Myocardial Interstitial Fibrosis Research Articles

Brief Repetitive Pressure Overload Elicits a Fibrosis-Independent Reduction in Left Ventricular Diastolic Compliance in Swine

Objective: We have previously shown that swine subjected to repetitive pressure overload (RPO) via daily 2-hr infusions of phenylephrine (PE) develop a reduction in left ventricular (LV) diastolic compliance that coincides with increased interstitial myocardial fibrosis. The objective of the present study was to determine if brief episodes of RPO produce a similar cardiac phenotype. Methods: Swine (n=6) were subjected to a single 30-min PE infusion (300 μg/min) to determine if brief pressure overload causes myocardial injury (circulating cardiac troponin I; cTnI), inflammation (IL-6), and cardiac dysfunction (echocardiography). A separate group of swine (n=5) were subsequently instrumented with an indwelling venous catheter to enable daily 30-min PE infusions for 2 weeks (“Brief RPO”). LV diastolic compliance (ΔLVEDV/ΔLVEDP during PE) and interstitial fibrosis (picrosirius red staining) were compared to values derived from swine subjected to prolonged RPO (2-hr PE/day; n=8) and age-matched controls (n=8). Results: A single episode of brief pressure overload led to an increase in circulating cTnI (from 22±6 ng/L at baseline to 365±12 ng/L 3-hours post-PE) and IL-6 (from 10±2 to 34±4 pg/mL), along with a transient reduction in LV ejection fraction (from 65±2 to 45±5 %, all p<0.05). Brief RPO led to a significant reduction in LV diastolic compliance (ΔLVEDV/ΔLVEDP: 0.59±0.13 mL/mmHg vs. 1.87±0.12 mL/mmHg in controls; p<0.01) that was nearly identical to that observed after prolonged RPO (0.58±0.17 mL/mmHg, p=0.95). Surprisingly, in contrast to prolonged RPO (10.0±1.4% collagen) the brief RPO-induced reduction in LV compliance was not accompanied by an increase in interstitial fibrosis (5.0±0.3 % collagen vs. 5.0±0.3 % collagen in controls, p=0.95). Conclusion: Brief pressure overload initially causes myocardial injury and inflammation, with repetitive exposure leading to a reduction in LV compliance that is similar to that observed following prolonged RPO. However, the brief RPO-induced reduction in LV compliance occurs in the absence of fibrosis, suggesting that mechanisms of repetitive stretch-induced myocardial stiffening may depend on the duration of episodic pressure overload. Supported by funding from the U.S. Department of Veterans Affairs and National Institutes of Health. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Supramolecular self‐assembled nanoparticles for targeted therapy of myocardial infarction by enhancing cardiomyocyte mitophagy

AbstractMyocardial infarction accompanied by diabetes mellitus is accepted as the most serious type of coronary heart disease, and among the current treatment strategies, the precise delivery of protective drugs for inhibiting cardiomyocyte apoptosis is still a challenge. In this study, we developed a biodegradable nanoparticles‐based delivery system with excellent macrophage escape, cardiac targeting, and drug release properties to achieve targeted therapy of myocardial infarction. Specifically, a copolymer of p(DMA–MPC–CD) combining self‐adhesion, hydration lubrication, and targeting peptide binding site was successfully prepared by free radical copolymerization, and it was self‐assembled on the surface of melatonin‐loaded dendritic mesoporous silica nanoparticles (bMSNs) following the integration of adamantane‐modified cardiac homing peptide (CHP) based on supramolecular host–guest interaction. Importantly, a hydration layer formed around the zwitterionic phosphorylcholine groups of the multifunctional nanoparticles, which was confirmed by the enhancement in hydration lubrication and reduction in coefficient of friction, prevented the nanoparticles from phagocytosis by the macrophages. The in vivo bioluminescence imaging test indicated that the nanoparticles were endowed with satisfied cardiac targeting capability, and the in vivo mice study demonstrated that the intravenous injection of drug‐loaded nanoparticles (namely bMSNs–Mel@PDMC–CHP) effectively reduced cardiomyocyte apoptosis, alleviated myocardial interstitial fibrosis, and enhanced cardiac function.

New Mechanisms to Prevent Heart Failure with Preserved Ejection Fraction Using Glucagon-like Peptide-1 Receptor Agonism (GLP-1 RA) in Metabolic Syndrome and in Type 2 Diabetes: A Review.

