Role of Early Left Atrial Functional Decline in Predicting Cardiotoxicity in HER2 Positive Breast Cancer Patients Treated With Trastuzumab.

Trastuzumab is widely used in HER2 breast cancer. However, it may cause left ventricular (LV) dysfunction. A decrease in LV global longitudinal strain (GLS) has been previously demonstrated to be a good predictor of subsequent cancer therapy related dysfunction (CTRCD). Left atrial morphological remodeling during Trastuzumab therapy has also been shown. The aim of this study is exploring the relationship between early changes in left atrial function and the development of Trastuzumab-induced cardiotoxicity. Consecutive patients with diagnosis of HER2+non-metastatic breast cancer treated with Trastuzumab were prospectively enrolled. A clinical, conventional, and advanced echocardiographic assessment was performed at baseline and every three months, until a one-year follow-up was reached. One-hundred-sixteen patients completed the 12 months follow-up, 10 (9%) cases of CTRCD were observed, all after the sixth month. GLS and LVEF significantly decreased in the CTRCD group at 6 months of follow-up, with an earlier (3 months) significant worsening in left atrial morpho-functional parameters. Systolic blood pressure, early peak atrial longitudinal strain (PALS), peak atrial contraction (PACS) and left atrial volume (LAVI) changes resulted independent predictors of CTRCD at multivariable logistic regression analysis. Moreover, early changes in PALS and PACS resulted good predictors of CTRCD development (AUC 0.85; p = 0.008, p < 0.001 and 0.77; p = 0.008, respectively). This prospective study emphasizes that the decline in PALS and PACS among trastuzumab-treated patients could possibly increase the accuracy in identifying future CTRCD in non-metastatic HER2 breast cancer cases, adding predictive value to conventional echocardiographic assessment.

Comprehensive Angiography-Derived Functional Assessment of Epicardial and Microvascular Coronary Disease. Correlation With Non-invasive Myocardial Stress Imaging.

Coronary angiography (CA) is poorly correlated with non-invasive myocardial stress imaging (NSI) and myocardial ischemia is often observed in patients with unobstructed coronary arteries. Moreover, the diagnostic performance of combined epicardial and microcirculatory angiography-derived physiological assessment and its correlation with NSI remains unknown. A total of 917 coronary vessels in 319 patients who underwent both CA and NSI were included in this multicenter observational retrospective analysis. Quantitative flow ratio (QFR) and angiography-derived index of microcirculatory resistance (IMRangio) analyses were performed to estimate coronary epicardial and microcirculatory function respectively. NSI demonstrated evidence of myocardial ischemia in 76% of the cases. IMRangio (36 [22 to 50] vs 29 [21 to 41], p <0.001) was significantly higher and QFR (0.92 [0.78 to 0.99] vs 0.97 [0.91 to 0.99], p <0.001) was significantly lower in vessels subtending ischemic territories. Overall, the diagnostic accuracy of QFR was moderate (area under the curve of receiver operating characteristic [AUCROC] 0.632 [95% confidence interval [CI] 0.589 to 0.674], p <0.0001) but it was higher in patients with normal microcirculatory function (AUCROC = 0.726 [95% CI 0.669 to 0.784], p <0.0001, p Value for AUCROC comparison = 0.009). Combined QFR/IMRangio assessment provided incremental diagnostic performance compared with the evaluation of epicardial or microcirculatory districts in isolation (p Value for AUC comparison <0.0001) and it was able to identify the predominant mechanism of myocardial ischemia in 77% of the patients with positive NSI. Our study suggests the value of a combined angiography-derived assessment of epicardial and microvascular function for the definition of the predominant mechanism of myocardial ischemia in patients with suspected coronary artery disease.

Outpatient tricuspid regurgitation in the community: Clinical context and outcome.

