BACKGROUND AND AIMS:In cardio-kidney-metabolic (CKM) syndrome, comorbid cancer is common due to shared risk factors and overlapping pathophysiologic mechanisms. Whether treatment of CKM conditions with the non-steroidal mineralocorticoid receptor antagonist finerenone may influence or be influenced by comorbid cancer is unknown. Hence, this study aimed to describe clinical features, outcomes, and treatment responses to finerenone in patients with CKM conditions and history of cancer. METHODS:This was a post hoc analysis of FINE-HEART, a pooled participant-level analysis of the FIDELIO-DKD, FIGARO-DKD, and FINEARTS-HF trials. The risks of clinical outcomes according to history of cancer and randomization to finerenone were assessed using Cox proportional hazard models and Fine-Gray subdistribution hazard models. RESULTS:Among 18 991 participants, 1389 (7.3%) had cancer history, most commonly gastrointestinal, male reproductive, renal/urinary tract, and haematologic cancers. Among those without prior cancer, 915 participants (5.2%) were reported to newly develop cancer during a median follow-up of 2.9 years. Patients with comorbid cancer more often had advanced CKM stages and a greater burden of CKM conditions. History of cancer was associated with higher risks of all-cause mortality and all-cause hospitalization. Finerenone consistently reduced all-cause death, heart failure, and all-cause hospitalization, a composite kidney outcome, major adverse cardiovascular events, and new-onset atrial fibrillation, irrespective of history of cancer. Adverse events were more frequent in patients with history of cancer, but finerenone's safety profile was consistent. CONCLUSIONS:Comorbid cancer was frequent in CKM participants and independently associated with worse outcomes, but it did not attenuate the treatment benefit of finerenone.

BACKGROUND:The inflammasome pathway has been implicated in the progression of heart failure (HF). Preclinical studies suggest that angiotensin receptor-neprilysin inhibitor (ARNi) and sodium-glucose cotransporter-2 inhibitor (SGLT2i) therapies may attenuate inflammasome activation, yet evidence in the failing human myocardium remains sparse. Hence, we evaluated the associations between ARNi and SGLT2i therapies and myocardial priming of inflammasome pathway components in explanted hearts from heart transplantation (HTX) recipients. METHODS:Biobank samples from the left ventricular myocardium of 104 HTX recipients were analyzed. The mRNA and protein expression of inflammasome-related targets (absent in melanoma 2 [AIM2], NLR family pyrin domain containing 3 [NLRP3], caspase-1, gasdermin D, and nuclear factor kappa-light-chain-enhancer of activated B cells [NF-κB]) were quantified using qRT-PCR and Western blotting. Multivariable linear regression models were applied to assess the relationships between inflammasome component expression and clinical variables, including treatment with ARNi and SGLT2i. RESULTS:ARNi and SGLT2i therapies were associated with lower mRNA expression of AIM2, NLRP3, caspase-1, and NF-κB in univariate analyses. However, after adjustment for clinical covariates, these associations with inflammasome-related transcripts were no longer statistically significant. In multivariable models, only female sex, diabetes, time since heart transplantation, and serum potassium concentration remained associated with myocardial inflammasome pathway expression. CONCLUSIONS:In myocardial samples from patients with advanced HF, no clear differences in the expression of selected inflammasome priming-related targets were observed between treatment eras before and after the introduction of ARNi and SGLT2i therapies, despite their experimentally suggested anti-inflammatory effects, warranting further investigation.

