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Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Amsterdam Movement Sciences and the Dutch Olympic Committee. Background Cardiac magnetic resonance imaging (CMR) T1 mapping is an established tool for tissue characterisation. This is of particular interest in athletes as differentiation of the ‘grey zone’ between physiological adaptation to sports and pathology can be highly challenging. To correctly interpret individual T1 times, T1 times are conventionally compared to normal values derived from healthy controls. However, whether these values can be applied to elite athletes with different types of cardiac adaptation is unknown. Purpose To determine differences in native T1 times between elite athletes and healthy non-athletic controls and to determine differences in athletes with different types of cardiac remodelling. Methods This is a cross-sectional analysis of elite athletes included in the ELITE cohort. ELITE collects the preparticipation cardiovascular screenings data from all athletes that perform at the highest national, international and/or Olympic level in the Netherlands. All athletes were sixteen years or older. The screening includes cardiovascular magnetic resonance imaging on a Siemens Avanto fit 1.5T machine with cine-imaging, delayed hyperenhancement and a three-pulse shortened modified look-locker inversion recovery 5(3)3 sequence. For this analysis, all athletes with a history of cardiovascular disease or pathological late gadolinium enhancement were excluded. Athletes were classified according to the Mitchell Sports Classification based on the intensity (low (L) / moderate (M) / high (H)) of the dynamic (D) and static components (S). Native- and post-contrast T1 mapping times were calculated by manually tracing the endocardial- and epicardial contours. Results A total of 117 elite athletes (44% women; mean age 26±6.5; Mitchell sports classification: 47 HS/HD, 8 HS/LD, 5 HS/MD, 36 LS/HD, 16 MS/HD, 3 MS/MD, 3 missing) and 48 healthy non-athletic controls (54% women; mean age 39±15.1). Men had lower t1 times compared to women, both in athletes (949ms vs 964ms, p Conclusion Men demonstrate markedly shorter T1 times compared to women in both athletes and controls. Moreover, native T1 times were associated with markers for cardiac remodelling. Sex- and athlete-specific characteristics should be taken into account when interpreting T1 times in athletes.

Funding Acknowledgements Type of funding sources: Other. Main funding source(s): Amsterdam Movement Sciences (AMS); Dutch National Olympic Committee & National Sports Federation (NOC*NSF); Heart To Handle. Background Differentiating between exercise-induced cardiac remodelling (EICR) and pathology constitutes a central challenge in sports cardiology. To facilitate this differentiation, reference ranges for cardiovascular magnetic resonance imaging (CMR) are needed. However, female athletes, and especially, female elite athletes with potentially the most outspoken adaptation, are severely underrepresented. Moreover, no large studies including CMR data in female, elite athletes are currently available. Purpose To quantify EICR on CMR in a large cohort of female, elite athletes, compared with currently available reference values of the general female, and female athlete population. Methods We performed a cross-sectional CMR analysis in female elite athletes aged ≥16 years, included in the ELITE cohort. We excluded athletes with known cardiovascular disease. The primary outcome was EICR quantification as BSA indexed RV and LV end-diastolic volume (EDVi), LV wall mass (LVMi), LV remodelling index (LVMi/LVEDVi), and LV/RV ratio (LVEDi/RVEDVi). Second, we compared our parameters with reference ranges (1,2). CMR was performed according to a uniform protocol, and included cine-imaging and delayed hyperenhancement, preferentially on 1.5T. A dedicated core-lab analysed all CMRs in Circle Cardiovascular Imaging. Results We included 102 female elite athletes, 97% caucasian, mean age of 26.3 ±5.0, BSA 1.79 ±0.14 m2, and mean professional athlete years of 10.3 ±5. Main athlete disciplines (≥10 hours/week) were field hockey (15%), rowing (13%), road cycling (12%), and European style football (10%). Female elite athletes had marked EICR as compared with general population reference values, with higher LVEDVi (108 ±13.9 vs 69 ±12 ml/m2, p Conclusion EICR on CMR in female, elite athletes is mainly characterised by isolated increased volumes, with a considerable proportion (11%) demonstrating no EICR. Compared with the general population, female athletes have larger cardiac ventricular volumes and wall mass; compared with available elite athlete reference ranges comparable ventricular volumes, but a larger spread in cardiac wall mass. Our results constitute a first step towards sex-specific CMR reference ranges for female athletes.

Background/Introduction Specific athlete reference values for cardiac volumes and function using cardiac magnetic resonance (CMR) parameters have been reported and are used in clinical practice. Elite athletes are conventionally thought to demonstrate the highest levels of physiological adaptation to sports and therefore dictate the upper limit of normal for biventricular size and function in the athlete population. Purpose To compare volumetric parameters in a cohort of both male and female elite-level athletes to previously published reference values. Methods We used data from the prospective ELITE-cohort, which collects pre-participation data of elite athletes (national-, international-, Olympic-, Paralympic-level), including CMR imaging. Athletes suspected of pathology based on comprehensively investigated electrocardiograph, exercise test, echocardiogram and late gadolinium enhancement were excluded. Biventricular volumes were derived from short-axis cine images using Cvi42 (v5.1.2.) and indexed for body surface area (BSA). Volumetric parameters were compared to the previously reported gender- and Mitchell sports classification specific cardiac 95th percentile (95%tile) reference values, as reported by Luijkx et al.: left-ventricle (LV) end-diastolic volume (EDV) / BSA for high-static and high-dynamic sports (HS/HD; ♀ 142 ♂ 158); low-static and high-dynamic (LS/HD; ♀ 127 ♂ 149); high-static and low-dynamic (HS/LD; ♀ 114 ♂ 140); right ventricle (RV) EDV / BSA HS/HD (♀ 154 ♂ 184), LS/HD (♀ 136 ♂ 163), and HS/LD (♀ 120 ♂ 157). Results We analysed a total of 221 athletes (38% female), with a median age (IQR) of 26.0 (22.5–29.8) years, and mean ±SD BSA of 1.96±0.22 m2. Athletes were classified according to the Mitchell sports classification: HS/HD 116 (54%); LS/HD 61 (29%); moderate-static and high-dynamic (MS/HD) 20 (9.4%); HS/LD 16 (7.5%) (Table). We found smaller mean ±SD (95%tile) RV EDV/BSA in athletes participating in HS/HD sports (♀: 117±20 (148) and ♂: 133±20 (160)) and LS/HD sports (♀: 109±11 (129) and ♂: 119±15 (142)) and smaller LV EDV/BSA in male athletes in LS/HD sports (116±15 (138)) compared to reference values, (Figure). When using conventional cut-offs in our population we found 10 (4.5%) and 2 (0.9%) athletes above 95%tile for LVEDV/BSA and RVEDV/BSA, respectively (Figure). Conclusion In a cohort consisting of healthy, elite athletes, volumetric adaptations were less outspoken as compared with current reference ranges, specifically in the RV. Only 1 percent of our athletes exceeded conventional 95%tile references for the RV. Potentially, current athlete reference values could overestimate healthy upper limits of cardiac volumes in elite athletes. Our study could indicate that a stricter definition of volumetric reference values, including 95%tile, might be of added value in the specific group of elite athletes to help differentiate between pathology and sports adaptation. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Amsterdam Movement Sciences (P1A210AMC2018)

