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.

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.

When Aortic Stenosis Is Not Alone: Epidemiology, Pathophysiology, Diagnosis and Management in Mixed and Combined Valvular Disease.

Aortic stenosis (AS) may present frequently combined with other valvular diseases or mixed with aortic regurgitation, with peculiar physio-pathological and clinical implications. The hemodynamic interactions between AS in mixed or combined valve disease depend on the specific combination of valve lesions and may result in diagnostic pitfalls at echocardiography; other imaging modalities may be helpful. Indeed, diagnosis is challenging because several echocardiographic methods commonly used to assess stenosis or regurgitation have been validated only in patients with the single-valve disease. Moreover, in the developed world, patients with multiple valve diseases tend to be older and more fragile over time; also, when more than one valvular lesion needs to address the surgical risk rises together with the long-term risk of morbidity and mortality associated with multiple valve prostheses, and the likelihood and risk of reoperation. Therefore, when AS presents mixed or combined valve disease, the heart valve team must integrate various parameters into the diagnosis and management strategy, including suitability for single or multiple transcatheter valve procedures. This review aims to summarize the most critical pathophysiological mechanisms underlying AS when associated with mitral regurgitation, mitral stenosis, aortic regurgitation, and tricuspid regurgitation. We will focus on echocardiography, clinical implications, and the most important treatment strategies.

Right ventricular systolic function in severe tricuspid regurgitation: prognostic relevance of longitudinal strain.

AIMS: The aim of this study is to analyse the prognostic implications of right ventricular (RV) dysfunction as detected by strain analysis in patients with severe tricuspid regurgitation (TR). The evaluation of RV systolic function in presence of severe TR is of paramount importance for operative risk stratification; however, it remains challenging, as conventional echocardiographic indexes usually lead to overestimation. METHODS AND RESULTS: We enrolled 250 consecutive patients with severe TR referred to our centre. Baseline clinical and echocardiographic data and follow-up outcomes were collected. Patients were predominantly female, with multiple cardiovascular risk factors and comorbidities, history of heart failure, and atrial fibrillation. Most of them had presented with clinical signs of RV heart failure (RVHF) and advanced New York Heart Association class. The RV strain analysis [both RV free wall longitudinal strain (RVFWLS) and RV global longitudinal strain (RVGLS)] reclassified ∼42-56% of patients with normal RV systolic function according to conventional parameters in patients with impaired RV systolic function. RVFWLS ≤17% (absolute values, AUC: 0.66, P = 0.002) predicted the presence of RVHF [odds ratio (OR) 0.93, P = 0.01]. At follow-up, patients with RVFWLS >14% (absolute values, AUC: 0.70, P = 0.001, sensitivity 72%, specificity 54%) showed a better survival (P = 0.01). CONCLUSION: Different ranges of RVFWLS have different implications in patients with severe TR, allowing to identify a preclinical and a clinical window, with correlations to RVHF and survival.

Excess Mortality Associated with Progression Rate in Asymptomatic Aortic Valve Stenosis.

BACKGROUND: Aortic valve stenosis (AS) is a progressive condition characterized by gradual calcification of the aortic cusps. Progression rate evaluated using echocardiography has been associated with survival. However, data from routine practice covering the whole spectrum of AS severity and the rate of symptom onset are sparse. The aim of this study was to assess outcomes under medical management related to disease progression in asymptomatic patients with a wide range of AS severity. METHODS: Two hundred twenty-nine consecutive asymptomatic patients (mean age, 77 ± 10 years; 55% men) with AS, preserved left ventricular ejection fraction, and two or more echocardiographic examinations performed from 2004 to 2014 were retrospectively included. The median time between the two echocardiographic examinations was 24 months (interquartile range, 15-46 months). Patients were identified as rapid progressors if the annualized difference in peak aortic velocity between two echocardiographic examinations was ≥0.3 m/sec/y; others were labeled as slow progressors. The primary end point was mortality during medical follow-up (censoring on aortic valve interventions). The secondary end point was overall mortality. RESULTS: Rapid progressors accounted for 67 of the 229 patients (29%), and this feature was not associated with baseline characteristics. During a median of 5.8 years (interquartile range, 3.4-8.3 years) of follow-up from the first echocardiographic examination, 102 patients (45%) died, 86 (84%) during medical follow-up. Rapid progression rate predicted excess mortality (vs slow progression rate) after adjustment for age, sex, symptoms, baseline left ventricular ejection fraction, and baseline aortic valve area (hazard ratio, 2.50; 95% CI, 1.48-4.21; P = .0006) and after adjusting for peak aortic velocity and left ventricular ejection fraction obtained at the last echocardiographic examination (hazard ratio, 2.07; 95% CI, 1.25-3.46; P = .005). Among patients with baseline peak aortic velocity < 4 m/sec (nonsevere AS), rapid progression rate was associated with higher 5-year mortality compared with slow progression (57% vs 22% [P < .0001] under medical management and 44% vs 18% [P = .005] overall). Outcomes were comparable between nonsevere AS rapid progressors and baseline severe AS. Progression rate showed incremental prognostic value on receiver operating characteristic curve analysis versus AS severity. Of note, among slow progressors, 11 patients (5%) presented with high rates of symptom development and poor outcomes related to ventricular dysfunction or other advanced AS features. CONCLUSIONS: Progression rate is an individual, almost unpredictable feature among patients with AS. Rapid progression is an incremental marker of excess mortality in asymptomatic patients with AS, independent of clinical and hemodynamic characteristics. Rapid progression rate may identify patients with nonsevere AS at higher risk for events.