This review examines the impact of obesity on the pathophysiology of heart failure with preserved ejection fraction (HFpEF) and focuses on novel mechanisms for HFpEF prevention using a glucagon-like peptide-1 receptor agonism (GLP-1 RA). Obesity can lead to HFpEF through various mechanisms, including low-grade systemic inflammation, adipocyte dysfunction, accumulation of visceral adipose tissue, and increased pericardial/epicardial adipose tissue (contributing to an increase in myocardial fat content and interstitial fibrosis). Glucagon-like peptide 1 (GLP-1) is an incretin hormone that is released from the enteroendocrine L-cells in the gut. GLP-1 reduces blood glucose levels by stimulating insulin synthesis, suppressing islet α-cell function, and promoting the proliferation and differentiation of β-cells. GLP-1 regulates gastric emptying and appetite, and GLP-1 RA is currently indicated for treating type 2 diabetes (T2D), obesity, and metabolic syndrome (MS). Recent evidence indicates that GLP-1 RA may play a significant role in preventing HFpEF in patients with obesity, MS, or obese T2D. This effect may be due to activating cardioprotective mechanisms (the endogenous counter-regulatory renin angiotensin system and the AMPK/mTOR pathway) and by inhibiting deleterious remodeling mechanisms (the PKA/RhoA/ROCK pathway, aldosterone levels, and microinflammation). However, there is still a need for further research to validate the impact of these mechanisms on humans.

426 A Beat Away from Precision Medicine: Characterizing Human Cardiac Fibroblast Responsiveness to Hemodynamic Unloading in Heart Failure with Reduced Ejection Fraction

OBJECTIVES/GOALS: Myocardial interstitial fibrosis leads to high hemodynamic load resulting in heart failure (HFrEF). Previous studies show that treatment with a left ventricular assist device (LVAD) does not reduce fibrosis. We hypothesize that human cardiac fibroblasts are highly activated in HFrEF and remain unresponsive to hemodynamic unloading by LVAD. METHODS/STUDY POPULATION: Forty human subjects with HFrEF undergoing LVAD implantation were enrolled to provide a portion of myocardium routinely removed during LVAD placement. In addition, 7 biopsies previously collected from transplanted hearts with extended LVAD treatment were also evaluated (LVEX). RESULTS/ANTICIPATED RESULTS: Quantification of PSR-stained sections reveals a significant increase in collagen content in the HFrEF tissue (CVF = 2.8) compared to control tissues (CVF = 0.9) that remained elevated in LVEX hearts (CVF = 3.1). HCFs from LV biopsies were isolated and grown to confluence. HCFs from HFrEF patients and control HCFs were plated on substrates with stiffnesses reflective of normal myocardium (2kPa) or HFrEF myocardium (8kPa). Cells were collected at 4- and 7-day time points and levels of collagen I and alpha-smooth muscle actin were quantified by western blot analysis. Control HCFs were responsive to changes in substrate stiffness producing more Col I and a-SMA on 8kPa versus 2kPa, HCFs from HFrEF patients were unresponsive to changes in stiffness exhibiting no significant difference in protein production on 2 vs. 8kPa. DISCUSSION/SIGNIFICANCE: Our data suggests that HCFs isolated from the failing myocardium do not respond to changes in mechanical load and might contribute to persistent increases in fibrosis. These findings bring us one step closer to elucidating mechanisms behind fibrosis in HFrEF which could lead to targeted therapies to improve patient outcomes from LVAD support.

Deficiency of heme oxygenase 1a causes detrimental effects on cardiac function.

Humans lacking heme oxygenase 1 (HMOX1) display growth retardation, haemolytic anaemia, and vulnerability to stress; however, cardiac function remains unclear. We aimed to explore the cardiac function of zebrafish lacking hmox1a at baseline and in response to stress. We generated zebrafish hmox1a mutants using CRISPR/Cas9 genome editing technology. Deletion of hmox1a increases cardiac output and further induces hypertrophy in adults. Adults lacking hmox1a develop myocardial interstitial fibrosis, restrain cardiomyocyte proliferation and downregulate renal haemoglobin and cardiac antioxidative genes. Larvae lacking hmox1a fail to respond to hypoxia, whereas adults are insensitive to isoproterenol stimulation in the heart, suggesting that hmox1a is necessary for cardiac response to stress. Haplodeficiency of hmox1a stimulates non-mitochondrial respiration and cardiac cell proliferation, increases cardiac output in larvae in response to hypoxia, and deteriorates cardiac function and structure in adults upon isoproterenol treatment. Intriguingly, haplodeficiency of hmox1a upregulates cardiac hmox1a and hmox1b in response to isoproterenol. Collectively, deletion of hmox1a results in cardiac remodelling and abrogates cardiac response to hypoxia and isoproterenol. Haplodeficiency of hmox1a aggravates cardiac response to the stress, which could be associated with the upregulation of hmox1a and hmox1b. Our data suggests that HMOX1 homeostasis is essential for maintaining cardiac function and promoting cardioprotective effects.

Associations of Circulating Vascular Cell Adhesion Molecule-1 and Intercellular Adhesion Molecule-1 With Long-Term Cardiac Function.