Background/Introduction In the general population, cardiac magnetic resonance imaging (CMR) T1 mapping is an established tool used for cardiac tissue characterisation. Such characterisation is of particular interest in athletes, as differentiation of the “grey zone” between physiological adaptation to sports and myocardial pathology can be highly challenging. To correctly interpret individual T1 times, T1 times are conventionally compared with normal values derived from healthy controls. However, whether these normative T1 values can be applied to elite athletes, who commonly demonstrate the most extreme cardiac adaptation, is unknown. Purpose To determine whether there are gender-specific differences in normative T1 times between elite athletes and healthy controls. Methods This study is a cross-sectional assessment of healthy athletes included the ELITE-cohort. ELITE includes athletes at national, international, and Olympic level in the Netherlands, aged sixteen years or older and without a history of cardiovascular disease. All athletes undergo standard periodic preparticipation screening with cardiovascular magnetic resonance imaging (Phillips 1.5 Tesla), including native T1 mapping. For the current study, we compared athletes to healthy controls per gender group. T1 inversion times were calculated in Circle Cardiovascular software (v5.12); means for global and segmented myocardium, according to the AHA 16-segment model, were determined using R (v4.1.4). Results A total of 81 elite athletes (35 women, 43.2%) with a median (IQR) age of 26 (22.0–29.55) years and 55 healthy controls (27 women, 49.1%), with a mean age of 38.4±15 years were included (Table 1). Overall, mean global T1 times were markedly shorter in athletes compared with controls (959±21.1ms vs. 984±26.6ms, P Conclusion(s) Athletes demonstrate markedly shorter T1 times as compared with healthy controls, both in women and men. Sex-specific, athlete-normative T1 times should be taken into account when interpreting T1 times in athletes undergoing cardiac evaluation. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Amsterdam Movement Sciences and the Dutch Olympic Committee*Dutch Sports Federation

Background/Introduction SARS-CoV-2 (subclinical) myocarditis has been demonstrated in up to 5% in athletes, and is currently a topic being intensively investigated. However, more subtle changes in function and volumetric parameters have been less well documented, especially in elite athletes, who perform at the highest levels of sports, with potentially the most outspoken adaptation. Purpose To determine differences in cardiac function and volumetric parameters using cardiac magnetic resonance imaging (CMR) in elite athletes recovered from a SARS-CoV-2 infection as compared to non-infected elite athletes (controls). Methods We included elite athletes from the ELITE (Evaluation of Lifetime Intensive Top-level sports and Exercise) cohort, who voluntary undergo cardiovascular pre-participation screenings, which includes cardiac magnetic resonance imaging (CMR). SARS-CoV-2 infection was diagnosed with a positive-PCR or antibody test (if unvaccinated). The primary outcome was the incidence of structural cardiac changes on CMR, defined as LV/RV BSA indexed-EDV (EDVi), LV/RV BSA indexed-ESV (ESVi), LV/RV EF, presence of pathological late gadolinium enhancement (LGE) (excluding hinge point fibrosis), and T1 times. Results We included 234 elite athletes, mean age 27 (±7), 39% female, with main athletic disciplines (≥10 hours/week) of cycling (24%), field hockey (13%), and water polo (12%). In total 69 elite athletes had documented SARS-CoV-2 infection, and 165 were documented as not exposed to SARS-CoV-2. The majority reported mild symptoms 61/69 (88%), 1/69 (1%) severe symptoms, and 7/69 (11%) no symptoms. Mean time between infection and CMR was 2.8 (±2) months. CMR showed no significant difference between elite athletes with SARS-CoV-2 and without (Table) in mean LVEDVi (117±19 vs 120±19 ml/m2, p=0.29), LVESVi (50.6±11 vs 53.2±11 ml/m2, p=0.12), LVEF (56.9% ±5 vs 55.8% ±5, p=0.14), RVEDVi (120±20 vs 122±19 ml/m2, p=0.56), RVESVi (54.5±11 vs 56.2±11 ml/m2, p=0.29), and RVEF (54.6% ±4 vs 53.9% ±5, p=0.23). In 4/69 (4.7%) vs 1/165 (1.3%) pathological non-ischemic pattern of myocardial LGE was present (≤20% of total LV mass), of which one athlete (1.2%) showed increased T1 time, all with no deterioration in right and left ventricle function and volumetric parameters (Figure) after SARS-CoV-2 infection. All athletes made a full recovery and returned to elite competitive sports. Conclusion(s) This cross-sectional study of elite athletes demonstrates that infection with SARS-CoV-2 is not associated with deterioration in cardiac function and volumetric parameters on CMR compared with non-infected athletes, also in the small subset of athletes with pathological LGE patterns after SARS-CoV-2 infection. Prospective studies with long-term follow-up are needed to establish whether intensive sports is associated with long-term cardiac deleterious effects in elite athletes exposed to SARS-CoV-2. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Dutch Heart FoundationDutch National Olympic Committee & National Sports Federation (NOC*NSF)

