Objective: A negative relationship exists between diabetes mellitus (DM) and abdominal aortic aneurysms (AAA), which is possibly caused by use of metformin. The aim of this study was to examine the difference in smooth muscle cell (SMC) contractile phenotype, proliferation capacity, and metabolic activity of non-pathologic aortic controls, non-diabetic AAA patients, and diabetic AAA patients. In addition, the therapeutic effect of metformin on these SMC functions was investigated.

Abstract Background Due to limited regenerative capacity of the adult human heart, myocardial infarction causes irreversible damage by inducing the death of cardiomyocytes and the formation of a fibrotic scar. These remodeling mechanisms cause loss of contractility and eventually heart failure ensues in a significant proportion of patients. Purpose There is a need for a reliable model that can replicate the adult cardiac pathophysiology in order to test treatments against cardiac remodeling. Here, we developed a cardiac tissue culture model that can simulate in vitro the molecular changes occurring after cardiac injury using human cultured cardiac slices. Methods We obtained cardiac slices by sectioning ventricular myocardium from the surgical waste material of adult patients undergoing valve surgery or Morrow myectomy. Cardiac slices were cultured at a liquid-air interface and were viable up to 7 days of culture, even in the absence of stimulation. During this time cardiac slices underwent mechanical and chemical treatments to induce ischemia and/or local injury. Results We found that following these treatments we were able to simulate cardiac remodeling in terms of cardiomyocyte death, activation of cardiac fibroblasts and induction of inflammation and oxidative stress. Following small molecule screening, we discovered that addition of compounds with anti-inflammatory properties (e.g. dexamethasone) or targeting the TGF-β pathway (e.g. SB-431542) into our culture medium helped in preserving the microscopic structure of the slices. Additionally, we found that treatment with these compounds protected cardiac slices against remodeling following ischemic injury. Conclusions In conclusion, our model can emulate cardiac pathophysiology in culture, providing us a reliable platform to test therapies for cardiac regeneration and repair in an adult, multicellular, 3-D environment.

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Regenerative Medicine Across Borders (RegMedXB) Foundation Introduction Cardiovascular diseases (CVDs) are the number one cause of mortality among non-communicable diseases. Two mechanisms of cardiac remodelling after injury have been hypothesized. In the early phases, remodelling is caused by cardiomyocytes (CMs) death, while later it is due to the attempts at reconstruction from the surviving myocardium. Due to the inability of cardiomyocytes to divide, the adult mammalian heart has negligible endogenous regenerative capacity, and the injured myocardium heals through formation of a scar, while surviving CMs become hypertrophic. These mechanisms can lead to progressive left ventricular dilatation, loss of contractility and transition to heart failure. With significant effort from the research community, new therapies to treat cardiac injury are being investigated, with particular attention to regenerative cellular therapies. Purpose The aim of this study is to devise therapies able to target CMs to eventually replenish the heart of contractile units by inducing CMs proliferation. Methods Atrial appendage or ventricle wall samples were derived from the surgical waste material of adult patients who underwent heart surgery for heart valve disease and/or Morrow myectomy. Cardiac-resident mesenchymal progenitor cells and endothelial cells were derived and amplified from the atrial samples, while organotypic cardiac slices (thickness 300 um) were obtained by cutting the ventricular samples with a vibratome and then cultured at a liquid-air interface. Functionality was proven by viability staining and biochemical assays. Cells and slices were treated with compounds aimed to improve cell health (dexamethasone or SB-431542) and/or vectors carrying reporters (Fiber-modified HAdV vectors or nanoparticles enveloped in a lipid membrane). Results Human myocardial slices were viable up to 7 days in culture without electrical or mechanical stimulation. During this time in control conditions there was collagen deposition and onset of fibrosis. Treatment with dexamethasone (100 nM) prevented loss of collagen structure and activation of markers of cardiac remodelling. The specific inhibition of the remodelling marker Smad-3 with SB-431542 didn’t have any evident effect on the viability and structural integrity of the slices. Vectors HadV-5 and HadV-11 had highly efficient transduction in monolayers of human cells peaking around 48h, but low efficiency in myocardial slices. Nanoparticles had efficient transduction in monolayers of cells and myocardial slices, but shorter particle lifespan (<48h). Conclusions We established a quick and simple method for the preparation of vital tissue slices from human adult ventricular myocardium as well as their preservation in culture. This model represents a novel platform for testing vectors targeting CMs in a 3-D environment, highlighting the differences in transduction efficiency when compared to standard monolayer culture techniques.

