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Background: This study analyzed the utility of soluble ST2 (sST2) and GDF-15 as biomarkers of right ventricular (RV) function in patients with pulmonary hypertension (PH). Methods: GDF-15 and sST2 serum concentrations were measured in patients with PH (n = 628), dilated cardiomyopathy (n = 31) and left ventricular hypertrophy (n = 47), and in healthy controls (n = 61). Results: Median sST2 and GDF-15 levels in patients with left ventricular hypertrophy were higher than in patients with PH and dilated cardiomyopathy. In tertile analysis GDF-15 >1363 pg/ml and sST2 >38 ng/ml were associated with higher N-terminal pro-brain natriuretic peptide, RV systolic dysfunction, RV-pulmonary arterial uncoupling and hemodynamic impairment. Conclusion: GDF-15 and sST2 are potential biomarkers of RV dysfunction in patients with PH.

Background Fibroblast growth factor 23 (FGF-23) has been associated with left ventricular hypertrophy (LVH) and heart failure. However, its role in right ventricular (RV) remodeling and RV failure is unknown. This study analyzed the utility of FGF-23 as a biomarker of RV function in patients with pulmonary hypertension (PH). Methods In this observational study, FGF-23 was measured in the plasma of patients with PH (n = 627), dilated cardiomyopathy (DCM, n = 59), or LVH with severe aortic stenosis (n = 35). Participants without LV or RV abnormalities served as controls (n = 36). Results Median FGF-23 plasma levels were higher in PH patients than in healthy controls (p p 2. Association of FGF-23 with parameters of RV function was independent of the glomerular filtration rate in regression analysis. Conclusion FGF-23 may serve as a biomarker for maladaptive RV remodeling in patients with PH. Graphic abstract

Background Reference values for right ventricular function and pulmonary circulation coupling were recently established for the general population. However, normative values for elite athletes are missing, even though exercise-related right ventricular enlargement is frequent in competitive athletes. Methods We examined 497 healthy male elite athletes (age 26.1 ± 5.2 years) of mixed sports with a standardized transthoracic echocardiographic examination. Tricuspid annular plane excursion (TAPSE) and systolic pulmonary artery pressure (SPAP) were measured. Pulmonary circulation coupling was calculated as TAPSE/SPAP ratio. Two age groups were defined (18–29 years and 30–39 years) and associations of clinical parameters with the TAPSE/SPAP ratio were determined and compared for each group. Results Athletes aged 18–29 (n = 349, 23.8 ± 3.5 years) displayed a significantly lower TAPSE/SPAP ratio (1.23 ± 0.3 vs. 1.31 ± 0.33 mm/mmHg, p = 0.039), TAPSE/SPAP to body surface area (BSA) ratio (0.56 ± 0.14 vs. 0.6 ± 0.16 mm*m2/mmHg, p = 0.017), diastolic blood pressure (75.6 ± 7.9 vs. 78.8 ± 10.7 mmHg, p p = 0.013) and left atrial volume index (27.5 ± 4.5 vs. 30.8 ± 4.1 ml/m2, p p = 0.035) compared to athletes aged 30–39 (n = 148, 33.1 ± 3.4 years). TAPSE was not different between the age groups. The TAPSE/SPAP ratio was positively correlated with left ventricular stroke volume (r = 0.133, p = 0.018) and training amount per week (r = 0.154, p = 0.001) and negatively correlated with E/E′ lat. (r = −0.152, p = 0.005). Conclusion The reference values for pulmonary circulation coupling determined in this study could be used to interpret and distinguish physiological from pathological cardiac remodeling in male elite athletes.

Workload-indexed blood pressure response (wiBPR) to exercise has been shown to be superior to peak systolic blood pressure (SBP) in predicting mortality in healthy men. Thus far, however, markers of wiBPR have not been evaluated for athletes and the association with vascular function is unclear. We examined 95 male professional athletes (26±5 y) and 30 male controls (26±4 y). We assessed vascular functional parameters at rest and wiBPR with a graded bicycle ergometer test and compared values for athletes with those of controls. Athletes had a lower pulse wave velocity (6.4±0.9 vs. 7.2±1.5 m/s, p=0.001) compared to controls. SBP/Watt slope (0.34±0.13 vs. 0.44±0.12 mmHg/W), SBP/MET slope (6.2±1.8 vs. 7.85±1.8 mmHg/MET) and peak SBP/Watt ratio (0.61±0.12 vs. 0.95±0.17 mmHg/W) were lower in athletes than in controls (p

