Left Ventricular Research Articles

Large sample size MRI measurements to assess the relation between cardiac function and structure and white matter hyperintensity volumes

Abstract Background People with established cardiovascular disease (CVD) are at risk of early cognitive decline, and neurological diseases such as dementia. CVD and neurological diseases share common risk factors, such as blood pressure, sedentary lifestyle, as well as genomic risk factors such as mutations in APOE4 [1]. It's unclear to what extent the co-occurrence of CVD and neurological diseases is explained by these risk factors, or whether there is a direct association where CVD is a first step towards poorer neurological health. White matter hyperintensities (WMH) of presumed vascular origin are damaged areas in the brain observed through magnetic resonance imaging (MRI). These lesions are associated with progressive neurological disease such as vascular dementia, as well with risk factors for CVD [2]. Purpose We set out to determine to what extent CMR measurements associated with WMH independent of known cerebrovascular risk factors. Methods Cardiac and brain MRI images were analysed for 23,963 UK biobank (UKB) participants. WMH analysis included 5 brain regions (Frontal[F], Parietal[P], Temporal[T], Occipital[O], Basal Ganglia and Thalami [BGT]) and total brain WMH volume. Cardiac traits included stroke volumes, atrial volumes, ejection fractions of right and left chambers, left ventricular (LV) strain, LV wall thickness and aortic areas. Multivariable regression analysis was carried out, where each cardiac trait was regressed on each brain region and adjusted for: age, difference between age at initial visit and imaging visit, sex, systolic and diastolic blood pressure, Hba1c, household income, educational status, Townsend score and family history of disease (Alzheimer’s, Parkinson's, high blood pressure, stroke, heart disease) . Results were evaluated against a multiple testing correct p-value threshold of 0.05, reflecting the number of principle components(n=10) necessary to explain 90% of the cardiac trait variability. Results For 5 cardiac traits (right ventricular stroke volume, left atrial stroke volume, left ventricular stroke volume, left ventricular ejection fraction and right ventricular end diastolic volume) higher values were associated with lower WMH volumes in all brain regions. Additionally, some cardiac traits such as LV cardiac output associated with specific brain regions (T, O, BGT). Additionally, APOE- ε4 stratified analyses indicated, homozygous carriers show a greater association between higher minimum LA and RA volumes and higher WMH volumes in the occipital lobe. Conclusions This study gives an insight into the WMH burden in a large population of adults. It highlights the associations of cardiac traits with white matter hyperintensity volumes in different brain regions independent of known risk factors. Using cardiac traits as surrogate markers of different cardiac disease could explain how cardiac functionality defines WMH volume distribution and subsequently the wider relationship between CVD and cerebrovascular disease.Figure 1Graphical Abstract

Prospective longitudinal evaluation of AI-ECG in newly diagnosed heart failure (PLANE-HF)

Abstract Background * In the United Kingdom, there are one million people suffering from heart failure (HF), with more than 60,000 new cases annually (1). * Monitoring for declining left ventricular ejection fraction (LVEF) could optimise treatment approaches and avert healthcare episodes. * Easy home-based tracking of cardiac function would be transformative. * Previous studies have validated the capability of artificial intelligence-enabled electrocardiogram (AI-ECG) to correlated with changes in LVEF (2). * We hypothesize that longitudinal changes in AI-ECG probability score is associated with changes in the left ventricular (LV) function. Method * A prospective multicentre longitudinal study recruiting newly diagnosed HF with reduced ejection fraction (HFrEF) cases to investigate application of AI-ECG using longitudinal single-lead ECG recordings via patient-administered smart ECG-stethoscope examination – Figure 1. * A total of 36 patients were included in the analysis, with invitation to return for repeat echocardiography at 6-8 weeks. * Adjusted logistic regression was performed to analyze changes in LVEF by 10% as the outcome variable, investigating the relationship with the trajectory of AI-ECG probability scores. This study was approved by the UK Health Research Authority (reference 22/LO/0701). Result * Out of 36 patients, 19 patients had ischaemic and 17 had a non-ischaemic HF. * The mean age was 56.3 years, 97.2% patients were male and 46.6% were White. * 328 longitudinal single-lead ECGs were captured and used in the analysis. * 12 (33.3%) patients had an increase of their LVEF by 10%; preceding AI-ECGs was predictive of this recovery (OR 1.36; 95% CI, 1.05 – 1.65, p value = 0.016 – Table 1) Clinical Importance: * Individualised predictions of deterioration and improvement * Proactive medication adjustment * Enhanced triage for echocardiography Conclusion * AI-ECG designed to identify left ventricular systolic dysfunction (LVSD) can predict changes in LVEF% among newly diagnosed HFrEF patients. * Such results can place AI-ECG as a remote monitoring tool to track improvement or deterioration in patients’ LVEF%, which facilitate a proactive management and prevention strategies.

The correlation between cardiac magnetic resonance imaging and echocardiography in patients with severe ischaemic cardiomyopathy