The progression rate of aortic stenosis: key to tailoring the management and potential target for treatment.

Aortic stenosis is the most frequent valvular disease to require intervention in the western world and has always been featured as a progressive disease. The rate of progression can be assessed by carefully performed Doppler echocardiography and can vary greatly between individuals with a profound impact on prognosis. Unfortunately, the determinants of disease progression had been insufficiently studied and remain challenging to define, particularly in the outpatient setting. Multiple factors have been proposed and tested, but at present, there are no proven therapies to slow the course of the stenotic process. Heart valve clinics may be particularly important to define the progression rate and tailor follow-up and management at an individual level. This review enlightens knowledge and gaps regarding the progression-rate of aortic valve stenosis, from the historical perspective to the molecular one.

Usefulness of the Right Parasternal Echocardiographic View to Improve the Hemodynamic Assessment After Valve Replacement for Aortic Stenosis.

Right-parasternal-view (RPV) often provides the best hemodynamic assessment of the aortic-valve-stenosis by echocardiography. However, no detailed study on patients with aortic prosthesis is available. Thus, RPV usefulness is left as an anecdotical notion in this context. We aimed to define feasibility and clinical-impact of RPV before and soon-after percutaneous implantation (TAVI) or surgical (SAVR) aortic-valve-replacement (AVR) for AS. Patients with severe-AS electively referred for AVR between September-2019 and February-2020 were prospectively evaluated. Echocardiographic examinations inclusive of apical and RPV to measure aortic-peak-velocity , gradients and area (AVA) were performed the day before AVR and at hospital discharge and compared by matched-pair-analysis. Forty-seven patients (mean age 79 ± 8 years, 63% female, ejection-fraction 61 ± 6%) referred for SAVR (24 [51%]) or TAVI (23 [49%]) were enrolled. RPV was feasible in 45 patients (96%) before-AVR but in only 32 after-AVR (68%), particularly after SAVR (50%) than TAVI (87% p = 0.005). RPV remained the best acoustic window after TAVI in 75% of cases. Hemodynamic assessment of TAVI, but not SAVR, invariably benefit from RPV versus apical evaluation (aortic-peak-velocity: 2.57 ± 0.39 vs 2.23 ± 0.47 m/sec, p = 0.002; mean gradient: 15 ± 5 vs 12 ± 5 mm Hg, p = 0.01). Five (11%) patients presented severe patient-prosthesis-mismatch, 4 of which were detectable only by RPV. This pilot-experience demonstrates that RPV feasibility is slightly reduced after AVR. RPV can improve the hemodynamic assessment of the prosthetic valve versus apical view, including the detection of patient-prosthesis-mismatch. Furthermore, when RPV is the best acoustic windows in patients with severe AS, it generally remains so after-TAVI.

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.

Interventricular conduction disorders after orthotopic heart transplantation: risk factors and clinical relevance.

BACKGROUND: Causes and significance of interventricular conduction disorders (IVCDs) after orthotopic heart transplantation (OHT) are still unknown. METHODS: We retrospectively researched the presence of IVCDs in 240 patients who underwent bicaval OHT in three time periods: at day 1, after 1 year, and after 3 years from OHT. To evaluate the impact of the surgical technique, a control population treated with biatrial anastomosis was used. RESULTS: The most common IVCD was right bundle branch block (RBBB). Its presence at day 1 correlated with transpulmonary gradient before OHT. Its presence after 1 year and its development correlated with a 1-month acute rejection score≥2 (p = .050 and p = .006). The incidence of RBBB was higher in the biatrial control population (40.7% vs 23.8%, p < .001). CONCLUSIONS: RBBB is the most common IVCD. Its presence can be explained by a susceptibility of the right branch to heart positioning, pressure overload, and acute rejection. IVCDs do not affect prognosis.