Was ist neu? Vortestwahrscheinlichkeit In den aktualisierten Leitlinien der Europäischen Gesellschaft für Kardiologie (European Society of Cardiology, ESC) wird die stabile koronare Herzkrankheit zum chronischen Koronarsyndrom (CCS) umbenannt. Unter CCS werden 6 verschiedene Szenarien definiert, die der Heterogenität Rechnung tragen. Die diagnostische Beurteilung der Vortestwahrscheinlichkeit spielt auch in der aktuellen Leitlinie bei möglichem Vorliegen einer stenosierenden KHK eine wichtige Rolle. Die Hinzunahme von Dyspnoe und der klinischen Wahrscheinlichkeit als zusätzliche Variablen zur besseren Abschätzung der Vortestwahrscheinlichkeit sind 2 wichtige Neuerungen. Diagnostische Verfahren Bildgebende Verfahren wie die CT-Angiografie wurden als diagnostische Verfahren zur Detektion von KHK deutlich aufgewertet, während das Belastungs-EKG diesbezüglich nicht mehr routinemäßig empfohlen wird. Die invasive Koronarangiografie mit Revaskularisationsoption bleibt ein zentrales diagnostisches und therapeutisches Verfahren. Therapie Neben der antianginösen, lipidsenkenden und antithrombotischen Therapie wird in der aktuellen CCS-Leitlinie ein besonderes Augenmerk auf Prävention mittels Lebensstilmodifikation gelegt.

The main aim of this study was to assess the prognostic utility of TAPSE/PASP as an echocardiographic parameter of maladaptive RV remodeling in cardiomyopathy patients using cardiac magnetic resonance (CMR) imaging. Furthermore, we sought to compare TAPSE/PASP to TAPSE. The association of the echocardiographic parameters TAPSE/PASP and TAPSE with CMR parameters of RV and LV remodeling was evaluated in 111 patients with ischemic and non-ischemic cardiomyopathy and cut-off values for maladaptive RV remodeling were defined. In a second step, the prognostic value of TAPSE/PASP and its cut-off value were analyzed regarding mortality in a validation cohort consisting of 221 patients with ischemic and non-ischemic cardiomyopathy. A low TAPSE/PASP (

The aim of this study was to evaluate the cartilage intermediate layer protein 1 (CILP1) as a biomarker of right ventricular dysfunction in patients with ischemic cardiomyopathy (ICM). CILP1 plasma concentrations were measured in 98 patients with ICM and 30 controls without any cardiac abnormalities. All participants underwent cardiac magnetic resonance imaging. Median CILP1 concentrations were higher in ICM than in controls. In the tertile analysis, low right ventricular ejection fraction (RVEF) and high right ventricular end-systolic volume index and N-terminal pro-brain natriuretic peptide (NT-proBNP) were associated with higher CILP1 levels in ICM. However, there were no associations between CILP1 concentrations and left ventricular (LV) parameters in this group. In receiver-operating characteristic (ROC) analysis CILP1 was a good predictor of RVEF 40% with an optimal cut-off value of 3545 pg/ml in ICM, whereas it was not predictive of LV ejection fraction (LVEF) 40% (area under the curve [AUC] = 0.57) There was no significant difference between the ROC curves of CILP1 (AUC = 0.72) and NT-proBNP (AUC = 0.77) for RVEF 40% (

SARS-CoV-2 may affect the cardiovascular system and vascular impairment has been reported in healthy young adults recovering from COVID-19. However, the impact of SARS-CoV-2 infection on the vascular function of elite athletes is unknown. We examined 30 healthy male elite athletes (age 25.8 ± 4.6 years) pre-season and at a 6-month follow-up (182 ± 10 days). Vascular function and central blood pressure were calculated using transfer function-based analysis of peripheral arterial waveforms obtained by oscillometry. We performed a two-way repeated-measures ANOVA on the biomarker data, with SARS-CoV-2 status as the between-groups factor and time as the within-groups factor. Subjects who tested positive for SARS-CoV-2 were studied 18 ± 4 days after their positive testing date at follow-up. Of 30 athletes, 15 tested positive for SARS-CoV-2 after the first examination and prior to the follow-up. None had severe COVID-19 or reported any persisting symptoms. The results of the two-way repeated measures ANOVA revealed that there was no significant main effect of COVID-19 on any of the investigated biomarkers. However, there was a significant interaction between the effects of SARS-CoV-2 exposure and time on augmentation index (Aix) (p = 0.006) and augmentation index normalized to a heart rate of 75 beats per minute (Aix@75), (p = 0.0018). The observation of an interaction effect on Aix and Aix@75 in the absence of any main effect indicates a cross-over interaction. Significant vascular alterations in male elite athletes recovering from COVID-19 were observed that suggest vascular impairment. Whether these alterations affect athletic performance should be evaluated in future studies.