Abstract Background Left ventricular ejection fraction is the single metric that guides therapeutic decision-making, risk stratification and prognosis in patients with severely impaired systolic function. Although cardiac magnetic resonance imaging (CMR) is the current reference standard for quantification of ventricular volume and function, echocardiography is used more often as it is more widely available and less expensive.(1) Aims To evaluate the correlation between CMR and echocardiography in quantifying left ventricular (LV) volume and function and to determine whether these measurements are associated with clinical outcomes in patients with severe ischemic cardiomyopathy (ICM). Methods Participants recruited to the REVIVED-BCIS2 trial who had undergone baseline CMR or echocardiography were included in this analysis. All scans were analyzed in blinded core laboratories as previously reported.(2,3) All volumes were indexed to body surface area. Spearman correlation, Bland Altman analysis and coverage probability methods were performed to assess the correlation between the two modalities. A Cox proportional hazards model was used to assess the association between imaging metrics and the primary outcome, a composite of all-cause death and aborted sudden death. A sensitivity analysis was conducted a priori, restricted to patients undergoing both scans within 60 days of each other. Results A total of 373 participants with paired imaging data were included: mean age 69±9 years, 87% male, BMI 28±5. A moderate correlation was detected for volume measurements between the modalities (end diastolic volume index (EDVI) r=0.66 end systolic volume index (ESVI) r=0.68), with a weaker correlation for LV ejection fraction (EF) (r=0.41). Bland-Altman plots showed moderate agreement in LVEF measurements (Table 1). The sensitivity analysis included 199 patients, and showed similar results (EDVI r=0.72, ESVI r=0.73 LVEF r=0.43, all p<0.000). Only 7.5% of the paired LVEF measurements were within 5% of each other. 30% of participants were misclassified by echocardiography as having an LVEF>35%. (Figure 1) CMR ESVI was associated with the occurrence of the primary outcome (HR 1.05 per 10ml increment, 95% CI 1.00-1.10) however echo ESVI (HR 1.05 per 10ml increment 95% CI 0.99 – 1.10) and all other imaging metrics were not. Conclusion Left ventricular volumes and ejection fraction on CMR and echocardiography were only modestly correlated in this population with severe ICM. When using the binary EF threshold of 35% that is commonly used to select patients of implantable defibrillator therapy, almost a third of patients at risk would have been missed by echocardiography alone. The additional insights provided by CMR, including scar burden, further support preferential use of this modality in the assessment such patients.

Locally increased dysferlin expression improves left-ventricular function by stabilizing membrane nanodomains of cardiomyocytes in the myocardial infarction border zone

Abstract Introduction Dysferlin, a transmembrane protein with multiple Ca2+-binding C2-domains, is expressed in the sarcolemma and vesicle membranes of striated muscle cells. Upon Ca2+ entry, Dysferlin is thought to mediate vesicle fusion and membrane repair events in order to rapidly seal sarcolemmal lesions. Dysferlin mutations are associated with progressive muscular dystrophies and dilated cardiomyopathy. However, the precise role of Dysferlin in protection of membrane nanodomains in ventricular myocytes (VMs) after myocardial infarction (MI) remains elusive. Purpose We hypothesized that Dysferlin is crucial to prevent VMs from loss-of-function and cell death by stabilizing membrane nanodomains like the transverse-axial tubule (TAT) system and the intercalated disc (ICD) cell-cell contact sites post-MI. Methods and Results 1 week post-MI induced by LAD artery ligation, investigator-blinded echocardiography revealed increased infarct sizes and decreased left-ventricular (LV) ejection fraction of Dysferlin-knockout (KO) vs. WT mice (mean±SEM: 21±2 vs. 28±2%, n=20/30 mice, P<0.05). Immunoblotting of WT LV tissue lysates showed an upregulated Dysferlin expression to 148% compared to sham-operated controls. Importantly, immunohistology identified a maximal Dysferlin expression of 230% in the MI border zone that faces a high ischemic and mechanical stress. Hence, we used data-independent mass spectrometry (DIA-MS) to analyse the proteomic profile of the infarction zone, border zone and remote zone from WT vs. KO hearts 1 week post-MI (each n = 5 mice). Overall, we reproducibly quantified 4360 proteins across all LV samples, identifying local genotype-specific proteotypes post-MI. In WT vs. KO samples, DIA-MS revealed 725 differentially abundant proteins in the zone pairwise comparison, highlighting a vital role of Dysferlin for LV remodelling post-MI. In addition, superresolution stimulated emission depletion (STED) microscopy was applied to study the subcellular localization and function of Dysferlin in the MI border zone. Here, we observed VMs with disrupted TAT endomembrane networks and significantly extended ICD regions. Interestingly, STED imaging revealed Dysferlin clusters that highly decorated residual TAT structures and interdigitated ICD membrane folds in the MI border zone. DIA-MS analysis of anti-Dysferlin co-imunoprecipitation experiments from WT vs. KO LV tissues characterized the cardiac interactome of Dysferlin, confirming interactions with proteins of the TAT system and the gap junction hemichannel Connexin-43. Conclusions Our data demonstrate Dysferlin as an endogenous membrane repair protein necessary to stabilize sarcolemmal nanodomains in the MI border zone. Dysferlin not only prevents from loss of TAT structures, but also compensates for increased mechanical stress at the ICDs. Hence, Dysferlin emerges as a novel therapeutic target to control membrane integrity in VMs to prevent from loss-of-function and cell death post-MI.

Long term outcomes of patients with decompensated aortic stenosis undergoing urgent transcatheter aortic valve implantation: a TAVI-NOR subs-study

Abstract Background Aortic stenosis (AS) is a progressive disease, which untreated leads to irreversible myocardial damage and potentially death. Patients with AS may present with acute decompensation (ADAS) even during active surveillance. Purpose In this TAVI-NOR sub-study, we investigate the clinical profile, risk factors, epidemiology and long-term outcomes of patients treated with TAVI after presenting with ADAS compared to stable patients who underwent elective TAVI (no ADAS). Method A total of 600 patients with severe AS consecutively treated with TAVI between January 2012 and July 2019 were enrolled in TAVI-NOR study. Predictors and long-term clinical outcomes were explored in binary logistic and Cox regression models. Results A total of 68 patients (11.3%) received urgent TAVI due to acute hospitalization with ADAS. Age (80±8.0 years vs 81±6.0 years, p=0.662), gender (56% males vs 50% males, p=0.361) and other comorbidities at baseline such as cardiovascular disease, chronic lung disease and atrial fibrillation (AF) were comparable in patients with ADAS and no ADAS (n=532) (p>0.05 for all). However, patients with ADAS had greater symptom burden (NYHA III-IV 81% vs 51%, p<0.001), lower blood pressure, higher heart rate and lower estimated glomeruli filtration rate (52.0±10.8 vs 54.6±9.8 mL/min/1.73m2, p<0.045). They had also higher prevalence of ECG left ventricular (LV) hypertrophy (40% vs 27%, p=0.027), more often reduced LV ejection fraction (<50%) (41% vs 16%, p<0.001), lower stroke volume (39±11 ml/m2 vs 42±11 ml/m2 vs, p=0.030) a trend of abnormal ECG (p=0.055) and longer hospital stay (11.5 ±8.7 days 6.6± 4.9 days, p<0.001). Patients with ADAS were comparable with no ADAS in terms of early short-term (<30 days) all-cause mortality (p>0.05). Although 1-year mortality was comparable (1.5% in ADAS vs 2.1% in no ADAS, p>0.99), mid- to late-term mortality rates were significantly higher in patient with ADAS receiving urgent TAVI, with 3-, 5- and 7 years mortality of 22% vs 11%, p=0.008; 46% vs 29%, p=0.005; 53% vs 39%, p=0.033, respectively. In a Kaplan-Meier analysis, event-free survival was significantly reduced for patients with ADAS undergoing urgent TAVI compared with stable patients undergoing elective TAVI HR 1.63, 95% CI 1.15-2.31, p=0.006), confirmed by a multivariable-adjusted model (HR 1.54; 95% CI 1.05-2.25, p=0.026) independent of age, gender, AF, LV ejection fraction and time from diagnosis to TAVI (Fig). Conclusion Patients with AS presenting with acute decompensation and treated with urgent TAVI had excellent short-term survival. This was irrespective of increased symptom burden, adversely remodeled and functionally reduced LV at baseline. These findings might explain the observed higher mid- and long-term mortality compared with stable patients undergoing elective TAVI. It is essential to identify patients at risk of acute decompensation and treat them timely before irreversible myocardial damage occur.

