Functional Assessment Research Articles

The impact of AAOCA anatomical characteristics in coronary blood supply

Abstract Background Impact of AAOCA in coronary blood flow and myocardial perfusion is an unknown field although it is well-accepted that the anomaly is one of the leading causes of sudden death during effort. The risk factors for AAOCA are the anatomical characteristics of the abnormal vessel, such as the presence of intramural (IM) segment, the ostium shape, and the take-off angle. Purpose We aim to evaluate the impact of AAOCA anatomical risk profile in the blood flow using the thermodilution technique, an accurate and reproducible method used to investigate coronary physiology. Methods This is a single-centre prospective study that included AAOCA subjects who underwent invasive thermodilution functional coronary assessment. We divided patients into two groups according to the anatomical risk profile: a) ischemic risk (IR): concomitant presence of IM segment, take-off angle<45°, and slit-like/oval shape ostium, or a IM length>10 mm; b) no-ischemic risk (no-IR): absence of IM segment, take-off angle>45°, round ostium. We obtained coronary functional measures using the thermodilution method. We measured the absolute flow, and coronary resistance at rest and maximal hyperemia. Data were reported as median and IQR and we used Wilcoxon signed-rank test for paired data in the rest vs. hyperaemia comparison. Results We included 28 AAOCA pts (22 male, 6 female, median age: 48.6 (IQR: 18.9) ) that were 20 anomalies of the right coronary and 8 of the left. Symptomatic subjects (n=16) presented with angina (n=12), syncope (n=1), presyncope (n=1), fatigue (n=1), and dyspnea associated with arrhythmia (n=1). The IR group (26 pts; R-AAOCA=24, L-AAOCA=2) has an IM segment with a median length of 10 mm (IQR: 5.5), a median take-off angle of 28° and the ostium was slit-like (n=16), oval (n=10), and round (n=1). The no-IR group consisted of 9 (R-AAOCA=3, L-AAOCA=6), median take-off angle of 69° and the ostium was oval (n=1), and round (n=8). The absolute flow and coronary resistance at rest of the IR group did not have significant differences compared to no-IR. Hyperemia determines an increment of coronary flow in both groups although the IR had a 2.9 fold increase and the no-IR as 3.5 fold increase compared to rest. In particular, the absolute flow of the IR group was significantly lower compared to the no-IR group (185 vs. 330 mL/min, p=0.012) and there was a greater coronary resistance (419 vs. 268 mmHg/(mL/min), p=0.027), as shown in Fig. 1. Conclusions Anatomical risk factors of AAOCA, such as IM take-off angle and ostium morphology, have a negative impact on the coronary blood supply that is reduced when compared to AAOCA without such anatomical features. Such impact can be revealed also at rest using the thermodilution method that induces maximal coronary vasodilatation that is the natural coronary response to physical effort. Further studies are needed to validate benefit of functional assessment in AAOCA risk stratification.

Global myocardial work index is an independent predictor of functional capacity on 6-minute walk test in stable non-ischaemic cardiomyopathy

Abstract Background Reduction in 6-minute walk test distance (6MWD) in heart failure (HF) is associated with impaired quality of life and adverse cardiovascular outcomes. Myocardial work (MW) indices are novel non-invasive measures of left ventricular (LV) function which characterise myocardial contractile efficiency and energy utility. Purpose We aim to assess the predictive capacity of MW indices for functional capacity in stable non-ischaemic cardiomyopathy (NICM). Methods We prospectively recruited consecutive patients with stable NICM from our HF service from January 2021 to December 2023. All patients received optimal guideline direct therapy (OGDT) for 3-months before undergoing a comprehensive transthoracic echocardiogram and functional assessment with 6-minute walk test (6MWT). We excluded patients with prior cardiac surgery, severe airways disease, valvular heart disease, and those in atrial fibrillation (AF) or had mechanical limitations to their mobility at time of 6MWT. We collected demographic, clinical, and echocardiographic factors to identify the determinates of reduced 6MWD defined as <300 metres. Results Of 249-patients included (69.9% male; age 57.3±16.5yrs), 65-patients had reduced 6MWD. They were significantly older (62.3±17.2 vs 55.5±16.0yrs, p=0.005), had shorter height (166.3±10.3 vs 171.3±9.8cm, p=0.001), higher prevalence of AF history (39.1 vs 21.4%, p=0.001), lower LV-ejection-fraction (38.1±13.3 vs 43.3±10.2%, p=0.001), lower LV-global-longitudinal-strain (LV-GLS; 10.5±4.4 vs 12.7±3.9%, p<0.001), lower global-work-index (GWI; 943±487 vs 1230±455mmHg%, p<0.001), lower global-constructive-work (GCW; 1286±561 vs 1590±494mmHg%, p<0.001), lower global-work-efficiency (GE; 81.2±9.9 vs 85.4±8.1mmHg%, p=0.04), larger indexed left atrial volume (LAV; 45.0±18.4 vs 40.1±24.5ml/m2, p=0.038), higher E/e’ ratio (14.6±8.9 vs 11.8±6.0, p=0.003), and lower right-ventricular-free-wall-strain (RV-FWS; 19.2±6.7 vs 21.8±6.4, p=0.008; Table 1.). On receiver-operating-characteristics-curve analysis, GWI best predicted 6MWD reduction (Figure 1; AUC 0.68) compared to GCW, GE, LVEF and LVGLS (AUC: 0.62, 0.40, 0.62, and 0.62 respectively). Accounting for covariates, our multiple regression was run to predict 6MWD from age, height, AF history, LAV, E/e’, GWI and RV-FWS. These variables statistically significantly predicted 6MWD, F(4,239)=23.5, p<0.001, R2=0.34). With each 100mmHg% rise in GWI being independently associated with a 6.5m increase in 6MWD. Conclusion GWI was independently associated with 6MWD in our cohort of NICM patients on OGDT. MW indices provide some mechanistic insights into exercise capacity in patients with NICM.Table 1.Baseline CharacteristicsFigure 1.ROC of GWI Discriminating 6MWD

Effect of exogenous ketone supplementation on cardiac energetics, function, and perfusion in type 2 diabetes, heart failure, and healthy participants- A single center, open labelled clinical study

