As part of the TACTICS (Transnational Alliance for Regenerative Therapies in Cardiovascular Syndromes) series to enhance regenerative medicine, here, we discuss the role of preclinical studies ...designed to advance stem cell therapies for cardiovascular disease. The quality of this research has improved over the past 10 to 15 years and overall indicates that cell therapy promotes cardiac repair. However, many issues remain, including inability to provide complete cardiac recovery. Recent studies question the need for intact cells suggesting that harnessing what the cells release is the solution. Our contribution describes important breakthroughs and current directions in a cell-based approach to alleviating cardiovascular disease.
Abstract
Aims
Significant efforts are currently undertaken to reduce functional mitral regurgitation (FMR) in patients with chronic heart failure in the hope to improve prognosis. We aimed to assess ...the prognostic impact of FMR in heart failure with reduced ejection fraction (HFrEF) under optimal medical therapy (OMT) and various conditions of HFrEF. We further intended to identify a heart failure phenotype, where FMR is most likely a driving force and not a mere bystander of the disease.
Methods and results
We prospectively included 576 consecutive HFrEF patients into our long-term observational study. Functional i.e. New York Heart Association (NYHA) class, echocardiographic, invasive haemodynamic, and biochemical (i.e. NT-proBNP, MR-proANP, MR-proADM, CT-proET-1, copeptin) measurements were performed at baseline. During a median follow-up of 62 months (interquartile range 52–76), 47% of patients died. Severe FMR was a significant predictor of mortality hazard ratio (HR) 1.76, 95% confidence interval (CI) 1.34–2.30; P < 0.001, independent of clinical (adjusted HR 1.61, 95% CI 1.22–2.12; P = 0.001), and echocardiographic (adjusted HR 1.46, 95% CI 1.09–1.94; P = 0.01) confounders, OMT (adjusted HR 1.81, 95% CI 1.25–2.63; P = 0.002), and neurohumoral activation (adjusted HR 1.38, 95% CI 1.03–1.84; P = 0.03). Subanalysis revealed that severe FMR was associated with poor outcome in an intermediate-failure phenotype of HFrEF i.e. patients with NYHA class II (adjusted HR 2.17, 95% CI 1.07–4.44; P = 0.03) and III (adjusted HR 1.80, 95% CI 1.17–2.77; P = 0.008), moderately reduced left ventricular function (adjusted HR 2.37, 95% CI 1.36–4.12; P = 0.002), and within the second quartile (871–2360 pg/mL) of NT-proBNP (adjusted HR 2.16, 95% CI 1.22–3.86; P = 0.009).
Conclusion
In a patient cohort under OMT, the adverse prognostic impact of FMR is given predominantly in a sub-cohort of a specific intermediate-failure phenotype—well-defined functionally, haemodynamically, biochemically, and morphologically.
Purpose
It is currently unclear whether management and outcomes of critically ill patients differ between men and women. We sought to assess the influence of age, sex and diagnoses on the probability ...of intensive care provision in critically ill cardio- and neurovascular patients in a large nationwide cohort in Switzerland.
Methods
Retrospective analysis of 450,948 adult patients with neuro- and cardiovascular disease admitted to all hospitals in Switzerland between 01/2012 and 12/2016 using Bayesian modeling.
Results
For all diagnoses and populations, median ages at admission were consistently higher for women than for men 75 (64;82) years in women vs. 68 (58;77) years in men,
p
< 0.001. Overall, women had a lower likelihood to be admitted to an intensive care unit (ICU) than men, despite being more severely ill odds ratio (OR) 0.78 (0.76–0.79). ICU admission probability was lowest in women aged > 65 years (OR women:men 0.94 (0.89–0.99),
p
< 0.001). Women < 45 years had a similar ICU admission probability as men in the same age category OR women:men 1.03 (0.94–1.13), in spite of more severe illness. The odds to die were significantly higher in women than in men per unit increase in Simplified Acute Physiology Score (SAPS) II (OR 1.008 1.004–1.012).