Prognostic value of combined myocardial performance index in patients with acute ST-elevation myocardial infarction

Abstract Background Myocardial performance index (MPI) also known as Tei index is a unique echocardiographic parameter which can estimate both systolic and diastolic performances of left and right ventricles. We previously suggested the echocardiographic parameter combined MPI (CMPI) as a new predictor of the prognosis of acute ST-elevation myocardial infarction (STEMI). The CMPI is the sum of left ventricular (LV) MPI and right ventricular (RV) MPI (CMPI = LV MPI + RV MPI). We supposed that CMPI might be a better predictor in STEMI, because it reflects both ventricular systolic and diastolic functions. Objectives The purpose of this study is to assess the prognostic value of a new echocardiographic parameter CMPI in STEMI patients calculated in acute phase. Methods 240 STEMI patients who underwent primary PCI have been included in the study. Echocardiography (EchoCG) was performed, and LV MPI and RV MPI were assessed within 24 hours after the symptom onset, prior to primary PCI. The MPI was calculated as the sum of isovolumic contraction time (ICT) and isovolumic relaxation time (IRT), divided by the ejection time (ET): MPI = (ICT + IRP) / ET. 50 % of the patients had anterior STEMI. 30 patients (12.5%) had concomitant RV myocardial infarction (MI). Patients were divided into two groups: Group 1 – CMPI > 0.9 (110 patients), Group 2 – CMPI ≤ 0.9 (130 patients). Baseline demographic and clinical characteristics were similar in both groups. Also, there were no differences in LV MI localization and concomitant RV MI between the groups. Primary endpoints were in-hospital and the one-year cardiovascular mortality rates. The secondary endpoint was the one-year heart failure hospitalization rate. Results In Group 1 the in-hospital mortality rate was 9.1%, and 3.1% in Group 2 (p = 0.0489). One-year cardiovascular mortality rate was 12.7% in and 5.4%, respectively (p = 0.0465). One-year heart failure hospitalization was also significantly lower in Group 2 (22.7% vs. 12.3%, p = 0.0332). Conclusion CMPI can be offered as a new predictor for the in-hospital and one-year cardiovascular mortality and one-year heart failure hospitalization rate in patients with acute STEMI.

Prevalence and prognostic significance of restriction versus systolic dysfunction in patients with transthyretin and light chain cardiac amyloidosis

Abstract The tenet of cardiac amyloidosis (CA) as a paradigm of heart failure with restrictive ventricular physiology and preserved systolic function has come under scrutiny. Thus, we aimed to evaluate the prevalence and clinical significance of left ventricular (LV) systolic dysfunction versus restriction in a large real-world cohort with CA, assessed at the time of diagnosis. Methods This is a multicenter retrospective analysis including 540 transthyretin (ATTR)-CA and 280 light chain (AL)-CA. Patients were divided into 3 phenotypes: 1) preserved LV function: LV ejection fraction (EF) ≥50% associated with grade 0/I diastolic dysfunction; 2) restriction: LV-EF≥50% associated with grade II/III diastolic dysfunction; 3) systolic dysfunction: LV-EF<50% irrespective of diastolic function. We analysed progression from preserved LV function towards the other two phenotypes and their survival. Results In ATTR-CA, prevalence of preserved LV function was 27%, restriction was 44% and systolic dysfunction was 28%. Among patients with preserved LV function, annual conversion rate to restriction was 24% and to systolic dysfunction was 17%. At 3 years, survival free from all-cause mortality was 88%, 76% and 63% respectively (figure A). In AL-CA, prevalence of preserved LV function was 30%, restriction was 49% and systolic dysfunction was 20%. Among patients with preserved LV function, annual conversion rate to restriction was 28% and to systolic dysfunction was 8%. At 3 years, survival free from all-cause mortality was 56%, 39% and 29% respectively (figure B). Conclusions Restriction was the presenting phenotype in less than half of patients, while systolic dysfunction in approximately one quarter. The annual rate of progression form preserved LV function towards restriction or systolic dysfunction was high. In ATTR systolic dysfunction was associated with worse outcome, compared to restriction; in AL both restriction and systolic dysfunction were associated with equally ominous outcome.

