices of left ventricular structure and function and each SAECG parameter. In conclusion, the prevalence of LP in patients with AS is higher than in controls and the presence of LP in AS might be related to factors other than coronary artery disease and left ventricular mass and/or function.

Left Ventricular Remodeling in Valvular Aortic Stenosis: Echocardiographic and Clinical Changes in Two Patients During Follow-up

Left ventricular (LV) response to chronic pressure overload of aortic stenosis (AS) is usually characterized by an increase of wall thickness without cavity enlargement ("concentric hypertrophy"). During follow-up, two patients with AS developed relevant structural and functional changes of the left ventricle, ie, progressive LV dilatation, wall thinning, and reduction of systolic performance. At the same time, the patients had clinical symptoms of congestive heart failure. The pathophysiologic relevance of this form of LV remodeling in AS is discussed.