Abstract Background Type 2 diabetes (T2D) confers loss of cardiac metabolic flexibility in fuel selection and impaired mitochondrial function. Enhanced ketone metabolism observed in T2D may represent a compensatory adaptive mechanism as ketones are a more energy efficient resource than carbohydrates or fatty acids. Favorable energetic properties of ketones may potentially mitigate the energy starved state in T2D and heart failure (HF). Purpose To test whether exogenous oral ketone supplementation would reverse cardiac energetic deficit, as well as improve cardiac function and perfusion in patients with T2D, with HF with reduced ejection fraction (HFrEF), and healthy volunteers (HV). Methods Three groups of patients were recruited: patients with T2D (n=33); patients with HFrEF (n=29, 14 with T2D); and HVs(n=25). Participants underwent cardiovascular magnetic resonance and spectroscopy to assess left ventricular (LV) function, rest and dobutamine stress perfusion and energetics (phosphocreatine/adenosine triphosphate ratio[PCr/ATP]). After the initial visit, participants had an identical second visit following 2 weeks of oral ketone supplementation (30g daily). Results Participants were matched in age and sex distribution. There were no significant differences in LV ejection fraction (LVEF) between T2D and HV groups with significantly lower LVEF in HFrEF group. Both the T2D group and the HFrEF group showed significant reductions in PCr/ATP ratio and the rest and stress GLS compared to the HV. The resting and dobutamine-stress myocardial blood flow (MBF) were only significantly reduced in patients with HFrEF compared to T2D and HV groups. Subgroup analyses of HFrEF group with and without T2D showed no significant differences in energetics, perfusion, or functional assessments. Significant increase in PCr/ATP ratio was seen only in T2D group from baseline after 2 weeks of ketone supplementation (Visit-1:1.6[1.5,1.8] vs Visit-2:1.9[1.7,2.1]; P=0.01). This significant increment was not observed in HFrEF or HV groups. Two weeks of ketone supplementation was not associated with any significant changes in LVEF, GLS, rest or dobutamine-stress myocardial blood flow, or in myocardial lipid content (Table-1). Conclusions Short-term ketone supplementation is associated with isolated significant improvements in resting cardiac energetics in patients with T2D and preserved LVEF, without changes cardiac function or perfusion. In contrast to patients with T2D and preserved LVEF, short-term ketone supplementation does not lead to any significant improvements in energetics in patients with HFrEF suggesting loss of mitochondrial plasticity with transition to HFrEF. Moreover, healthy volunteers experience no further increments of myocardial energetics from the normal range values at baseline with ketone supplementation.

Predictors of Right vEntricular Failure aftER LVAD implantation: PREFER LVAD study

Abstract Introduction The use of left ventricular assist devices (LVAD) is increasing both as bridge-to-transplantation or destination therapy, considering the lack of heart donors for transplantation in advanced heart failure (AHF) population. Right ventricular post-implantation failure, major bleedings and infective events remain the principal adverse events in LVAD carriers, thus an accurate selection of candidates is needed. Purpose To identify between clinical, laboratory, standard and advanced (Speckle Tracking, STE) echocardiography, and right heart catheterization (RHC) indices, the best predictors of outcome after LVAD implantation. Materials and Methods We screened in our third-level center 30 patients with AHF, followed up from May 2013 to February 2022, for the assessment of LVAD implantation suitability. They all underwent a complete cardiological history collection, electrocardiography, standard and STE left ventricular (LV) and left atrial (LA) size and function assessment. Regarding the right ventricle, SIENA score parameters, including RV sphericity index, RV free wall longitudinal strain (LS), right ventricular fractional area change (RVFAC), and 3D ejection fraction were used for exclude RV disfunction. RHC was performed on the same day of echocardiography. Follow-up was conducted at 1, 3, 6, 9 and 12 months repeating all the assessments, for the occurrence of RV failure, all-causes mortality, hemorrhagic events and re-hospitalization for heart failure. With a univariate and multivariate statistical analysis, we went to test among all the parameters the possible predictors of outcome. Results The final population consists of 29 patients (93% male, mean age of 63±11 years), in NYHA class III or IV and a severe reduction of left ventricular (LV) ejection fraction (EF), in whom arterial hypertension and smoking, present or previous, were present in 58% and 65% of cases, respectively. The population was divided into two groups according to the occurrence of at least one cardiovascular event. 11 major events were recorded: including 4 hemorrhagic events, 3 all-causes mortality and 4 hospital admission for HF. No RV failure occurred in the first 12 months of follow-up. No differences were identified between the two groups in terms of echocardiographic indices and RV function, including RVFAC or RV-FWLS. At univariate analysis (see Table 1), the only parameter able to predict major CV events was central venous pressure (CVP)/pulmonary capillary wedge pressure (PCWP) ratio, obtained by RHC, an index of balance between right and left heart filling pressure. Conclusions A careful application of SIENA score indices before LVAD implantation can significantly reduce the incidence of post-operative RV failure, as in our small population. Our results also confirmed the paramount role of RHC in the diagnostic work up of AHF.

Relationship between NT-proBNP, echocardiographic abnormalities and functional status in patients with subclinical diabetic cardiomyopathy

