Proteomic Profiling of Dilated Cardiomyopathy Plasma Samples ─ Searching for Biomarkers with Potential to Predict the Outcome of Therapy.

Determination of the prognosis and treatment outcomes of dilated cardiomyopathy is a serious problem due to the lack of valid specific protein markers. Using in-depth proteome discovery analysis, we compared 49 plasma samples from patients suffering from dilated cardiomyopathy with plasma samples from their healthy counterparts. In total, we identified 97 proteins exhibiting statistically significant dysregulation in diseased plasma samples. The functional enrichment analysis of differentially expressed proteins uncovered dysregulation in biological processes like inflammatory response, wound healing, complement cascade, blood coagulation, and lipid metabolism in dilated cardiomyopathy patients. The same proteome approach was employed in order to find protein markers whose expression differs between the patients well-responding to therapy and nonresponders. In this case, 45 plasma proteins revealed statistically significant different expression between these two groups. Of them, fructose-1,6-bisphosphate aldolase seems to be a promising biomarker candidate because it accumulates in plasma samples obtained from patients with insufficient treatment response and with worse or fatal outcome. Data are available via ProteomeXchange with the identifier PXD046288.

4D Flow Cardiac MR in Primary Mitral Regurgitation.

BACKGROUND: Four-dimensional-flow cardiac MR (4DF-MR) offers advantages in primary mitral regurgitation. The relationship between 4DF-MR-derived mitral regurgitant volume (MR-Rvol) and the post-operative left ventricular (LV) reverse remodeling has not yet been established. PURPOSE: To ascertain if the 4DF-MR-derived MR-Rvol correlates with the LV reverse remodeling in primary mitral regurgitation. STUDY TYPE: Prospective, single-center, two arm, interventional vs. nonintervention observational study. POPULATION: Forty-four patients (male N = 30; median age 68 [59-75]) with at least moderate primary mitral regurgitation; either awaiting mitral valve surgery (repair [MVr], replacement [MVR]) or undergoing "watchful waiting" (WW). FIELD STRENGTH/SEQUENCE: 5 T/Balanced steady-state free precession (bSSFP) sequence/Phase contrast imaging/Multishot echo-planar imaging pulse sequence (five shots). ASSESSMENT: Patients underwent transthoracic echocardiography (TTE), phase-contrast MR (PMRI), 4DF-MR and 6-minute walk test (6MWT) at baseline, and a follow-up PMRI and 6MWT at 6 months. MR-Rvol was quantified by PMRI, 4DF-MR, and TTE by one observer. The pre-operative MR-Rvol was correlated with the post-operative decrease in the LV end-diastolic volume index (LVEDVi). STATISTICAL TESTS: Included Student t-test/Mann-Whitney test/Fisher's exact test, Bland-Altman plots, linear regression analysis and receiver operating characteristic curves. Statistical significance was defined as P < 0.05. RESULTS: While Bland-Altman plots demonstrated similar bias between all the modalities, the limits of agreement were narrower between 4DF-MR and PMRI (bias 15; limits of agreement -36 mL to 65 mL), than between 4DF-MR and TTE (bias -8; limits of agreement -106 mL to 90 mL) and PMRI and TTE (bias -23; limits of agreement -105 mL to 59 mL). Linear regression analysis demonstrated a significant association between the MR-Rvol and the post-operative decrease in the LVEDVi, when the MR-Rvol was quantified by PMRI and 4DF-MR, but not by TTE (P = 0.73). 4DF-MR demonstrated the best diagnostic performance for reduction in the post-operative LVEDVi with the largest area under the curve (4DF-MR 0.83; vs. PMRI 0.78; and TTE 0.51; P = 0.89). DATA CONCLUSION: This study demonstrates the potential clinical utility of 4DF-MR in the assessment of primary mitral regurgitation. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 5.

Left atrial conduit strain derived from cardiac magnetic resonance is an independent predictor of left ventricular reverse remodeling in patients with nonischemic cardiomyopathy.