Echocardiographic predictors of cardiovascular outcome in heart failure with preserved ejection fraction

Abstract Background The optimal echocardiographic predictors of cardiovascular outcome in heart failure with presereved ejection fraction (HFpEF) are unknown. Purpose We aimed to identify independent echocardiographic predictors of cardiovascular outcome in patients with HFpEF. Methods Systematic literature search of three electronic databases was conducted from date of inception until November 2022. Hazard ratios (HRs) and their 95% confidence intervals (CIs) for echocardiographic variables from multivariate prediction models for the composite primary endpoint of cardiovascular death and heart failure (HF) hospitalization were pooled using a random effects meta-analysis. Specific subgroup analyses were conducted for studies that enrolled patients with acute versus chronic HF, and for those studies that included E/e’, pulmonary artery systolic pressure (PASP), renal function, natriuretic peptides and diuretic use in multivariate models. Results Forty-six studies totalling 20,056 patients with HFpEF were included. Three echocardiographic parameters emerged as independent predictors in all subgroup analyses: Decreased left ventricular (LV) global longitudinal strain (HR 1.24, 95% CI 1.10-1.39 per 5% decrease), decreased left atrial (LA) reservoir strain (HR 1.30, 95% CI 1.13-1.1.50 per 5% decrease) and lower tricuspid annular plane systolic excursion (TAPSE) to PASP ratio (HR 1.17, 95% CI 1.07-1.25) per 0.1 unit decrease). Other independent echocardiographic predictors of the primary endpoint were a higher E/e’, moderate to severe tricuspid regurgitation, LV mass index and LA ejection fraction, although these variables were less robust. Conclusion Impaired LV global longitudinal strain, lower LA reservoir strain and lower TAPSE/PASP ratio predict cardiovascular death and HF hospitalization in HFpEF and are independent of filling pressures, clinical characteristics and natriuretic peptides. These echocardiographic parameters reflect key functional changes in HFpEF, and should be incorporated in future prospective risk prediction models.

Prognostic implications and alterations in left atrial deformation following transcatheter aortic valve implantation for severe aortic stenosis

Abstract Background Left atrial reservoir strain (LARS) as a single parameter estimate of left ventricular (LV) diastolic dysfunction (DD), may provide important prognostic insights into patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve implantation (TAVI). Purpose To evaluate the prognostic implications of pre- and post TAVI LARS-defined DD (LARS-DD) grade in patients undergoing TAVI for severe AS and its association with new-onset atrial fibrillation. Methods Pre-TAVI LARS-DD was evaluated by speckle-tracking echocardiography and was assigned as grade 0 to 1 (LARS ≥24%), grade 2 (LARS ≥19 to <24%) and grade 3 (LARS <19%). Patients were followed-up for the primary endpoint of all-cause mortality from the date of TAVI. For the secondary endpoint, patients with pre- and post-TAVI LARS measurements, no history of atrial fibrillation and with clinical/ECG follow-up following the post-TAVI follow-up echocardiogram were evaluated for the occurrence of new-onset atrial fibrillation. Results A total of 601 patients (median age 81 [76-85] years, 53% male) undergoing TAVI for severe AS were included. Overall, 169 patients (28%) were LARS-DD grade 0/1, 96 patients (16%) were LARS-DD grade 2 and 336 (56%) were LARS-DD grade 3. Over a median follow-up of 40 (IQR 26 to 58) months, a total of 258 (43%) patients died (Figure 1). In a comprehensive multivariable Cox regression model adjusted for age, sex, EuroSCORE II, New York Heart Association class III to IV symptoms, LV ejection fraction, atrial fibrillation, LA volume index and LV stroke volume index, LARS-DD grade was independently associated with all-cause mortality (adjusted HR 1.28 per one grade increase above LARS-DD grade 0/1, 95% CI 1.07 to 1.53, P=0.007). For the secondary endpoint of new-onset atrial fibrillation, a total of 285 patients were evaluated (Figure 2). On multivariable Fine and Gray regression analyses adjusting for age and LA volume index, post-TAVI LARS (SDHR 1.14 per 1% <20%, 95% CI 1.05 to 1.23, P=0.0009), rather than pre-TAVI LARS (SDHR 1.00 per 1% <20%, 95% CI 0.91 to 1.11, P=0.93) was associated with the occurrence of new-onset atrial fibrillation. Conclusions Increasing LARS-DD grade was independently associated with long-term post-TAVI survival in patients with severe AS and may enhance risk stratification. In addition, post-TAVI LARS, but not pre-TAVI LARS, was closely related to the occurrence of new-onset atrial fibrillation, likely better reflecting intrinsic LA dysfunction.Figure 1:All-Cause MortalityFigure 2:New-Onset Atrial Fibrillation

Left ventricular volume as a predictor of exercise capacity and functional independence in individuals with preserved ejection fraction

Abstract Background Cardiorespiratory fitness (CRF) is vital for independent living and is a powerful prognostic marker. Increased left ventricular (LV) volume has been linked with high CRF in athletes, but its utility as a diagnostic marker of low CRF across the entire health-disease continuum has yet to be tested. Methods This multi-center international cohort from Australia and Belgium examined the relationship between ventricular size on resting echocardiography and CRF (peakVO2 from cardiopulmonary exercise testing [CPET] or CPET with simultaneous echocardiography) in individuals with preserved LV ejection fraction (≥50%). LV end-diastolic volume (LVEDV) and LVEDV indexed to body surface area (LVEDVi) were tested as predictors of very low CRF (CRF associated with functional disability - peakVO2 < 1100ml or <18 ml/kg/min) and compared against other candidate measures of systolic and diastolic cardiac function that have been associated with heart disease. Thresholds for absolute and indexed LVEDV which best distinguished between lower and higher CRF status were identified. Results 2876 individuals (251 healthy non-athletes, 309 elite endurance athletes, 1969 individuals with unexplained dyspnea, 347 individuals with heart failure with preserved ejection fraction) were included. For the entire cohort, LVEDV had the strongest univariate association with peakVO2 (R2 = 0.45, standardized [std] β 0.67, p< 0.001) and, remained the strongest independent predictor of peakVO2 after adjusting for age, sex and body mass index (std β 0.44, p < 0.001). The relationship between LVEDV and VO2peak differed based on health/disease status (Figure 1). LVEDV demonstrated the greatest diagnostic capability in identifying functional disability (LVEDV AUC 0.72; LVEDVi AUC 0.71, Figure 2), outperforming ejection fraction, diastolic velocities, atrial volumes and pulmonary artery pressure estimates. The probability of achieving a peak VO2 below the threshold required for functional independence was highest for smaller ventricular volumes with LVEDV and LVEDVi of 88ml and 57 ml/m2 proving the optimal cut-points, respectively. Conclusions A small LVEDV is associated with a higher probability of poor exercise capacity, failure to achieve the peak VO2 required for functional independence and is the strongest independent echocardiographic predictor of CRF across the health-disease continuum.Figure 1.Ventricular Size and CRFFigure 2.Predictors of CRF status