Abstract Background Persons with diabetes are at risk for developing a cardiomyopathy through several pathophysiological mechanisms independent of traditional risk factors for heart failure. Among those with so-called diabetic cardiomyopathy (DbCM), the relationship between natriuretic peptides, cardiac structural abnormalities and functional capacity is largely unknown. Purpose This study aimed to evaluate associations between NT-proBNP concentrations, clinical characteristics, echocardiographic findings, health status and activity, and outcomes from cardiopulmonary exercise testing Methods The Aldose Reductase Inhibition for Stabilization of Exercise Capacity in Heart Failure Trial (ARISE-HF) trial is evaluating the effects of AT-001, a novel aldose-reductase inhibitor in participants with DbCM without a prior history of heart failure (1). Participants were included if they had a known diagnosis of type 2 diabetes and age ≥60 (or ≥45 with a duration of diabetes of ≥10 years or estimated glomerular filtration rate ≤60 mL/min/1.73m2). Participants were required to have evidence of one of: structural cardiac abnormality, elevated cardiac biomarkers, or impaired exercise tolerance, defined as a peak oxygen uptake (VO2) ≤75% of predicted. In this prespecified subgroup analysis of the ARISE-HF trial, 685 participants with baseline echocardiography data, laboratory investigations, and functional assessment were included. Participants were stratified by N-terminal pro-B type natriuretic peptide (NT-proBNP) quartiles, and correlation with echocardiographic and functional parameters were assessed using Spearman correlation test. Results The mean age of participants was 67.4 years and 50% were female. The mean duration of type 2 diabetes was 14.5 years with a mean hemoglobin A1c of 6.98. The median NT-proBNP was 71 (Q1, Q3: 33, 135) ng/L. No association was observed between NT-proBNP concentrations and echocardiographic parameters of either diastolic or systolic dysfunction including global longitudinal strain, left ventricular ejection fraction, left ventricular mass index, left atrial volume index, E/e’, or right ventricular systolic pressure (Figure 1). In contrast, NT-proBNP was significantly correlated with components of the Kansas City Cardiomyopathy Questionnaire (P<0.001), the Physical Activity Scale in the Elderly (P=0.004), duration of cardiopulmonary exercise testing (P<0.001), peak VO 2 (P<0.001), and ratio of minute ventilation/carbon dioxide production (P=0.002; Figure 2). Conclusion Among highly selected patients with subclinical DbCM, elevated NT-proBNP concentrations are associated with worse health status, lower activity levels, and reduced functional capacity, but not with cardiac structural abnormalities. These findings suggest that regardless of cardiac structural abnormalities, biomarker concentrations reflect important deterioration in functional capacity in affected individuals.

Frailty and associated outcomes in patients with transthyretin cardiac amyloidosis

Abstract Introduction Despite older age at diagnosis, the prevalence and clinical impact of frailty, an age-related geriatric syndrome, in patients with transthyretin cardiac amyloidosis (ATTR-CA) is poorly described. Purpose To determine: (1) the prevalence of frailty in ATTR amyloidosis patients; (2) the clinical frailty phenotype in ATTR amyloidosis (3) the independent and incremental prognostic value of frailty. Methods All consecutive patients diagnosed with ATTR-CA who underwent frailty assessment at two high-volume tertiary care centres from September 2019 to April 2023 were included in the study. Functional assessment was performed with the Rockwood Clinical Frailty Scale (CFS), an established frailty screening tool that stratifies patients on a nine-point scale ranging from 1 (very well) to 9 (terminally ill) providing a useful measure of physiological reserve. Frailty was defined as CFS >4. Functional status was further categorized as follows: 'non-frail' (CFS 1-3), ‘mild’ frailty (CFS 4-5), and 'moderate-to-severe' frailty (CFS 6-9). Logistic regression analysis was used to identify factors associated with CFS 6-9. Cox regression analysis was used to determine the independent and incremental prognostic value of frailty. Results The study comprised 880 patients with ATTR-CA (719 [81.7%] with wt-ATTR-CA, 85 [9.7%] with p.(V142I) hATTR-CA and 76 [8.6%] with a non-p.(V142I) hATTR-CA. Overall, 43.0% (N=378) were considered ‘non-frail’ (CFS 1-3). Prevalence of ‘mild’ frailty (CFS 4-5) was 41.4% (N=364), while prevalence of 'moderate-to-severe' frailty (CFS 6-9) was 15.7% (N=138). Frail patients were older, more symptomatic and with advanced disease stage as assessed with the National Amyloidosis Centre (NAC) staging system. At logistic regression analysis, age, female gender, non-p.(V142I) variants and NAC stage were associated with 'moderate-to-severe' frailty. Over a median 22 months, 16.8% died, with mortality rising with higher CFS levels. At Cox multivariable analysis, CFS was strongly associated with mortality (CFS 4-5 vs 1-3: Hazard Ratio [HR] 2.821, 95% C.I. 1.724-4.613; CFS 6-9 vs 1-3: HR 6.179, 95% C.I. 3.694-10.335, overall p-value<0.001), along with NAC stage and age. The addition of CFS to the NAC staging system significantly improved the goodness-of-fit of the model (X2: 73.26, p<0.00001), and significantly improved the discriminatory ability of the NAC alone (Figure, Harrell’s C statistics: 0.78, 95% C.I. [0.72-0.83] vs 0.69, 95% C.I. [0.64-0.75], p<0.0001). CONCLUSION Frailty is highly prevalent in patients with ATTR-CA, with up to 57% of patients living with some degree of frailty. Older age, female gender, non-p.(V142I) hATTR-CA variants and advanced disease stage were independently associated with moderate to severe frailty. Frailty was independently associated with all-cause mortality after adjusting for known predictors and increased the global predictivity of the NAC Score.Survival by Frailty Status and NAC

Relationships between 18-month kinetics and functional capacity and left ventricular remodeling and cardiac fibrosis in dilated cardiomyopathy

Abstract Introduction Myocardial fibrosis is a primary pathogenetic process in dilated cardiomyopathy (DCM) that is responsible for progressive cardiac remodeling and functional capacity impairment. We sought to verify whether there were differences between 18-month kinetics of functional capacity and left ventricular remodeling in DCM patients with different types and advancement of fibrosis who were up-titrated with guideline directed pharmacotherapy (GDMT). Methods Between May 2019 and September 2020, 99 DCM patients (88 male, mean age 45.2 ± 11.8 years, mean EF 29.7 ± 10%) underwent cardiac magnetic resonance with assessment of replacement fibrosis via late gadolinium enhancement (LGE) and interstitial fibrosis via extracellular volume (ECV). Each patient had serial (baseline, 6-, 12-, 18 month) functional assessment: NYHA class and 6- minute walking test (6-MWT) and follow-up echocardiography, including measurement of left ventricular end-diastolic volume (LVEDvol) and ejection fraction (EF). Patients were divided into LGE-negative and LGE-positive groups, whereas based on median ECV – they were divided into those with ECV below and above median values. Results Overall, LGE was identified in 44 (44%) of patients, whereas median ECV was 27.7%. NYHA class was significantly worse in patients with LGE (1.5±0.5 vs. 1.9±0.6) and with higher ECV (1.93±0.6 vs. 1.6±0.5) in comparison to those without LGE and lower ECV. However, NYHA class improved during observational period in all groups. There were no differences in 6-MWT distance in LGE positive and negative groups at all time points. Baseline 6-MWT distance in LGE positive group was 494.2±88.2 vs. 453.9±98.8 meters in LGE negative group. Baseline 6-MWT distance in upper median ECV group was (408.8±103.5 vs. 492.4±92.9 meter) was significantly lower ECV group (p=0.03). During 18 months 6-MWT distance increased only in LGE negative group but in both ECV groups (Figure 1 A-D). There were no differences in EF between patients with and without LGE and also with higher and lower ECV. Baseline EF in LGE positive group was 27.4±11.2% and 31.7±10.6% in LGE negative. Baseline indexed LVEDvol in LGE positive group was 107.7±40.7 vs. 91.8±37.8 ml/m2 (p=0.09) in LGE negative group. EF increased significantly in both groups, whereas indexed LVEDvol decreased only in LGE negative group (Figure 2 A-D). Conclusions Regardless of the presence of replacement and to some extent of interstitial fibrosis, functional and cardiac morphological improvement was observed during 18 months observation in DCM patients on GDMT. The greatest improvement occurred during the first 3 (occasionally 6) months which was associated with the greatest escalation of GDMT. Further dose escalation was not associated with a significant improvement in both functional and morphological parameters.