BACKGROUND AND AIMS: Epidemiology of tricuspid regurgitation (TR) is poorly known and its burden in the community is challenging to define. We aimed to evaluate the prevalence of TR in a geographically defined area and its outcome, in particular overall survival and hospitalization, considering different clinical contexts. METHODS: We retrospectively analyzed consecutive outpatients referred between 2006 and 2013 for echocardiography and clinical evaluation. Patients with at least moderate TR were included and five different clinical settings were defined: concomitant significant left-sided valvular heart disease (LVHD-TR), heart failure (HF-TR), previous open-heart valvular surgery (postop-TR), pulmonary hypertension (PHTN-TR) and isolated TR (isolated-TR). Primary endpoint was a composite outcome of all-cause mortality or first hospitalization for HF. RESULTS: Of 6797 consecutive patients with a clinical visit and echocardiograms performed in routine practice in a geographically defined community, moderate or severe TR was found in 4.8% of patients (327) . During median follow-up of 6.1 years, TR severity was a determinant of event-free survival. Analyzed for each clinical subset, eight-year event-free survival was 87 ± 7% for postop-TR subgroup, 75 ± 7% for isolated-TR, 67 ± 6% for PHTN-TR, 58 ± 6% for LHVD -TR and 52 ± 11% for HF-TR. CONCLUSION: Moderate or more TR is a notable finding in the community and has impact on event-free survival in all clinical settings, with the worst outcomes when associated with relevant left-sided valvular heart disease and HF.

Right Atrial Function Role in Tricuspid Regurgitation-Related Systemic Venous Congestion.

Tricuspid regurgitation (TR) is a frequent valvular pathology and when significant, may cause systemic venous congestion (SC). The right atrium (RA) is an intermediate structure between the tricuspid valve and the venous system and its role in SC is not yet defined. A total of 116 patients with a measurable TR effective regurgitant orifice area (EROA) and regurgitant volume (RVol) were selected from 2020 to 2022. SC was estimated by echocardiography using inferior vena cava diameter and estimated right atrial pressure (eRAP) and by clinical congestive features. TR grade was mild in 23 patients (20%), moderate in 53 patients (46%), and severe in 40 patients (34%). There was a significant decrease in RA function measured by strain with increasing TR severity (p <0.001). There was a marked difference in RA strain between the groups with eRAP >10 and ≤10 mm Hg (25 ± 11% vs 11 ± 7%, p <0.0001). Variables independently associated with inferior vena cava diameter were RA strain (ß -0.532, p <0.001), RA volume indexed (ß 0.249, p = 0.002), RVol (ß 0.229, p = 0.005) and EROA (ß 0.185, p = 0.016), and independently associated with eRAP >10 mm Hg were EROA (odds ratio [OR] 1.024, 95% confidence interval [CI] 1.002 to 1.046), RVol (OR 1.039, 95% CI 1.007 to 1.072) and RA strain (OR 0.863, 95% CI 0.794 to 0.940). The addition of RA strain to models containing EROA or RVol significantly improved the power of the model. RA strain was independently associated with the presence of 3 or more congestive features. In conclusion, echocardiographic and clinical signs of SC are frequent in higher degrees of TR, and RA function seems to play a key role in modulating the downstream effect of TR.

Aortic stiffness plays a role in the discrepancy between mitral valve lesion severity and hemodynamic burden of secondary mitral regurgitation.