Background Severe aortic stenosis (AS) is associated with left ventricular (LV) pressure overload that leads to myocardial remodelling and inflammatory processes. Interleukin 6 (IL6) is secreted by leukocytes as an early response to infection and tissue damage as well as high senisitve C-reactive Protein (hsCRP), which is subsequent in the same pathway. Several studies have suggested an association of elevated serum levels with a higher risk of cardiovascular events. GDF-15 and MR-proADM are also associated with inflammatory processes in cardiovascular diseases and are predictors for adverse events and mortality in patients with AS. The aim of the present study was to evaluate their potential prognostic value regarding the patients all-cause mortality. Methods A total of 92 consecutive patients (mean age: 80,8 [±5,3] years) undergoing TAVI were included in this study. TAVI was performed according to standard clinical practice. Venous blood samples for biomarker analysis were collected prior to and 6 months after TAVI, these were processed immediately and frozen at −80°C until the assay was performed. Safety events, physiological- and echocardiographical parameters, were assessed at the baseline and the 6-month follow-up. Furthermore, we compiled the all-cause mortality of our patients after two years. Results TAVI was performed successfully in all patients. During the two-year follow-up period 24 patients met the endpoint of all-cause mortality. At baseline, serum levels of the inflammatory biomarkers were significantly higher in patients who died within the follow-up period, when compared to survivors (IL6:14,450pg/ml [IQR:7,550; 42,150] vs. 4,200pg/ml [IQR:2,515; 13,875],p=0,0004; hsCRP:5,360 mg/l [IQR:2,248; 26,790] vs. 2,900mg/l [IQR:1,208; 8,210],p=0,022); MR-proADM:1,347nmol/l [IQR:1,038–1,678] vs. 0,922nmol/l [IQR:0,706; 1,202],p=0,0003 and GDF-15:2770,0pg/ml [IQR:2401,0; 3701,0] vs. 1675,2pg/ml [IQR:1141,6; 2524,4],p=0,001). The area under the curve was 0,767 for IL-6, 0,665 for hsCRP, 0,735 for MR-proADM and 0,735 for GDF-15. In addition, there was a significant decrease of IL-6 (baseline: 4,200pg/ml [IQR:2,525; 13,875] vs. 6FU:2,600pg/ml [IQR:1,500; 7,000],p Conclusions In the present study there was a significant decrease of inflammatory biomarkers after TAVI in high risk patients with severe aortic stenosis and good clinical outcome. In this regard, IL-6, hsCRP, MR-proADM and GDF-15 were predictors of all-cause mortality in patients, who underwent TAVI. Funding Acknowledgement Type of funding sources: None.

Aim: This study assessed the utility of osteopontin (OPN) and galectin-3 (Gal-3) as biomarkers of maladaptive right ventricular remodeling in pulmonary hypertension (PH). Materials & methods: We examined plasma levels of OPN and Gal-3 in patients with PH (n = 62), dilated cardiomyopathy (n = 34), left ventricular hypertrophy (LVH; n = 47), and controls without right ventricle (RV) or LV abnormalities (n = 38). Results: OPN and Gal-3 levels were higher in PH, dilated cardiomyopathy and LVH than in the controls. OPN concentrations in PH patients with maladaptive RV were significantly higher than in those with adaptive RV. Gal-3 did not differentiate between adaptive and maladaptive RV remodeling in PH. OPN and Gal-3 levels did not correlate with parameters of LV remodeling. Conclusion: OPN is a potential biomarker of RV maladaptation.