Coronary microvascular dysfunction as assessed by cardiac MRI and its association with aerobic exercise capacity in dilated cardiomyopathy

Abstract Background Dilated cardiomyopathy (DCM) has a poor prognosis. Aerobic exercise capacity (peak VO2) is an independent predictor of mortality but the central mechanisms contributing to exercise intolerance in DCM are unknown. Purpose To characterise myocardial perfusion reserve (MPR) and determine if cardiovascular magnetic resonance (CMR) measures of structure, function and microvascular function are associated with aerobic exercise capacity in DCM. Methods Single centre, prospective, case-control comparison of adults with DCM and matched controls. Adenosine-stress perfusion CMR to assess cardiac structure, function and quantitative perfusion, and cardiopulmonary exercise testing (CPET) to determine peak VO2, was performed. Controls were propensity matched based on age, sex, body mass index and diabetes status, and between group comparison was adjusted for other key clinical characteristics (CMR: ethnicity and systolic blood pressure; CPET: ethnicity, systolic blood pressure, smoking history and lung disease). Comparison of perfusion in segments with and without late gadolinium enhancement was performed using mixed effects linear regression taking into account individual patient segmental perfusion. Pre-specified multivariable linear regression, including key clinical and cardiac variables, was undertaken in patients with DCM to identify independent associations with percentage predicted peak VO2, which incorporates age, sex, height and weight. Results Sixty-six patients with DCM (median age 61 years, 71% male) were matched to 66 controls (median age 59 years, 71% male). The DCM group had greater left ventricular (LV) end-diastolic and end-systolic volumes, lower systolic and diastolic function, and had more focal and diffuse fibrosis compared to controls (Table 1). There was lower rest (0.58±0.14 versus 0.65±0.17 mL/min/g; P=0.033) and stress (1.53±0.49 versus 2.01±0.60 mL/g/min; P<0.001) myocardial blood flow, and lower MPR (2.69±0.84 versus 3.15±0.84 mL/g/min; P=0.002) in the DCM group. In DCM patients, mixed effects linear regression demonstrated lower rest (adjusted mean 0.54(95% CI 0.50-0.57) versus 0.58(0.55-0.62) mL/g/min; P<0.001) and stress MBF (1.38(1.25-1.51) versus 1.55(1.43-1.67) mL/g/min; P<0.001) in segments with LGE compared to segments without LGE, but there was no difference in MPR (2.71(2.47-2.96) versus 2.76(2.55-2.97) mL/g/min; P=0.496). DCM patients had markedly lower peak VO2 (19.8±5.5 versus 25.2±7.3 mL/kg/min; P<0.001). Multivariable linear regression demonstrated that LV ejection fraction, extracellular volume fraction and MPR, but not LV mass, were independently associated with percentage predicted peak VO2 in DCM (R squared=0.531, P<0.001; Table 2). Conclusions DCM patients have lower rest and stress myocardial blood flow and lower MPR compared to controls. In DCM, MPR, LV ejection fraction and fibrosis are independently associated with aerobic exercise capacity.

Left ventricular pressure-strain loops for the assessment of myocardial work in a low-risk community-based cohort: associations with long-term prognosis

Abstract Background Non-invasive left ventricular (LV) pressure-strain loop analysis is a novel technique for the evaluation of global myocardial work (GMW) that provides additional insights on LV contractility and energetics beyond traditional metrics, such as ejection fraction (EF) and global longitudinal strain (GLS). Despite its established value in numerous cardiac diseases, there remains limited data on its predictive power in a low-risk population. Purpose Our objective was to determine the long-term prognostic value of GMW in a population-based screening sample comprising low-risk adult individuals. Methods We retrospectively identified 1562 volunteers from a population-based screening program (mean age 54±15 years, 59% female), with a median follow-up time of 11 years. All subjects underwent 2D echocardiography to measure LV EF, GLS, peak atrial longitudinal strain (PALS), GMW index (GMWI), global wasted work (GWW), and GMW efficiency (GMWE). The primary endpoint was all-cause mortality. Results 191 subjects (12,2%) met the primary endpoint. Subjects who experienced adverse outcomes exhibited significantly lower LV EF (dead vs. alive; 49.7±8.3 vs. 52.7 ±6.4 %, p<0.001), GLS (-18.7±4.1 vs. -20.4±3.6 %, p<0.001), PALS (33.6±15.7 vs. 44.2±15.2 %, p<0.001), and GMWI (2181.7±591.3 vs. 2286.8±482.5 mmHg%, p=0.008). Furthermore, subjects with adverse outcomes had significantly higher GWW (132.6±249.4 vs 95.1±113.4 mmHg%, p<0.001) and, consequently, lower GMWE (0.95±0.05 vs. 0.96±0.03, p<0.001). Univariate Cox regression analysis revealed GMWI to be a significant predictor of mortality (hazard ratio for 100 units 0.957 [95% CI: 0.929-0.986], p=0.004), alongside GMWE (hazard ratio for 1 percent 0.940 [95% CI: 0.912-0.968], p<0.001), and GWW (hazard ratio for 100 units 1.124 [95% CI: 1.063-1.188], p<0.001). By multivariable Cox regression encompassing age, sex, GMWI, LVEF, GLS, PALS, and systolic blood pressure, GMWI remained an independent predictor of all-cause mortality (hazard ratio 0.932 [95% CI: 0.874-0.995], p=0.035), while GLS was not an independent predictor. Moreover, integrating the Atherosclerosis Risk in Communities (ARIC)-HF risk factors (age, sex, race, coronary artery disease, antihypertensive medication, blood pressure, diabetes mellitus, body mass index, heart rate, and smoking status), we constructed a multivariate model with GMWI. GMWI was still an independent predictor of mortality (hazard ratio for 100 units 0.941 [95% CI: 0.903-0.980], p=0.004). Using the GMWI cut-off value of 1576 mm Hg% (based on a large-scale healthy population study), the population was divided into 2 groups. Using Kaplan-Meier curves (Figure), the outcomes of the groups differed significantly (log-rank p<0.001). Conclusions GMW provides added value in clinical outcome prediction, even in low-risk individuals. Myocardial work analysis is a promising approach for a comprehensive evaluation of cardiac function and for cardiovascular risk stratification.