BACKGROUND: By the framework of proportionate/disproportionate secondary mitral regurgitation (sMR), disproportionate sMR is characterized by a low left ventricular stroke volume (SV) and an out of proportion regurgitant fraction (RF) for the same effective regurgitant orifice area (EROA). The degree of aortic stiffness is a determinant of the ventricular forward SV. We aim to analyze the importance of aortic stiffness in influencing the discrepancy between measures of mitral valve lesion severity (EROA) and sMR hemodynamic burden (regurgitant volume [RV] and RF). METHODS: We enrolled stable patients with heart failure with reduced ejection fraction (HFrEF) and at least mild sMR. Mitral EROA, RV, RF and aortic pulse wave velocity (PWV) were measured by echocardiography. We defined three groups based on the degree of actual RF deviation from RF estimated by the linear regression equation of RF on EROA (concordant, low-discordant [residuals lower-than -5%] and high-discordant RF [residuals higher-than 5%]). RESULTS: 117 patients were analyzed (68±13 years; female 30%; LVEF 33±8%; EROA 16±12mm2; RV 24±15 ml; RF 27±13%; PWV 6.6 ± 3.2 m/s). LVEF, end-diastolic-volume and EROA didn't differ among groups. PWV and RV were higher in patients with high-discordant RF (p ≤ 0.01), whereas total left ventricular-SV and left ventricular outflow tract-SV (LVOT-SV) were lower (p ≤ 0.0004). PWV was associated with LVOT-SV (r=-0.3;p = 0.0008) and RV (r = 0.3;p = 0.0009). High-discordant RF was predicted by PWV (p = 0.001) independently of LVOT-SV and RV. CONCLUSION: In this HFrEF cohort with sMR, higher PWV was associated with higher-than-expected RF for a given EROA. Aortic stiffness might play a role in the discrepancy between mitral valve lesion severity and sMR hemodynamic burden.

Turbulent blood dynamics in the left heart in the presence of mitral regurgitation: a computational study based on multi-series cine-MRI.

In this work, we performed a computational image-based study of blood dynamics in the whole left heart, both in a healthy subject and in a patient with mitral valve regurgitation. We elaborated multi-series cine-MRI with the aim of reconstructing the geometry and the corresponding motion of left ventricle, left atrium, mitral and aortic valves, and aortic root of the subjects. This allowed us to prescribe such motion to computational blood dynamics simulations where, for the first time, the whole left heart motion of the subject is considered, allowing us to obtain reliable subject-specific information. The final aim is to investigate and compare between the subjects the occurrence of turbulence and the risk of hemolysis and of thrombi formation. In particular, we modeled blood with the Navier-Stokes equations in the arbitrary Lagrangian-Eulerian framework, with a large eddy simulation model to describe the transition to turbulence and a resistive method to manage the valve dynamics, and we used a finite element discretization implemented in an in-house code for the numerical solution.

Left Atrial Strain in the Assessment of Diastolic Function in Heart Failure: A Machine Learning Approach.

BACKGROUND: Diastolic dysfunction (DD) assessment in heart failure is still challenging. Peak atrial longitudinal strain (PALS) is strongly related to end-diastolic pressure and prognosis, but it is still not part of standard DD assessment. We tested the hypothesis that a machine learning approach would be useful to include PALS in DD classification and refine prognostic stratification. METHODS: In a derivation cohort of 864 heart failure patients in sinus rhythm (age, 66.6±12 years; heart failure with reduced ejection fraction, n=541; heart failure with mildly reduced ejection fraction, n=129; heart failure with preserved ejection fraction, n=194), machine learning techniques were retrospectively applied to PALS and guideline-recommended diastolic variables. Outcome (death/heart failure rehospitalization) of the identified DD-clusters was compared with that by guidelines-based classification. To identify the best combination of variables able to classify patients in one of the identified DD-clusters, classification and regression tree analysis was applied (with DD-clusters as dependent variable and PALS plus guidelines-recommended diastolic variables as explanatory variables). The algorithm was subsequently validated in a prospective cohort of 189 heart failure outpatients (age, 65±13 years). RESULTS: Three distinct echocardiographic DD-clusters were identified (cluster-1, n=212; cluster-2, n=376; cluster-3 DD, n=276), with modest agreement with guidelines-recommended classification (kappa=0.40; P<0.001). DD-clusters were predicted by a simple algorithm including E/A ratio, left atrial volume index, E/e' ratio, and PALS. After 36.5±29.4 months follow-up, 318 events occurred. Compared to guideline-based classification, DD-clusters showed a better association with events in multivariable models (C-index 0.720 versus 0.733, P=0.033; net reclassification improvement 0.166 [95% CI, 0.035-0.276], P=0.013), without interaction with ejection fraction category. In the validation cohort (median follow-up: 18.5 months), cluster-based classification better predicted outcome than guideline-based classification (C-index 0.80 versus 0.78, P=0.093). CONCLUSIONS: Integrating PALS by machine learning algorithm in DD classification improves risk stratification over recommended current criteria, regardless of ejection fraction status. This proof of concept study needs further validation of the proposed algorithm to assess generalizability to other populations.