INTRODUCTION:Pressure overload (PO) induces adverse myocardial remodelling, whereas efficient pressure unloading interventions can promote reverse remodelling at structural and molecular levels. This study seeks to identify a metric of left ventricular (LV) performance that reflects the degree of myocardial remodelling and reverse remodelling. METHODS:Male and female rats underwent surgical aortic constriction/banding (AB) to generate PO and subsequent debanding (DB) to induce pressure unloading. The architecture and function of the left ventricle were evaluated using echocardiography and pressure-volume analysis. Exploratory proteome profiling via LC-MS/MS on left ventricular samples was followed by Least Absolute Shrinkage and Selection Operator-based feature selection on existing data to determine LV parameters linked to myocardial proteomic changes. RESULTS:Tau (τ), the time constant of LV isovolumic pressure decay and an index of active relaxation, and LV mass showed the strongest associations with proteome-wide abundance changes. With 842 associated proteins and 154 overrepresented gene ontology terms, Tau demonstrated a strong correlation with LV proteomic changes during myocardial remodelling, and reverse remodelling. Nineteen Tau-associated proteins had an AUC > 0.85 when discriminating remodelled proteomes of AB rats from non-banded counterparts. Network analysis reveals varied protein-protein correlations across circumstances and indicates transcription factors regulating Tau-associated proteome changes. Across sham (Co), 6- and 12-week banding (AB6/AB12), and debanding after 6 weeks followed by 6 weeks unloading (DB), τ showed the largest set of associated proteins (n = 842) and enriched processes. CONCLUSION:Left ventricular active relaxation, quantified by Tau, most comprehensively reflects myocardial proteomic remodelling during pressure overload and unloading. Indices of diastolic relaxation may therefore represent integrative functional readouts of molecular remodelling and potential translational markers of reverse remodelling.

BACKGROUND AND PURPOSE:Novel heart failure (HF) pharmacotherapies, including angiotensin receptor-neprilysin inhibitor (ARNI) and sodium-glucose cotransporter 2 inhibitors (SGLT2is), may confer cardiovascular benefits by attenuating myocardial fibrosis. However, direct evidence from human failing myocardial samples is limited. Thus, we assessed the associations of ARNI and SGLT2i therapies with fibrosis on myocardial samples from advanced HF patients undergoing heart transplantation (HTX). EXPERIMENTAL APPROACH:Ninety-three patients receiving stable combined HF pharmacotherapy (uninterrupted use of β-blockers, mineralocorticoid receptor antagonists, angiotensin-converting enzyme inhibitors or ARNI, and optionally SGLT2is) without the need for pharmacological or mechanical circulatory support for at least three months pre-HTX, were enrolled. Standardized regions of the left ventricular anterior wall from explanted hearts were analysed. The primary outcome was the percentage of interstitial myocardial fibrosis area measured via histology. The expression of pro-fibrotic and pathological remodelling markers was quantified with qRT-PCR. KEY RESULTS:Both ARNI and SGLT2i therapies were associated with reduced interstitial collagen accumulation in adjusted analyses. None of the tested clinical parameters (sex, age, serum creatinine, presence of hypertension or diabetes) interacted with the effects of ARNI or SGLT2i on fibrosis. Additionally, no interaction was observed between ARNI and SGLT2i use regarding collagen content. Among the examined genes, ARNI was linked to a decreased beta-to-alpha myosin heavy chain expression ratio, while in SGLT2i-treated patients, reduced mRNA levels of matrix metalloproteinase 9 (MMP9) and tissue inhibitor of metalloproteinases 2 (TIMP2) were observed in adjusted models. CONCLUSIONS AND IMPLICATIONS:ARNI and SGLT2i therapies might exert anti-fibrotic effects in advanced HF.