Cardiac amyloidosis (CAM), the most common cardiac storage disease is associated with significant changes in left-ventricular (LV) morphology and function. To gain particular insights into LV systolic longitudinal myocardial mechanics we investigated seven parameters derived by speckle-tracking-echocardiography (STE) in patients with confirmed CAM ( n = 59). The results were compared with those of individuals with healthy heart ( n = 150) and another primary myocardial disease with also thickened myocardium and severe diastolic and systolic LV-dysfunction (symptomatic LV-non-compaction-cardiomyopathy, LV-NC, n = 30). In addition to standard echocardiographical measures, the STE-derived data were evaluated and documented utilizing polar-diagrams to obtain overviews of longitudinal myocardial mechanics of the entire LV. Compared with healthy individuals, patients with CAM and LV-NC showed significantly reduced LV-ejection-fraction (EF), global longitudinal systolic peak-strain, strain-rate, and displacement. Pre-systolic stretch-index, post-systolic index, and the EF/global peak-longitudinal-strain-ratio (EF/S) were increased. In contrast to healthy-hearts and the LV-NC group only patients with CAM demonstrated significantly reduced time-to-peak systolic longitudinal strain and time-to-peak strain-rate. Although the level of the segmental values in longitudinal mechanics was significantly different between the groups, comparable intraventricular baso-apical parameter-gradients were found for systolic longitudinal peak-strain and strain-rate, pre-systolic-stretch-index, post-systolic-index, and peak systolic displacement. Compared to ATTR-amyloidosis (ATTR-CAM), patients with AL-amyloidosis (AL-CAM) demonstrated significantly lower end-diastolic and end-systolic LV-volumes, LV-mass-indices, relative apical strain, time-to-peak systolic longitudinal strain, and time-to-peak longitudinal strain-rate. CAM and LV-NC demonstrated altered myocardial mechanics with significantly different STE-derived echocardiographical parameters. ATTR-amyloidosis and AL-amyloidosis had at least significantly different time-to-peak strain, time-to-peak strain-rate and relative apical sparing values.

BACKGROUND:Left ventricular (LV) non-compaction cardiomyopathy (LV-NC) is rare, and data of segmental myocardial mechanics are largely lacking. We investigated myocardial longitudinal mechanics in adults with symptomatic LV-NC (n = 30) versus individuals with healthy hearts (n = 150). The contribution of compacted and non-compacted myocardial layer to systolic LV function has to be determined.METHODS:Seven parameters derived from speckle tracking echocardiography were evaluated and documented utilizing polar-diagrams to obtain overviews of myocardial mechanics of the entire LV.RESULTS:According to embryonal myocardial development, non-compacted myocardium was mostly located in mid-ventricular and apical segments of the free LV wall. LV ejection fraction was reduced in LV-NC (34 ± 15%, healthy 63 ± 5%, P < .0001). The compact wall layer in LV-NC demonstrated increasing systolic radial thickness (diastolic 5.6 ± 1.4, systolic 6.5 ± 1.4mm, P = .016), whereas the non-compacted layer remained unchanged or tended to decrease in thickness (diastolic 17.6 ± 5.3, systolic 16.0 ± 4.6mm, P = .22). Compared with heart-healthy individuals in LV-NC peak systolic longitudinal strain (healthy -21.1% vs. LV-NC -8.8, P < .0001), peak systolic longitudinal strain-rate (-1.23%/s vs. -0.64, P < .0001), and peak longitudinal displacement (12.1 vs. 5.6 mm, P < .0001) were reduced, while pre-systolic stretch index (1.31% vs. 3.2%, P < .0001) and post-systolic index (2.5% vs. 15.9%, P < .0001) increased. Time-to-peak longitudinal strain (371 vs. 389 ms, P = .065) and time-to-peak longitudinal strain rate (181 vs. 200 ms, P = .0677) did not differ significantly. In LV-NC, there were no significant differences between analyses using an interpolated endocardial border along the edges of the recesses and the endocardial edge of the compact wall layer. Hence, LV function appeared to depend only on the thin compact wall layer.CONCLUSION:In LV-NC, myocardial efficiency is severely diminished compared with healthy controls and LV function seemed to depend mainly on the compact myocardial wall layer.