Left atrial strain predicts exercise capacity in heart failure independently of left ventricular ejection fraction.

AIMS: We hypothesized that left atrial (LA) remodelling and function are associated with poor exercise capacity as prognostic marker in chronic heart failure (CHF) across a broad range of left ventricular ejection fraction (LVEF). METHODS AND RESULTS: One hundred seventy-one patients with CHF were analysed [age 65 ± 11 years, 136 males (80%); 86 heart failure with reduced ejection fraction (HFrEF), 27 heart failure with mid-range ejection fraction (HFmrEF), 58 heart failure with preserved ejection fraction (HFpEF)]. All patients underwent echocardiography and maximal cardiopulmonary exercise testing and were classified according to a prognostic cut-off of peak VO2 (pVO2 ; 14 mL/kg/min). Seventy-seven (45%) patients reached pVO2  < 14 and 94 (55%) pVO2  ≥ 14 mL/kg/min. Between the two groups, there was a considerable difference in both left atrial volume (LAVi, 53 ± 24 vs. 44 ± 18 mL/m2 , P = 0.005) and function (LA reservoir strain 12 ± 5 vs. 20 ± 10%, P < 0.0001). Receiver-operating characteristic curves identified LA reservoir strain (area under the curve: 0.73 [0.65-0.80], P < 0.0001) as strong predictor for impaired pVO2 among all echocardiographic variables; LA reservoir strain < 23% had 37% specificity but a very high sensitivity (96%) in identifying a severely reduced pVO2 . In logistic regression analysis, LA reservoir strain < 23% was associated with a highly increased risk of pVO2  < 14 mL/kg/min (odds ratio 16.0 [4.7-54.6]; P < 0.0001). The multivariate analysis showed that a reduced LA reservoir strain was associated with pVO2  < 14 mL/kg/min after adjustment for age, body mass index (BMI), and clinical variables, that is, New York Heart Association class, atrial fibrillation, haemoglobin, and creatinine (b 0.22 [95% confidence interval, CI, 0.12-0.31]; P < 0.0001), and after adjustment for echocardiographic variables, that is, LVEF or left ventricular global longitudinal strain (LVGLS) and tricuspid annular plane systolic excursion (TAPSE) (b 0.16 [95% CI 0.08-0.24]; P < 0.0001). Patients with HFrEF, HFmrEF, and HFpEF were separately analysed. Among LA reservoir strain, LAVi, LVEF, LVGLS, and TAPSE, LA reservoir strain was the only one significantly associated with pVO2 in all subgroups (after adjustment for sex and BMI, P = 0.003, 0.04, and 0.01, respectively). CONCLUSIONS: In patients with CHF, an impaired LA reservoir function is independently associated with a severely reduced pVO2 . LA dysfunction represents a marker of poor prognosis across LVEF borders in the CHF population.

Impact of Loop Diuretic on Outcomes in Patients with Heart Failure and Reduced Ejection Fraction.