Interventional cardiovascular medicine has seen constant progress over the last few decades. Since the first angiograms and percutaneous transluminal coronary angioplasty were carried out, this progress has been tremendous and has led to a substantial decline in cardiovascular morbidity and mortality. The purpose of this article is to report and review the latest developments and evidence in robotics-assisted percutaneous coronary intervention (rPCI) and its potential future applications, opportunities, and limitations. Contemporary evidence shows that rPCI can lead to a significant reduction in radiation exposure as well as medical hazards for cardiologists. Rates of device and procedural success remain high and there is no evidence of a disadvantage for the patient. The accuracy of implantation with a reduced geographic mismatch is a further advantage that can result in a higher quality of treatment. Even in complex coronary lesions and procedures, rPCI seems to be safe and efficient. The latest developments include telestenting over hundreds of kilometers from a remote platform. Currently, the main limitations are the absence of large-scale randomized trials for the valid assessment of the benefits and disadvantages of rPCI as well as the technical limitations of the currently available rPCI systems. rPCI is a forward-looking innovation in cardiology that is applicable to a wide range of coronary interventions. Despite the present lack of knowledge and the limited data concerning the outcome for the patient, the available literature reveals promising results that should lead to improvements for physicians and patients.

Current risk scores used for patients undergoing transcatheter aortic valve implantation (TAVI) do not reliably predict adverse events after TAVI. Procalcitonin (PCT) is associated with increased atherosclerotic burden and adverse outcomes in patients with cardiovascular disease. The aim of our study is to assess the predictive value of preprocedural serum PCT levels in comparison with established risk scores in TAVI patients. A total of 243 patients undergoing transfemoral TAVI at our institution were included prospectively in the study and 230 of these patients participated in the follow-up 1 year after TAVI. The primary endpoints were mortality at 30 days and 1 year. Multivariable analysis revealed that preprocedural PCT was the only independent predictor of 30-day mortality (HR 2.84; 95% CI 1.59–5.06; p

Background Chronic thromboembolic pulmonary hypertension (CTEPH) is a sub group of pulmonary hypertension (PH). CTEPH is characterized by the existence of thromboemboli and vascular remodeling in pulmonary vessels. The effect of increase in pulmonary artery pressures causes right ventricle (RV) hypertrophy and dilatation and finally leads to right heart failure and death. Surgical intervention in operable patients makes the CTEPH as an only curable and unique form of ph. Pulmonary endarterectomy (PEA) is the surgical procedure to remove the thromboembolic clots from the pulmonary vasculature, which restores RV function back to normal with significant improvements in cardiovascular magnetic resonance. Purpose The aim of this study is to use transcriptomic profiling to identify signaling pathways, master regulators, and potentially new biomarkers that specifically indicate the effect of PEA on the RV of patients with chronic thromboembolic pulmonary hypertension. Results RNA -sequencing (RNA-seq) was performed on RV biopsies obtained from CTEPH patients at PEA baseline (before PEA surgery) and the results were compared with those from RV biopsies obtained during follow-up evaluation. Bioinformatic analysis of RNA-seq data identified 2799 genes (n=14, −0.585 ≤ Log2 fold change ≥0.585, FDR ≤0.05) differentially regulated between the PEA baseline and follow-up sample groups. The great number of genes (2799) differentially expressed after PEA surgery in CTEPH patients confirms a major shift in the transcriptional landscape of RV in these patients. To further identify potential biomarker candidates from the large pool of 2799 differentially expressed genes (DEGs), extensive bioinformatic analysis of different data sets shortlisted 250 DEGs that were functionally associated with cardiovascular development or disease. The findings of this study reveal prominent transcriptional changes that occur in response to PEA. Gene ontology enrichment and pathway analysis confirmed altered regulation of hypoxia-inducible factor 1 (HIF-1) signaling, advanced glycation end products and their receptors (AGE-RAGE), mitogen-activated protein kinase (MAPK) signaling, hippo signaling, the Janus kinase/ signal transducers and activators of transcription (Jak-STAT) signaling pathway, and proteoglycans after PEA compared with before PEA. Conclusion Comparison of the results of RNA-seq analysis of RV biopsies of CTEPH patients, pre and post PEA, revealed a major shift in the transcriptional landscape of these patients after reducing the pressure overload of the RV by PEA. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): German Research Foundation (DFG)