Degenerative aortic valve stenosis (AVS) is a common valvular heart disease in patient older than 65 years with a prevalence of 2-7% in the European and North American population. It has been shown that elevated LP (a) levels are associated with an increased risk for AVS across various ethnic groups

ObjectiveWe investigated physiological systolic left ventricular (LV) myocardial mechanics and gradients to provide a database for later studies of diseased hearts.MethodsThe analyses were performed in 131 heart‐healthy individuals and included seven parameters of myocardial mechanics using speckle tracking echocardiography (STE).ResultsBasal to apical and circumferentially significant physiological intraventricular parameter gradients of myocardial activity were determined. Global mean values and segmental ranges were peak systolic longitudinal strain −21.2 ± 3.3%, 95% confidence interval [CI] −21.8% to −20.6%), gradient (basal to apical) −16.0% to −26.7%; peak systolic longitudinal strain rate −1.24 ± 0.31%/s, 95% CI −1.29% to −1.19%/s, gradient (basal to apical) −0.91% to −1.61%/s; post‐systolic index 2.6 ± 3.2%, 95% CI 3.15%–2.05%, gradient (basal/medial/apical) 7.0/1.2/2.4%; pre‐systolic stretch index 1.3 ± 2.7%, 95% CI 1.77%–0.83%, gradient (basal/medial/apical) 6.5/0.2/1.3%; peak longitudinal displacement 12.2 ± 2.6 mm, 95% CI 12.6–11.8 mm, gradient (basal to apical) 21.0–3.4 mm; time‐to‐peak longitudinal strain 370 ± 43 ms, 95% CI 377–363 ms, gradient (basal to apical) 396–361 ms; and time‐to‐peak longitudinal strain rate 180 ± 47 ms, 95% CI 188–172 ms, gradient (basal to apical) 150–200 ms.ConclusionThis study generated a database of seven STE‐derived parameters of physiological segmental and global myocardial LV mechanics. The resulting sets of three‐dimensional intraventricular mappings of the entire LV provide physiological parameter gradients in baso‐apical and circumferential direction by applying the 17‐segment polar model. This will facilitate comparison of systolic myocardial activity of the healthy LV with diseased or otherwise altered (eg, sports) hearts.

Defects in motile cilia and sperm flagella cause primary ciliary dyskinesia (PCD), characterized by chronic airway disease, infertility and left-right body axis disturbance. Here we report maternally inherited and de novo mutations in PIH1D3 in four men affected with PCD. PIH1D3 is located on the X chromosome and is involved in the preassembly of both outer (ODA) and inner (IDA) dynein arms of cilia and sperm flagella. Loss-of-function mutations in PIH1D3 lead to absent ODAs and reduced to absent IDAs, causing ciliary and flagellar immotility. Further, PIH1D3 interacts and co-precipitates with cytoplasmic ODA/IDA assembly factors DNAAF2 and DNAAF4. This result has clinical and genetic counseling implications for genetically unsolved male case subjects with a classic PCD phenotype that lack additional phenotypes such as intellectual disability or retinitis pigmentosa. 14759_TPaff_BW.indd 56 19-09-17 13:08