Conclusion
In the care of the critically ill, our study suggests that women are less likely to receive ICU treatment regardless of disease severity. Underuse of ICU care was most prominent in younger women < 45 years. Although our study has several limitations that are imposed by the limited data available from the registries, our findings suggest that current ICU triage algorithms could benefit from careful reassessment. Further, and ideally prospective, studies are needed to confirm our findings.
As advanced heart failure (HF) with elevated NT-proBNP is characterized by an activated coagulation system, coronary events clinically noticed as sudden or HF death may be more common after treatment ...with first- compared to newer-generation DES. Our study evaluates (1) if patients with left ventricular dysfunction (LVSD) who underwent percutaneous coronary intervention have a better survival with first- or newer-generation DES, and (2) if the survival benefit is predicted by NT-proBNP. Our observational study evaluated patients with LVSD who were registered in the coronary catheter laboratory database of the Medical University of Vienna. Multivariate Cox regression analyses tested an interaction in the risk of death between those with lower or elevated NT-proBNP levels and the stent-generation. The relative risk of newer- compared to first-generation DES as reference was calculated for patients with low and elevated NT-proBNP levels. In 340 patients (178 newer- and 162 first-generation DES) stent-generation and NT-proBNP were independent predictors of death. When the stent-generation*NTproBNP interaction was forced into a Cox regression model, this term independently predicted death. The relative risk of first- compared to newer-generation DES was similar in patients with lower NT-proBNP (HR 1.02, 95% CI 0.95-1.10, p = 0.560), but was higher in patients with elevated NT-proBNP (HR 1.06, 95% CI 1.01-1.10, p = 0.020). Death is associated to stent-generation. NT-proBNP is a predictor for the stent generation used: elevated levels demonstrated a higher mortality risk when using first- compared to newer-generation DES, while lower levels showed a similar risk when using either DES-generation.
Left ventricular ejection fraction (LVEF) is the most important parameter in the assessment of cardiac function. A machine-learning algorithm was trained to guide ultrasound-novices to acquire ...diagnostic echocardiography images. The artificial intelligence (AI) algorithm then estimates LVEF from the captured apical-4-chamber (AP4), apical-2-chamber (AP2), and parasternal-long-axis (PLAX) loops. We sought to test this algorithm by having first-year medical students without previous ultrasound knowledge scan real patients. Nineteen echo-naïve first-year medical students were trained in the basics of echocardiography by a 2.5 h online video tutorial. Each student then scanned three patients with the help of the AI. Image quality was graded according to the American College of Emergency Physicians scale. If rated as diagnostic quality, the AI calculated LVEF from the acquired loops (monoplane and also a “best-LVEF” considering all views acquired in the particular patient). These LVEF calculations were compared to images of the same patients captured and read by three experts (ground-truth LVEF GT-EF). The novices acquired diagnostic-quality images in 33/57 (58%), 49/57 (86%), and 39/57 (68%) patients in the PLAX, AP4, and AP2, respectively. At least one of the three views was obtained in 91% of the attempts. We found an excellent agreement between the machine’s LVEF calculations from images acquired by the novices with the GT-EF (bias of 3.5% ± 5.6 and r = 0.92, p < 0.001 in the “best-LVEF” algorithm). This pilot study shows first evidence that a machine-learning algorithm can guide ultrasound-novices to acquire diagnostic echo loops and provide an automated LVEF calculation that is in agreement with a human expert.
