Aims Diastolic heart failure is a frequent entity but difficult to diagnose. N-terminal pro-B type natriuretic peptide (NT-proBNP) was therefore investigated as a possible non-invasive parameter to ...diagnose isolated diastolic dysfunction. Methods and results Sixty-eight symptomatic patients with isolated diastolic dysfunction and preserved left ventricular ejection fraction (LVEF) (≥50%) and 50 patients with regular left ventricular (LV) function were examined by conventional echocardiography, tissue Doppler imaging (TDI), and left and right heart catheterization. Plasma NT-proBNP levels were determined simultaneously. Median NT-proBNP plasma levels were elevated 189.54 pg/mL (86.16–308.27) vs. 51.89 pg/mL (29.94–69.71); P<0.001 and increased with greater severity of the diastolic dysfunction (R=0.67, P<0.001). According to the recevier operating characteristic analysis, LV end-diastolic pressure area under the curve (AUC) 0.84 was the most specific parameter, which had a low sensitivity (61%), however. The reliability of NT-proBNP was similar to TDI indices (AUC 0.83 vs. 0.81) and improved when compared with conventional echocardiography (AUC 0.59–0.70). NT-proBNP levels had the best negative predictive value of all methods (94%) and correlated strongly with indices of LV filling pressure, as determined by invasive measurements. Multivariable linear regression analysis confirmed NT-proBNP as an independent predictor of diastolic dysfunction with an Odds ratio of 1.2 (1.1–1.4, CI 95%) for every unit increase of NT-proBNP. Conclusion NT-proBNP can reliably detect the presence of isolated diastolic dysfunction in symptomatic patients and is an useful tool to rule out patients with reduced exercise tolerance of non-cardiac origin.
Despite the ongoing global pandemic, the impact of COVID-19 on cardiac structure and function is still not completely understood. Myocarditis is a rare but potentially serious complication of other ...viral infections with variable recovery, and is, in some cases, associated with long-term cardiac remodeling and functional impairment.
To assess myocardial injury in patients who recently recovered from an acute SARS-CoV-2 infection with advanced cardiac magnetic resonance imaging (CMR) and endomyocardial biopsy (EMB).
In total, 32 patients with persistent cardiac symptoms after a COVID-19 infection, 22 patients with acute classic myocarditis not related to COVID-19, and 16 healthy volunteers were included in this study and underwent a comprehensive baseline CMR scan. Of these, 10 patients post COVID-19 and 13 with non-COVID-19 myocarditis underwent a follow-up scan. In 10 of the post-COVID-19 and 15 of the non-COVID-19 patients with myocarditis endomyocardial biopsy (EMB) with histological, immunohistological, and molecular analysis was performed.
In total, 10 (31%) patients with COVID-19 showed evidence of myocardial injury, eight (25%) presented with myocardial oedema, eight (25%) exhibited global or regional systolic left ventricular (LV) dysfunction, and nine (28%) exhibited impaired right ventricular (RV) function. However, only three (9%) of COVID-19 patients fulfilled updated CMR-Lake Louise criteria (LLC) for acute myocarditis. Regarding EMB, none of the COVID-19 patients but 87% of the non-COVID-19 patients with myocarditis presented histological findings in keeping with acute or chronic inflammation. COVID-19 patients with severe disease on the WHO scale presented with reduced biventricular longitudinal function, increased RV mass, and longer native T1 times compared with those with only mild or moderate disease.
In our cohort, CMR and EMB findings revealed that SARS-CoV-2 infection was associated with relatively mild but variable cardiac involvement. More symptomatic COVID-19 patients and those with higher clinical care demands were more likely to exhibit chronic inflammation and impaired cardiac function compared to patients with milder forms of the disease.