The 2019 guidelines of the European Society of Cardiology (ESC) rename stable coronary heart disease to chronic coronary syndrome (CCS). Under CCS, six different scenarios have been defined, which take its heterogeneity into account. An important part of the current guideline plays the diagnostic assessment of the pre-test probability in the event of the possible presence of stenosing coronary heart disease. The addition of dyspnea and clinical probability as additional variables for better estimation of the pre-test probability are two important new features. Imaging techniques such as CT angiography have been significantly upgraded as diagnostic procedures for the detection of CHD, while exercise ECG is no longer routinely recommended in this regard. Invasive coronary angiography with revascularization option remains a central diagnostic and therapeutic procedure. In addition to antianginal, lipid-lowering and antithrombotic therapy, the current CCS guideline places special emphasis on prevention by means of lifestyle modification.In den aktualisierten Leitlinien der Europäischen Gesellschaft für Kardiologie (European Society of Cardiology, ESC) wird die stabile koronare Herzkrankheit zum chronischen Koronarsyndrom (CCS) umbenannt. Unter CCS werden 6 verschiedene Szenarien definiert, die der Heterogenität Rechnung tragen. Die diagnostische Beurteilung der Vortestwahrscheinlichkeit spielt auch in der aktuellen Leitlinie bei möglichem Vorliegen einer stenosierenden KHK eine wichtige Rolle. Die Hinzunahme von Dyspnoe und der klinischen Wahrscheinlichkeit als zusätzliche Variablen zur besseren Abschätzung der Vortestwahrscheinlichkeit sind 2 wichtige Neuerungen.Bildgebende Verfahren wie die CT-Angiografie wurden als diagnostische Verfahren zur Detektion von KHK deutlich aufgewertet, während das Belastungs-EKG diesbezüglich nicht mehr routinemäßig empfohlen wird. Die invasive Koronarangiografie mit Revaskularisationsoption bleibt ein zentrales diagnostisches und therapeutisches Verfahren.Neben der antianginösen, lipidsenkenden und antithrombotischen Therapie wird in der aktuellen CCS-Leitlinie ein besonderes Augenmerk auf Prävention mittels Lebensstilmodifikation gelegt.

Aim: This study assessed the utility of SPARC-like protein 1 (SPARCL1) as a biomarker of maladaptive right ventricular (RV) function in patients with pulmonary hypertension (PH). Methods: In this prospective study, we examined SPARCL1 levels in 105 patients with adaptive (n = 34) and maladaptive RV (n = 32) pressure overload caused by PH, dilated cardiomyopathy (DCM, n = 18) with LVEF < 35% and preserved RV function and controls without LV or RV abnormalities (n = 21). Results: The median SPARCL1 concentration in patients with maladaptive RV function was higher than in those with adaptive RV function (p p p p p Conclusion: SPARCL1 shows potential as novel biomarker of RV pathological remodelling and is associated with RV maladaptation and ventriculoarterial uncoupling in PH.

The aim of our study was to analyse the protein expression of cartilage intermediate layer protein (CILP)1 in a mouse model of right ventricular (RV) pressure overload and to evaluate CILP1 as a biomarker of cardiac remodelling and maladaptive RV function in patients with pulmonary hypertension (PH).Pulmonary artery banding was performed in 14 mice; another nine mice underwent sham surgery. CILP1 protein expression was analysed in all hearts using Western blotting and immunostaining. CILP1 serum concentrations were measured in 161 patients (97 with adaptive and maladaptive RV pressure overload caused by PH; 25 with left ventricular (LV) hypertrophy; 20 with dilative cardiomyopathy (DCM); 19 controls without LV or RV abnormalities)In mice, the amount of RV CILP1 was markedly higher after banding than after sham. Control patients had lower CILP1 serum levels than all other groups (p−1) was associated with lower tricuspid annular plane excursion/pulmonary artery systolic pressure ratios (pCILP1 is a novel biomarker of RV and LV pathological remodelling that is associated with RV maladaptation and ventriculoarterial uncoupling in patients with PH.