Predictive value of plaque characteristics assessed by coronary computed tomography angiography and optical coherence tomography for identification of lesions causing ischemia

Abstract Background In patients with intermediate coronary stenosis, the functional assessment with fractional flow reserve (FFR) and the anatomical assessment with optical coherence tomography (OCT) have been widely used in clinical practice. Additionally, coronary computed tomography angiography (CTA) is commonly used non-invasive imaging technique for evaluating suspected coronary artery disease before being referred for angiography. Objectives This study sought to investigate the association between FFR and plaque characteristics assessed by coronary CTA and OCT in intermediate coronary stenosis. Methods Based on the prospective multicentre registry, a total of 159 patients including 339 coronary lesions with intermediate stenosis were included. All patients underwent coronary CTA before being referred for coronary angiography and both FFR measurement and OCT examination were performed during angiography. The stenotic lesion with FFR ≤0.80 was considered diagnostic of lesion causing ischemia. The predictive value of plaque characteristics assessed by coronary CTA and OCT for identifying lesions causing ischemia was analyzed. Results Stenosis severity and plaque characteristics on coronary CTA and OCT were different between the lesions causing ischemia versus not causing ischemia. On multivariate analysis, low attenuation plaque on coronary CTA (odds ratio [OR]= 2.78; P=0.038) and thrombus (OR=5.13; 0.042), plaque rupture (OR=3.25; P=0.017), and intimal vasculature on OCT (OR=2.57; P=0.012) were independent predictors for the lesions causing ischemia. Increasing number of these plaque characteristics offered incremental improvement in predicting the lesions causing ischemia. Conclusions Comprehensive anatomical evaluation of coronary stenosis may be able to provide additional supportive information for predicting the lesions causing ischemia.

Left atrial reservoir strain and global longitudinal strain associates with re-hospitalization and mortality in patients admitted for acute heart failure

Abstract Background Left atrial reservoir strain (LAr) and global longitudinal strain (GLS) have emerged as useful parameters for the assessment of left ventricular diastolic function and the estimation of left ventricular filling pressures. Yet, there remains a gap of knowledge regarding the possible association of LAr and GLS with re-hospitalization and mortality in patients with acute heart failure (HF). Aims This study aims to investigate the association between LAr and GLS with re-hospitalization and mortality in patients admitted for acute HF. Methods Out of 526 enrolled patients admitted for acute HF, 142 (mean age 71, 25% women) were systematically evaluated for LAr and GLS using speckle tracking echocardiography. Multivariable Cox regression analyses, adjusting age, sex, current smoking prevalent atrial fibrillation, hypertension, kidney disease and plasma glucose, were used to assess the associations between continuous values of LAr and GLS with all-cause mortality and HF-related re-hospitalization. Results The median follow-up time to death of any cause and HF rehospitalization was 39 (interquartile range 14-66) and 22 (4-51) months, respectively. During follow up, 63 (44%) patients died, and 63 (44%) were re-hospitalized due to HF. Lower values of LAr were significantly associated with higher risk of mortality (HR 0.93; 95%CI 0.89-0.98, p=0.008). Similarly, lower GLS was associated with higher risk of mortality (HR 0.94; 95%CI 0.89-0.99, p=0.045). Only lower values of LAr were associated with higher risk of HF re-hospitalization in the multivariable model (HR 0.93; 95%CI 0.88-0.98, p=0.004). Conclusion In this prospective, long-term follow-up study of patients with acute heart failure, lower values of LAr and GLS showed prognostic significance, with lower values being indicative of poorer outcomes. Notably, LAr was associated with higher risk of both death and rehospitalization for heart failure, whereas GLS was solely associated with higher mortality risk. These echocardiographic parameters could be further investigated for risk assessment of patients with heart failure in order to identify those at higher risk of rehospitalization and death, thereby facilitating targeted interventions to improve their prognosis.KM-curves for or the Quartiles of LAr

Catheter ablation increases cerebral blood flow and cognitive function in elderly patients with atrial fibrillation

Abstract Background Atrial fibrillation (AF) has been considered to have an increased risk for cognitive impairment independent of a stroke and a silent micro-infarction. The mechanism of this interaction is unclear. One of the potential explanations is brain hypoperfusion due to a reduced cardiac output. To date, there are no reports focusing on the cerebral blood flow and cognitive impairment in patients undergoing AF ablation. Purpose The purpose of this study was to investigate whether catheter ablation of AF would increase cerebral blood flow and restore cognitive impairment. Methods AF patients aged 75 years or older with mild or more cognitive impairment were selected. The assessment of cognitive function using Mini-Mental State Examination (MMSE) and Hasegawa's Dementia Scale-Revised (HDS-R), and measurement of cerebral blood flow using 99mTc-ECD SPECT imaging were examined before and 3 months after ablation. Results A total of 25 elderly patients (mean age 83, 14 males and 11 females) were included in this study. Of them, 23 patients had persistent AF. Twenty-three patients (92%) maintained sinus rhythm after ablation. There was a significant improvement in MMSE score (from 24.6±4.5 to 25.9±4.0, p<0.05) and HDS-R (from 23.2±5.5 to 24.8±5.1, p<0.05) after ablation. Cerebral blood flow also significantly increased after ablation (right lobe: from 34.4±4.6 to 38.5±4.4 ml/100g/min, p<0.01, left lobe: from 35.3±9.7 to 38.8±3.7 ml/100g/min, p<0.01). Overall average cerebral blood flow increased by 10.1±9.4% after ablation. There was a positive correlation between the changes in MMSE score and the changes in cerebral blood flow (r=0.65, p<0.05). Conclusion AF ablation in elderly patients increased cerebral blood flow and cognitive function. AF ablation would be one of the therapeutic options to improve cognitive function in elderly patients with cognitive impairment.