Background/Introduction Multidisciplinary teams (MDT) are an integral part of cardiology. In sports cardiology wide area of expertise is required to differentiate between extraordinary pathophysiological adaption and pathology. In Addition, expertise-based sports advice should be prescribed with great care considering the great impact on (professional) sports careers. Specific guidelines for the composition of MDT's for sports cardiology are currently lacking. We established a sports cardiology MDT in April 2020 (Amsterdam UMC), consisting of experts in the fields of sports medicine, cardiogenetics and paediatric cardiology, cardiovascular imaging and electrophysiology, with bi-monthly meetings. Cases were contributed from cardiologists or referred nationally for expertise with patients/athletes varying from recreational to elite-level sports. Purpose To describe our infrastructure and utilization of a sports cardiology MDT, and to justify the need for a sports cardiology MDT. Methods We retrospectively analysed all MDT reviewed cases (from April 2020 to April 2021), and collected follow-up data 1 year after initial MDT review. Data were classified according to type/level of sports. We compared diagnosis and/or reason for referral and sports advice at initial MDT application and after panel review. In addition we abstracted data on occurrence of cardiac symptoms and/or cardiac events, and adherence to sports advice. Results 112 cases underwent MDT review, with a mean age of 32 (SD 16.0) years. In total 12% were women, 38% professional athletes, and 30% engaged in high dynamic/low static sports. Reasons for referral were personalised sports advice in 48%, expert opinion in 28%, and abnormal ECG/CMR/CPX in 24%. The diagnosis was revised in 55% (n=61), main groups; 1) suspicion of (non-specified) cardiomyopathy (CMP) to no cardiac pathology in 20% (n=12), and 2) “cardiac abnormalities with no clear diagnosis” to “no cardiac pathology” in 36% (n=22) (Figure 1). Sports advice was revised to more personalized sports advice in 30% (n=34) (Figure 2), main groups; no restriction to no peak load/specific maximum load in 38% (n=13), and no restrictions to no competitive sports in 26% (n=9). At 1 year follow-up, the (sports) advice was adhered in 99,98% (n=111), and cases with no sports restrictions reported no cardiac symptoms in 99% (n=72/73), and no major acute cardiovascular events in 100% (73/73). No further revisions of diagnoses were found to have taken place. Conclusion Our experience with a comprehensive, sports cardiology MDT demonstrates that such an approach is feasible, and leads to more personalised treatment- and sports advice in athletes. Medium-term adherence to sports advice given is high. A team-based approach also leads to a higher percentage definitive diagnoses. Our findings serve as a proof-of-concept of the added value of the sports cardiology team in care for athletes and patients who wish to engage in sports and exercise. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Dutch Olympic Committee*Dutch Sports Federation (NOC*NSF)Amsterdam Movement Sciences (AMS) Figure 1. Revised diagnosis before and after panel review (N=61)Figure 2. Revised sports advice before and after panel review (N=34)

Funding Acknowledgements Type of funding sources: Public hospital(s). Main funding source(s): The Netherlands Organisation for Health Research and Development (ZonMw) University of Amsterdam Research Priority Area Medical Integromics OnBehalf CAPACITY-COVID19 Registry Background The electrocardiogram (ECG) is an easy to assess, widely available and inexpensive tool that is frequently used during the work-up of hospitalized COVID-19 patients. So far, no study has been conducted to evaluate if ECG-based machine learning models are able to predict all-cause in-hospital mortality in COVID-19 patients. Purpose With this study, we aim to evaluate the value of using the ECG to predict in-hospital all-cause mortality of COVID-19 patients by analyzing the ECG at hospital admission, comparing a logistic regression based approach and a DNN based approach. Secondly, we aim to identify specific ECG features associated with mortality in patients diagnosed with COVID-19. Methods and results We studied 882 patients admitted with COVID-19 across seven hospitals in the Netherlands. Raw-format 12-lead ECGs recorded after admission ( Conclusion This study shows that ECG-based prediction models at admission may be a valuable addition to the initial risk stratification in admitted COVID-19 patients. The DNN model showed similar performance to the logistic regression that needs time-consuming manual annotation. Several ECG features associated with mortality were identified. Figure 1: Overview of methods, using and example case: (left) logistic regression and (right) deep learning. This specific case had a high probability of in-hospital mortality (above the threshold of 30%). Follow-up of this case showed that the patient had died during admission. Abstract Figure. Overview of ML methods used

RNA-binding proteins are key regulators of post-transcriptional processes such as alternative splicing and mRNA stabilization. Rbm24 acts as a regulator of alternative splicing in heart and skeletal muscle, and is essential for sarcomere assembly. Homozygous inactivation of Rbm24 in mice disrupts cardiac development and results in embryonic lethality around E12.5. In the present study, we generated somatic Rbm24 knockout (KO) mice and investigated the effects of reduced levels of Rbm24 in the adult heart. Due to the embryonic lethality of Rbm24 KO mice, we examined cardiac structure and function in adult Rbm24 heterozygotes (HETs). Rbm24 protein expression was 40% downregulated in HET hearts compared to WT hearts. Force measurements on isolated membrane-permeabilized myocytes showed increased sarcomere slack length and lower myofilament passive stiffness in adult Rbm24 HET compared to wildtype cardiomyocytes. As a result of the differences in sarcomere slack length, the relations between force development and sarcomere length differed between WT and Rbm24 HET hearts. No differences in sarcomere structure and titin isoform composition were observed. Likewise, in vivo cardiac function and myocardial structure was unaltered in Rbm24 HET mice compared to WT, at baseline and upon pressure overload after transverse aortic constriction. In conclusion, we generated a somatic Rbm24 KO model and recapitulated the previously reported embryonic phenotype. In adult Rbm24 HET cardiomyocytes we observed increased sarcomere slack length, but no difference in sarcomere structure and cardiac function.

Background The growing availability of mobile phones increases the popularity of portable telemonitoring devices. An atrial fibrillation diagnosis can be reached with a recording of 30s on such telemonitoring devices. However, current commercially available automatic algorithms still require approval by experts. Purpose In this research we aimed to build an artificial intelligence (AI) algorithm to improve automatic distinction of atrial fibrillation (AF) from sinus rhythm (SR), to ultimately save time, costs, and to facilitate telemonitoring programs. Methods We developed a deep convolutional neural network (CNN), based on a residual neural network (ResNet), tailored to single-lead ECG analysis. The CNN was trained using publicly available single-lead ECGs from the 2017 PhysioNet/ Computing in Cardiology Challenge. This dataset consists of 60% SR, 9% AF, 30% alternative rhythm, and 1% noise ECGs. The 8528 available ECGs were divided into a training (90%) and validation set (10%) for model development and hyperparameter optimization. Results The trained CNN was applied to an independent set containing single-lead ECGs of 600 patients equally divided into two groups: SR and AF. Both groups comprised of 300 unique ECGs (SR; 60% male, 63±11 years, AF; 38% male, 56±14 years). In distinguishing between AF and SR, the method achieved an accuracy of 0.92, an F1-score of 0.91, and area under the ROC-curve of 0.98. Conclusion The results demonstrate that distinguishing SR and AF by a fully automatic AI algorithm is feasible. This approach has the potential to reduce cost by minimizing expert supervision, especially when extending the algorithm to other heart rhythms, like premature atrial/ventricular contractions and atrial flutter. Figure 1. ROC curve Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Dekkerbeurs - Hartstichting