Abstract In patients with aortic stenosis (AS) evaluating left ventricular (LV) systolic function is challenging due to the influence of increased afterload on traditional measures. Myocardial work (MW) analysis, a novel echocardiographic method, adjusts myocardial deformation to instantaneous LV pressure, providing a more accurate reflection of LV contractile state. Notably, prolonged LV pressure overload induces significant backward effects beyond the LV; the classification of this extravalvular cardiac damage effectively represents the cardiopulmonary system's involvement in AS. Both MW analysis and cardiac damage staging may possess significant prognostic value in the clinically complex cohort of transcatheter aortic valve replacement (TAVR) candidates. Thus, our objective was to evaluate the prognostic value of MW analysis and cardiac damage staging in TAVR patients. We enrolled 314 patients (79±6 years, 40% female) prior to TAVR. Echocardiographic assessments were conducted one day before the procedure. LV ejection fraction (EF) was calculated, global longitudinal strain (GLS) was measured using speckle-tracking echocardiography. LV pressure was estimated from systolic blood pressure and transaortic mean gradient, and global constructive work (GCW) was quantified using dedicated software. Based on echocardiographic data, we determined the extent of cardiac damage associated with AS, categorizing patients into Stage 0 (no cardiac damage), Stage 1 (LV damage), Stage 2 (mitral valve or left atrial damage), Stage 3 (pulmonary artery vasculature or tricuspid valve damage), or Stage 4 (right ventricular damage). The primary endpoint was all-cause mortality, reached by 69 patients during a median follow-up period of 25 months. Preprocedural EF was 47±13 %, GLS was -12.3±4.2 %, GCW was 2043±769 mmHg%. 14 (5%) patients were classified as Stage 0, 61 (20%) as Stage 1, 133 (43%) as Stage 2, 22 (7%) as Stage 3, and 74 (24%) as Stage 4. GCW showed a decline through AS Stages (from Stage 0-4: 2963±652 vs. 2154±621 vs. 2174±706 vs. 2044±827 vs. 1553±757 mmHg%; p<0.001). Using univariate Cox analysis GCW (HR 0.968 [95% CI 0.938-0.998] per 100 unit change; p=0.034) and AS Staging (HR 1.236 [95% CI 1.016-1.505]; p=0.034) were associated with all-cause mortality, while EF (HR 0.982 [95% CI 0.964-1.001]; p=NS) and GLS (HR 1.047 [95% CI 0.989-1.108]; p=NS) were not. In multivariate Cox regression models, both GCW (HR 0.958 [95% CI 0.923-0.994] per 100 unit change; p=0.022) and AS cardiac damage staging (HR 1.281 [95% CI 1.040-1.577]; p=0.020) were significant independent predictors of all-cause mortality. In TAVR patients, preoperative GCW values continuously decreased across all AS Stages. GCW and AS Staging showed strong association with all-cause mortality in our cohort, while EF and GLS did not. Furthermore, GCW and AS Staging had higher prognostic value than any other echocardiographic measure, highlighing their role in preprocedural assessment before TAVR.

AIMS:Targeting inflammasomes in heart failure (HF) might represent a novel therapeutic option. Nevertheless, previous studies focused only on myocardial inflammasome alterations, and data are scarce regarding their regulation and role in HF-associated multiorgan dysfunction. Therefore, we aimed to determine the myocardial, pulmonary, hepatic and renal expression of various inflammasome components in a rat model of advanced HF. METHODS AND RESULTS:Rats underwent transverse aortic constriction (TAC) and were followed-up for 15 weeks. Animals featuring two to three clinical signs of advanced HF were included in the TAC-HF group (n = 6). TAC rats with mild HF were also investigated (0-1 signs, TAC-M group, n = 6). Six sham-operated animals served as controls. The expressions of inflammasome component proteins in left ventricle (LV), right ventricle (RV), lung, liver and kidney tissue were measured with Western blot. Despite the differences between the clinical state of the TAC-HF and TAC-M groups, severe cardiac dysfunction and myocardial remodelling developed in all TAC animals. Absent in melanoma 2 (AIM2) and NLR family CARD domain-containing protein 4 (NLRC4) inflammasome sensors were up-regulated in both the LV and RV of the TAC-HF group compared with sham. AIM2 and NLR family pyrin domain-containing protein 3 (NLRP3), but not NLRC4 expression were elevated in the lungs of the TAC-HF animals. Additionally, pulmonary congestion and CD68-positive leukocyte infiltration were observed in both TAC groups. Inflammasome components were down-regulated in the liver and remained unchanged in the kidneys of the TAC-HF group, despite the presence of renal atrophy and fibrosis. Inflammasome changes were predominantly absent in TAC-M animals. CONCLUSIONS:Inflammasome expression shows distinct patterns in specific organs in advanced HF. Future studies aiming to antagonize inflammation in HF should take these findings into consideration.