Attention as the dimension that deteriorates first in patients with cognitive impairment after myocardial infarction

Abstract Background Previous publications by our team indicated a high prevalence (approximately 35%) of cognitive impairment (CI) in patients after myocardial infarction (MI). Moreover, we observed that the presence of peri-infarction deficits was not always associated with their occurrence after 6 months of follow-up and vice versa. This was the basis for distinguishing 4 groups of patients: a) group 1 – CI present peri-infarction and after 6 months; b) group 2 – CI present only peri-infarction; c) group 3 – CI present only after 6 months; d) group 4 – no CI during the study. Purpose The aim of the current study is to analyse the type of CI in patients after MI with a focus on its changes within the 4 groups mentioned. Methods The study included 326 patients hospitalised for MI treated by percutaneous coronary intervention. Cognitive function was assessed twice using the Mini–Mental State Examination (MMSE) and the Clock Drawing Test (CDT)-Shulman version during the first hospitalisation (on day 2-3 after MI) and 6 months later. In addition, the occurrence of sleep, aggression and mood disorders was assessed. The constructed research model was analysed with artificial intelligence algorithms. Results Persistent CI (group1) was found in 8.9%, peri-infarct CI (group 2) in 16.3%, and only after 6 months (group 3) in 7.7% of study participants (as assessed by MMSE). Analysis of the cognitive domains showed that in those who improve (group 2) or worsen cognitive function (group 3), analogous changes in attention function occurred, respectively improving in 81% and worsening in 100% of subjects in a given group. It was observed that there is a group of patients with a CI on the MMSE who perform CDT correctly, 12% peri-infarct and 11% at 6-month follow-up, respectively. Patients with a normal CDT score but CIs found in the MMSE have impaired attentional function regardless of the time of assessment. Conclusion CIs can occur both immediately after MI and during subsequent follow-up. However, after 6 months of intensive anti-atherosclerotic treatment (post-MI), cognitive functions improve in some patients, and deteriorate in others. At the same time, the cognitive function that undergoes similar changes in these groups is attention. The uniform type of impaired cognitive function and the lack of specific differences between the 4 groups allow us to assume a uniform etiology of cognitive deficits. Patients with normal CDT and disorders present in MMSE show deficits in attention functions. Performing CDT and using the MMSE component assessing attention function could prove sufficient for the initial assessment of cognitive functions in the population of patients after MI. The results require confirmation in a larger patient population.

Decreased left atrial volume and preserved left atrial function in children with congenital Zika syndrome

Abstract Introduction The infection caused by Zika virus during pregnancy leads to congenital Zika syndrome (CZS). In a previous study of our group, we found that the heart is smaller in children with CZS, with few functional alterations. Left atrial strain imaging enables quantitative assessment of left atrial function, and recently its application has also shown promise in the pediatric population. Purpose To evaluate left atrial function in children affected by CZS, using echocardiogram and speckle tracking imaging technique. Methods This observational study was conducted with children with CZS using a two-dimensional speckle tracking technique to measure left atrial reservoir strain (LAS-r), conduit strain (LAS-cd), and contraction strain (LAS-ct). Also, to investigate the relationship between LAS-r and systolic excursion of the septum and lateral mitral annular plane (MAPSE), left atrial volume index and E/e’ ratio. Results A total of 52 patients were included, the median age of the studied population was 5 years (3 to 6), 59.6% male, and the body surface area was 0.66 [0.51, 0.90]. In the echocardiographic evaluation the left atrium volume index (ml/m²) was 13.15 [6.80, 18.00], considered smaller by the reference value. Also, the LAS-r (%) was 40.99 [24-70.5], LAS-cd (%) was 30,94 [32.5-52.5], LAS-cd (%) was 10,91 [5.2-24], values considered normal by the literature. Lateral MAPSE (cm) was 1.25 [0.81, 1.86] and septal MAPSE (cm) was 0.98 [0.78, 1.66] and E/e' ratio was 7.52 [4.57, 10.78]. A positive linear correlation was found between LAS-r and lateral MAPSE (r = 0.51, P = 0.019). Conclusion This original study with children with CZS shows that despite reduced atrial volume, the left atrial function remains normal, and correlates with left ventricular function evaluated by MAPSE. Further studies are needed to prospectively analyze the follow-up of left atrial morphology and function in this population.

Ferroptosis contributes to the development of cardiac dysfunction in iron overload cardiomyopathy