Objective— Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the fibrillin-1 gene. Patients with MFS are at risk of aortic aneurysm formation and dissection. Usually, blood pressure–lowering drugs are used to reduce aortic events; however, this is not sufficient for most patients. In the aorta of smooth muscle cell–specific sirtuin-1–deficient mice, spontaneous aneurysm formation and senescence are observed. Resveratrol is known to enhance sirtuin-1 activity and to reduce senescence, which prompted us to investigate the effectiveness of resveratrol in inhibition of aortic dilatation in the Fbn1 C1039G/+ MFS mouse model. Approach and Results— Aortic senescence strongly correlates with aortic root dilatation rate in MFS mice. However, although resveratrol inhibits aortic dilatation, it only shows a trend toward reduced aortic senescence. Resveratrol enhances nuclear localization of sirtuin-1 in the vessel wall and, in contrast to losartan, does not affect leukocyte infiltration nor activation of SMAD2 and extracellular signal–regulated kinases 1/2 (ERK1/2). Interestingly, specific sirtuin-1 activation (SRT1720) or inhibition (sirtinol) in MFS mice does not affect aortic root dilatation rate, although senescence is changed. Resveratrol reduces aortic elastin breaks and decreases micro-RNA-29b expression coinciding with enhanced antiapoptotic Bcl-2 expression and decreased number of terminal apoptotic cells. In cultured smooth muscle cells, the resveratrol effect on micro-RNA-29b downregulation is endothelial cell and nuclear factor κB-dependent. Conclusions— Resveratrol inhibits aortic root dilatation in MFS mice by promoting elastin integrity and smooth muscle cell survival, involving downregulation of the aneurysm-related micro-RNA-29b in the aorta. On the basis of these data, resveratrol holds promise as a novel intervention strategy for patients with MFS.

Heart failure (HF) is a complex clinical syndrome that can result from any structural or functional cardiac disorder. Due to increased survival of acute cardiac diseases (eg, myocardial infarction) in the last decades, the prevalence of HF is increasing. Therefore, the development of new therapeutics to prevent or even reverse HF progression is of crucial importance. In recent years, it has become evident that a novel class of small noncoding RNAs, microRNAs (miRNAs), play a key role in the cardiac remodeling process in the progression to HF. Preclinical studies using synthetic miRNA inhibitors have shown that it is relatively easy to inhibit miRNA expression in the heart. Moreover, these studies revealed profound functions of specific miRNAs in numerous biological processes in the heart. In this chapter, we will discuss the currently used approaches to overexpress or inhibit miRNAs in the heart, ranging from synthetic miRNA inhibitors to viral-based delivery systems. We will also present several examples of miRNAs (ie, miR-208, miR-25, miR-29, miR-92, miR-155, miR-1, and miR-15) that are currently explored for their therapeutic potential for HF and explain how these studies have advanced our understanding into the pathogenesis of HF. Finally, we will discuss the potential of using circulating miRNAs as new biomarkers for HF and the challenges before they can be used clinically as biomarker.

Recent developments in basic and clinical science have turned the spotlight to miRNAs for their potential therapeutic efficacy. Since their discovery in 1993, it has become clear that miRNAs act as posttranscriptional regulators of protein expression. Their clinical potential was further highlighted by the results of miRNA-based interventions in small laboratory animals. More importantly, their therapeutic effectiveness has been shown recently in phase 2a clinical studies in patients with hepatitis C virus infection, where inhibition of miRNA-122 showed prolonged and dose-dependent viral suppression. A recent study surprisingly revealed the presence of plant-derived miRNAs in the blood of healthy humans. This finding opens up the possibility to explore miRNA-mediated therapeutics derived from (genetically modified) food. Having arrived at this point in our understanding of miRNAs, we provide an overview of current evidence and future potential of miRNA-based therapeutics, focusing on their application in cardiac fibrosis.

AIMS: Hypertrophic cardiomyopathy (HCM) is a frequent cause of sudden cardiac death (SCD) due to exercise-related ventricular arrhythmias (ERVA); however the pathological substrate is uncertain. The aim was to determine the prevalence of ERVA and their relation with fibrosis as determined by cardiac magnetic resonance imaging (CMR) in carriers of an HCM causing mutation. METHODS: We studied the prevalence and origin of ERVA and related these with fibrosis on CMR in a population of 31 HCM mutation carriers. RESULTS: ERVA occurred in seven patients (23%) who all showed evidence of fibrosis (100% ERVA(+) vs. 58% ERVA(-), p = 0.04). No ventricular tachycardia or ventricular fibrillation occurred. In patients with ERVA, the extent of fibrosis was significantly larger (8 ± 4% vs. 3 ± 4%, p = 0.02). ERVA originated from areas with a high extent of fibrosis or regions directly adjacent to these areas. CONCLUSIONS: ERVA in HCM mutation carriers arose from the area of fibrosis detected by CMR; ERVA seems closely related to cardiac fibrosis. Fibrosis as detected by CMR should be evaluated as an additional risk factor to further delineate risk of SCD in carriers of an HCM causing mutation.

Cardiac disease is a common clinical manifestation of neuromuscular disorders, particularly of muscular dystrophies. Heart muscle cells as well as specialized conducting myocardial fibres may be affected by the dystrophic process. The incidence and nature of cardiac involvement vary with different types of muscular dystrophies. Some mainly lead to myocardial disease, resulting in cardiomyopathy and heart failure, while others particularly affect the conduction system, leading to arrhythmias and sudden death. As prognosis of muscular dystrophy patients may be directly related to cardiac status, surveillance and timely management of cardiac complications are important. However, recognition of cardiac involvement requires active investigation and remains challenging since typical signs and symptoms of cardiac dysfunction may not be present and progression is unpredictable. In this review, we present a comprehensive overview of hereditary muscular dystrophies associated with cardiac disease to provide an efficient strategy for the expertise and management of these diseases. (C) 2010 Elsevier B.V. All rights reserved.