Abstract Background Chest compressions and ventilation are lifesaving tasks during cardio-pulmonary resuscitation (CPR). Besides oxygenation, endotracheal intubation (ETI) during CPR is performed to ...avoid aspiration of gastric contents. If intubation is difficult or impossible, supraglottic airway devices are utilized. We tested six different airway devices regarding their potential to protect against regurgitation and aspiration during CPR in a randomized experimental human cadaver study. Methods Five-hundred ml of 0.01% methylen-blue-solution were instilled into the stomach of 30 adult human cadavers via an oro-gastric tube. The cadavers were then randomly assigned to one of six groups, resulting in 5 cadavers in each group. Airway management was performed with either bag-valve ventilation, Laryngeal Tube, EasyTube, Laryngeal Mask (Classic), I-Gel, or ETI. Thereafter 5 minutes of CPR were performed according to the 2010 Guidelines of the European Resuscitation Council. Pulmonary aspiration was defined as the presence of methylen-blue-solution below the vocal cords or the ETI cuff as assessed by fiber-optic bronchoscopy. Results Thirty cadavers were included (14 females, 16 males). Aspiration was detected in three out of five cadavers receiving bag-valve ventilation and in two out of five intubated with LMA or I-Gel. In cadavers intubated with the LT, aspiration occurred in one out of five cases. No aspiration could be detected in cadavers intubated with ETI and EasyTube. Conclusion This study provides experimental evidence that, during CPR, ETI offers superior protection against regurgitation and pulmonary aspiration of gastric contents than supraglottic airway devices or bag-valve ventilation.
The aim of this work was to identify the key morphological and functional features in secondary mitral regurgitation (sMR) and their prognostic impact on outcome.
Secondary sMR in patients with heart ...failure and reduced ejection fraction typically results from distortion of the underlying cardiac architecture. The morphological components which may account for the clinical impact of sMR have not been systematically assessed or correlated with clinical outcomes.
Morphomic and functional network profiling were performed on a cohort of patients with stable heart failure optimized on guideline-based medical therapy. Principal component (PC) analysis and subsequent cluster analysis were used to condense the morphomic and functional data first into PCs with varimax rotation (PCVmax) and second into homogeneous clusters. Clusters and PCs were tested for their correlations with clinical outcomes.
Morphomic and functional data from 383 patients were profiled and subsequently condensed into PCs. PCVmax 1 describes high loadings of left atrial morphological information, and PCVmax 2 describes high loadings of left ventricular (LV) topology. Based on these components, 4 homogeneous clusters were derived. sMR was most prominent in clusters 3 and 4, with the morphological difference being left ventricular size (median end-diastolic volume 188 mL interquartile range: 160 mL-224 mL vs 315 mL 264 mL-408 mL; P < 0.001). Clusters were associated with mortality (P < 0.001), but sMR remained independently associated with mortality after adjusting for the clusters (adjusted HR: 1.42; 95% CI: 1.14–1.77; P < 0.01). The detrimental association of sMR with mortality was mainly driven by cluster 3 (HR: 2.18; 95% CI: 1.32-3.60; P = 0.002), the “small LV cavity” phenotype.
These results challenge the current perceptions that sMR in heart failure with reduced ejection fraction results exclusively from global or local LV remodeling and are suggestive of a potential role of the left atrial component. The association of sMR with mortality cannot be purely attributed to cardiac morphology alone, supporting other complementary key aspects of mitral valve closure consistent with the force balance theory. Unsupervised clustering supports the association of sMR with mortality predominantly driven by the small LV cavity phenotype, as previously suggested by a conceptional framework and termed disproportionate sMR.
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Subendocardial strain analysis is currently feasible in two-dimensional and three-dimensional (3D) echocardiography; however, there is a lack of clarity regarding the most useful strain component for ...subclinical disease detection. The aim of this study was to test the hypothesis that strain analysis along the direction of strongest and weakest systolic compression (referred to as principal and secondary strain, respectively) circumvents the need for multidirectional strains and provides a more simplified assessment of left ventricular subendocardial function.
Strain analyses were performed by using two-dimensional and 3D echocardiography in 41 consecutive subjects with normal results on electron-beam computed tomography, including 15 controls and 26 patients with systemic hypertension. The direction of principal strain referenced the myofiber geometry obtained from diffusion tensor magnetic resonance imaging of a normal autopsied human heart. The incremental value of principal strain over multidirectional two-dimensional and 3D strain was analyzed.
In healthy subjects, 50 ± 3% of the subendocardial shortening occurred in the cross-fiber direction (left-handed helical); this balance was significantly altered in patients with hypertension (P = .01). The magnitude of longitudinal and circumferential strain was similar in patients with hypertension and controls. However, the alteration of the directional contraction pattern resulted in reduced secondary strain magnitude in patients with hypertension (P = .01), and the differences were further exaggerated when the secondary strain was normalized by the principal strain magnitude (P = .004).