Although VCAM-1 (vascular cell adhesion molecule-1) and ICAM-1 (intercellular adhesion molecule-1) have been associated with incident heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF), the associations of VCAM-1 and ICAM-1 with sensitive measures of cardiac structure/function are unclear. The objective of this study is to evaluate associations between VCAM-1, ICAM-1, and measures of cardiac structure and function as potential pathways through which cellular adhesion molecules promote HFpEF and AF risk. In MESA (Multi-Ethnic Study of Atherosclerosis), we evaluated the associations of circulating VCAM-1 and ICAM-1 at examination 2 (2002-2004) with measures of cardiac structure/function on cardiac magnetic resonance imaging at examination 5 (2010-2011) after multivariable adjustment. Mediation analysis of left atrial (LA) strain on the association between VCAM-1 or ICAM-1 and AF or HFpEF was also performed. Overall, 2304 individuals (63±10 years; 47% men) with VCAM-1 or ICAM-1, cardiac magnetic resonance imaging, and covariate data were included in analysis. Higher VCAM-1 and ICAM-1 were associated with lower LA peak longitudinal strain and worse global circumferential left ventricular strain but were not associated with left ventricular myocardial scar or interstitial fibrosis. Lower LA peak longitudinal strain mediated 8% (95% CI, 2-30) of the relationship between VCAM-1 and HFpEF and 9% (95% CI, 2-21) of the relationship between VCAM-1 and AF. Higher VCAM-1 and ICAM-1 were associated with lower LA function and left ventricular systolic function but were not associated with myocardial scar or interstitial fibrosis. VCAM-1 and ICAM-1 may promote HFpEF and AF risk through impaired LA reservoir function.

Aerobic Exercise Attenuates Pressure Overload-Induced Myocardial Remodeling and Myocardial Inflammation via Upregulating miR-574-3p in Mice.

Exercise training can promote cardiac rehabilitation, thereby reducing cardiovascular disease mortality and hospitalization rates. MicroRNAs (miRs) are closely related to heart disease, among which miR-574-3p plays an important role in myocardial remodeling, but its role in exercise-mediated cardioprotection is still unclear. A mouse myocardial hypertrophy model was established by transverse aortic coarctation, and a 4-week swimming exercise training was performed 1 week after the operation. After swimming training, echocardiography was used to evaluate cardiac function in mice, and histopathologic staining was used to detect cardiac hypertrophy, myocardial fibrosis, and cardiac inflammation. Quantitative real-time polymerase chain reaction was used to detect the expression levels of miR-574-3p and cardiac hypertrophy markers. Western blotting detected the IL-6 (interleukin-6)/JAK/STAT inflammatory signaling pathway. Echocardiography and histochemical staining found that aerobic exercise significantly improved pressure overload-induced myocardial hypertrophy (n=6), myocardial interstitial fibrosis (n=6), and cardiac inflammation (n=6). Quantitative real-time polymerase chain reaction detection showed that aerobic exercise upregulated the expression level of miR-574-3p (n=6). After specific knockdown of miR-574-3p in mouse hearts with adeno-associated virus 9 using cardiac troponin T promoter, we found that the protective effect of exercise training on the heart was significantly reversed. Echocardiography and histopathologic staining showed that inhibiting the expression of miR-574-3p could partially block the effects of aerobic exercise on cardiac function (n=6), cardiomyocyte cross-sectional area (n=6), and myocardial fibrosis (n=6). Western blotting and immunohistochemical staining showed that the inhibitory effects of aerobic exercise on the IL-6/JAK/STAT pathway and cardiac inflammation were partially abolished after miR-574-3p knockdown. Furthermore, we also found that miR-574-3p exerts cardioprotective effects in cardiomyocytes by targeting IL-6 (n=3). Aerobic exercise protects cardiac hypertrophy and inflammation induced by pressure overload by upregulating miR-574-3p and inhibiting the IL-6/JAK/STAT pathway.

Insights into the effects of Friedreich ataxia on the left ventricle using T1 mapping and late gadolinium enhancement.

The left ventricular (LV) changes which occur in Friedreich ataxia (FRDA) are incompletely understood. Cardiac magnetic resonance (CMR) imaging was performed using a 1.5T scanner in subjects with FRDA who are homozygous for an expansion of an intron 1 GAA repeat in the FXN gene. Standard measurements were performed of LV mass (LVM), LV end-diastolic volume (LVEDV) and LV ejection fraction (LVEF). Native T1 relaxation time and the extracellular volume fraction (ECV) were utilised as markers of left ventricular (LV) diffuse myocardial fibrosis and late gadolinium enhancement (LGE) was utilised as a marker of LV replacement fibrosis. FRDA genetic severity was assessed using the shorter FXN GAA repeat length (GAA1). There were 93 subjects with FRDA (63 adults, 30 children, 54% males), 9 of whom had a reduced LVEF (<55%). A LVEDV below the normal range was present in 39%, a LVM above the normal range in 22%, and an increased LVM/LVEDV ratio in 89% subjects. In adults with a normal LVEF, there was an independent positive correlation of LVM with GAA1, and a negative correlation with age, but no similar relationships were seen in children. GAA1 was positively correlated with native T1 time in both adults and children, and with ECV in adults, all these associations independent of LVM and LVEDV. LGE was present in 21% of subjects, including both adults and children, and subjects with and without a reduced LVEF. None of GAA1, LVM or LVEDV were predictors of LGE. An association between diffuse interstitial LV myocardial fibrosis and genetic severity in FRDA was present independently of FRDA-related LV structural changes. Localised replacement fibrosis was found in a minority of subjects with FRDA and was not associated with LV structural change or FRDA genetic severity in subjects with a normal LVEF.