Background Atrial fibrillation (AF) is common in patients with chronic heart failure (HF). Nevertheless, some patients with HF remain in sinus rhythm (SR) even with marked left atrial (LA) dilatation and fibrosis. The underlying mechanisms for the differences in atrial arrhythmogenicity are poorly uncovered. Recent findings indicate that distinct microRNAs (miRNA) might induce left atrial (LA) structural and molecular alterations. However, the impact of miRNA dysregulation on AF development in the context of HF has not been studied independently of LA remodeling. Objective This study aimed to evaluate the differences in LA miRNA expressions in patients with HF with AF or SR. Methods LA myocardial samples were obtained from patients with advanced HF with AF (n = 12; paroxysmal n = 4, chronic as persistent/permanent n = 8) or SR (n = 12) undergoing heart transplantation. The extent of LA interstitial fibrosis was evaluated using picrosirius red staining. The LA load was estimated by measuring LA mRNA expression of the NPPA gene encoding atrial natriuretic peptide with quantitative real-time polymerase chain reaction and circulating N-terminal pro-atrial natriuretic peptide (NT-proANP) by enzyme-linked immunosorbent assay. The LA miRNA screening was performed using the NanoString technology. Results LA dilatation, fibrosis, NPPA gene expression, as well as circulating NT-proANP levels were similar between the AF and SR groups, suggesting a comparable extent of atrial remodeling and load among the study groups. The miRNA analysis revealed no differences in atrial miRNA expression between the groups, even after AF subgroup analysis. Conclusions The LA miRNA expression profile shows no distinction between AF and SR in patients with advanced HF with similar levels of pathological atrial remodeling.

BACKGROUND:Research projects have focused on exercise-induced alterations of the right ventricle (RV) of the heart, because the exercise-associated disproportionate load on the RV might lead to pathological consequences, such as interstitial fibrosis, chamber dilation or pro-arrhytmic remodelling. We aimed at providing a complex characterization of RV alterations induced by regular training in a rat model of exercise-induced cardiac remodelling. METHODS:Young, adult rats were divided into control (Co) and exercised (Ex) groups. Exercised rats swam 200 min/day for 12 weeks. In vivo cardiac electrophysiological study and in vitro force measurements on isolated permeabilized RV cardiomyocytes were performed to investigate electrical and functional alterations, respectively. Molecular biological and histological investigations were carried out. RESULTS:Exercise training was associated with mild increased RV hypertrophy (cardiomyocyte diameter: 12.5 ± 0.1 μm Co vs. 13.7 ± 0.2 μm Ex, p < 0.05) and corresponding hyperphosphorylation of protein kinase B (Akt). Absence of pathological remodelling was revealed by unchanged pro-fibrotic and pro-apoptotic markers. We found increased maximal force development (12.1 ± 1.0kN/m2 Co vs. 16.7 ± 1.1 kN/m2 Ex, p < 0.05) and improved calcium sensitivity in the cardiomyocytes of exercised animals. Sarcomere protein investigations revealed marked overall and site-specific (Ser22/23, Ser43 and Thr143) hypophosphorylation of troponinI. We found prolonged QT interval (repolarization) and RV effective refracter period along with decreased gene expression of potassium channels. We could not induce any ventricular arrhythmia by programmed stimulation. CONCLUSIONS:Regular swim training induced physiological RV hypertrophy that was associated with functional improvement related to unique hypophosphorilation pattern of troponin I. A balanced exercise program without excessive exercise sessions might not be associated with induction of pathological alterations.