Background Ultrasound guided cardiac shock wave therapy (CSWT) is a noninvasive therapeutic option in the treatment of chronic-refractory angina. Clinical trials have shown that CSWT reduces angina symptoms, improves regional systolic function, LV ejection fraction, myocardial perfusion and quality of life parameters. Absolute measurements of myocardial perfusion before and after CSWT have not been performed so far.Methods and results We studied a total of 21 CCS III patients with history of CAD and multiple interventions who suffered from disabling angina despite individually optimized medical therapy. An N-13 NH3 PET perfusion scan under adenosine was performed before and after CSWT treatment. CSWT was well tolerated in all patients. Absolute perfusion under adenosine of the global left-ventricular myocardium did not change under therapy or minimal coronary resistance. The treated segments, however, showed in terms of both perfusion and resistance a mild but significant improvement, by 11 and 15 %, respectively, whereas no change could be observed in the remote segments. Considering a threshold of increased perfusion of 5 %, 10 (77 %) out of 13 patients with a better target perfusion improved in their CCS class, whereas 3 (43 %) out of 7 patients without improved target perfusion improved in their CCS class too.Conclusion Standard CSWT has the potential to improve myocardial perfusion of the therapy zone and clinical CAD symptomatology without affecting global myocardial perfusion. As a noninvasive and well tolerated therapeutic option, these data suggest the use of CSWT in patients with end-stage CAD.

AIMS:In patients with type 2 diabetes mellitus (T2DM) exercise training is recommended to improve glycemic control. Electrical myostimulation (EMS) of skeletal muscles is a new method to increase exercise capacity in patients with chronic heart failure. The aim of this study was to investigate the effects of EMS in T2DM on glucose metabolism, body composition, and exercise performance using a newly designed stimulation suit that involves trunk, leg, and arm muscles.SUBJECTS AND METHODS:Fifteen individuals (nine males; 61.7±14.8 years old) were trained for 10 weeks twice weekly for 20 min with EMS. Effects on glucose, glycosylated hemoglobin (HbA(1c)), oxygen consumption, and body composition were evaluated.RESULTS:There was a significant increase of oxygen uptake at the aerobic threshold from 12.3±0.8 to 13.3±0.7 mL/kg/min (P=0.003) and of maximal work capacity from 96.9±6.4 to 101.4±7.9 W (P=0.046), with a concomitant trend for improved maximal oxygen uptake (from 14.5±0.9 to 14.7±0.9 mL/kg/min [P=0.059]). Fasting blood glucose level decreased from 164.0±12.5 to 133.4±9.9 mg/dL (P=0.001), and HbA(1c) level decreased from 7.7±0.3% to 7.2±0.3% (P=0.041), whereas mean total weight (from 101.5±4.0 to 103.1±4.3 kg) and proportion of body fat (from 38.8±3.2% to 40.3±3.4%) remained statistically unchanged.CONCLUSIONS:EMS can improve glucose metabolism and functional performance in T2DM patients. These data suggest that EMS might emerge as a novel additional therapeutic mode of exercise training and might help patients to overcome their sedentary lifestyle.

Detection of dysfunctional mitral valve prostheses (MP) remains complex even though being optimized by considering echocardiographically derived prosthetic effective orifice area (VA). The purpose was to compare VA in MP, calculated by the continuity equation (CE) using peak velocities (CEVpeak), mean velocities (CEVmean), velocity–time integrals (CEVTI) and the pressure half time method using 220 ms as constant first (PHT220) as well as optimized constants. In 267 consecutive patients with normally functioning MP, we investigated VA within the first postoperative month. With increasing prosthetic sizes, mean VA values also increase in all calculations. The statistical curves demonstrate no significant difference in graphical steepness but show different levels. Comparison of mean VA showed the known systematic higher values of PHT220 and significantly decreased results when using CEVTI. This systematic difference between mean VA applying PHT220 versus CEVTI is approximately 1.0 cm2 for all prosthetic sizes. Calculations via CEVpeak were close to the results of CEVTI. CEVmean produced values, which graphically correspond to the PHT220 curve. Only PHT220 detected the constructional equal prosthetic inner ring width between 29 and 31 mm. To compensate the systematic difference between CEVTI and PHT220, an optimized constant of 140 ms was calculated to be applied in PHT (PHT140). VA is a robust and, therefore, preferable parameter for investigating MP. If needed, both CE and PHT are applicable with a systematical difference between CEVTI and PHT220. An optimized constant of 140 ms (PHT140) should be applied when calculating VA of mitral valve prostheses via PHT.