Cardiac Magnetic Resonance Visualization of the Myocardial Microstructure in Non-Ischemic Cardiomyopathies

Cardiac magnetic resonance (CMR), a non-radiation based type of examination, can achieve the simultaneous comprehensive multi-parameter, multi-plane, and multi-sequence evaluation of the anatomical structure of the heart; and at the same time, determine systolic and diastolic function, and blood perfusion and tissue characteristics. Traditional late gadolinium enhancement imaging based on CMR reflects focal replacement fibrosis, in contrast to normal myocardial signal intensity, but cannot effectively identify diffuse myocardial fibrosis. T1 mapping and its derived extracellular volume fraction can be used to quantitatively analyze the extracellular space in myocardial tissue and evaluate diffuse myocardial interstitial fibrosis that is invisible to the naked eye. Diffusion tensor imaging reveals the direction of cardiomyocyte aggregates by quantifying the anisotropy of water molecule diffusion, and can be applied to evaluate the integrity of myocardial tissue and arrangement structure of myocardial microstructural characteristics. On the basis of the micro-motion of myocardial tissue, feature tracking analysis decomposes myocardial deformation into three dimensions of micro-mechanical changes, and can identify early systolic and diastolic dysfunction before heart enlargement or ejection fraction reduction. This Commentary discusses current research advances in these new techniques, as well as their clinical application prospects and limitations for non-ischemic cardiomyopathies.

Myocardial Interstitial Fibrosis in Hypertensive Heart Disease: From Mechanisms to Clinical Management.

Hypertensive heart disease (HHD) can no longer be considered as the beneficial adaptive result of the hypertrophy of cardiomyocytes in response to pressure overload leading to the development of left ventricular hypertrophy. The current evidence indicates that in patients with HHD, pathological lesions in the myocardium lead to maladaptive structural remodeling and subsequent alterations in cardiac function, electrical activity, and perfusion, all contributing to poor outcomes. Diffuse myocardial interstitial fibrosis is probably the most critically involved lesion in these disorders. Therefore, in this review, we will focus on the histological characteristics, the mechanisms, and the clinical consequences of myocardial interstitial fibrosis in patients with HHD. In addition, we will consider the most useful tools for the noninvasive diagnosis of myocardial interstitial fibrosis in patients with HHD, as well as the most effective available therapeutic strategies to prevent its development or facilitate its regression in this patient population. Finally, we will issue a call to action for the need for more fundamental and clinical research on myocardial interstitial fibrosis in HHD.

Coronary Microvascular Dysfunction and Hypertension: A Bond More Important than We Think.

Coronary microvascular dysfunction (CMD) is a clinical entity linked with various risk factors that significantly affect cardiac morbidity and mortality. Hypertension, one of the most important, causes both functional and structural alterations in the microvasculature, promoting the occurrence and progression of microvascular angina. Endothelial dysfunction and capillary rarefaction play the most significant role in the development of CMD among patients with hypertension. CMD is also related to several hypertension-induced morphological and functional changes in the myocardium in the subclinical and early clinical stages, including left ventricular hypertrophy, interstitial myocardial fibrosis, and diastolic dysfunction. This indicates the fact that CMD, especially if associated with hypertension, is a subclinical marker of end-organ damage and heart failure, particularly that with preserved ejection fraction. This is why it is important to search for microvascular angina in every patient with hypertension and chest pain not associated with obstructive coronary artery disease. Several highly sensitive and specific non-invasive and invasive diagnostic modalities have been developed to evaluate the presence and severity of CMD and also to investigate and guide the treatment of additional complications that can affect further prognosis. This comprehensive review provides insight into the main pathophysiological mechanisms of CMD in hypertensive patients, offering an integrated diagnostic approach as well as an overview of currently available therapeutical modalities.

Imaging for the assessment of the arrhythmogenic potential of mitral valve prolapse.