Abstract Background Ferroptosis is a novel form of cell death, and its role in iron overload cardiomyopathy (IOC) has not been elucidated. Purpose To explore whether ferroptosis of cardiomyocytes contributes to cardiac dysfunction in IOC by cardiac MR (CMR) and molecular biology techniques in vivo. Methods A total of 14 Sprague-Dawley (SD) rats were randomly divided into two groups: the control group (n=6) and the IOC group (n=8). The latter was induced by intraperitoneal injection of iron dextran on alternate days for 9 weeks and underwent a 7T CMR for assessment of cardiac function, including left ventricular ejection fraction (LVEF) and global longitude strain (GLS), along with the assessment of iron overload severity and fibrosis using Cine, T2 mapping, and late gadolinium enhancement (LGE), respectively. Circulating iron overload was determined via blood biochemistry analysis, measuring serum iron, ferritin, and transferrin levels. Furthermore, Prussian blue and Masson staining were employed to identify iron and fibrosis deposition within the myocardium, respectively. Cardiac ultrastructure, especially mitochondria, was examined via transmission electron microscopy (TEM). A sensitive fluorescent probe, dihydroethidium (DHE), was employed for the detection of reactive oxygen species (ROS) levels. Malondialdehyde (MDA), prostaglandin-endoperoxide synthase 2 (PTGS2), and glutathione peroxidase 4 (GPX4) were utilized to identify and quantify levels of lipid peroxidation, thereby providing comprehensive insights into cardiac cellular ferroptosis. Results 6 rats survived in the control group and 5 in the IOC group. Compared with the control group, the IOC rats had reduced T2 values of the cardiac septum (P<0.001), with normal LVEF (P>0.05) but decreased GLS (P<0.01), seen in Fig 1A. Based on blood biochemistry and Prussian blue staining, they were evident that IOC rats exhibited both circulating and cardiac iron overload, as seen in Figure 1B, C. Masson staining showed no obvious myocardial fibrosis, which was consistent with negative CMR LGE results, seen in Fig 1A, B. TEM further elucidated cardiac mitochondrial injuries in IOC rats, including focal vacuolization, swelling, crest disruption, and even disappearance, seen in Fig 2A. The fluorescent probe results revealed a striking increase in red fluorescence within the myocardium of IOC rats, seen in Fig 2B. Additionally, IOC rats exhibited significantly elevated levels of MDA and PTGS2mRNA (P<0.001), accompanied by notable downregulation of GPX4mRNA expression (P<0.001), seen in Fig 2C. These findings suggested the occurrence of ferroptosis in the myocardium of IOC rats. Conclusions In IOC, ferroptosis rather than necrosis is the primary driver of cardiac dysfunction, which is characterized by maintaining normal LVEF but experiencing a reduction in GLS without accompanying myocardial fibrosis. Our study sheds light on the potential involvement of ferroptosis in the pathogenesis of IOC.

Predictors of adverse cardiac events in a large cohort of patients with antiphospholipid syndrome

Abstract Background Non-valvular cardiac disease in antiphospholipid syndrome (APS) has been modestly evaluated. Aim We wanted to assess the prevalence and evolution of major adverse cardiovascular events(MACE) in a cohort of APS patients. Material and Methods From a large cohort of 181 APS patients included in a study from 2011-2012.year data for the occurrence of MACE in 10 years of follow-up were evaluated in 82 patients (86.6% females, 62.2% with primary (PAPS), and 37.8% patients with APS associated with systemic lupus erythematosus (SLE) (sAPS)). At the inclusion in all patients, a transthoracic echocardiography study for the assessment of dimensions and functionality of the left and right heart along with valvular functions and morphology. Standard atherosclerotic risk factors prevalence was analyzed. Antiphospholipid antibodies(aPL) analysis included the detection of aCL (IgG/IgM), ß2GPI (IgG/IgM), and LA, and all patients were treated according to the valid guidelines by the rheumatologist. Data regarding the occurrence of new myocardial infarction (MI), cerebrovascular events (CVI), arterial and/or venous thrombosis, heart failure (HF), and cardiovascular death (considered as MACE) have been collected 10 years after inclusion. Results The prevalence of standard atherosclerotic risk factors was less than 40% in both study groups. Left ventricle ejection fraction(LVEF) was over 45% in more than 90% of patients in both groups (p=0.246) with valvular dysfunction present in 49% of PAPS and 58.1% of sAPS patients (p=0.426). 9.8% PAPS and 12.9% sAPS had coronary artery disease(CAD) (p=0.724) and HF was present in 7.8% PAPS and 3.2% sAPS (p=0.645). MACE occurred in 17.6% of PAPS and 22.6% of sAPS (p=0.585). The new MI occurred in 9.8% of PAPS and 9.7% of sAPS (p=1.000), CVI in 5.9% of PAPS and 3.2% of sAPS (p=1.000), HF in 5.9% of PAPS and 3.2% of sAPS (p=1.000) and cardiovascular death in 9.8% of PAPS and 12.9% of sAPS (p=0.724). New thrombotic events (arterial and/or venous) occurred in 15.7% of PAPS and 17.2% of sAPS (p=1.000). During the follow-up period, 66.7% of PAPS and 55.2% of SAPS (p=0.313) were treated with aspirin, 25.5% of PAPS and 25.0% of sAPS with warfarin, and chloroquine was administered in 46.8% of PAPS and 53.6% of sAPS (p=0.571). Age (p=0.008), gender (p=0.034), thrombotic APS (p=0.033), hypertension (p=0.003), diabetes mellitus (p=0.043), and cardiovascular manifestations present at the time of APS diagnosis (p=0.035), namely CAD (p=0.001) and HF (p=0.005) were significantly associated with 10y MACE. aPL type and category were not associated with 10y MACE. In a multivariate logistic model, age. hypertension, and HF were independent predictors for 10y MACE. Conclusions APS patients develop new cardiovascular events despite optimal medical therapy. Cardiovascular evaluation at the time of diagnosis and proper cardiologist follow-up with the rigorous treatment of standard atherosclerotic risk factors is of utmost importance.

Treatment of Post-COVID-19 POTS by inhibiting FcRn: a phase 2 randomized, placebo controlled, double-blind, proof of concept study with efgartigimod