Fractional flow reserve (FFR) guided percutaneous coronary intervention (PCI) has been validated in patients with stable coronary artery disease (CAD) but has not yet been verified under specific conditions such as heart failure or microvascular dysfunction. The aim of the present study was to examine the influence of specific patient comorbidities on FFR values and thus the frequency of PCI in patients with intermediate coronary stenosis.A total of 652 patients with CAD and intermediate coronary stenosis who were assessed for FFR were included in this retrospective study. In a subgroup analysis, specific comorbidities such as heart failure with non-ST-segment-elevated acute coronary syndrome (NSTE-ACS), heart failure, diabetes mellitus, atrial fibrillation (AF), and left ventricular hypertrophy (LVH) were considered.In all lesions with an FFR ≤ 0.80 (n = 227/808, 28.1%), PCI was performed using drug-eluting stents. Pathological FFR values (FFR ≤ 0.80) before PCI were most frequently observed in the left anterior descending artery (LAD; n = 168/418, 39.9%) followed by the right coronary artery (RCA; n = 37/178, 20.7%) and the left circumflex artery (LCX; 22/223, 9.8%). The comorbidities NSTE-ACS (p = 0.28), heart failure with reduced ejection fraction (HFrEF; p = 0.63), heart failure with preserved ejection fraction (HFpEF; p = 0.3719), diabetes mellitus (p = 0.177), or LVH (p = 0.407) had no major impact on the occurrence of pathological FFR values; there was also no association between FFR and the occurrence of lesions in the different target vessels.The occurrence of pathological FFR values, most frequently documented in the LAD, was the same in patients with or without HFrEF, HFpEF, diabetes mellitus, AF, and LVH, demonstrating that these comorbidities did not influence FFR values and, thus, the indication for PCI.HINTERGRUND: Die mittels der fraktionellen Flussreserve (FFR) gesteuerte perkutane Koronarintervention (PCI) ist für Patienten mit stabiler koronarer Herzkrankheit (KHK) validiert, jedoch nicht unter speziellen Bedingungen wie Herzinsuffizienz oder mikrovaskuläre Dysfunktion bestätigt worden. Ziel der vorliegenden Studie war es, den Einfluss spezifischer Komorbiditäten auf die FFR-Werte und somit die PCI-Häufigkeit bei Patienten mit mittelgradiger Koronarstenose zu untersuchen.Insgesamt wurden 652 Patienten mit KHK und mittelgradiger Koronarstenose, bei denen die FFR ermittelt wurde, in diese retrospektive Studie aufgenommen. In einer Subgruppenanalyse wurden spezifische Komorbiditäten wie Herzinsuffizienz mit akutem Koronarsyndrom ohne ST-Strecken-Hebung (NSTE-ACS), Herzinsuffizienz, Diabetes mellitus, Vorhofflimmern (VF) und linksventrikuläre Hypertrophie (LVH) berücksichtigt.Bei sämtlichen Läsionen mit einer FFR ≤ 0,80 (n = 227/808; 28,1 %) wurde die PCI unter Verwendung von medikamentenfreisetzenden Stents durchgeführt. Pathologische FFR-Werte (FFR ≤ 0,80) vor PCI wurden am häufigsten im Ramus interventricularis anterior (RIVA) beobachtet (n = 168/418; 39,9 %), an zweiter Stelle kam die rechte Koronararterie (RCA; n = 37/178; 20,7 %) und dann der Ramus circumflexus der linken Koronararterie (LCX; 22/223, 9,8 %). Die Komorbiditäten NSTE-ACS (p = 0,28), Herzinsuffizienz mit reduzierter Ejektionsfraktion (HFrEF; p = 0,63), Herzinsuffizienz mit erhaltener Ejektionsfraktion (HFpEF; p = 0,3719), Diabetes mellitus (p = 0,177) oder LVH (p = 0,407) hatten keinen wesentlichen Einfluss auf das Auftreten pathologischer FFR-Werte; auch bestand kein Zusammenhang zwischen FFR und dem Auftreten von Läsionen in den verschiedenen Zielgefäßen.Pathologische FFR-Werte, die am häufigsten im RIVA dokumentiert wurden, kamen gleichermaßen bei Patienten mit oder ohne HFrEF, HFpEF, Diabetes mellitus, VF und LVH vor, was zeigt, dass diese Komorbiditäten keinen Einfluss auf die FFR-Werte und somit die Indikation zur PCI hatten.