PURPOSE OF REVIEW: Loop diuretics are the cornerstone of the treatment of congestion in heart failure patients. The manuscript aims to summarize the most updated information regarding the use of loop diuretics in heart failure. RECENT FINDINGS: Diuretic response can be highly variable between patients and needs to be carefully evaluated during and after the hospitalization. Diuretic resistance can lead to residual congestion which affects prognosis and can be difficult to detect. The effect of loop diuretics on long-term prognosis remains uncertain but patients with advanced heart failure typically have renal dysfunction and are more inclined to develop loop diuretic resistance, which may lead to an incomplete decongestion and thus to a worse prognosis. Loop diuretics are the most potent diuretics available and their use is recommended in order to alleviate symptoms, improve exercise capacity, and reduce hospitalizations in patients with heart failure. Their use should be limited to the lowest dose necessary to maintain euvolemia because a low dose does not increase the risk of decompensation but reduce the risk of adverse effects and allow the up-titration of disease-modifying drugs.

Determinants of exercise intolerance symptoms considered non-specific for heart failure in patients with stage A and B: role of the left atrium in the transition phase to overt heart failure.

To assess to what extent left atrial (LA) structure and function are associated with non-specific heart failure symptoms, so that patients were classified as HF stage A and B. Mechanisms underlying the transition to overt HF in patients with stage A and B HF are unclear. Consecutive outpatients undergoing echocardiography and clinical evaluation and classified as HF stage A and B with preserved left ventricular ejection fraction (LVEF) were included. The association between LA measures [volume (LAVi), peak longitudinal-(PALS), contraction-(PACS) and conduit-strain] and non-specific HF symptoms was assessed using adjusted logistic regression analyses. The incremental value of atrial myopathy in symptoms prediction on top of clinical or echocardiographic confounders was assessed through ROC curves analyses. The cohort comprehended 185 patients (63 ± 16 years, 47% women) of whom 133 (72%) were asymptomatic, and 52 (28%) reported non-specific HF symptoms. After adjustment for clinical and echocardiographic confounders for HF symptoms, LAVi, PALS and PACS were associated with symptoms (p < 0.05). Among echocardiographic variables, only LA parameters were significantly associated with symptoms on top of clinical confounders (for LAVi OR [95% CI] 1.56 [1.21-2.00], p < 0.0001; for PALS 1.45 (1.10-1.91), p = 0.0009; for PACS 2.10 [1.33-3.30], p = 0.002). After adjustment for age, hypertension and COPD or E/E', LV mass-i and mitral ERO, atrial myopathy added predictive value for symptoms presence compared to the clinical variables or echocardiographic parameters described (AUC increase 0.80 to 0.88, p = 0.004, and 0.79 to 0.84, p = 0.06, respectively). In patients with HF stages A-B and preserved LVEF, measures of LA structure and function were associated with non-specific HF symptoms. A comprehensive LA remodeling evaluation may help clinicians in the appropriate identification of overt HF.

Left atrial structural and mechanical remodelling in heart failure with reduced ejection fraction.

AIMS: In patients with heart failure with reduced ejection fraction (HFrEF), an association between left atrial (LA) dilatation and dysfunction is expected, but the degree of coexistence of the two abnormalities and their relative prognostic role is not known. METHODS AND RESULTS: A total of 626 HFrEF patients formed the study population. All of them underwent a comprehensive echocardiographic evaluation. LA maximal volume was indexed to body surface area (LAVi); LA function was assessed using strain analysis during the reservoir phase: peak atrial longitudinal strain (PALS) analysis. Study primary endpoint was overall mortality or hospitalization for worsening heart failure. Four groups of patients were included in this study according to LAVi (≤34 or >34 mL/m2 ) and PALS (≤23% or >23%); 61 (10%) patients had normal LA volume and function (Group 1), 58 (9%) had LA dilatation but normal function (Group 2), 100 (16%) had normal volume but abnormal function (Group 3), and 407 (65%) had enlarged left atrium and abnormal function (Group 4). PALS was associated with primary endpoint in patients with both normal-size [Groups 1 and 3: hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.88-0.96; P = 0.0006] and dilated left atria (Groups 2 and 4: HR 0.93, 95% CI 0.91-0.96; P < 0.0001). In contrast, LAVi was associated with the primary endpoint in patients with abnormal LA function (Groups 3 and 4: HR 1.018, 95% CI 1.011-1.024; P < 0.00001) but not in those with normal PALS (Groups 1 and 2: HR 1.023, 95% CI 0.99-1.057; P = 0.1). CONCLUSIONS: Left atrial dilatation and dysfunction frequently but not invariably coexist. PALS emerged as a significant prognostic parameter in HFrEF even in the absence of LA dilation.