Background. With the improvement in genetic testing over time, double-heterozygous mutations are more often found by coincidence in families with hypertrophic cardiomyopathy (HCM). Double heterozygosity can be a cause of the wellknown clinical diversity within HCM families.Methods and results. We describe a family in which members carry either a single mutation or are double heterozygous for mutations in myosin heavy chain gene (MYH7) and cysteine and glycine-rich protein 3 (CSRP3). The described family emphasises the idea of a more severe clinical phenotype with double-heterozygous mutations. It also highlights the importance of cardiological screening where NT-proBNP may serve as an added diagnostic tool.Conclusion. With a more severe inexplicable phenotype of HCM within a family, one should consider the possibility of double-heterozygous mutations. This implies that in such families, even when one disease-causing mutation is found, all the family members still have an implication for cardiological screening parallel to extended genetic screening. (Neth Heart J 2009;17:458-63.).

Congestive heart failure constitutes one of the major causes of morbidity and mortality in Western countries. However, it is often misdiagnosed and the validity of the diagnosis is often difficult to establish. The clinical signs are not very sensitive and symptoms are nonspecific. Secretion of natriuretic peptides is increased in situations of cardiac overload. Testing the levels of these peptides, especially BNP and NT-proBNP, appears to offer a significant advance in the diagnosis and treatment of heart failure. In this article we would like to discuss the value of natriuretic peptides in congestive heart failure and give a short review of the literature.

Objectives. To determine dose-related clinical and neurohumoral effects of angiotensin-converting enzyme (ACE) inhibitors in patients with chronic heart failure (CHF), we conducted a double-blind, placebo-controlled, randomized study of three doses (2.5 mg, 5 mg and 10 mg) of the long-acting ACE inhibitor imidapril. Background. The ACE inhibitors have become a cornerstone in the treatment of CHF, but whether high doses are more effective than low doses has not been fully elucidated, nor have the mechanisms involved in such a dose-related effect. Methods. In a parallel group comparison, the effects of three doses of imidapril were examined. We studied 244 patients with mild to moderate CHF (New York Heart Association class II–III: ±80%/20%), who were stable on digoxin and diuretics. Patients were treated for 12 weeks, and the main end points were exercise capacity and plasma neurohormones. Results. At baseline, the four treatment groups were well-matched for demographic variables. Of the 244 patients, 25 dropped out: 3 patients died, and 9 developed progressive CHF (3/182 patients on imidapril vs. 6/62 patients on placebo, p Conclusions. Already within 3 months after treatment initiation, high-dose ACE inhibition (with imidapril) is superior to low-dose. This is reflected by a more pronounced effect on exercise capacity and some of the neurohormones, but it does not appear to be related to the extent of suppression of plasma ACE.

(1) Increased vascular resistance in chronic heart failure (CHF) has been attributed to stimulated neurohumoral systems. However, local mechanisms may also importantly contribute to set arterial tone. Our aim, therefore, was to test whether pressure-induced myogenic constriction of resistance arteries in vitro--devoid of acute effects of circulating factors--is increased in CHF and to explore underlying mechanisms. (2) At 12 weeks after coronary ligation-induced myocardial infarction or SHAM-operations in rats, we studied isolated mesenteric arteries for myogenic constriction, determined as the active constriction (% of passive diameter) in response to stepwise increase in intraluminal pressure (20 - 160 mmHg), in the absence and presence of inhibitors of potentially involved modulators of myogenic constriction. (3) We found that myogenic constriction in mesenteric arteries from CHF rats was markedly increased compared to SHAM over the whole pressure range, the difference being most pronounced at 60 mmHg (24+/-2 versus 4+/-3%, respectively, P0.001). (4) Both removal of the endothelium as well as inhibition of NO production (L-N(G)-monomethylarginine, 100 micro M) significantly increased myogenic constriction (+16 and +25%, respectively), the increase being similar in CHF- and SHAM-arteries (P=NS). Neither endothelin type A (ET(A))-receptor blockade (BQ123, 1 micro M) nor inhibition of perivascular (sympathetic) nerve conduction (tetrodotoxin, 100 nM) affected the myogenic response in either group. (5) Interestingly, increased myogenic constriction in CHF was fully reversed after angiotensin II type I (AT(1))-receptor blockade (candesartan, 100 nM; losartan, 10 micro M), which was without effect in SHAM. In contrast, neither angiotensin-converting enzyme (ACE) inhibition (lisinopril, 1 micro M; captopril, 10 micro M) or AT(2)-receptor blockade (PD123319, 1 micro M), nor inhibition of superoxide production (superoxide dismutase, 50 U ml(-1)), TXA(2)-receptor blockade (SQ29,548, 1 micro M) or inhibition of cyclooxygenase-derived prostaglandins (indomethacin, 10 micro M) affected myogenic constriction. (6) Sensitivity of mesenteric arteries to angiotensin II (10 nM - 100 micro M) was increased (P0.05) in CHF (pD(2) 7.1+/-0.4) compared to SHAM (pD(2) 6.2+/-0.3), while the sensitivity to KCl and phenylephrine was not different. (7) Our results demonstrate increased myogenic constriction in small mesenteric arteries of rats with CHF, potentially making it an important target for therapy in counteracting increased vascular resistance in CHF. Our results further suggest active and instantaneous participation of AT(1)-receptors in increased myogenic constriction in CHF, involving increased sensitivity of AT(1)-receptors rather than apparent ACE-mediated local angiotensin II production.

We investigated changes in genetic expression of atrial and brain natriuretic peptides (ANP and BNP) and sarcoplasmic reticulum Ca(2+)-ATPase (SERCA) in patients with stable mild to moderate chronic heart failure (CHF), since data on this topic were primarily obtained in end-stage CHF.We studied tissue from 25 patients with idiopathic dilated cardiomyopathy (IDC) in New York Heart Association (NYHA) class II (n=12) and III-IV (n=13). Myocardial tissue from normal hearts (n=10) served as controls. Messenger RNA (mRNA) expression of ANP, BNP, and SERCA was isolated, and correlated with severity of CHF, left ventricular function (LVEF), peak oxygen uptake (peak VO(2)), and wedge pressure.A significant trend for gradual changes in mRNA expression according to increasing NYHA class was found for ANP, BNP (P0.0001) and SERCA (P=0.04), with a marked increase in patients with more advanced CHF (ANP and BNP: P0.01 vs. controls; SERCA: NS) and less pronounced changes in patients with mild CHF. mRNA of ANP and BNP correlated strongly with LVEF (-0.621 and -0.621, respectively, both P0.01) and peak VO(2) (-0.625 and -0.555, respectively, both P0.01) and, to a lesser extent, with wedge pressure (0.440 and 0.488, respectively, both P0.05). SERCA correlated most strongly with wedge pressure (-0.623, P0.01), and weak, non-significant correlations with LVEF and peak VO(2) were found.Genetic expression of ANP, BNP, and SERCA is progressively altered in proportion to the severity of CHF, although this is more marked for ANP and to a lesser extent BNP, than for SERCA. These changes support the concept that already early in CHF, genetic expression is affected, which has implications for the understanding of the pathophysiology of CHF.