Mitral valve prolapse (MVP) is the most common valve disease in the western world and recently emerged as a possible substrate for sudden cardiac death (SCD). It is estimated an annual risk of sudden cardiac death of 0.2 to 1.9% mostly caused by complex ventricular arrhythmias (VA). Several mechanisms have been recognized as potentially responsible for arrhythmia onset in MVP, resulting from the combination of morpho-functional abnormality of the mitral valve, structural substrates (regional myocardial hypertrophy, fibrosis, Purkinje fibers activity, inflammation), and mechanical stretch. Echocardiography plays a central role in MVP diagnosis and assessment of severity of regurgitation. Several abnormalities detectable by echocardiography can be prognostic for the occurrence of VA, from morphological alteration including leaflet redundancy and thickness, mitral annular dilatation, and mitral annulus disjunction (MAD), to motion abnormalities detectable with "Pickelhaube" sign. Additionally, speckle-tracking echocardiography may identify MVP patients at higher risk for VA by detection of increased mechanical dispersion. On the other hand, cardiac magnetic resonance (CMR) has the capability to provide a comprehensive risk stratification combining the identification of morphological and motion alteration with the detection of myocardial replacement and interstitial fibrosis, making CMR an ideal method for arrhythmia risk stratification in patients with MVP. Finally, recent studies have suggested a potential role in risk stratification of new techniques such as hybrid PET-MR and late contrast enhancement CT. The purpose of this review is to provide an overview of the mitral valve prolapse syndrome with a focus on the role of imaging in arrhythmic risk stratification. CLINICAL RELEVANCE STATEMENT: Mitral valve prolapse is the most frequent valve condition potentially associated with arrhythmias. Imaging has a central role in the identification of anatomical, functional, mechanical, and structural alterations potentially associated with a higher risk of developing complex ventricular arrhythmia and sudden cardiac death. KEY POINTS: • Mitral valve prolapse is a common valve disease potentially associated with complex ventricular arrhythmia and sudden cardiac death. • The mechanism of arrhythmogenesis in mitral valve prolapse is complex and multifactorial, due to the interplay among multiple conditions including valve morphological alteration, mechanical stretch, myocardial structure remodeling with fibrosis, and inflammation. • Cardiac imaging, especially echocardiography and cardiac magnetic resonance, is crucial in the identification of several features associated with the potential risk of serious cardiac events. In particular, cardiac magnetic resonance has the advantage of being able to detect myocardial fibrosis which is currently the strongest prognosticator.

Blockade of BLyS inhibits B-cell responses and antibody production for the prevention of chronic transplant rejection

BACKGROUNDChronic rejection, closely related to the activation of B cells and donor-specific antibody (DSA) production, has unsatisfactory therapeutic outcomes. B lymphocyte stimulator (BLyS) is a major regulatory factor that controls the activation and differentiation of B cells. However, it remains unclear whether BLyS blockade can regulate B and plasma cells in the transplantation setting and affect chronic rejection. Here, we investigated the efficacy of the BLyS inhibitors belimumab and telitacicept in controlling B-cell response and preventing chronic rejection. METHODSThe effects of belimumab and telitacicept on B-cell activation, differentiation and antibody production in vitro were determined. A chronic rejection model in mouse was established by allogeneic cardiac transplantation with CTLA4-Ig treatment. Allograft survival, histology, DSA levels, and B-cell responses were analyzed to evaluate the chronic rejection-preventive effects of belimumab and telitacicept. RESULTSIn vitro experiments confirmed that belimumab and telitacicept inhibited B-cell activation and differentiation and reduced antibody production. In vivo experiments indicated that they significantly prolonged allograft survival, attenuated chronic rejection through significant suppression of myocardial ischemic necrosis and interstitial fibrosis, and reduced DSA-IgG levels, C4d deposition, and inflammatory cell infiltration. Furthermore, the frequencies of B cells, plasma cells and IgG producing cells in the recipients’ spleen, lymph nodes, bone marrow, and blood were decreased after BLyS inhibitors treatment. CONCLUSIONSThis study demonstrated that belimumab and telitacicept inhibit B-cell responses and antibody production and alleviate chronic transplant rejection. Therefore, BLyS inhibitors are expected to be used for the prevention of chronic rejection in clinical practice.

Is there a role for cardiovascular magnetic resonance imaging in the assessment of biological aortic valves?

Patients with biological aortic valves (following either surgical aortic valve replacement [SAVR] or trans catheter aortic valve implantation [TAVI]) require lifelong follow-up with an imaging modality to assess prosthetic valve function and dysfunction. Echocardiography is currently the first-line imaging modality to assess biological aortic valves. In this review, we discuss the potential role of cardiac magnetic resonance imaging (CMR) as an additional imaging modality in situations of inconclusive or equivocal echocardiography. Planimetry of the prosthetic orifice can theoretically be measured, as well as the effective orifice area, with potential limitations, such as CMR valve-related artefacts and calcifications in degenerated prostheses. The true benefit of CMR is its ability to accurately quantify aortic regurgitation (paravalvular and intra-valvular) with a direct and reproducible method independent of regurgitant jet morphology to accurately assess reverse remodelling and non-invasively detect focal and interstitial diffuse myocardial fibrosis. Following SAVR or TAVI for aortic stenosis, interstitial diffuse fibrosis can regress, accompanied by structural and functional improvement that CMR can accurately assess.

Association of Lipoprotein(a) Levels With Myocardial Fibrosis in the Multi-Ethnic Study of Atherosclerosis.