Clinical impact of mitral regurgitation in aortic valve stenosis: Insight from effective regurgitant orifice area.

PURPOSE: Mechanisms leading to heart failure (HF) symptoms in aortic valve stenosis (AS) are contentious. We examined the impact of secondary mitral regurgitation (MR) on the symptomatic status in patients with AS. METHODS: Outpatients performing echocardiography with any degree of AS, without organic mitral valve disease, mitral valve intervention, or aortic insufficiency were enrolled. MR was quantitatively defined through mitral effective regurgitant orifice area (EROA) using the proximal isovelocity surface area method. Patients were divided into two groups (New York Heart Association [NYHA] class I-II vs. NYHA class III-IV). RESULTS: Five hundred and eighty-four patients were enrolled (484 NYHA I-II, 100 NYHA III-IV). More symptomatic patients had smaller aortic valve area (AVA), lower left ventricular ejection fraction (LVEF) and stroke volume, higher E/E', and LV global afterload. MR was present in 178 (30%) patients and EROA was <.20 cm2 in 158 (89%). NYHA III-IV patients showed higher prevalence of MR (78% vs 21%, P < 0.0001) and larger EROA (.13±.08 cm2 vs .09±.07 cm2 , P < 0.0001). An association between EROA and symptoms was present in the total cohort and in subgroups with preserved LVEF, AVA ≥ 1 and <1 cm2 , EE' 8-14 and ≥14 (P < 0.05 for all). EROA was associated with severe symptoms after adjustment for LVEF, E/E', and AVA in the overall population (OR 1.10 [1.06-1.15]; P < 0.0001) and in the 516 patients with preserved LVEF (OR 1.13 [1.08-1.19]; P < 0.0001). CONCLUSION: In patients with AS, greater EROA values are associated with HF symptoms, even though MR degree is far from the threshold of MR severity. Therefore, even a mild MR represents a supportive marker of HF symptoms presence.

Left atrial function and maximal exercise capacity in heart failure with preserved and mid-range ejection fraction.