Abstract Background With increasing life expectancy and aging of the population, aortic valve stenosis (AS) is now the most prevalent valvular disease in developed nations. Left ventricular (LV) functional assessment is challenging in this pressure-overloaded disease state, however, myocardial work analysis may overcome this issue by proving load-adjusted measures of LV function. Notably, long-standing severe AS results in progressive damage of the heart, starting from left ventricular (LV) remodeling to significant backward effects eventually leading to manifest right ventricular dysfunction. Myocardial work parameters, being less load-dependent markers of LV function may follow the extent of cardiac damage. However, the relationship of cardiac damage staging and myocardial work measures is scarcely investigated. Purpose Accordingly, we aimed to examine the relationship of myocardial work indices and AS staging in a transcatheter aortic valve replacement (TAVR) candidate AS cohort. Methods 296 patients (79±7 years, 41% female) with severe AS were enrolled. Medical history was obtained and we performed detailed echocardiography prior to TAVR. Aortic valve area (AVA) was calculated using the continuity equation. LVEDVi was measured using the biplane Simpson method. Based on the echocardiographic data, we determined the extent of cardiac damage caused by AS, patients were classified as Stage 0 (no cardiac damage), Stage 1 (LV damage), Stage 2 (mitral valve or left atrial damage), Stage 3 (pulmonary artery vasculature or tricuspid valve damage), or Stage 4 (right ventricular damage). We determined the LV ejection fraction (EF) and via speckle-tracking echocardiography global longitudinal strain (GLS) was also measured. Then, utilizing left ventricular volume curves derived from systolic blood pressure and mean transaortic gradient, we calculated global myocardial work index (GWI). Results 14 (5%) patients were classified as Stage 0, 61 (21%) as Stage 1, 132 (45%) as Stage 2, 16 (5%) as Stage 3, and 73 (25%) as Stage 4. EF (from Stage 0-4: 61±6 vs. 48±12 vs. 48±11 vs. 45±14 vs. 40±15%, p≤0.01) and GLS (-16.9±3.4 vs.-13.2±3.3 vs. -12.6±3.8 vs. -11.8±4.8 vs. -9.8±4.4%, p≤0.01) only differed in Stages 3 and 4, while GWI values formed a more defined spectrum through the Stages (2481±543 vs. 1726±588 vs. 1717±686 vs. 1581±867 vs. 1185±692 mmHg%, p≤0.001). Using multivariate regression analysis, examining relevant clinical and echocardiographic parameters, age (β=0.15, p=0.02), cardiac damage stage (β=-0.19, p≤0.01), AVA (β=0.21, p≤0.01), LVEDVi (β=-0.33, p≤0.001) and having a pacemaker (β=-0.15, p=0.01) were independent predictors of GWI (R²= 0.41, p≤0.0001). Conculsions LV GWI show distinct changes throughout the spectrum of cardiac damage associated with severe AS. Beyond age, AVA, LVEDVi and having a pacemaker, cardiac damage stage is also an independent determinant of GWI in this population.

Hidden cardiotoxicity is defined as cardiotoxicity of a drug that manifests only in the diseased heart. We have previously shown that the proarrhythmic hidden cardiotoxic properties of a model drug, the selective cyclooxygenase-2 inhibitor rofecoxib, can be revealed in preclinical models of ischemia/reperfusion injury. As metabolic comorbidities, such as hypercholesterolemia (HC), may exacerbate hidden cardiotoxicity, we aimed to investigate the hidden cardiotoxic effects of the model drug, rofecoxib, in the presence of hypercholesterolemia. Rats were fed a high-cholesterol diet for 12 weeks and treated with 5.12 mg/kg rofecoxib. Four weeks of rofecoxib treatment surprisingly improved HC-induced mild cardiac dysfunction by restoring end-diastolic pressure, stroke work, and mechanical efficiency. Then, RNA sequencing revealed that the expression of 28 miRNAs and 300 genes was significantly altered in the HC-fed group. The HC-induced expression changes of miR-27a-5p and miR-30d-5p were reversed by rofecoxib treatment. Cdc42ep4, Cox5, and Cxcl9 genes were also counter-regulated following rofecoxib treatment compared to HC-induced changes. This is the first demonstration that rofecoxib improves HC-induced cardiac dysfunction, with the mechanism involving changes in the gene expression profile, including some key regulators of rofecoxib action.