Histopathological myocardial changes in patients with severe aortic stenosis referred for surgical valve replacement: a CMR correlation study

Abstract Background Myocardial fibrosis (MF) takes part in left ventricular (LV) remodeling in patients with aortic stenosis (AS), driving the transition from hypertrophy to heart failure. The structural events that occur in this transition are not fully enlightened. Aim To describe histopathology changes at endomyocardial biopsy (EMB) in patients with severe AS referred to surgical aortic valve replacement (AVR); to correlate them with LV tissue characterization from pre-operative cardiac magnetic resonance (CMR). Methods One-hundred-fifty-eight patients (73[68-77]years, 50%women) referred for surgical AVR because of severe symptomatic AS, with pre-operative CMR (n=143) with late gadolinium enhancement (LGE), T1, T2 mapping and extracellular volume fraction (ECV) quantification. Intra-operative septal EMB was obtained in 129 patients. MF was assessed through Masson ́s Trichrome histochemistry. Immunohistochemistry was performed for both inflammatory cells and extracellular matrix (ECM) characterization (Type I Collagen, Fibronectin, Tenascin C). Results Non-ischemic LGE was present in 106 patients (67.1%) (median fraction: 5.0% [2.0-9.7]). Native T1 was above normal: 1053ms[1024-1071] and T2 within normal range (39.3ms[37.3-42.0]). Median MF was 11.9%[6.54-19.97], with predominant type I collagen perivascular distribution (95.3%). Subendocardial cardiomyocyte ischemic-like changes were identified in 45% of EMB. There was no inflammation, despite ECM remodeling expression. MF quantification at EMB was correlated with LGE mass and indexed ECV (p=0.008; p=0.017, respectively). Conclusion Patients with severe symptomatic AS referred for surgical AVR have unspecific histological myocardial changes, including signs of cardiomyocyte ischemic insult. ECM remodeling is ongoing, with MF heterogeneity. These features may be recognized by comprehensive CMR involving LGE, T1 mapping derived indexes and their combination with LV morphofunctional characterization.

Endomyocardial biopsy in the diagnosis of cardiac sarcoidosis

Abstract Background Definite diagnosis of cardiac sarcoidosis (CS) requires proof of sarcoid granulomas in the heart. Endomyocardial biopsy (EMB) is considered a risky procedure with poor sensitivity (<25%) in CS (1), although comprehensive studies on its diagnostic performance are not available. Purpose We investigated the sensitivity, complications, and prognostic significance of EMB in a large cohort of patients with CS to help to choose diagnostic strategy when the disease is suspected. Methods We analysed the data of 260 consecutive patients diagnosed with CS in 1988-2022 at our institution. All met the diagnostic criteria of the Heart Rhythm Society (1). The use, findings, and complications of EMB were retrospectively noted in addition to patients’ demographics, presenting phenotype, diagnostic examinations, and future serious cardiac events. The data were retrieved from hospital records and an ongoing CS registry (2). Advanced imaging studies (cardiac magnetic resonance, positron emission tomography) were re-analysed and the follow-up information was updated until June 2023. EMB’s performance was assessed also in 30 cardiac transplant recipients having CS at the histopathologic study of the explanted heart. Results Of the 260 patients (mean age 49, 60% females), 216 (83%) underwent diagnostic EMB, 48 with repeat procedures. The sensitivity of EMB was 38%, rising to 49% after repeats. The predictors of positive EMB (Table 1) included the presenting phenotype and characteristics of the activity, extent, and location of myocardial involvement. Presentation with ventricular tachyarrhythmia, left ventricular (LV) ejection fraction ≤45%, elevation of cardiac troponins, and presence of middle or apical LV septal late gadolinium enhancement on magnetic resonance imaging were independent predictors (p<0.05) of positive biopsy. The sensitivity of EMB was directly related to the count of the predictors present (Figure 1). The rate of procedural complications was 9.7% overall and 0.7% for major events. One pericardial effusion needed drainage, but no deaths or long-term sequels followed the biopsies. Minor complications included 10 paroxysms of ventricular tachycardia and 6 small pericardial effusions. The 10-year rate (95% CI) of the composite of cardiac death, end-stage heart failure, or ventricular tachyarrhythmia was 55% (44-67%) with positive EMB vs 29% (17-44%) with negative EMB (p<0.001). When adjusted for the presenting phenotype and LV ejection fraction, EMB did not predict outcome events. In the 30 patients with CS in explanted hearts, the sensitivity of EMB, including the repeats, was 60%. Conclusion The sensitivity of EMB is better than usually presented in CS and the higher the more extensive myocardial involvement is. Risk of serious complications is <1%. In patients with suspect CS, the pre-test likelihood and value of positive EMB should be weighed against the procedural risks in shared decision-making when choosing the diagnostic pathway.