AIMS: Exercise intolerance is the leading manifestation of heart failure with preserved or mid-range ejection fraction (HFpEF or HFmrEF), and left atrial (LA) function might contribute to modulating left ventricular filling and pulmonary venous pressures. We aim to assess the association between LA function and maximal exercise capacity in patients with HFpEF or HFmrEF. METHODS AND RESULTS: Sixty-five patients, prospectively enrolled in the German HFpEF Registry, were analysed. Inclusion criteria were New York Heart Association functional class ≥ II, left ventricular ejection fraction > 40%, structural heart disease or diastolic dysfunction, and elevated levels of N terminal pro brain natriuretic peptide (NT-proBNP). LA function was evaluated through speckle-tracking echocardiography by central reading in the Charité Academic Echocardiography core lab. All patients underwent maximal cardiopulmonary exercise test and were classified according to a peak VO2 cut-off of prognostic value (14 mL/kg/min). NT-pro-BNP was measured. Twenty-nine patients (45%) reached a peak VO2  < 14 mL/kg/min (mean value 12.4 ± 1.5) and 36 patients (55%) peak VO2  ≥ 14 mL/kg/min (mean value 19.4 ± 3.9). There was no significant difference in left ventricular ejection fraction (60 ± 9 vs. 59 ± 8%), left ventricular mass (109 ± 23 vs. 112 ± 32 g/m2 ), LA volume index (45 ± 17 vs. 47 ± 22 mL/m2 ), or E/e´ (13.1 ± 4.7 vs. 13.0 ± 6.0) between these groups. In contrast, all LA strain measures were impaired in patients with lower peak VO2 (reservoir strain 14 ± 5 vs. 21 ± 9%, P = 0.002; conduit strain 9 ± 2 vs. 13 ± 4%, P = 0.001; contractile strain 7 ± 4 vs. 11 ± 6%, P = 0.02; reported lower limits of normality for LA reservoir, conduit and contractile strains: 26.1%, 12.0%, and 7.7%). In linear regression analysis, lower values of LA reservoir strain were associated with impaired peak VO2 after adjustment for age, sex, body mass index, heart rhythm (sinus/AFib), and log-NTproBNP [ß 0.29, 95% confidence interval (CI) 0.02-0.30, P = 0.02], with an odds ratio 1.22 (95% CI 1.05-1.42, P = 0.01) for peak VO2  < 14 mL/kg/min for LA reservoir strain decrease after adjustment for these five covariates. Adding left ventricular ejection fraction, it did not influence the results. On the other hand, the addition of LA strain to the adjustment parameters alone described above provided a significant increase of the predictive value for lower peak VO2 values (R2 0.50 vs. 0.45, P = 0.02). With receiver operating characteristic curve analysis, we identified LA reservoir strain < 22% to have 93% sensitivity and 49% specificity in predicting peak VO2  < 14 mL/kg/min. Using this cut-off, LA reservoir strain < 22% was associated with peak VO2  < 14 mL/kg/min in logistic regression analysis after comprehensive adjustment for age, sex, body mass index, heart rhythm, and log-NTproBNP [odds ratio 95% CI 10.4 (1.4-74), P = 0.02]. CONCLUSIONS: In this HFpEF and HFmrEF cohort, a reduction in LA reservoir strain was a sensible marker of decreased peak exercise capacity. Therefore, LA reservoir strain might be of clinical value in predicting exercise capacity in patients with HFpEF or HFmrEF.

Relevance of Functional Mitral Regurgitation in Aortic Valve Stenosis.

The clinical relevance of functional-mitral-regurgitation (FMR) in patients with aortic valve stenosis (AS) has been poorly studied using a quantitative approach. In addition, FMR prognostic value has mostly been analyzed after aortic valve replacement. Between 2010 and 2014 the echocardiograms of consecutive AS patients were retrospectively reviewed. Inclusion criteria were calcified aortic valve with transaortic-velocity >2.5 m/s and calculated mitral effective regurgitant orifice area (ERO) in the presence of mitral regurgitation. Organic mitral valve disease was an exclusion-criteria. Primary endpoint was heart failure or death under medical management. Secondary endpoint was heart failure or death. Eligible patients were 189, age 79 ± 8 years, 61% NYHA I/II, indexed aortic valve area (AVA) 0.55 ± 0.17 cm2/m2. Mitral ERO was 7.6 ± 4.2 mm2 (>10 mm2 in 30% of patients). Longitudinal function (by S'-TDI) was associated with mitral ERO independently of ejection fraction and ventricular volumes (p = 0.01). Mitral ERO greater than 10 mm2 (threshold identified by spline survival-modeling) was associated with severe symptoms (Odds ratio [OR] 3.1 [1.6 to 6.0]; p = 0.0006) and higher pulmonary-arterial-pressure (OR 3.0 [1.4 to 5.9]; p = 0.002). Follow-up was completed for 175 patients. After 4.7 [1.4 to 7.2] years, 87 (50%) patients underwent AVR, 66 (38%) had heart-failure, 64 (37%) died. No procedure on FMR was required. Mitral ERO was independently associated with primary and secondary endpoints both as continuous variable (Hazard ratio [HR] 1.15 [1.00 to 1.30]; p = 0.04 and HR 1.23 [1.05 to 1.43]; p = 0.01 per 5 mm2 ERO increase) or as ERO> versus ≤10 mm2. Adjustment for S'-TDI or subgroup-analysis did not affect results. The analysis by AVA revealed the incremental prognostic role of mitral ERO over AS severity. In conclusion, AS patients with concomitant FMR >10 mm2 holds a higher risk during medical follow-up. FMR quantitation, even for volumetrically modest regurgitation, provides incremental prognostic information over AS severity.

