Positive Inotropy Research Articles

Retrospective evaluation of the effect of xylazine infusion on survival to discharge in horses undergoing exploratory laparotomy for colic.

To determine the influence of xylazine infusion on survival to discharge and describe the associated intraoperative requirement for isoflurane, use of positive inotropes and vasopressors, and recovery time in horses undergoing exploratory laparotomy. Retrospective cohort study. A total of 352 horses. Medical records of horses undergoing anesthesia for exploratory laparotomy from January 2018 to December 2023 were reviewed. Data collected included survival to discharge, results of diagnostic tests, end tidal isoflurane concentration (FE'Iso), use of vasopressors/inotropes, and duration of recovery in horses with (WX) or without (WOX) intraoperative xylazine infusion. For survival to discharge, univariable and multivariable logistic regression was performed adjusting for the effects of other infusions. For all other variables, descriptive statistics were performed. Survival to discharge was 80.6% and 78.5% for WX and WOX, respectively (p= 0.431). Mean ± standard deviation FE'Iso was 0.82 ± 0.21% and 0.94 ± 0.21% for WX and WOX, respectively. Dobutamine was given to 159/166 (95.8%) and 176/186 (94.6%) horses at a rate of 1 (0.1-3.0) μg kg-1 minute-1 and 1 (0.25-3.0) μg kg-1 minute-1 in WX and WOX, respectively. Norepinephrine infusion was given to 15/166 (9%) and 27/186 (15%) horses at a rate of 0.2 (0.025-0.4) μg kg-1 minute-1 and 0.2 (0.05-0.7) μg kg-1 minute-1 in WX and WOX, respectively. Median (range) recovery times were 70 (15-310) minutes and 75 (20-313) minutes for WX and WOX, respectively. The use of xylazine as a part of a balanced anesthesia protocol in horses undergoing exploratory laparotomy did not negatively affect survival to discharge. Xylazine infusion as part of a balanced anesthesia protocol appears promising based on this single-center study. Further research is required to fully explore the risks and benefits of xylazine infusions in this context.

Current Targets and Future Directions of Positive Inotropes for Heart Failure.

While a congestive heart failure patient will ultimately need an assist device or even a replacement heart as the disease progresses, not every patient is qualified for such advanced therapy. Such patients awaiting better circulatory support benefit from positive inotropes in the meantime as palliative care. These agents are often prescribed in patients with acute decompensated heart failure, with reduced left ventricular ejection fraction and symptoms of organ dysfunction. Although positive inotropes, for example, digoxin, dobutamine, milrinone, levosimendan, etc., are successfully marketed and in use, a lot of their adverse effects, like arrhythmias, hypotension, and even sudden cardiac death, are rather encouraging further research on the development of novel positive inotropes. This review has investigated the molecular mechanisms of some of these adverse effects in terms of the proteins they target, followed by research on newer targets. Studies from 2013-2023 that have reported new small molecules with positive inotropic effects have been revisited in order to determine the progress made so far in drug discovery.

Abstract 4136181: Automated Personalized Modulation of the Sympathetic “fight-or-flight” Reflex In Vivo Using Implantable Microdevices for Enhancing Neurocardiac Function and Reducing Mortality Risk.

Background: The sympathetic nervous system (SNS) is a critical regulator of cardiovascular function. Whereas acute SNS activation elicits positive inotropy and confers survival advantage, persistent SNS hyperactivity is maladaptive and can lead to arrhythmias, cardiac arrest and heart failure. Hypothesis: Automated optogenetic modulation of the sympathetic stress response in vivo enhances neurocardiac function while avoiding sympathetic hyperactivity-mediated pathological effects. Methods: In normal guinea pigs, we virally transduced excitatory and/or inhibitory channelrhodopsins to the stellate ganglia (SG), the primary sympathetic input to the heart. We studied in situ effects of graded activation of SG opsins (e.g., phasic vs tonic) on cardiac function (e.g., ECG, heart rate) with and without perfusing agents (e.g., β-blockers, antioxidants). In vivo studies used novel implanted µLED devices for wireless body signal streaming (e.g., ECG) and neurophotonic SG opsin modulation closed-loop to dynamic analyses of physiological demand versus ECG-based cardiac risk prediction. Results: Compared to baseline heart rate (218±16 bpm), pulsed activation of inhibitory opsins reduced heart rate by ~25% (156±12; delta=67±14 bpm; p<0.0003; N=5). Pulsed activation of excitatory opsins increased heart rate by ~30% (285±28; delta=65±19 bpm; p<0.0002; N=5). Interestingly, prolonged (>20 min) tonic excitation of the SG caused desensitization, possibly as an intrinsic safety mechanism. Whereas graded SG excitation or inhibition at different LED intensities elicited prompt changes in heart rate, repeated activation of excitatory opsins led to quick desensitization. Our ongoing studies are aimed at understanding how and when SG modulation can enhance cardiac function, trigger intrinsic cardioprotective mechanisms, or cause pathological effects. Conclusion: Automated neurophotonic optogenetic excitation or inhibition of the SG is a robust personalized strategy for modulating cardiovascular function. The ability to rapidly and accurately modulate the sympathetic stress reflex in a graded manner can lead to more timely, effective, and appropriate physiological responses while avoiding undesired pathophysiological responses.