BACKGROUND: In some patients with nonischemic cardiomyopathy (NICM), left ventricular (LV) function improves with medical assistance, resulting in left ventricular reverse remodeling (LVRR). However, predictors of LVRR are not fully understood. The left atrium (LA) has been reported as a prognostic predictor in patients with heart failure (HF). The present study aimed to evaluate clinical predictors of LVRR related to LA function on cardiac magnetic resonance (CMR). METHODS: A total of 103 patients with reduced left ventricular ejection fraction (LVEF) were enrolled in this retrospective study between September 2015 and July 2021. CMR parameters, including strain data, were measured in all patients. Echocardiographic data obtained approximately 2 years after enrollment were analyzed to assess LVRR. RESULTS: LVRR occurred in 46 patients (44.7%) during follow-up. The value of LA conduit strain was higher in the LVRR group than in the non-LVRR group (6.6 [interquartile range (IQR): 5.6-9.3]% versus 5.0 [IQR: 3.0-6.2]%; p < 0.001). The multivariate logistic regression analysis showed that LA conduit strain was an independent predictor of LVRR (odds ratio [OR]: 1.216, 95% confidence interval [CI]: 1.050-1.408; p = 0.009). The area under the receiver operating characteristic (ROC) curve of the LA conduit strain was 0.746, and the cutoff value was 6.2%. The Kaplan‒Meier analysis revealed that the incidence of adverse cardiac events was significantly lower in patients with LA conduit strain > 6.2% compared to those with ⩽6.2%. (log-rank test, p = 0.019). CONCLUSIONS: LA conduit strain derived from CMR is an independent predictor of LVRR in patients with NICM.

Association Between Late Gadolinium Enhancement with or Without Reverse Remodeling and Prognosis.

Late gadolinium enhancement (LGE) in cardiovascular magnetic resonance imaging (CMR) prevents left ventricular reverse remodeling (LVRR), resulting in a poor prognosis. However, the prognosis of patients who have LGE and achieve LVRR and patients who do not have LGE and do not achieve LVRR remains unknown. This study aimed to answer this question by sorting patients with heart failure based on the presence of LGE and LVRR and comparing their prognoses. Another aim was to identify useful factors for predicting LVRR.All patients were followed-up for 24 months. LVRR was defined as a ≥ 10% increase at the last follow-up at 12 ± 6 months from baseline, on echocardiography. The primary endpoint was a composite of cardiovascular death and hospitalization due to worsening heart failure within 18 ± 6 months. Baseline data and data from each outpatient visit were collected and analyzed. We enrolled 80 consecutive patients with heart failure and reduced left ventricular ejection fraction (< 50%) who underwent CMR.LGE was positive in 40 patients (50.0%) and LVRR was observed in 50 patients (63%). The incidence of the primary endpoint was significantly lower in the group that achieved LVRR, regardless of LGE status (LGE-positive group, P = 0.01; LGE-negative group, P = 0.02). In the multivariate analysis, the percentage change in NT-pro BNP levels at 3 months, NT-pro BNP levels at 6 months, and age were independent predictors of LVRR.LGE-positive patients may have a better prognosis if they achieve LVRR. Serial NT-pro BNP testing may be a valuable predictor of LVRR.

Effect of Ivabradine on Left Ventricular Reverse Remodeling in Relatively Stable Heart Failure Outpatients With Reduced Ejection Fraction.

Background: Elevations of resting heart rate (HR) in patients with heart failure (HF) with reduced ejection fraction (HFrEF) are often missed, resulting in some patients with an indication for ivabradine reportedly being missed. Methods and Results: We studied 30 relatively stable HFrEF outpatients, and ivabradine was administered when regular follow-up echocardiography showed a resting HR ≥75 beats/min. Significant left ventricular reverse remodeling was observed 10.1±3.9 months after administration of ivabradine. Conclusions: This finding may well make this procedure a potential new approach for preventing worsening of HF for relatively stable patients with HFrEF.

Restrictive annuloplasty or replacement on reverse remodeling for nonischemic dilated cardiomyopathy.