Increased levels of interleukin-6 (IL-6) have been observed in patients with acute myocarditis and are associated with poor prognosis. This study was designed to examine whether treatment with ...anti-IL-6 receptor antibody improves cardiac dysfunction and left ventricular (LV) remodeling in experimental Coxsackie virus B3 (CVB3)-induced myocarditis. C57BL6/J mice were subjected to acute CVB3 infection. One day after viral infection mice were treated with a single injection of an anti-IL-6 receptor antibody (MR16-1, tocilizumab) or control IgG. Seven days after viral infection, LV function was examined by conductance catheter technique, cardiac remodeling assessed by estimation of titin phosphorylation, cardiac fibrosis, and inflammatory and antiviral response by immunohistochemistry, RT-PCR and cell culture experiments. Compared to controls, infected mice displayed an impaired systolic and diastolic LV function associated with an increase in cardiac inflammation, fibrosis and impaired titin phosphorylation. IL-6 receptor blockade led to a shift of the immune response to a Th1 direction and significant reduction of viral load. In addition, cardiac immune response, extracellular matrix regulation and titin function improved, resulting in a preserved LV function. IL-6 receptor blockade exerts cardiac beneficial effects by antiviral and immunomodulatory actions after induction of an acute murine CVB3 virus myocarditis.
Objective
To evaluate the regulation of matrix metalloproteinase (MMP)-2 in diabetic cardiomyopathy.
Methods
Left ventricle (LV) function was determined by a micro-tip catheter in streptozotocin ...(STZ)-induced diabetic rats, 2 or 6 weeks (w) after STZ-application. LV total collagen, collagen type I and III content were immunohistologically analyzed and quantified by digital image analysis. LV collagen type I, III and MMP-2 mRNA expression was quantified by real-time RT-PCR. LV pro- and active MMP-2 levels were analyzed by zymography; Smad 7, membrane type (MT)1-MMP and tissue inhibitor metalloproteinase (TIMP)-2 protein levels by Western Blot.
Results
STZ-induced diabetes was associated with a time-dependent impairment of LV diastolic and systolic function. This was paralleled by a time-dependent increase in LV total collagen content, despite reduced LV collagen type I and III mRNA levels, indicating a role of post-transcriptional/post-translational changes of extracellular matrix regulation. Six weeks (w) after STZ-injection, MMP-2 mRNA expression and pro-MMP-2 levels were 2.7-fold (
P
< 0.005) and 1.3-fold (
P
< 0.05) reduced versus controls, respectively, whereas active MMP-2 was decreased to undetectable levels 6 w post-STZ. Concomitantly, Smad 7 and TIMP-2 protein levels were 1.3-fold (
P
< 0.05) and 10-fold (
P
< 0.005) increased in diabetics versus controls, respectively, whereas the 45 kDa form of MT1-MMP was undetectable in diabetics.
Conclusion
Under STZ-diabetic conditions, cardiac fibrosis is associated with a dysregulation in extracellular matrix degradation. This condition is featured by reduced MMP-2 activity, concomitant with increased Smad 7 and TIMP-2 and decreased MT1-MMP protein expression, which differs from mechanisms involved in dilated and ischemic heart disease.
Aims
We aim to assess the reproducibility of QRS fragmentation (fQRS) on a multi‐centre dataset of patients with acute myocarditis (AM), including a histopathological validation in a subgroup with ...biopsy‐proven disease. Electrocardiogram (ECG) in patients with myocarditis is usually considered aspecific. ST changes and conduction anomalies have been commonly reported so far. We have previously described fQRS in patients with AM.
Methods and results
Patients admitted between 2008 and 2019 in two centres with a diagnosis of AM were included. Standard ECG, echocardiography, and cardiac magnetic resonance (CMR) findings were recorded at baseline and at follow‐up (FU). Eighty patients were analysed, 66 men (82%), with median age of 34 (26–43) years. Twenty‐two patients had biopsy‐proven AM. At presentation, 61 patients (76%) displayed fQRS. Median ejection fraction (EF) was 55% (43–60). Seventy‐two patients (90%) underwent CMR and displayed late gadolinium enhancement (LGE). ECG leads showed that fQRS correlated with distribution of LGE. In patients with positive biopsy, fQRS was present in 18 (81%). Median FU was 419 days (224–956). Complete FU was available for 64 patients (80%), and 33 patients (52%) displayed persistence of fQRS. Median EF was 60% (57–64). Eleven patients underwent a repeated biopsy at FU, eight of whom had persistent inflammation and fQRS. Fifteen patients (23%) had ventricular tachycardia, 14 of whom still showed fQRS.