Abstract It is well known that left ventricular (LV) performance is substantially influenced by the corresponding loading conditions and LV synchrony. Notably, data are scarce about the interaction of these factors: previous studies suggest that patients with left bundle branch block (LBBB) has increased afterload sensitivity. This phenomenon may have special importance in certain clinical situations, such as aortic stenosis (AS) patients with concomitant right ventricular pacing (RVP). Accordingly, our aim was to investigate the effects of RVP on LV function in patients with severe AS before and after transcatheter aortic valve replacement (TAVR). Patients with a previously implanted pacemaker and significant AS undergoing TAVR in our Institute were screened. Only subjects with intrinsic non-LBBB QRS were enrolled (n=31). Detailed echocardiographic protocol suitable for speckle-tracking and myocardial work analysis was obtained. Myocardial work measures were calculated by estimating LV pressure as the sum of the systolic blood pressure and the mean aortic gradient. The patients underwent two sets of echocardiographic examinations: one with their narrow QRS rhythm and one with RVP. Those patients (n=19), who did not develop LBBB or complete AV-block also underwent a post-TAVI protocol. We measured LV ejection fraction (EF), global longitudinal strain (GLS) and also global work index (GWI) and global wasted work (GWW). Preoperatively, RVP resulted in significantly lower LV EF (55±9 vs. 49±10%, p≤0.001), GLS (-14.2±3.6 vs. -11.9±3.5%, p≤0.001) and GWI (1830±502 vs. 1322±546 mmHg%, p≤0.001) compared to narrow QRS rhythm, while GWW was markedly higher (222±129 vs. 344±146 mmHg%, p≤0.001). After TAVR, LV EF was comparable (55±9 vs. 52±8%, p=0.11), while GLS (-13.8±.3.8 vs. -11.4±3.8%, p≤0.001) and GWI (1360±403 vs. 1018±385 mmHg%, p≤0.01) was lower in RVP. Notably, the relative change in GWI in response to RVP was significantly lower after TAVR (-31±21 vs. -22±20%, p≤0.05). In patients with severe AS, LV dyssynchrony associated with RVP results in markedly lower LV functional measures. TAVR alleviates LV pressure overload, and the detrimental effect of RVP may dampen with the afterload reduction. Significant AS and RVP may have a highly unfavorable interaction raising the need for early interventions in this population.

Abstract Introduction A growing body of evidence suggests that in the presence of left bundle branch block-induced electromechanical dyssynchrony, the function of the left ventricle (LV) becomes extremely sensitive to arterial afterload. However, data is scarce whether right ventricular pacing (RVP) also sensitizes the LV to alterations in afterload. Purpose Hence, in the present translational study we aimed to characterize the acute effect of RVP on LV hemodynamics under standard laboratory conditions using a rat model of chronic LV pressure overload (PO). Methods Transverse aortic constriction (TAC group) was carried out in male Wistar rats to evoke sustained LV PO for six weeks. Age- and sex-matched sham-operated animals served as controls (Sham group). LV hemodynamics was assessed in anesthetized rats by pressure-volume analysis using a pressure-conductance micro-catheter (SPR-838) introduced to the LV via the right carotid artery. To evoke RVP, the right jugular vein was cannulated and an ultra-miniature octopolar electrophysiology catheter (EPR-800) was placed into the right ventricle. Pressure-volume loops were registered in the TAC and the Sham groups during intrinsic narrow QRS rhythm (termed as TAC-Vsense and Sham-Vsense) as well as during RVP (termed as TAC-Vpace and Sham-Vpace). Results RVP was associated with impaired diastolic function (active relaxation time constant [τ]: 8.6±0.3 vs. 9.6±0.3ms, Sham-Vsense vs. Sham-Vpace and 8.0±0.3 vs. 9.6±0.4ms, TAC-Vsense vs. TAC-Vpace; P<0.001 for both comparisons) and decreased LV contractility (preload recruitable stroke work [PRSW]: 139±9 vs. 114±9mmHg, Sham-Vsense vs. Sham-Vpace and 255±23 vs. 169±17mmHg, TAC-Vsense vs. TAC-Vpace; P<0.001 for both comparisons) in both the TAC and the Sham groups. Nevertheless, the extent of RVP-evoked active relaxation prolongation (Δτ: 12±2 vs. 20±2%, Sham vs. TAC, P=0.005) and LV contractility reduction (ΔPRSW: -18±4 vs. -34±3%, Sham vs. TAC, P=0.007) was found to be more robust in rats with sustained LV PO compared to controls. Conclusion Our experimental results indicate that RVP-induced LV dysfunction is exaggerated in case of sustained LV PO.