Lipoprotein(a) (Lp[a]) has been identified as an emerging risk factor for adverse cardiovascular (CV) outcomes, including heart failure. However, the connections among Lp(a), myocardial fibrosis (interstitial and replacement), and cardiac remodeling as pathways to CV diseases remains unclear. This study investigated the relationship between Lp(a) levels and myocardial fibrosis by cardiac magnetic resonance (CMR) T1 mapping and late gadolinium enhancement, as well as cardiac remodeling by cine CMR, in the MESA (Multi-Ethnic Study of Atherosclerosis) cohort. The study included 2,040 participants with baseline Lp(a) measurements and T1 mapping for interstitial myocardial fibrosis (IMF) evaluation in 2010. Lp(a) was analyzed as a continuous variable (per log unit) and using clinical cutoff values of 30 and 50mg/dL. Multivariate linear and logistic regression were used to assess the associations of Lp(a) with CMR measures of extracellular volume (ECV fraction [ECV%]), native T1 time, and myocardial scar, as well as parameters of cardiac remodeling, in 2,826 participants. Higher Lp(a) levels were associated with increased ECV% (per log-unit Lp[a]; β=0.2%; P=0.007) and native T1 time (per log-unit Lp[a]; β=4%; P< 0.001). Similar relationships were observed between elevated Lp(a) levels and a higher risk of clinically significant IMF defined by prognostic thresholds per log-unit Lp(a) of ECV% (OR: 1.20; 95%CI: 1.04-1.43) and native T1 (OR: 1.2; 95%CI: 1.1-1.4) equal to 30% and 955ms, respectively. Clinically used Lp(a) cutoffs (30 and 50mg/dL) were associated with greater prevalence of myocardial scar (OR: 1.85; 95%CI: 1.1-3.2 and OR: 1.9; 95%CI: 1.1-3.4, respectively). Finally, higher Lp(a) levels were associated with left atrial enlargement and dysfunction. Elevated Lp(a) levels are linked to greater subclinical IMF, increased myocardial scar prevalence, and left atrial remodeling.

Thrombotic Thrombocytopenic Purpura (TTP) Survivors Exhibit Impaired Stress Perfusion on Cardiac MRI

Introduction: Thrombotic thrombocytopenic purpura (TTP) survivors have increased rates of cardiovascular morbidity and mortality when compared with the general population. In this prospective pilot study, we sought to further characterize the long-term cardiovascular sequelae of TTP survivors through pharmacologic stress cardiac magnetic resonance imaging (CMR). Stress CMR has been increasingly utilized to detect clinical and subclinical structural and functional changes. A CMR biomarker of myocardial remodeling is extracellular volume (ECV); an increase in ECV may indicate the development of interstitial myocardial fibrosis. ECV was chosen for structural assessment as it has been implicated with diastolic dysfunction and other cardiac issues in other hematologic diseases, like sickle cell anemia. Methods: Adult patients (age ≥18 years of age) with TTP (immune-mediated or congenital) in the Ohio State University (OSU) TTP registry were prospectively consented and enrolled from March 2023 through July 2023 to undergo adenosine stress CMR at standard clinical dosing. All patients in the TTP cohort had confirmed diagnosis based on ADAMTS13 activity &amp;lt;15% during an acute episode and were in clinical remission at the time of CMR testing. Standard baseline and stress CMR parameters were obtained and compared with an age and sex matched control population, selected from patients without TTP who underwent identical stress CMR protocol for other indications and demonstrated normal stress perfusion. Patients in the control cohort predominantly had diagnoses of arrhythmia, stable angina, or heart failure. We collected data on patient demographics, details of TTP history, and underlying comorbidities. On CMR standard structural measurements were evaluated, and ECV was calculated (normal range 25.3 ± 3.5%). Perfusion was measured per standard protocols via global myocardial blood flow (MBF) as ml/min/g. Differences between the TTP and control populations were tested using the Fischer's exact test for categorical variables and Mann-Whitney U test for continuous variables. Results: A total of 10 TTP patients (9 immune-mediated, 1 congenital) were enrolled between March and July 2023. Median age at enrollment was 44.5 years (IQR 40.8-49.5) and 80% (8/10) were female. Patients were in documented clinical and ADAMTS13 activity remission with median ADAMTS13 activity of 68% (64.0-84.5), excluding the activity level of the congenital patient. Median time from initial diagnosis was 15 years (range 0.5 - 41 years) and median number of acute TTP episodes was 2 (IQR 1.0-4.5). Characteristics of the study (n= 10) and control cohort (n = 13) are summarized in Table 1. There were no significant differences in the TTP and control cohorts with respect to age, sex, race, and presence of hypertension or diabetes. Patients in the TTP cohort had significantly higher BMI (median 34.5 mg/m 2 vs 26.5 mg/m 2, p = .012), diastolic blood pressure (94 mmHg vs 82 mmHg, p = .003), and a lower rate of known cardiac disease (10% vs 85%, p&amp;lt;.001). Stress CMR showed reduced myocardial perfusion in TTP survivors: Nine out of 10 (90%) TTP survivors had evidence of structural or perfusion deficits on CMR. The median ECV in the TTP cohort (28.5%, 24.8 - 31.5) was increased compared with controls (26%, 23.5 - 27.5) though it did not reach significance (p = .08). There were no significant differences in median global MBF at rest in the TTP group (1.30, 1.16 - 1.37) compared with controls (1.18, 1.07 - 1.31, p = .210). However, TTP survivors had significantly reduced stress MBF (3.28, 2.21 - 3.53) vs controls (4.1, 3.88 - 4.22, p &amp;lt;.001) with adenosine. Reductions in quantitative stress perfusion in the TTP cohort was primarily noted in the subendocardium as shown in Figure 2. Conclusion: Asymptomatic structural changes and reduction in quantitative perfusion are common in TTP survivors. The study is ongoing to recruit more patients to ensure clinical significance and generalizability of these preliminary findings. Stress CMR may detect subclinical myocardial damage in TTP survivors who otherwise do not exhibit overt cardiovascular symptoms until a later time and may provide the basis to understand increased cardiovascular morbidity and mortality in this population.