The QUO VADIS study was designed to explore whether 1 year of angiotensin-converting enzyme inhibition with quinapril (40 mg/day) would decrease ischemia in patients who underwent coronary artery bypass grafting (CABG). Patients (n = 149) scheduled for CABG were randomized 4 weeks before surgery. Study medication was used from randomization up to 1 year after CABG. Exercise testing was performed at randomization; the exercise test was repeated 1 year after CABG and patients underwent 48-hour Holter monitoring. Clinical ischemic events were recorded and defined as death, revascularization, myocardial infarction, recurrence of angina pectoris, ischemic stroke, or transient ischemic attack. Baseline characteristics were similar between groups. Total exercise time increased overall by 75 +/- 76 seconds 1 year after CABG (placebo +79 +/- 75 seconds, quinapril +72 +/- 79 seconds, p = 0.6). All patients had ischemic ST-segment changes at randomization; 33% of patients had ischemic ST-segment changes 1 year after CABG (placebo 29%, quinapril 37%, p = 0.4). On Holter monitoring, the number of patients experiencingor = 1 episodes of ischemia was equal in both groups. Treatment with quinapril significantly reduced clinical ischemic events after CABG: 15% in patients on placebo versus 4% of patients on quinapril (hazard ratio 0.23, 95% confidence interval 0.06 to 0.87, p = 0.02). Long-term quinapril treatment significantly reduced clinical ischemic events within 1 year after CABG, although ischemia at exercise testing and Holter monitoring was unchanged.

The QUO VADIS (the effects of QUinapril On Vascular Ace and Determinants of ISchemia) study was a randomized, double-blind, placebo-controlled trial designed to evaluate the effects of long-term angiotensin-converting enzyme (ACE) inhibition on angiotensin II formation in human vasculature. Patients (n = 187) scheduled for coronary artery bypass surgery used study medication 27 +/- 1 days before surgery. Segments of internal mammary arteries were exposed to increasing doses (0.1 nM-1 microM) of angiotensin I and II in organ baths. The rate of local angiotensin II formation is a function of the reciprocal of the difference between the pEC50's of the dose response curves to angiotensin I and II (-log/mol) and of the area between the curves (units). Quinapril (40 mg) and captopril (3 x 50 mg) similarly and significantly reduced mean blood pressure compared with placebo (p = 0.04). Difference between pEC50's was 0.90 +/- 0.08 in quinapril patients compared with 0.60 +/- 0.08 for placebo (p = 0.01); the area between curves was 91 +/- 8 for quinapril patients compared with 67 +/- 8 for placebo (p = 0.03). Angiotensin II formation was decreased to a lesser extent with captopril and was not statistically different from placebo (p = 0.3); the difference between pEC50's was 0.83 +/- 0.15; the area between curves was 84 +/- 12. This is the first randomized study to demonstrate that long-term oral treatment with an ACE inhibitor reduces vascular angiotensin II formation in humans.

To date, the use of beta-blockers in treating patients with chronic heart failure gains support, this since several large clinical trials reported reduced mortality after chronic beta-blockade. Part of these beneficial effects may result from inhibition of deleterious neurohormone activation that accompanies progression of chronic heart failure. The present study evaluates whether this neurohormone inhibition is preserved after chronic beta-blockade.In a retrospective analysis the neurohormonal profiles of patients with moderate to severe chronic heart failure were studied from three treatment subgroups: (1) Without beta-blockers or ACE-inhibitors (n=15), (2) without beta-blockers, with ACE-inhibitors (n=324), (3) with beta-blockers and ACE-inhibitors (n=31). Patients were on beta-blockers for an average period of 3.8 years. Plasma samples were obtained under controlled conditions.Despite uneven group sizes, the groups were well matched for clinical characteristics. Plasma renin levels were significantly lower in patients treated adjunctively with beta-blockers. Plasma aldosterone and endothelin-I levels also tended to be lower after chronic beta-blockade, however, this did not reach statistical significance.Chronic adjunctive beta-blocker treatment shows significantly lower plasma renin levels when compared to single ACE-inhibition. This persistent reduction of plasma neurohormone activation may concomitantly reduce the chance of neurohormones to escape from inhibition.

To determine dose-related clinical and neurohumoral effects of angiotensin-converting enzyme (ACE) inhibitors in patients with chronic heart failure (CHF), we conducted a double-blind, placebo-controlled, randomized study of three doses (2.5 mg, 5 mg and 10 mg) of the long-acting ACE inhibitor imidapril.The ACE inhibitors have become a cornerstone in the treatment of CHF, but whether high doses are more effective than low doses has not been fully elucidated, nor have the mechanisms involved in such a dose-related effect.In a parallel group comparison, the effects of three doses of imidapril were examined. We studied 244 patients with mild to moderate CHF (New York Heart Association class II-III: +/-80%/20%), who were stable on digoxin and diuretics. Patients were treated for 12 weeks, and the main end points were exercise capacity and plasma neurohormones.At baseline, the four treatment groups were well-matched for demographic variables. Of the 244 patients, 25 dropped out: 3 patients died, and 9 developed progressive CHF (3/182 patients on imidapril vs. 6/62 patients on placebo, p0.05). Exercise time increased 45 s in the 10-mg group (p = 0.02 vs. placebo), but it did not significantly change in the 5-mg (+16 s), and 2.5-mg (+11 s) imidapril group, compared to placebo (+3 s). Physical working capacity also increased in a dose-related manner. Plasma brain and atrial natriuretic peptide decreased (p0.05 for linear trend), while (nor)epinephrine, aldosterone and endothelin were not significantly affected. Renin increased in a dose-related manner, but plasma ACE activity was suppressed similarly (+/-60%) on all three doses.Already within 3 months after treatment initiation, high-dose ACE inhibition (with imidapril) is superior to low-dose. This is reflected by a more pronounced effect on exercise capacity and some of the neurohormones, but it does not appear to be related to the extent of suppression of plasma ACE.