Aortic stenosis has become the most prevalent valvular disease with increasing life expectancy and the ageing of the population, representing a significant clinical burden for health care providers. Its treatment has been revolutionized by transcatheter aortic valve replacement (TAVR) as a safe and minimally invasive option for elderly patients. Left ventricular (LV) functional measurement is of particular importance before TAVR, however, increased afterload significantly influences the conventional echocardiographic parameters. Non-invasive myocardial work examines myocardial deformation in the context of instantaneous LV pressure, thus, it might be a more reliable measure of LV function. Accordingly, we aimed to study non-invasive myocardial work and its relationship with functional outcome following TAVR. We enrolled 90 TAVR candidates (80 [75–84] years; 44

Bevezetés: Számos klinikai megfigyelés igazolja a nem befolyásoló szerepét a fokozott nyomásterhelés megszüntetését követő kardiális reverz remodelláció folyamatában, azonban ezeket a vizsgálatokat különböző tényezők korlátozzák. Ezért célul tűztük ki, hogy standard laboratóriumi körülmények között vizsgáljuk meg a nemi különbségeket és hasonlóságokat egy releváns kisállatmodellben. Módszerek: Hím és nőstény patkányokban a bal kamra fokozott nyomásterhelését az abdominalis aorta műtéti beszűkítésével (abdominal aortic banding, AB) idéztük elő 6 és 12 hét időtartamra. Korban illesztett, áloperált állatok szolgáltak kontrollként. A 6. héten a szűkület eltávolításával (debanding) szüntettük meg a nyomásterhelést. A miokardiális remodelláció különböző aspektusait echokardiográfiával, nyomás-térfogat analízissel, hisztológiával, qRT-PCR-rel, valamint proteomikai vizsgálattal jellemeztük. Eredmények: Az AB-csoportokat mindkét nemben kifejezett szívizom-hipertrófia, emelkedett fötális génexpresszió és fokozott fibrózis jellemezte a 6. héten. A szerkezetbeli átépülés mellett, bár a szisztolés funkció megtartott volt, az aktív relaxáció jelentősen károsodott. Azonban a szisztolés funkció dekompenzációja és a diasztolés funkció további romlása csak a hím AB-állatoknál következett be a 12. héten. Az AB mindkét nem esetén hasonló proteomikai változásokhoz vezetett a 6. hétre, míg a 12. hétre jellegzetes nemi különbségek alakultak ki. A nyomásterhelés megszüntetése után, a szívizom-hipertrófia visszaalakulása és a diasztolés funkció normalizációja mindkét nemben hasonló mértékben ment végbe. Azonban a nőstényekben a fibrózis, a fötális génexpresszió és a proteomikai változások nagyobb mértékű visszaalakulást mutattak a hím állatokhoz képest. A nyomásterhelés megszüntetése a hímeknél funkcionális szinten okozott nagyobb antiremodellációs hatást, mivel a nyomásterhelés megszüntetése erőteljesen gátolta a progresszív funkcionális hanyatlást a hímeknél. Következtetések: A nyomásterhelés megszüntetése jelentős reverz remodellációhoz vezetett mindkét nemben. A nőstényekben a fibrózis, a fötális génexpresszió és a proteomikai változások nagyobb mértékű visszaalakulást mutattak. A hímeknél funkcionális szinten alakult ki nagyobb reverz remodellációs hatás.