Two-component principal and secondary strain analysis can be related to left ventricular myofiber geometry and may simplify the assessment of 3D left ventricular deformation by circumventing the need to assess multiple shortening and shear strain components.
The myocardium exhibits an adaptive tissue-specific renin-angiotensin system (RAS), and local dysbalance may circumvent the desired effects of pharmacologic RAS inhibition, a mainstay of heart ...failure with reduced ejection fraction (HFrEF) therapy.
This study sought to investigate human myocardial tissue RAS regulation of the failing heart in the light of current therapy.
Fifty-two end-stage HFrEF patients undergoing heart transplantation (no RAS inhibitor: n = 9; angiotensin-converting enzyme ACE inhibitor: n = 28; angiotensin receptor blocker ARB: n = 8; angiotensin receptor neprilysin-inhibitor ARNi: n = 7) were enrolled. Myocardial angiotensin metabolites and enzymatic activities involved in the metabolism of the key angiotensin peptides angiotensin 1-8 (AngII) and Ang1-7 were determined in left ventricular samples by mass spectrometry. Circulating angiotensin concentrations were assessed for a subgroup of patients.
AngII and Ang2-8 (AngIII) were the dominant peptides in the failing heart, while other metabolites, especially Ang1-7, were below the detection limit. Patients receiving an ARB component (i.e., ARB or ARNi) had significantly higher levels of cardiac AngII and AngIII (AngII: 242 interquartile range (IQR): 145.7 to 409.9 fmol/g vs 63.0 IQR: 19.9 to 124.1 fmol/g; p < 0.001; and AngIII: 87.4 IQR: 46.5 to 165.3 fmol/g vs 23.0 IQR: <5.0 to 59.3 fmol/g; p = 0.002). Myocardial AngII concentrations were strongly related to circulating AngII levels. Myocardial RAS enzyme regulation was independent from the class of RAS inhibitor used, particularly, a comparable myocardial neprilysin activity was observed for patients with or without ARNi. Tissue chymase, but not ACE, is the main enzyme for cardiac AngII generation, whereas AngII is metabolized to Ang1-7 by prolyl carboxypeptidase but not to ACE2. There was no trace of cardiac ACE2 activity.
The failing heart contains considerable levels of classical RAS metabolites, whereas AngIII might be an unrecognized mediator of detrimental effects on cardiovascular structure. The results underline the importance of pharmacologic interventions reducing circulating AngII actions, yet offer room for cardiac tissue-specific RAS drugs aiming to limit myocardial AngII/AngIII peptide accumulation and actions.
Abstract Background Post-infarction cardiac rupture (CR) such as ventricular septal rupture (VSR), free wall rupture (FWR), atrial septal rupture (ASR) or papillary muscle rupture (PMR) is a rare but ...dreaded complication in patients with acute myocardial infarction (AMI) associated with a very poor prognosis with reported mortality rates between 60 and 100%. Therefore suitable risk stratification for secondary prevention seems crucial, but data on long-term survival und risk prediction in this especially vulnerable patient collective remains scarce. Methods Out of 11 641 patients presenting with AMI a total of 28 individuals suffering post-infarction CR were identified and stratified in “acute survivors of CR” (n = 10) and “non-survivors of CR” (n = 18). Cox regression hazard analysis was used to assess prognosticators on long-term survival. Results Ten patients (35.7%) survived the initial event. After a median follow-up time of 9 years 2 (20%) of the survivors died, both due to cardiovascular causes. Younger age (p = 0.023) and higher systolic blood pressure at admission (p = 0.018) turned out to be significant predictors of long-term survival. Systolic blood pressure 48 hours after CR proved to be a strong and independent predictor for survival with an adjusted hazard ratio per one standard deviation of 0.89 (95% CI: 0.72-0.99; 0.048). Conclusion Hemodynamic stabiliziation and severity of cardiogenic shock were detected as clinically most common among patients suffering post-infarction CR and proved to be of major importance for survival. If survival of the initial event was achieved, satisfying long-term mortality could be reached.
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