BACKGROUND: For patients with nonischemic dilated cardiomyopathy (NIDCM), the indications for and results of mitral surgery remain controversial. We reviewed a strategy of mitral repair and replacement for clinically relevant secondary mitral regurgitation (MR) in patients with NIDCM. METHODS: We retrospectively reviewed 65 patients with advanced NIDCM (LVEF < 40%) who underwent mitral surgery. Of them, 47 (72%) underwent mitral annuloplasty and 18 (28%) replacement for secondary MR. The primary endpoint was postoperative reduction in indexed LV end-systolic volume (LVESVI). RESULTS: At baseline, there was no intergroup difference in LVESVI (123 ± 47 vs. 147 ± 37 ml/m2, P = 0.055), LVEF (27 ± 8% vs. 25 ± 6%, P = 0.41), incidence of severe MR (57% (27/47) vs. 72% (13/18), P = 0.40), or EuroSCORE II score (6.2% vs. 7.6%, P = 0.90). At 6 months, the annuloplasty group reduced LVESVI to a greater degree than the replacement group (P < 0.001), yielding significantly smaller postoperative LVESVI (96 ± 59 vs. 154 ± 61 ml/m2, P < 0.001) and better LVEF (P < 0.001). The rates of moderate/severe recurrent MR were 17% (8/47) and 0%, respectively. Multivariable analysis demonstrated that mitral annuloplasty (OR 6.10, 95% CI 1.14-32.8, P = 0.035) was significantly associated with postoperative LV reverse remodeling. Cumulative survival was not different between the groups (P = 0.26). CONCLUSIONS: In patients with NIDCM, mitral annuloplasty reduced LV volume to a greater degree than did mitral replacement. These findings may assist with surgical options for secondary MR associated with NIDCM.

Left ventricular reverse remodeling and reduction of interstitial fibrosis in patients with severe aortic stenosis who underwent transcatheter aortic valve implantation.

BACKGROUND: Left ventricular (LV) structural and functional changes have been reported in patients with aortic stenosis (AS) who have undergone transcatheter aortic valve implantation (TAVI); however, the relationship between change in LV structure and systolic function and tissue characteristics assessed via cardiovascular magnetic resonance imaging (CMRI) post-TAVI has been not fully elucidated. This study aimed to investigate this relationship in patients with severe AS who underwent TAVI and CMRI. METHODS: In this retrospective study, 65 patients who underwent TAVI and CMRI at the 6-month follow-up were analyzed. The relationship between percent changes in LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), LV ejection fraction (LVEF), and LV mass (LVM) (⊿LVEDV, ⊿LVESV, ⊿LVEF, and ⊿LVM) and those in the native T1 value (⊿native T1) was analyzed using a correlation analysis. Moreover, extracellular volume fraction (ECV) value changes were analyzed. RESULTS: The ⊿native T1 significantly decreased from 1292.8 (1269.9-1318.4) ms at pre-TAVI to 1282.3 (1262.6-1310.2) ms at the 6-month follow-up (P = 0.022). A significant positive correlation between ⊿LVEDV, ⊿LVESV, and ⊿LVM and ⊿native T1 (r = 0.351, P = 0.004; r = 0.339, P = 0.006; r = 0.261, P = 0.035, respectively) and a tendency toward a negative correlation between ⊿LVEF and ⊿native T1 (r = -0.237, P = 0.058) were observed. The ECV value increased significantly from 26.7 % (25.3-28.3) to 28.2 % (25.7-30.5) (P = 0.002). CONCLUSIONS: The decrease in native T1 might be associated with LV reverse remodeling. Evaluating structural and functional changes using CMRI may be useful for patient management.

Effectiveness of Vericiguat on right ventricle to pulmonary artery uncoupling associated with heart failure with reduced ejection fraction.