Reproductive Factors Linked With Myocardial Fibrosis: MESA (Multi-Ethnic Study of Atherosclerosis)

BackgroundRecent evidence has shown that reproductive factors are associated with an increased risk of heart failure with preserved ejection fraction in women. However, the pathogenic pathways underlying this relationship are unclear. Subclinical myocardial fibrosis has been found to be a common pathway in a large proportion of patients with heart failure with preserved ejection fraction. ObjectivesThis study examined the relationship between vital reproductive factors (parity, pregnancy, age at menopause, and use of hormone replacement therapy [HRT]) with interstitial myocardial fibrosis (IMF) and myocardial scar measured by cardiac magnetic resonance imaging (CMR) T1 mapping and late gadolinium enhancement, respectively. MethodsThere were 596 female participants (mean age 67 ± 8 years) enrolled in MESA (Multi-Ethnic Study of Atherosclerosis) who had complete parity data and underwent CMR. Parity was categorized as 0 live births, 1 to 2, 3 to 4, and ≥5 live births. Multivariable regression models were constructed to assess the associations of parity status, history of null gravidity, age at menopause and HRT with CMR obtained measures of IMF (extracellular volume [ECV], native-T1 time) and myocardial scar. ResultsWomen with a history of nulliparity had greater ECV% (β = 0.95 ± 0.28, P = 0.001) and native-T1 ms (β = 10.6 ± 4.9, P = 0.03) than those who had 1 to 2 live births. These associations were independent of age, traditional cardiovascular risk factors, and interim cardiovascular events. Similar associations were found for women with a history of null gravidity compared to those with a history of pregnancy (ECV% [β = 0.7 ± 0.3, P = 0.02] and native-T1 ms [β = 10.6 ± 5.2, P = 0.04]). There was no association between age at menopause and HRT with markers of IMF. There were no associations between parity status, null gravidity, and age of menopause with the presence of myocardial scar; however, those who used HRT were independently associated with a lesser risk of myocardial scar (OR: 0.20; 95% CI: 0.05-0.82). ConclusionsIn a multiethnic cohort, women with a history of nulliparity or null gravidity had greater IMF defined by CMR, while those who used HRT were less likely to have myocardial scar.

Higher HDL cholesterol levels are associated with increased markers of interstitial myocardial fibrosis in the MultiEthnic Study of Atherosclerosis (MESA)

Emerging research indicates that high HDL-C levels might not be cardioprotective, potentially worsening cardiovascular disease (CVD) outcomes. Yet, there is no data on HDL-C's association with other CVD risk factors like myocardial fibrosis, a key aspect of cardiac remodeling predicting negative outcomes. We therefore aimed to study the association between HDL-C levels with interstitial myocardial fibrosis (IMF) and myocardial scar measured by CMR T1-mapping and late-gadolinium enhancement (LGE), respectively. There were 1863 participants (mean age of 69 years) who had both serum HDL-C measurements and underwent CMR. Analysis was done among those with available indices of interstitial fibrosis (extracellular volume fraction [ECV]; N = 1172 and native-T1; N = 1863) and replacement fibrosis by LGE (N = 1172). HDL-C was analyzed as both logarithmically-transformed and categorized into < 40 (low),40–59 (normal), and ≥ 60mg/dL (high). Multivariable linear and logistic regression models were constructed to assess the associations of HDL-C with CMR-obtained measures of IMF, ECV% and native-T1 time, and myocardial scar, respectively. In the fully adjusted model, each 1-SD increment of log HDL-C was associated with a 1% increment in ECV% (p = 0.01) and an 18-ms increment in native-T1 (p < 0.001). When stratified by HDL-C categories, those with high HDL-C (≥ 60mg/dL) had significantly higher ECV (β = 0.5%, p = 0.01) and native-T1 (β = 7 ms, p = 0.01) compared with those with normal HDL-C levels. Those with low HDL-C were not associated with IMF. Results remained unchanged after excluding individuals with a history of myocardial infarction. Neither increasing levels of HDL-C nor any HDL-C category was associated with the prevalence of myocardial scar. Increasing levels of HDL-C were associated with increased markers of IMF, with those with high levels of HDL-C being linked to subclinical fibrosis in a community-based setting.

Clonal haematopoiesis of indeterminate potential predicts incident cardiac arrhythmias.