1. Angiotensin converting enzyme (ACE) is thought to be the main enzyme to convert antiotensin I to the vasoactive angiotensin II. Recently, in the human heart, it was found that the majority of angiotensin II formation was due to another enzyme, identified as human heart chymase. In the human vasculature however, the predominance of either ACE or non-ACE conversion of angiotensin I remains unclear. 2. To study the effects of ACE- and chymase-inhibition on angiotensin II formation in human arteries, segments of internal mammary arteries were obtained from 37 patients who underwent coronary bypass surgery. 3. Organ bath experiments showed that 100 microM captopril inhibited slightly the response to angiotensin I (pD2 from 7.09+/-0.11-6.79+/-0.10, P0.001), while 100 microM captopril nearly abolished the response to [pro10] angiotensin I, a selective substrate for ACE, and the maximum contraction was reduced from 83+/-19%-23+/-17% of the control response (P=0.01). A significant decrease of the pD2 of angiotensin I similar to captopril was observed in the presence of 50 microM chymostatin (pD2 from 7.36+/-0.13-6.99+/-0.15, P0.039), without influencing the maximum response. In the presence of both inhibitors, effects were much more pronounced than either inhibitor alone, and a 300 times higher dose was needed to yield a significant contraction response to angiotensin I. 4 These results indicate the presence of an ACE and a non-ACE angiontensin II forming pathway in human internal mammary arteries.

Peptides produced by the renin-angiotensin system play a major role in the development and progression of various cardiovascular diseases. One of these peptides, angiotensin II, is a potent vasoconstrictor that exerts most of its effects through the human AT1 receptor. Following the discovery of a functional variation in the angiotensin-converting enzyme gene, research has identified other genetic variations in the renin-angiotensin system that may contribute to cardiovascular disorders. Of the described polymorphisms in the AT1-receptor gene, the A1166C transversion is associated with human essential hypertension. We have used the TGR(alpha MHC-h AT1) rat model, which overexpresses the human AT1 receptor in the myocardium, to study some of the associations between an increased AT1-receptor number and cardiovascular disorders. Our results suggest that under physiological conditions overexpression of the AT1 receptor causes no changes in cardiovascular structure; however, pressure and volume overload lead to hypertrophic growth in this model. While the AT1-receptor polymorphism may not cause cardiovascular disorders directly, it can perhaps contribute to a process that is started by other factors, such as increased activity or uptake by tissues of plasma renin, which leads to local activation of the renin-angiotensin system. Our data indicate that the AT1-receptor polymorphism is probably associated with an increased responsiveness to angiotensin II. Under basal conditions, this increased responsiveness does not seem to affect the heart, but it may exert adverse effects under loading or high-renin conditions.

1. Desensitization of the myocardial beta-adrenergic signal transduction pathway is an important mechanism which is involved in the progression of hypertensive heart disease. The aim of the present study was to evaluate the differential effects of chronic pharmacotherapy with an angiotensin converting enzyme (ACE)-inhibitor, an AT1-receptor antagonist and a direct vasodilator on blood pressure, cardiac hypertrophy and the beta-adrenergic signal transduction. Therefore, transgenic TG(mREN2)27 (TG) rats overexpressing the mouse renin gene were used. This strain is characterized by the development of fulminant hypertension with cardiac hypertrophy. 2. Seven week old heterozygous TG(mREN2)27 rats were treated for 11 weeks with the AT1-receptor antagonist losartan (10 mg kg[-1]), the ACE-inhibitor quinapril (15 mg kg[-1]) and the direct vasodilator hydralazine (30 mg kg[-1]). Untreated TG and normotensive Sprague-Dawley rats (SD) served as controls. 3. TG(mREN2)27-rats were characterized by arterial hypertension (TG 194+/-3.2 mmHg vs SD 136+/-2.9 mmHg systolic blood pressure), increased left ventricular weights (TG 4.3+/-0.3 vs SD 3.0+/-0.1 mg g(-1) body weight), decreased myocardial neuropeptide Y (NPY) concentrations (TG 1143+/-108 vs SD 1953+/-134 pg g(-1) wet weight), reduced beta-adrenoceptor densities (TG 51.1+/-1.9 vs SD 63.4+/-3.7 fmol mg[-1]) as assessed by [125I]-cyanopindolol binding studies, and increased Gi(alpha)-activities (TG 4151+/-181 vs SD 3169+/-130 densitometric units) as assessed by pertussis toxin catalyzed [32P]-ADP-ribosylation. Downregulation of beta-adrenoceptors and increased Gi(alpha) were accompanied by significantly reduced isoprenaline-, Gpp(NH)p- and forskolin-stimulated adenylyl cyclase activity. Catalyst activity as determined by forskolin plus Mn2+ co-stimulation of adenylyl cyclase did not differ between TG(mREN2)27- and SD control-rats. 4. Losartan and quinapril significantly restored systolic blood pressures, left ventricular weights, beta-adrenoceptor densities, myocardial neuropeptide Y-concentrations, adenylyl cyclase activities and Gi(alpha)-activities towards the values in Sprague-Dawley-controls. No differences were observed between the effects of quinapril- and losartan-treatment. In contrast, hydralazine had only minor effects on blood pressure reduction, regression of left ventricular hypertrophy and neuroeffector defects in TG(mREN2)27. 5. In conclusion, direct vasodilatation is not able to overcome the pathophysiological alterations in TG caused by transgene overexpression. In contrast, ACE-inhibitors and AT1-receptor antagonists, which inhibit the renin angiotensin system, equally exert beneficial effects on blood pressure, myocardial hypertrophy and neuroeffector mechanisms. Modulation of the sympathetic tone and resensitization of the beta-adrenergic signal transduction system may contribute to the special effectiveness of these drugs in the treatment of the hypertensive cardiomyopathy.

The renin-angiotensin system has been implicated in vascular function and disease. Angiotensin-converting enzyme and angiotensin II are believed to be the most important components. However, alternative factors, such as angiotensin-I/II-(1-7) and chymase, have also been shown to be of significance in animal models. In this paper, we review some facts and provide additional proof for the functional significance of angiotensin-I/II-(1-7) and chymase in humans.