Mitral regurgitation and dyspnoea: the expanding role of mitral effective regurgitant orifice among un-selected patients.

AIMS: Mitral regurgitation is frequent in the general population and among suspected heart failure patients; however, to what extent it contributes to dyspnoea is unclear. We hypothesized mitral regurgitation to have a role in determining dyspnoea in unselected ambulatory patients. METHODS: Consecutive outpatients referred for echocardiography were retrospectively screened and included. We excluded patients with mitral stenosis or prosthesis, congenital heart disease, cardiac surgery (previous 6 months) and atrial fibrillation. Patients were classified into four dyspnoea grades based on how they perceived their disability. We assessed mitral regurgitation severity through the effective regurgitant orifice area (ERO). RESULTS: One hundred and fifty-four patients (58% men; age 67 ±â€Š14 years; mean ejection fraction 54 ±â€Š12%) formed the study population; 76 (49%) classified asymptomatic (grade I), 63 (41%) dyspnoea grade II and 15 (10%) grade III; none was in grade IV. Mitral regurgitation was present in 102 patients (66%): primary in 14 (14%) and secondary in 88 (86%); among grades I, II and III patients, mitral regurgitation was present in 35 (46%; ERO 0.05 ±â€Š0.10 cm), 52 (82%; ERO 0.10 ±â€Š0.13 cm) and 15 (100%; ERO 0.20 ±â€Š0.11 cm) patients, respectively (P < 0.0001). After adjusting for clinical (age, hypertension, ischemic heart disease, chronic kidney injury, chronic pulmonary disease) and echocardiographic confounders (ejection fraction, E/e'), ERO remained associated with symptoms presence (grade I versus II - III; P = 0.01 and P = 0.03, respectively). CONCLUSION: Among unselected heterogeneous ambulatory patients, mitral ERO was associated with the presence of dyspnoea and could therefore help in identifying symptomatic patients and in clinical characterization of patients with perceived dyspnoea.

Mitral regurgitation, left atrial structural and functional remodelling and the effect on pulmonary haemodynamics.

AIMS: To assess the association between mitral regurgitation (MR) and left atrial (LA) structural and functional remodelling and their effect on pulmonary haemodynamics. METHODS AND RESULTS: Consecutive unselected patients undergoing comprehensive echocardiography were enrolled. Parameters of cardiac structure and function were obtained as well as mitral effective regurgitant orifice area (ERO) and estimation of pulmonary artery systolic pressure (PASP). Measures of LA structure [LA volume (LAV)] and function [peak atrial longitudinal strain (PALS), peak atrial contraction strain (PACS) and conduit strain (CS)] were also calculated. The study population included 102 patients (mean age 70 ± 14 years, 42% women), with a mean ejection fraction of 52 ± 13%. MR was classified as organic due to mitral valve prolapse in 14 patients (14%) and functional in 88 patients (86%). Mean ERO was 0.12 ± 0.12 cm2 and 86 patients (84%) had an ERO ≤0.2 cm2 . ERO was significantly associated with worse measures of LA structure and function. Despite the low burden of MR, the association remained significant after adjusting for clinical and echocardiographic confounders (ß: 3.7, P = 0.022 for LAV; ß: -3.0, P = 0.003 for PALS; ß: -1.8, P = 0.027 for PACS) and was significantly related with functional MR (P for interaction <0.001). ERO was also significantly associated with PASP, and measures of LA function (PALS and PACS) significantly modified this relationship (P for interaction <0.001). CONCLUSIONS: Even a mild degree of MR contributes to LA remodelling and this relationship plays an active role in pulmonary circulation, suggesting a potential mechanism by which these parameters contribute to the development of heart failure.