Rationale and study design of the international randomized control trial MYocarditis THerapy with Steroids: the MYTHS trial

Abstract Background Immunosuppression is generally suggested in patients with specific subtypes of acute myocarditis, such as eosinophilic myocarditis or giant cell myocarditis or associated with systemic autoimmune disorders. In contrast, no specific treatment for most acute myocarditis complicated by acute heart failure (HF) or cardiogenic shock is recommended beyond the management of acute HF and supportive therapy. Nevertheless, large registries commonly reported using corticosteroids in severe forms without data supporting this strategy. Purpose To assess the safety and efficacy of high-dose pulse intravenous (IV) corticosteroid therapy to treat patients with complicated/fulminant acute myocarditis based on clinical suspicion. Methods An international pragmatic investigator-initiated single-blinded randomized controlled trial that screens patients between 18 and 70 years admitted to the hospital for suspected acute myocarditis (cardiac symptoms onset within three weeks) complicated by acute HF/cardiogenic shock and left ventricular (LV) ejection fraction<41% without significant LV dilation is ongoing. Patients are randomized in a 1:1 ratio to pulsed IV methylprednisolone (1 g) in saline solution (250 mL) daily for three days or placebo (saline without methylprednisolone) on top of standard therapy and maximal supportive care. A final diagnosis of myocarditis is confirmed by histology or cardiac magnetic resonance imaging. A population of 288 patients has been planned to assess a reduction in the probability of reaching the primary endpoint from 25% in the placebo arm to 12% in the methylprednisolone arm with a power of 0.80 (Figure). The main analysis will be conducted on an intention-to-treat basis. Results The primary efficacy endpoint of the trial is defined as the time from randomization to the first event occurring within 6 months, including all-cause death, heart transplantation, or long-term LV assist device implant, or need for an upgrading of the temporary mechanical circulatory support (t-MCS), or ventricular tachycardia (VT)/fibrillation (VF) treated with direct current (DC) shock, or first rehospitalization due to HF or VT/VF, or advanced atrioventricular block. The safety endpoints include a composite of potential complications that can occur, including serious infections, acute gastrointestinal bleeding, and other complications that can be related to corticosteroid therapy or prolonged stay on t-MCS. There are 32 active centers, and 48 patients have been randomized since December 2021. The trial is expected to be completed by the end of 2028. Conclusion The results of the MYTHS trial can define the role of IV methylprednisolone in the initial treatment of patients with complicated forms of acute myocarditis that currently have an unacceptably high mortality rate.

Left atrioventricular coupling index: association with diastolic dysfunction and prognostic implications in heart failure patients

Abstract Background Left atrioventricular coupling index (LACI), an index coupling left atrial (LA) to left ventricular (LV) volume at end-diastole (Figure 1), showed to be associated with prognosis in different clinical settings. However, the relation between LACI and LV diastolic dysfunction (DD) remains to be established. Purpose The present study aimed to investigate the association between LACI and LV DD and to assess its prognostic value in patients with heart failure (HF). Methods We retrospectively analyzed 1158 stable HF patients (mean age 66±12 years, 75% men) on optimal medical therapy (derivation cohort). Clinical and echocardiographic features were characterized across LACI tertiles. The independent prognostic value of LACI (endpoint: all-cause death/HF-hospitalization) was assessed by Cox regression and spline curve analyses. Results were validated in an external cohort of 242 HF patients. Results In the derivation cohort, the median LACI value was 0.29 (IQR:0.19-0.42). Patients in the third tertile (LACI>0.36) were older and presented with more advanced HF symptoms. While prevalence of grade-1 DD (ASE/EACVI classification) progressively decreased across LACI tertiles, the prevalence of grade-3 DD significantly increased (8%,23%, and 46% respectively, P<0.0001). A cut-off value ³0.26 identified moderate-to-severe DD with an area-under the-curve of 0.75. During follow-up (median 28 months, IQR:11-53), 407 (35%) patients reached the endpoint. On multivariable analysis, LACI was independently associated with outcomes (HR for 1-unit-increase 2.34; 95%CI 1.35-4.03; P=0.002 – Figure 2), showing incremental predictive value over the DD grading system (net reclassification improvement=0.150, P<0.0001). The prognostic value of LACI was consistent in the external validation cohort. Conclusions LACI is associated with DD severity and is an independent predictor of outcomes in HF patients.How to assess LACIPrognostic value of LACI in HF

The prognostic role of left atrial mechanics but not left ventricular function in functional mitral regurgitation

Abstract Introduction When atrial dilatation or ventricular dysfunction underline the development of functional mitral regurgitation (FMR), FMR has been categorized into ventricular and atrial type. Due to limited evidence of surgical correction, majority of patients with FMR were left untreated. We therefore investigated the clinical outcomes related to different phenotypes of FMR and the prognostic factors. Methods Subjects with severe or moderate to severe FMR, diagnosed by transthoracic echocardiography were eligible for this analysis. Three phenotypes of FMR, including atrial, ischemic and ventricular FMR were then classified. The left atrial (LA) strain and left ventricular (LV) global longitudinal strain (GLS) were measured. The study population were followed for a year. Results A total of 298 subjects (mean age 72.3 ± 14.0 years; 68% male) were enrolled, including 165 subjects of ischemic-type FMR (iFMR), 77 subjects of non-ischemic ventricular-type FMR (vFMR), and 56 subjects of atrial-type FMR (aFMR). The baseline characteristics, including age, gender, demography, and morbidities were similar between three groups, but aFMR group had higher LA reservoir strain and better LV GLS. During a mean follow-up duration of 283 days, there were 50 (17%) cases died within the first year. The Kaplan Meier curve analysis showed similar survival rate between three phenotypes of FMR. Body mass index (BMI), systolic blood pressure, diastolic blood pressure, history of myocardial infarction (MI), RV dysfunction, and a lower LA reservoir strain, but not LV GLS were crudely related to one-year mortality. In the multivariable Cox proportional regression analysis, LA reservoir strain was independently predictive of mortality (Hazard ratio for 1% increase and 95% confidence intervals: 0.943, 0.895-0.994). Conclusions Patients with aFMR also have despaired clinical outcomes as patients with vFMR or iFMR. LA reservoir function but not LV systolic function was predictive of worse clinical outcomes. The results may encourage the transcatheter therapy, approved for ventricular-type FMR, for the treatment of aFMR.Kaplan Meier curve analysisMultivariable CPH regression model

Early impairment of endothelial and myocardial function in patients with hidradenitis suppurativa