Conclusions
In this cohort fQRS was confirmed as an additional useful ECG sign. Persistence of fQRS was associated with ongoing inflammation and with a poorer outcome in terms of ventricular function and occurrence of arrhythmias.
Aims
Increasing attention is being given to patients with heart failure and ‘mid‐range’ left ventricular ejection fraction (LVEF, ≥40% and <50%) for whom there are no approved therapies that improve ...prognosis. We aim to assess for the first time the effects of cardiac contractility modulation (CCM) therapy in this patient population.
Methods and results
We assessed the effects of 6‐ month CCM therapy on functional status, exercise tolerance and quality of life in a subgroup of 53 patients with a LVEF of 40–45% recruited in previous CCM studies, including 37 patients in the CCM group and 16 in the control group. New York Heart Association classification improved by ≥1 class from baseline to 24 weeks in 80.6% (95% confidence interval 62.5%, 92.5%) of patients in the CCM group compared with 57.1% in the control group (95% confidence interval 28.9%, 82.3%, P = 0.15). Six‐minute walk distance increased significantly in the CCM group with a net between‐group treatment effect of 53.9 ± 74.2 m (P = 0.05). Peak VO2 improved in the CCM group with a net between‐group treatment effect of 2.0 ± 2.8 mL/kg/min (P = 0.02). Minnesota Living with Heart Failure Questionnaire score decreased from baseline to 24 weeks with a net between‐group treatment effect of −13.1 ± 21.0 (P = 0.10). There were no significant differences in the adverse event rate between the CCM and control groups.
Conclusions
These preliminary results suggest that CCM exerts favourable effects on exercise tolerance and quality of life in patients with LVEF in the range of 40–45% with an acceptable safety profile. Further randomized controlled studies are planned to prove these effects.
Increased risk of cardiovascular complications during and post‐COVID‐19 infection is more and more recognized—including myocarditis, arrhythmias, and myocardial infarctions (MIs). The mechanisms ...leading to these complications are direct virus‐induced injuries, as well as potential thrombotic and inflammatory‐induced mechanisms. To the latter, inflammatory plaque instability and plaque rupture are discussed entities contributing to MI‐induced post‐COVID‐19 complications. Our case report describes the first time, when a temporary impairment of LVEF in the COVID‐19‐convalescence phase unmasks a silent MI due to coronary plaque rupture by using invasive (OCT) and non‐invasive (CMR) modalities. Myocardial infarction might be an important differential diagnosis to consider in deteriorating patients with COVID‐19, especially if dyspnoea persists after acute infection.
Fibroblasts are widely distributed cells and are responsible for the deposition of extracellular matrix (ECM) components but also secrete ECM-degrading matrix metalloproteases. A finely balanced ...equilibrium between deposition and degradation of ECM is essential for structural integrity of tissues. In the past, fibroblasts have typically been understood as a uniform cell population with comparable functions regardless of their origin. Here, we determined growth curves of fibroblasts derived from heart, skin, and lung and clearly show the lowest proliferation rate for cardiac fibroblasts. Furthermore, we examined basal expression levels of collagen and different MMPs in these three types of fibroblasts and compared these concerning their site of origin. Interestingly, we found major differences in basal mRNA expression especially for MMP1 and MMP3. Moreover, we treated fibroblasts with TNF-α and observed different alterations under these proinflammatory conditions. In conclusion, fibroblasts show different properties in proliferation and MMP expression regarding their originated tissue.
Aims
The alarmin S100A8/S100A9 (S100A8/A9) is released by activated monocytes/macrophages and neutrophils in the setting lymphocytic myocarditis (MC). We recently demonstrated its therapeutic ...potential in experimental acute MC. Now, we investigated the diagnostic relevance of S100A8/A9 serum levels in patients with suspected acute and chronic MC and in patients with heart failure without cardiac inflammation.