BACKGROUNDS: A soluble guanylyl cyclase stimulator vericiguat has been shown to reduce cardiovascular mortality or hospitalization for heart failure in patients with worsening heart failure in the VICTORIA study. However, little is known about the effects of vericiguat on biventricular structure and function. METHODS AND RESULTS: A retrospective analysis of 63 consecutive patients with heart failure with reduced ejection fraction (HFrEF) who were treated with vericiguat was performed. Clinical data and echocardiographic parameters were compared between baseline and follow-up after the initiation of vericiguat. The median follow-up duration was 266 days. Treatment with vericiguat significantly reduced the plasma BNP levels (log-transformed) compared to baseline (2.46 ± 0.51 vs. 2.14 ± 0.58, p < 0.0001). Left ventricular end-diastolic volume index and left ventricular end-systolic volume index were significantly reduced (LVEDVI, 113.5 ± 46.3 vs. 103.6 ± 51.0, p = 0.0056; LVESVI, 82.0 ± 41.9 vs. 72.8 ± 44.7, p = 0.0077; respectively). The tricuspid annular plane systolic excursion to pulmonary artery systolic pressure (TAPSE/PASP) ratio, an indicator of right ventricle-pulmonary artery (RV-PA) coupling, increased significantly after the treatment (0.56 ± 0.29 vs. 0.92 ± 1.09, p < 0.0001). Univariate and multivariate analyses showed that the treatment effects of vericiguat on BNP levels, LV reverse remodeling, and RV-PA coupling were not correlated with the achievement of the quadruple therapy with beta-blockers, renin-angiotensin system inhibitors, mineralocorticoid inhibitors, and sodium-glucose cotransporter-2 inhibitors, nor with worsening heart failure (WHF). CONCLUSION: Treatment with vericiguat improved adverse LV remodeling and RV-PA uncoupling in HFrEF patients. These effects were independent of WHF and achieving the quadruple therapy. Patients with HFrEF may benefit from early initiation of vericiguat to prevent biventricular adverse remodeling.

Heart failure with improved ejection fraction: Beyond diagnosis to trajectory analysis.

Left ventricular (LV) systolic dysfunction represents a highly treatable cause of heart failure (HF). A substantial proportion of patients with HF with reduced ejection fraction (EF;HFrEF) demonstrate improvement in LV systolic function (termed HF with improved EF [HFimpEF]), either spontaneously or when treated with guideline-directed medical therapy (GDMT). Although it is a relatively new HF classification, HFimpEF has emerged in recent years as an important and distinct clinical entity. Improvement in LVEF leads to decreased rates of mortality and adverse HF-related outcomes compared to patients with sustained LV systolic dysfunction (HFrEF). While numerous clinical and imaging factors have been associated with HFimpEF, identification of which patients do and do not improve requires further investigation. In addition, patients improve at different rates, and what determines the trajectory of HFimpEF patients after improvement is incompletely characterized. A proportion of patients maintain improvement in LV systolic function, while others experience a recrudescence of systolic dysfunction, especially with GDMT discontinuation. In this review we discuss the contemporary guideline-recommended classification definition of HFimpEF, the epidemiology of improvement in LV systolic function, and the clinical course of this unique patient population. We also offer evidence-based recommendations for the clinical management of HFimpEF and provide a roadmap for future directions in understanding and improving outcomes in the care of patients with HFimpEF.

The Inflammation-Fibrosis Combined Index: A Novel Marker for Predicting Left Ventricular Reverse Remodeling and Prognosis in Patients with HFrEF.

Background: Inflammation and cardiac fibrosis are important pathogenic drivers of heart failure. The fibrosis-4 index (FIB-4) is associated with a higher degree of fibrosis. The systemic immune inflammation index (SII) is associated with a higher degree of systemic inflammation status. Previous studies have shown that they are associated with a poor prognosis for cardiovascular disease. We sought to investigate the value of FIB-4 combined with the SII as a novel inflammation-fibrosis combined index (IFCI) in predicting left ventricular reverse remodeling (LVRR) and prognosis among reduced ejection fraction heart failure (HFrEF) patients. Methods: A total of 895 patients with HFrEF were continuously recruited. Receiver operating characteristic curves were drawn to assess the abilities of inflammation-fibrosis indicators to predict LVRR. Multivariable Cox regression analysis was used to examine independent predictors of composite cardiac events and all-cause death. Results: After six months of follow-up, 344 (38.4%) patients experienced LVRR. The IFCI had the largest area under the curve (0.835, P < 0.001). In multivariate-adjusted logistic regression analyses, FIB-4, SII, and IFCI were predictive of LVRR (P value < 0.05). The IFCI was associated with a 3.686-fold higher risk of non-LVRR (odds ratio [OR] = 3.686, P < 0.001). Moreover, an increased IFCI predicted a poor prognosis in HFrEF patients. The highest risk of composite cardiac events (hazard ratio [HR] = 2.716, P < 0.001) was observed in the top IFCI-tertile group, and similar results were found regarding independent risk indicators of all-cause death. Conclusion: In summary, this study indicated that increased IFCI at admission offers good predictability regarding non-LVRR and predicts the risk of all-cause mortality or composite cardiovascular events due to HFrEF patients and could be used as a novel marker.