Abstract Background While the underlying pathophysiology is unknown, post–COVID-19 postural orthostatic tachycardia syndrome (POTS) may be related to immune dysfunction and autoimmunity precipitated by SARS-CoV-2 infection. Various autoantibodies, including those targeting G-protein coupled receptors (GPCRs), have been observed in patients with POTS. Binding of these autoantibodies to adrenergic receptors, which are prototypical GPCRs, has been hypothesized to modulate receptor activity, increase sympathetic tone, and cause tachycardia. Moreover, IgG anti-GPCR autoantibodies, acting as partial agonists, are thought to decrease the effect of peripheral vasomotor control, leading to an increased sympathetic response to upright posture that can result in postural tachycardia in the absence of hypotension. Purpose We hypothesize that a reduction in autoantibody levels by efgartigimod, a FcRn-antagonist, will ameliorate the underlying immune-mediated pathogenesis and lead to clinical improvements in patients who developed POTS following COVID-19 infection. We propose a phase II multicenter, randomized, placebo-controlled, double-blind, proof-of-mechanism study initiated to evaluate the safety and efficacy of efgartigimod in adults with post–COVID-19 POTS. Methods Adult patients diagnosed with new-onset of POTS following SARS-CoV-2 infection are eligible for participation in the study. Prior COVID-19 must be confirmed by documentation of historical PCR test, and POTS diagnosis must meet consensus criteria. Study subjects must have moderate to severe autonomic symptoms (COMPASS-31 score ≥ 35 points at screening). Approximately 42 patients will be randomly allocated (2:1) to receive weekly intravenous efgartigimod or placebo for 24 weeks. At the end of the treatment period, participants who complete the study may roll over into an open-label extension (OLE). The co-primary endpoints are change from baseline to week 24 in the COMPASS-31 and Malmo POTS Symptom Score as well as safety and tolerability outcomes. Key secondary endpoints include assessments of disease activity, fatigue, cognitive function, walking capacity and quantitative autonomic testing. Additional exploratory endpoints include intraepidermal small fiber densities (optional), sudomotor innervation (optional) and peripheral blood biomarkers to define histopathological and immune determinants associated with treatment response. Conclusions This phase II study of efgartigimod will evaluate the effect of FcRn inhibition on disease pathology and the potential for therapeutic benefit in patients with post–COVID-19 POTS.

Assessment of right ventricular function in patients with severe secondary tricuspid regurgitation, following to the TVARC recommendations: association with outcome

Abstract Introduction Severe tricuspid regurgitation (TR) is associated with increased mortality if left untreated. Recently, the Tricuspid Valve Academic Research Consortium (TVARC) has published standardized definitions of disease aetiology and severity, as well as endpoints for future clinical trials. Right ventricular (RV) function assessment represents one of the cornerstones for risk stratification in these patients, but current guidelines do not propose specific cut-off values for the echocardiographic measures. Also, the thresholds proposed by the TVARC have been derived from normative value and not yet validated in large cohorts of TR patients. Purpose To test the prognostic value of the TVARC proposed echocardiographic cut-offs for grading RV-dysfunction (figure1) in a large real-world cohort of patients with severe secondary TR (STR). Methods Consecutive patients from a single centre with first diagnosis of severe secondary STR, and without a cardiac implantable electronic device, were included. Tricuspid annulus plane systolic excursion (TAPSE), RV global and free wall strain (RVGLS and RVFWLS) and fractional area change (FAC) were used to measure RV function. The study endpoint was all-cause mortality, censored for tricuspid valve intervention. Results A total of 1043 patients (mean age 69 ± 13 years, 43% male), were included. Approximately half of the population (45%) was in NYHA class III or IV and 52% was treated with loop diuretics. Overall patients showed mild RV-dilatation (RV end-diastolic area indexed 12.2 [10.1-15.2cm2/m2]) and moderate-to-severe right atrial dilatation (right atrial maximal area indexed: 13.9 [11.0-17.5cm2/m2]). Using the proposed cut-off values, strain analysis identified a higher number of patients with impaired RV function as compared to standard echocardiographic parameters (89% based on RVGLS; 80% based on RVFWS, 61% based on TAPSE and 54% based on RVFAC). During a median follow-up of 51 [IQR 6 - 98] months, 445 (43%) patients died. The Kaplan-Meier survival curves for each echocardiographic parameter of RV-function are shown in Figure 1. TAPSE, which is the most widely used RV-function parameter, was able to clearly identify patients at high and intermediate risk when mildly, moderately and severely impaired. However, patients with normal TAPSE were still at intermediate risk when RVFWLS was (even mildly) reduced (figure 2). We therefore propose a stepwise practical approach including the measure of RVFWLS when measuring normal TAPSE, in order to possibly re-stratify patients into a higher risk group (Figure 2). This novel grading approach remained independently associated with all-cause mortality after correcting for relevant clinical and echocardiographic variables on multivariable analysis. Conclusion Novel TAVRC cut-off values for RV function show prognostic value in patients with severe STR; particularly the combination of TAPSE and RVFWLS could be use in clinical practice for risk stratification.Figure 1Figure 2

Titin hyper-phosphorylation in the peripheral skeletal muscle but not the diaphragm of HFpEF: association with muscle atrophy and dysfunction

Abstract Background Titin hypo-phosphorylation is an important regulatory mechanism for myocardial stiffness in heart failure with preserved ejection fraction (HFpEF). In contrast, a hyper-phosphorylation of titin in the peripheral skeletal muscle (SKM) was reported in mouse models exhibiting muscle atrophy. In former studies it, was shown that SKM atrophy occurs in HFpEF and is associated with muscle dysfunction and a fiber type shift from type I, towards type II fibers. However, these alterations were not seen in the diaphragm muscle (Dia) and a fiber type shift towards type I was documented. So far, no information about the phosphorylation status of titin is available for SKM and the Dia and its association with muscle dysfunction in HFpEF. Purpose To assess titin phosphorylation in SKM and Dia of a HFpEF animal model and to relate it to muscle function and atrophy. Methods To confirm the development of HFpEF echocardiography was performed in female ZSF1-lean (con, n=18) and ZSF1-obese rats (HFpEF, n=18) at the age of 32 weeks. Skeletal muscle function (soleus) was measured in an organ bath setting after the animals were sacrificed. Tissue of the tibialis anterior muscle (TA) and the diaphragm (Dia) was collected and fixed in formalin or snap frozen in liquid nitrogen. To detect titin expression homogenized TA and Dia tissue samples were resolved on a vertical agarose gel. Phosphorylated titin was detected by staining the gel with Pro-Q Diamond, whereas total titin was visualized using Sypro Ruby. Cross sectional area (CSA) of TA and Dia was quantified after Hematoxylin/eosin staining of tissue section. Myosin heavy chain (MHC) ubiquitination was assessed by western blot. Results Assessment of SKM function revealed significantly reduced maximal absolute (-12 %) and maximal specific force (-22 %) in HFpEF animals when compared to controls. In the TA a significantly reduced CSA was evident in HFpEF (1911±103 vs. 1394±103 µm2, p=0.002), whereas in the diaphragm an increased CSA was noted (438±11 vs. 560±18 µm2, p<0.001). In TA of HFpEF animals, the proportion of phosphorylated titin was significantly elevated whereas the total amount of titin was reduced (Fig. 1A, C). In addition, a significantly higher proportion of ubiquitinated MHC was detected (Figure 1E). However in the Dia these alterations were not observed, even a higher amount of total titin was seen (Fig. 1B, D, F). Furthermore, a significant negative correlation between phosphorylated titin and absolute force (r=-0.461, p=0.035, Fig. 2A) as well as specific force (r=-0.693, p=0.0005, Fig. 2B) was evident. Conclusion In contrast to the heart, the TA showed a titin hyper-phosphorylation in HFpEF, going along with a degradation of total titin. This hyper-phosphorylation could be correlated with a loss of force in the SKM. Additionally a higher ubiquitination of MHC was prevalent in the TA, which may be connected to molecular remodeling and fiber type shift towards a more glycolytic type.