Abstract Background/Introduction Hidradenitis suppurativa (HS) is a chronic, recurrent, debilitating, inflammatory skin disease manifested by painful, deep-seated, inflamed lesions of the apocrine gland-bearing areas of the body (axillae, submammary folds, inguinal and anogenital region). HS has been associated, among others, with an increased cardiovascular risk. Purpose We aimed to investigate the endothelial, arterial and left ventricular (LV) myocardial function in patients with severe HS. Methods Twenty-eight, not previously treated patients (mean age: 36 ± 13 years) with Hurley stage III disease and a mean score of 19±8 on the International Hidradenitis Suppurativa Severity Score System (IHS4) scale, were studied. Twenty healthy sex-, age- and body mass index -matched individuals, who were also weighted for common cardiovascular risk factors, served as the control group. Both patients and controls were evaluated for: a) perfused boundary region (PBR) of the sublingual microvessels with a diameter of 5-25 μm (an increased PBR value is considered as an indicator of a decrease in thickness of the endothelial glycocalyx), using a dedicated camera (Microscan, GlycoCheck), b) carotid-femoral pulse wave velocity (PWV-Complior), c) flow-mediated dilation (FMD) of the brachial artery and d) LV global longitudinal strain (GLS) using the speckle-tracking echocardiography. Results Compared to healthy controls, HS patients had increased PBR value (2.32 ± 0.19 vs. 1.99 ± 0.14 μm, p < 0.001) and decreased FMD (5.7 ± 2.9 vs. 10.3 ± 1.9 %, p < 0.001) and GLS values (-18.6 ± 2.8 vs. -22.5 ± 2.3 %, p < 0.001). In contrast, similar PWV values (9.2 ± 2 vs. 9.1 ± 1.9 m/s, p = 0.937) were recorded between patients and controls (Table). Increased IHS4 score (more severe disease) was associated with increased PBR values (r = 0.42, p = 0.026) and decreased FMD values (r = -0.37, p = 0.045). Conclusion Patients with HS show early impairment of endothelial and LV myocardial function, which correlates with the severity of the underlying systemic inflammation.Table

Reduced stroke volume by resting 2-dimensional echocardiography negatively affects survival in patients with abnormal ejection fraction

Abstract Background Abnormal (<50%) ejection fraction (EF) is a cornerstone of risk stratification and therapy, but also an imperfect proxy of left ventricular (LV) cardiac pump function, better assessed with stroke volume (SV). Aim To assess the value of SV in stratifying risk of patients with abnormal EF. Methods In a prospective, observational, multicenter study, we recruited 746 patients (age 66± 11 years, 536 males, 72%, 359 with previous myocardial infarction, 48%) with chronic coronary syndromes (CCS) and EF <50% referred for resting transthoracic echocardiography with technically successful 2-dimensional volumetric echocardiography in 17 accredited laboratories. We quantitatively assessed LV end-diastolic volume (EDV) and end-systolic volume (ESV) by Simpson’s biplane method. EF (EDV-ESV/EDV) and SV (EDV-ESV) were calculated from LV volumes. The outcome end-point was all-cause death. Results EF was 39±9%, SV 48±20 ml. There were 100 all-cause deaths during a median follow-up of 796 days (interquartile range 420-1286 days). Receiver-operating curve analysis identified SV≤31.4 ml/b as the best cut-off for predicting mortality. At multivariable analysis, after adjustment for age and prior myocardial infarction, EF <40% and SV ≤31.4 ml/b were significantly associated with decreased survival (HR 2.09, 95%, confidence intervals 1.09-4.01, p=0.024). The annual mortality was lowest (3.19%) in the group with mildly reduced (40-49%) EF and normal (>31.4 ml) SV, and highest (8.30%) in patients with both reduced EF and abnormal SV: see figure. Conclusion Patients with CCS and abnormal EF are a prognostically heterogeneous group, and the mortality rate is almost 3-times worse in patients with reduced EF and abnormal SV compared to patients with mildly reduced EF and normal SV. A simple resting volumetric two-dimensional echocardiography can offer an efficient risk stratification, beyond EF, with no extra imaging or analysis time.Figure

Long-term efficacy of cardiac resynchronization therapy with triple-site ventricular stimulation in heart failure patients

Abstract Background Cardiac resynchronization therapy (CRT) reduces cardiac electrical dyssyncrhony and improves clinical outcomes in selected symptomatic patients with left ventricular (LV) systolic dysfunction. However, patients after conventional CRT (Bi-V) have residual cardiac electrical dyssynchrony. CRT with multi-site pacing has gained attention to improve short-term outcome refractory to BiV. However, long-term follow up outcome is still uncertain. We evaluated the efficacy of CRT with triple-site ventricular stimulation (Tri-V), involving 2 LV lead in 2 anatomically separated veins and a single RV lead in RV apex for long-term follow up period. Methods Ninety-two consecutive patients with New York Heart Association class II-IV heart failure, LV ejection fraction <0.35, and QRS interval >120ms, who underwent CRT implantation between 2010 and 2016, were enrolled. Acute hemodynamic responses to temporary dual-site and triple-site ventricular pacing were evaluated, and patients were assigned to either the Bi-V or Tri-V group based on the results. The primary endpoint was the HF clinical composite score, which scores patients as improved, unchanged, or worsened. The secondary endpoint included cumulative survival from any cause of death and HF hospitalization. Results Tri-V was successfully implanted in 32 patients. Five patients were excluded during follow-up because of uncaptured pacing in one of the LV leads. One year post-implantation, the clinical composite score significantly improved in 84% of Tri-V patients compared to 57% in the Bi-V group (p=0.026). After a median follow-up of 12.0 years, there was no significant difference about all-cause mortality between Tri-V and Bi-V (p=0.147). However, Tri-V group showed significant lower HF hospitalization (p=0.005) than Bi-V group. The number of battery exchange was not significantly different between Tri-V than Bi-V group (1.4±0.7 vs. 1.2±0.8, p=0.361). Conclusion CRT with Tri-V, characterized by stable lead parameters, appears to offer greater long-term benefits than Bi-V in terms of clinical status without excessive battery exchanges.figure