We hypothesized that angiotensin-converting enzyme (ACE) insertion/deletion polymorphism may be related to arterial phenotypic differences that could explain the adverse effects of deletion polymorphism. Accordingly, contractile responses to angiotensin I and II (0.1 nmol.1(-1)-1 micromol.1(-1), endothelium-dependent relaxation to methacholine (0.01-100 micromol.1(-1), and the effect of NG-monomethyl-L-arginine (L-NMMA; 100 micromol.1(-1) on phenylephrine (10 micromol.1(-1) induced contraction, were studied in isolated rings of internal mammary arteries obtained from patients undergoing coronary bypass surgery. The results were analysed according to the ACE genotype of the patient (II, n = 8; ID, n = 11; DD, n = 9) as well as the presence/absence of either allele. The arteries from patients with the D allele (ID/DD) displayed a lower sensitivity to methacholine (P0.05 vs II), which suggested that the capacity of the endothelium for nitric oxide release in response to stimulation was also lower. By contrast, the increase in phenylephrine-induced contraction, by pre-incubation with L-NMMA, was more pronounced in the group with the DD allele (31 +/- 5%) than with the ID (11 +/- 11%) and II alleles (1 +/- 11%, P0.05 vs DD), which suggested a higher level of basal nitric oxide release. Finally, the differences in the responses to angiotensin I and II, which were used to evaluate the vascular conversion of angiotensin I, indicated that the level of angiotensin I conversion was higher in patients with the D allele (ID/DD, P0.05 vs II). The findings of this study indicate that ACE insertion/deletion polymorphism is related to arterial phenotypic differences in endothelial function and angiotensin I conversion.

This study sought to determine whether patients who are homozygous for the deletion (D)-type allele of the angiotensin-converting enzyme gene display augmented ventricular dilation after myocardial infarction.Recent evidence suggests that the deletion-type allele of the angiotensin-converting enzyme gene (DD genotype) is associated with an increased prevalence of myocardial infarction and myocardial hypertrophy. However, it is unknown whether the DD genotype is associated with adverse cardiac remodeling. To address this question we determined the genotype in patients enrolled in the Captopril and Thrombolysis Study (CATS), a prospective trial in which patients received either captopril or placebo during and after thrombolysis for a first anterior myocardial infarction.Cardiac volume was determined by echocardiography immediately after thrombolysis and at 1-year follow-up. The genotype for the angiotensin-converting enzyme was determined in 96 patients. Norepinephrine levels were assessed during and immediately after thrombolysis.Immediately after thrombolysis, cardiac volume did not differ between genotype groups. However, at 1-year follow-up, both end-systolic and end-diastolic left ventricular volumes were significantly greater in the DD-genotype group. Norepinephrine increased to higher levels in the DD-genotype group that received placebo therapy. Captopril treatment effectively blunted both the norepinephrine increase and cardiac dilation in the DD-genotype group.This exploratory study suggests that homozygosity for the angiotensin-converting enzyme deletion-type allele is associated with augmented neurohumoral activation as well as augmented cardiac dilation after an acute anterior myocardial infarction, an effect that may be susceptible to angiotensin-converting enzyme inhibition.

It has been shown that converting enzyme inhibitors (CEI) attenuate ventricular dilatation and hypertrophy after myocardial infarction. In most studies, CEI treatment was started when ventricular dilatation and hypertrophy were already well under way. Therefore, we studied the effects on ventricular dilatation and hypertrophy, when CEI treatment was started in the acute phase of myocardial infarction. Immediately after a sham-operation or myocardial infarction in rats (sham: n = 8; MI: n = 17), treatment with zofenopril, a novel ACE-inhibitor, was started and continued during 42 days (long-term treatment). In a second group of rats, zofenopril was administered only during the first 5 days after myocardial infarction (short-term treatment); these rats were not treated with zofenopril during the remaining period of 37 days (sham: n = 5; MI: n = 13). Untreated rats served as controls (sham: n = 9; MI: n = 24). The results from this study showed that long-term treatment with zofenopril caused a significant reduction of left ventricular cavity volume in rats with moderate-to-large infarctions, which was accompanied by a significant reduction in the ratio of total heart weight to body weight. However, short-term treatment with zofenopril did not significantly reduce ventricular volume or total heart weight. Finally, both long- and short-term treatment resulted in a small, but statistically significant, reduction of septal wall thickness in sham-operated and infarcted rats. We conclude that CEI therapy decreases ventricular dilatation and hypertrophy after myocardial infarction, only when treatment is continued during the chronic phase.(ABSTRACT TRUNCATED AT 250 WORDS)

Background— Cardiac hypertrophy and subsequent heart failure triggered by chronic hypertension represent major challenges for cardiovascular research. Beyond neurohormonal and myocyte signaling pathways, growing evidence suggests inflammatory signaling pathways as therapeutically targetable contributors to this process. We recently reported that microRNA-155 is a key mediator of cardiac inflammation and injury in infectious myocarditis. Here, we investigated the impact of microRNA-155 manipulation in hypertensive heart disease. Methods and Results— Genetic loss or pharmacological inhibition of the leukocyte-expressed microRNA-155 in mice markedly reduced cardiac inflammation, hypertrophy, and dysfunction on pressure overload. These alterations were macrophage dependent because in vivo cardiomyocyte-specific microRNA-155 manipulation did not affect cardiac hypertrophy or dysfunction, whereas bone marrow transplantation from wild-type mice into microRNA-155 knockout animals rescued the hypertrophic response of the cardiomyocytes and vice versa. In vitro, media from microRNA-155 knockout macrophages blocked the hypertrophic growth of stimulated cardiomyocytes, confirming that macrophages influence myocyte growth in a microRNA-155 -dependent paracrine manner. These effects were at least partly mediated by the direct microRNA-155 target suppressor of cytokine signaling 1 (Socs1) because Socs1 knockdown in microRNA-155 knockout macrophages largely restored their hypertrophy-stimulating potency. Conclusions— Our findings reveal that microRNA-155 expression in macrophages promotes cardiac inflammation, hypertrophy, and failure in response to pressure overload. These data support the causative significance of inflammatory signaling in hypertrophic heart disease and demonstrate the feasibility of therapeutic microRNA targeting of inflammation in heart failure.