Clonal haematopoiesis of indeterminate potential (CHIP), the age-related expansion of blood cells with preleukemic mutations, is associated with atherosclerotic cardiovascular disease and heart failure. This study aimed to test the association of CHIP with new-onset arrhythmias. UK Biobank participants without prevalent arrhythmias were included. Co-primary study outcomes were supraventricular arrhythmias, bradyarrhythmias, and ventricular arrhythmias. Secondary outcomes were cardiac arrest, atrial fibrillation, and any arrhythmia. Associations of any CHIP [variant allele fraction (VAF) ≥ 2%], large CHIP (VAF ≥10%), and gene-specific CHIP subtypes with incident arrhythmias were evaluated using multivariable-adjusted Cox regression. Associations of CHIP with myocardial interstitial fibrosis [T1 measured using cardiac magnetic resonance (CMR)] were also tested. This study included 410 702 participants [CHIP: n = 13 892 (3.4%); large CHIP: n = 9191 (2.2%)]. Any and large CHIP were associated with multi-variable-adjusted hazard ratios of 1.11 [95% confidence interval (CI) 1.04-1.18; P = .001] and 1.13 (95% CI 1.05-1.22; P = .001) for supraventricular arrhythmias, 1.09 (95% CI 1.01-1.19; P = .031) and 1.13 (95% CI 1.03-1.25; P = .011) for bradyarrhythmias, and 1.16 (95% CI, 1.00-1.34; P = .049) and 1.22 (95% CI 1.03-1.45; P = .021) for ventricular arrhythmias, respectively. Associations were independent of coronary artery disease and heart failure. Associations were also heterogeneous across arrhythmia subtypes and strongest for cardiac arrest. Gene-specific analyses revealed an increased risk of arrhythmias across driver genes other than DNMT3A. Large CHIP was associated with 1.31-fold odds (95% CI 1.07-1.59; P = .009) of being in the top quintile of myocardial fibrosis by CMR. CHIP may represent a novel risk factor for incident arrhythmias, indicating a potential target for modulation towards arrhythmia prevention and treatment.

Relationship between myocardial strain, coronary microvascular dysfunction, and myocardial extracellular volume in patients with type 2 diabetes: a cross-sectional CMR study

Abstract Background Patients with diabetes often develop heart failure with preserved ejection and often demonstrate early indications of myocardial dysfunction by decreased strain, notably the global longitudinal (GLS). The underlying myocardial phenotypical changes in patients with diabetes are coronary microvascular dysfunction and myocardial interstitial fibrosis. The relation of these to strain-indicators of early systolic dysfunction is not established. Purpose We hypothesized that coronary microvascular function and interstitial fibrosis contribute to the subclinical myocardial dysfunction seen in patients with diabetes. Method With gadolinium contrast and adenosine-stress magnetic resonance imaging, we determined myocardial blood flow (MBF) and perfusion ratio (MPR) and extracellular volume (ECV; an imaging biomarker of diffuse fibrosis) in 211 patients with type 2 diabetes without macrovascular coronary artery disease and 25 control subjects. Left ventricular (LV) function was determined from its ejection fraction and 3D feature tracking of GLS, circumferential (GCS), and radial strains (GRS). Results Without a significant age- or sex-differences to control subjects, patients (median age 57 years [IQR 50, 67], 70% males) had a median diabetes duration of 12 [IQR 6, 18] years. LV ejection fraction was normal and similar to controls. Compared to control subjects (GLS -13.9±2.0%), GLS, GCS and GRS were reduced in the total diabetes cohort, and GLS was reduced also in the subgroup of patients without any diabetes complications (total -11.6±3.0%; without-complications -12.3±2.6%). GLS, but not GCS or GRS or LVEF, was associated with albuminuria (b (95%CI) 1.09 (0.22-1.96)) and autonomic neuropathy (b (95%CI) 1.43 (0.54-2.31)). Independently of ECV, a 10% increase in MBF at adenosine-stress and MPR was associated with improved GLS in uni- and multivariable regression analyses. A 10% increase in ECV was associated with a decrease in GLS in univariable and multivariable regression analysis, but this was abolished when adjusted for MPR. GLS showed a moderate ability to discriminate a significantly lowered myocardial blood flow at stress defined as &amp;lt;1.49 mL/min/g (AUC 0.72, GLS threshold -11.5%; sensitivity 75% and specificity 53%) and myocardial perfusion ratio defined as as &amp;lt;2.1 (AUC 0.73, GLS threshold -10.8% resulted in a sensitivity of 71% and a specificity of 70%). GLS had a poor ability to predict increased extracellular volume defined as &amp;gt; 31% (AUC 0.60, GLS threshold -13.5 resulted in a sensitivity of 72% and a specificity of 34%). Conclusion Of the two important phenotypical changes seen with type 2 diabetes, microvascular dysfunction and fibrosis, coronary microvacular dysfunction demonstrates the more important relation to early systolic compromise as determined from the left ventricle global longitudinal strain.Associations of Systolic parametersROC curve