CaM kinase II (CaMKII) has been suggested to drive pathological cardiac remodeling and heart failure. However, the evidence provided so far is based on inhibitory strategies using chemical compounds and peptides that also exert off-target effects and followed exclusively preventive strategies. Therefore, the aim of this study was to investigate whether specific CaMKII inhibition after the onset of cardiac stress delays or reverses maladaptive cardiac remodeling and dysfunction. Combined genetic deletion of the two redundant CaMKII genes δ and γ was induced after the onset of overt heart failure as the result of pathological pressure overload induced by transverse aortic constriction (TAC). We used two different strategies to engineer an inducible cardiomyocyte-specific CaMKIIδ/CaMKIIγ double knockout mouse model (DKO): one model bases on tamoxifen-inducible mER/Cre/mER expression under control of the cardiac-specific αMHC promoter; the other strategy bases on overexpression of Cre recombinase via cardiac-specific gene transfer through adeno-associated virus (AAV9) under control of the cardiac-specific myosin light chain promoter. Both models led to a substantial deletion of CaMKII in failing hearts. To approximate the clinical situation, CaMKII deletion was induced 3 weeks after TAC surgery. In both models of DKO, the progression of cardiac dysfunction and interstitial fibrosis could be slowed down as compared to control animals. Taken together, we show for the first time that "therapeutic" CaMKII deletion after cardiac damage is sufficient to attenuate maladaptive cardiac remodeling and to reverse signs of heart failure. These data suggest that CaMKII inhibition is a promising therapeutic approach to combat heart failure.

Background— Ca 2+ -dependent signaling through CaM Kinase II (CaMKII) and calcineurin was suggested to contribute to adverse cardiac remodeling. However, the relative importance of CaMKII versus calcineurin for adverse cardiac remodeling remained unclear. Methods and Results— We generated double-knockout mice (DKO) lacking the 2 cardiac CaMKII genes δ and γ specifically in cardiomyocytes. We show that both CaMKII isoforms contribute redundantly to phosphorylation not only of phospholamban, ryanodine receptor 2, and histone deacetylase 4, but also calcineurin. Under baseline conditions, DKO mice are viable and display neither abnormal Ca 2+ handling nor functional and structural changes. On pathological pressure overload and β-adrenergic stimulation, DKO mice are protected against cardiac dysfunction and interstitial fibrosis. But surprisingly and paradoxically, DKO mice develop cardiac hypertrophy driven by excessive activation of endogenous calcineurin, which is associated with a lack of phosphorylation at the auto-inhibitory calcineurin A site Ser411. Likewise, calcineurin inhibition prevents cardiac hypertrophy in DKO. On exercise performance, DKO mice show an exaggeration of cardiac hypertrophy with increased expression of the calcineurin target gene RCAN1-4 but no signs of adverse cardiac remodeling. Conclusions— We established a mouse model in which CaMKII’s activity is specifically and completely abolished. By the use of this model we show that CaMKII induces maladaptive cardiac remodeling while it inhibits calcineurin-dependent hypertrophy. These data suggest inhibition of CaMKII but not calcineurin as a promising approach to attenuate the progression of heart failure.

CaMKII delta and gamma are the major CaMKII genes expressed in the heart, and both are up-regulated in response to pressure overload. Recently, we have demonstrated that CaMKII delta single knockout mice are protected against cardiac hypertrophy and remodeling. However, the role of CaMKII gamma and potential redundant functions of CaMKII delta and gamma are still elusive. The aim of the present study was to evaluate the function of CaMKII delta and gamma by a cardiomyocyte-specific double knockout mouse model(delta/gamma-CKO). Strikingly, whereas delta and gamma single knockout mice displayed only slightly reduced levels of cardiac phospholamban (PLN) phosphorylation at the CaMKII phosphorylation site threonin 17, in delta/gamma-CKO mice there was almost no residual PLN-threonin-17 phosphorylation detectable. Surprisingly and in contrast to delta and gamma single knockout mice, delta/gamma-CKO mice did develop cardiac hypertrophy after transverse aortic constriction (TAC). Despite cardiac hypertrophy we observed markedly reduced cardiac fibrosis and apoptosis. Microarray analysis revealed a distinct different gene expression profile pointing to an activation of calcineurin in delta/gamma-CKO mice after TAC. Phosphorylation of calcineurin at serine 197, which leads to an inactivation of its enzymatic activity, was almost abolished in delta/gamma-CKO mice. To test the therapeutical implications of a complete myocardial CaMKII knockout, an tamoxifen-inducible knockout system was established. Knockout of CaMKII delta and gamma was induced by administration of tamoxifen three weeks after TAC surgery. Whereas control mice did develop overt heart failure and cardiac remodeling 16 weeks after TAC, delta/gamma-iCKO mice recovered from cardiac dysfunction. Taken together, our mouse genetic studies demonstrate that CaMKII delta and gamma are promising drug targets to restore cardiac function after pathological stress. These data also unmask a cross talk of CaMKII to endogenous calcineurin signaling, which results in adaptive cardiac hypertrophy and not pathological remodeling.