Clinical utility of QRS duration normalized to left ventricular volume for predicting cardiac resynchronization therapy efficacy in patients with "mid-range" QRS duration.

BACKGROUND: Cardiac resynchronization therapy (CRT) is effective for patients with heart failure with QRS duration (QRSd) ≥150 ms. However, its beneficial effect seems to be limited for those with "mid-range" QRSd (120-149 ms). Recent studies have demonstrated that modifying QRSd to left ventricular end-diastolic volume (LVEDV)-modified QRSd-improves the prediction of clinical outcomes of CRT. OBJECTIVE: The purpose of this study was to investigate the clinical impact of the modified QRSd on the efficacy of CRT in patients with "mid-range" QRSd. METHODS: We conducted a retrospective, multicenter, observational study, with heart failure hospitalization (HFH) after CRT as the primary endpoint. Modified QRSd is defined as QRSd divided by LVEDV, determined through the Teichholtz method of echocardiography. RESULTS: Among the 506 consecutive patients considered, 119 (mean age 61 ± 15 years; 80% male, QRSd 135 ± 9 ms) with a "mid-range" QRSd who underwent de novo CRT device implantation were included for analysis. During median follow-up of 878 days [interquartile range 381-1663 days], HFH occurred in 45 patients (37%). Fine-Gray analysis revealed modified QRSd was an independent predictor of HFH (hazard ratio [HR] 0.97; 95% confidence interval [CI] 0.96-0.99; P <.01). Receiver operating characteristic curve analysis revealed a cutoff value of 0.65 ms/mL for the modified QRSd in predicting HFH. Patients above the threshold exhibited a significantly lower incidence of HFH than patients below the threshold (HR 0.46; 95% CI 0.25-0.86; P = .01). CONCLUSION: Modified QRSd can effectively predict the efficacy of CRT in patients with a "mid-range" QRSd.

"Hiper-resposta" avaliada pelo eco 3D após terapia de ressincronização cardíaca / "Hyper-response" evaluated by 3D echocardiography after cardiac resynchronization therapy / "Hiperrespuesta" evaluada por el eco 3D después de la terapia de resincronización cardíaca

A terapia de ressincronização cardíaca consiste em tratamento promissor para pacientes com insuficiência cardíaca grave, porém cerca de 30 por cento dos pacientes não apresentam melhora clínica com este tratamento. Por outro lado, aproximadamente 10 por cento dos pacientes submetidos a essa terapia podem apresentar hiper resposta, e a ecocardiografia tridimensional pode oferecer uma opção interessante para a seleção e avaliação de tratamento desses pacientes.

Cardiac resynchronization therapy consists of a promising treatment for patients with severe heart failure, but about 30 percent of patients do not exhibit clinical improvement with this procedure. However, approximately 10 percent of patients undergoing this therapy may have hyperresponsiveness, and three-dimensional echocardiography can provide an interesting option for the selection and evaluation of such patients.

La terapia de resincronización cardíaca consiste en un tratamiento promisorio para pacientes con insuficiencia cardíaca grave, sin embargo cerca de un 30 por ciento de los pacientes, no presentan una mejoría clínica con ese tratamiento. Por otro lado, aproximadamente un 10 por ciento de los pacientes sometidos a esa terapia pueden presentar hiperrespuesta, y la ecocardiografía tridimensional puede ser una opción interesante para la selección y la evaluación del tratamiento de esos pacientes.