Methods and Results
Serum S100A8/A9 levels were analysed in patients with a recent onset of MC ≤ 30 days, n = 32; ejection fraction (EF): 45.4 ± 12.9%, dilated cardiomyopathy patients with inflammation (n = 112; EF: 29.0 ± 11.4%), or without inflammation (n = 58; EF: 26.6 ± 9.3%), and controls (n = 25; EF: 68.5 ± 4.6%), by using specific ELISAs. Blood samples were collected at Time Point 1 (T1), where also endomyocardial biopsies (EMBs) were withdrawn. Patients with a recent onset of MC showed a 4.6‐fold increase in serum S100A8/A9 levels vs. controls (MC: 1948 ± 1670 ng/mL vs. controls: 426 ± 307 ng/mL; P < 0.0001). Serum S100A8/A9 correlated with the disease activity, represented by EMB‐derived counts of inflammatory cells (CD3: r = 0.486, P = 0.0047, lymphocyte function‐associated antigen‐1: r = 0.558, P = 0.0009, macrophage‐1 antigen: r = 0.434, P = 0.013), the EMB mRNA levels of S100A8, S100A9 (r = 0.541, P = 0.002), and left ventricular ejection fraction (LVEF: r = 0.498, P = 0.0043). EMB immunofluorescence co‐stainings display macrophages/monocytes and neutrophils as the main source of S100A8 and S100A9 in recent onset MC. The diagnostic value of serum alarmin levels (cut‐off 583 ng/mL) was characterized by a specificity of 92%, a sensitivity of 90.6%, positive predictive value of 93.5%, negative predictive value of 88.5%, and an accuracy of 0.949 (95% confidence interval 0.89–1). In a subgroup of MC patients, S100A8/A9 serum levels and EMBs at T1 (n = 12) and a follow‐up visit (T2, n = 12, mean follow‐up 8.5 months) were available. A fall of serum S100A8/A9 (T1: 2208 ± 1843 ng/mL vs. T2: 888.8 ± 513.7 ng/mL; P = 0.00052) was associated with a reduced cardiac inflammation (CD3 T1: 70.02 ± 107.4 cells per square millimetre vs. T2: 59.18 ± 182.5 cells per square millimetre; P = 0.0342, lymphocyte function‐associated antigen‐1 T1: 133.5 ± 187.1 cells per square millimetre vs. T2: 74.12 ± 190.5 cells per square millimetre; P = 0.0186, and macrophage‐1 antigen T1: 132.6 ± 129.5 cells per square millimetre vs. T2: 54.41 ± 65.16 cells per square millimetre; P = 0.0015). Serum S100A8/A9 levels were only slightly increased in patients within the chronic phase of MC and in heart failure patients without inflammation vs. controls.
Conclusions
Serum S100A8/A9 might serve as an additional tool in the diagnostic workup of suspected acute MC patients.
CD4+ cells are implicated in the healing process after myocardial infarction (MI). We sought to investigate the role of interleukin-23 (IL-23) deficiency, a cytokine important in differentiation of ...CD4+ cells, in scar formation of the ischemic heart.
MI was performed in wild-type and IL23p19-/- mice. Thirty-day mortality, hemodynamic function 4 days after MI and myocardial inflammation, and remodeling 4 and 30 days after MI were examined. Differentiation of fibroblasts from infarcted and noninfarcted hearts into myofibroblasts was examined under basal conditions and after stimulation with interferon-γ, IL-17α and IL-23. Interleukin-23p19-/- mice showed higher expression of proinflammatory cytokines and immune cell infiltration in the scar early after MI compared with wild-type mice. A stronger interferon-γ/Th1 reaction seemed to be responsible for the increased inflammation under IL-23 deficiency. Expression of α-smooth muscle actin (α-SMA), collagen I and III was significantly higher in the heart tissue and isolated cardiac fibroblasts 4 days after MI in the wild-type mice. Interleukin-23p19-/- mice showed impaired healing compared with wild-type mice, as seen by significantly higher mortality because of ventricular rupture (40% higher after 30 days) and stronger left ventricular dilation early after MI. Stimulation of cardiac fibroblasts with interferon-γ, the main Th1 cytokine, but not with IL-23 or IL-17α, led to a significant downregulation of α-smooth muscle actin, collagen I and III and decreased migration and differentiation to myofibroblasts.
IL-23 deficiency leads to increased myocardial inflammation and decreased cardiac fibroblast activation, associated with impaired scar formation and adverse remodeling after MI.
PDF