Prognostic implications of right ventricular dysfunction in degenerative mitral regurgitation

Abstract Background The prevalence and impact of right ventricular dysfunction (RVD) in degenerative mitral regurgitation (DMR) is unknown. We aimed to determine whether RVD assessed by echocardiography in routine clinical practice is independently associated with survival in patients with DMR. Methods We used data from the Mitral Regurgitation International DAtabase-Quantitative (MIDA-Q) which included patients with isolated DMR due to mitral valve prolapse from January 2003 to January 2020 from 5 tertiary centers across North America, Europe, and the Middle East. A cohort of 4,379 (mean age: 67 years, 64.6% males, follow-up:5.3[3.3-8.2]years) consecutive patients with significant (≥moderate) DMR was included and long-term survival was analyzed. Results RVD, identified in 584(13.3%) patients, was associated with reduced 10-year survival (49±3% vs. 67±1%; p<0.001), overall and in all subgroups of patients, even after comprehensive adjustment including left ventricular dilatation and dysfunction, DMR severity, pulmonary pressures and surgery (adjusted HR[95%CI]=1.55[1.31-1.84]; p<0.001). This excess mortality was observed under medical management (adjusted HR[95%CI]=1.39[1.12-1.72]; p=0.003) and after surgical correction of mitral regurgitation (adjusted HR[95%CI]=1.56[1.08-2.27]; p=0.019). Patients with RVD undergoing surgery within 3 months of diagnosis experienced a better 10-year survival (73±4% vs. 38±4%; p<0.001), even after adjustment (adjusted HR[95%CI]=0.53[0.35-0.81]; p=0.003) despite an increase of 1-month post-operative mortality (5% vs 2.2% for patients without RVD; p<0.001). Conclusions RVD is observed in 13.3% of significant DMR and exhibits a powerful and independent association with excess mortality partially attenuated by mitral surgery. Therefore, assessment of right ventricular systolic function should be included in routine DMR evaluation and in the clinical decision-making process.determinant ans prognosis of RVD in MR

Application of the 2016 ase-eacvi criteria for the assessment of diastolic function in arterial hypertension

Abstract Background No data are available on diagnostic algorithms recommended by guidelines for the assessment of diastolic dysfunction (DD) in patients with arterial hypertension. Purpose To fill this gap, we evaluated left ventricular (LV) diastolic function in hypertensive patients matched with healthy subjects. Methods Healthy subjects, hypertensive patients without and with LV hypertrophy (LVH) were matched 1:1:1 based on age, sex, and body mass index from two prospective registries. All participants had normal LV ejection fraction (EF). Diastolic function was assessed basing on 2016 ASE-EACVI guidelines, by applying algorithm A, recommended in normal LVEF, and algorithm B recommended in reduced LVEF or normal LVEF and myocardial disease. Results A total of 717 participants were enrolled. By applying algorithm A, an indeterminate pattern was found in 0.4% of healthy subjects, in 6.3% of hypertensive patients without LVH (p=0.015 vs. healthy subjects), and in 21% of hypertensive patients with LVH (p=0.001 vs. healthy subjects). DD was absent in healthy individuals, whereas it was found in 2% and 8% of hypertensives without (p=0.06) and with LVH (p=0.001 vs. healthy subjects), respectively. By applying algorithm B, no cases of indeterminate diastolic function were found. DD was observed in 2.9% of healthy subjects, 7% and 10.5% of hypertensives without (p=0.001 vs. healthy subjects) and with LVH (p=0.002 vs. healthy subjects). Conclusion When diastolic function is assessed by echocardiography, the use of algorithm A should be limited only to truly normal subjects, whereas algorithm B should be applied to all patients with hypertension irrespective of LVH

Echocardiographic left atrial stiffness index predicts high left ventricular filling pressures in patients with acute heart failure: an observational study.

In acute heart failure (AHF) patients, non-invasive estimation of left ventricular filling pressures (LVFPs) appears crucial to guide management. Although poorly investigated, left atrial (LA) mechanics play a pivotal role in this setting. This report sought to assess the correlation of echocardiographic LA stiffness index with invasive LVFPs and its diagnostic accuracy as compared to other parameters used in clinical practice. In this observational, prospective study, 104 patients with suspected acute coronary syndrome and signs/symptoms of AHF were enrolled. Available invasive estimation of LVFPs was required. Comprehensive echocardiography was performed for all patients, including LA reservoir strain (LARS). LA stiffness index was derived by speckle-tracking analysis and Tissue Doppler imaging as early diastolic transmitral inflow velocity/mitral annulus early diastolic velocity [E/e']/LARS. Invasively measured LVFPs showed a strong correlation with LA stiffness index (Spearman ρ = 0.773, p < 0.0001), as well as with LARS and E/e'. Receiver operating characteristic (ROC) curve analysis was used to demonstrate better accuracy performed by LA stiffness index than average E/e', LA volume or LARS alone, in predicting high LVFPs. Guideline-recommended assessment of diastolic function was finally compared to LARS and LA stiffness index performances in an independent population group; we were hence able to obtain a LA stiffness threshold of 0.48 with a positive predictive value of 91.7% and a negative predictive value of 88.9% in identifying patients with high LVFPs. For the first time, diagnostic performance of LA stiffness index has been investigated in a heterogeneous AHF population, providing correlations with invasively measured LVFPs and comparisons with established diastolic function metrics.