Comparing the anti-remodeling effect of sacubitril/valsartan and angiotensin-converting enzyme inhibition on myocardial samples of advanced heart failure patients undergoing heart transplantation

Abstract Background In decreasing heart failure (HF) hospitalization and cardiovascular death in HF patients with reduced ejection fraction, Sacubitril/Valsartan (SAC/VAL) treatment was proved to be superior to angiotensin-converting enzyme inhibition (ACEi). According to recent experimental results and clinical data based on echocardiography and circulating biomarkers, this benefit might be at least partially attributed to a greater anti-remodeling effect. However, there is a lack of direct evidence from human myocardial samples for this assumption. Purpose Therefore, we aimed to compare the anti-remodeling effect of SAC/VAL treatment to ACEi on myocardial samples of HF patients undergoing heart transplantation (HTX). Methods We studied left ventricular (LV) samples of seventy advanced HF patients who underwent HTX and received either SAC/VAL (SAC/VAL group, N=32) or ACEi treatment (ACEi group, N=38) for at least three months prior to HTX. Furthermore, all patients received beta-blockers and mineralocorticoid receptor antagonists titrated to maximally tolerated or target dose. Our groups were matched for age, sex, ejection fraction and other clinical parameters. Patients with liver or kidney failure, mechanical circulatory support, systemic inflammatory/fibrotic diseases or positive inotrope treatment were excluded. Myocardial mRNA expression of fibrotic markers and B-type natriuretic peptide (BNP) were measured with qRT-PCR and normalized to glyceraldehyde 3-phosphate dehydrogenase expression. Interstitial fibrosis area was assessed histologically. Results Preoperative plasma N-terminal pro-BNP levels were similar in the two groups (SAC/VAL: 4363±752 pg/mL vs. ACEi: 4616±1020 pg/mL; p=0.911). In contrast, the mRNA level of BNP in the myocardium was lower in patients treated with SAC/VAL (SAC/VAL: 2.2±1.05 vs. ACEi: 5.2±1.74; p=0.006). TIMP metallopeptidase inhibitor 1 (SAC/VAL: 0.07±0.01 vs. ACEi: 0.13±0.02; p=0.011), TIMP metallopeptidase inhibitor 2 (SAC/VAL: 0.06±0.01 vs. ACEi: 0.11±0.01; p<0.001), collagen type I alpha 1 chain (SAC/VAL: 0.02±0.00 vs. ACEi: 0.08±0.02; p<0.001) and collagen type III alpha 1 chain (SAC/VAL: 0.12±0.02 vs. ACEi: 0.27±0.04; p<0.001) relative gene expressions were also decreased in the LV of SAC/VAL-treated patients. Histology analysis confirmed reduced interstitial myocardial fibrosis area in the SAC/VAL group as well (SAC/VAL: 7.2±0.4% vs. ACEi: 8.6±0.5%; p=0.031). Conclusions SAC/VAL treatment decreased the myocardial expression of BNP and fibrosis-related genes to a greater extent compared with ACEi in LV samples of patients undergoing HTX. Histological analysis also verified the differences in fibrosis. Thus, the anti-remodeling effect of SAC/VAL might be superior to ACEi even in advanced HF.

Troponin I versus Creatinine Kinase-MB as Predictor Markers of the Severity and Outcomes in Acute Theophylline Toxicity

Abstract Theophylline is a type of diethylxanthine that continues to be widely used in many developing countries for the treatment of acute and chronic bronchial asthma, chronic obstructive pulmonary disease (COPD) and apnea of prematurity. Methylxanthine cardiotoxicity is based on diverse, complex mechanisms. PDE inhibition and blocking adenosine receptors cannot explain all the cardiotoxic effects of methylxanthine. In addition, methylxanthines are cardiac stimulants and result in positive inotropy and chronotropy even with therapeutic dosing; myocardial ischemia and myocardial infarction (MI) are associated with acute theophylline poisoning. The current study aimed to investigate troponin I and creatine kinase-MB as predictors of the severity and outcomes in cases of acute theophylline intoxication. No previous studies have proposed early predictors of cardiovascular toxicities among methylxanthine users, early recognition of the severity of theophylline toxicity can be lifesaving and needs aggressive supportive care to improve clinical outcomes in patients. This study was a prospective cohort study conducted on 34 patients admitted to the Poison Control Center at Ain Shams University Hospitals (PCC-ASUH) for a 6-month duration from January 2022 to June 2022 with a history of acute exposure to theophylline toxicity. with history of acute exposure to theophylline toxicity. Patients were subjected to personal and toxicological history taking, vital signs collection, grading of acute theophylline toxicity and measurement of serum theophylline level. Both troponin I and creatine kinase-MB were measured at 6 and 12 hours post admission. Results revealed that, troponin I level at 6 hours post ingestion and 12 hours post ingestion in addition to creatine kinase-MB level at 12 hours post ingestion were significantly higher in cases with severe acute theophylline intoxication and patients who required intensive care unit admission and hemodialysis. It was concluded that, troponin I could predict the severity and the requirement of ICU admission and hemodialysis in patients with acute theophylline toxicity either with early or delayed presentation. On the other hand, CK-MB could be considered for patients with delayed presentation. Depending on time of admission, proper choosing of the biomarker to be investigated will allow for better evaluation of patients with saving extra cost.

Early postoperative outcomes of modified del Nido cardioplegia in coronary artery bypass surgery in patients with low ejection fraction.

This study aimed to investigate the intraoperative and early postoperative effects of modified del Nido cardioplegia (DNC) compared to classic blood cardioplegia (BC) in patients with impaired left ventricular ejection fraction (EF) who underwent isolated coronary artery bypass grafting (CABG). A total of 123 patients (108 males, 15 females; mean age: 62.2±8.5 years; range, 42 to 78 years) with an EF of 35% or lower who underwent on-pump CABG were included in the retrospective study between December 2022 and December 2023. The patients were divided into two groups according to the type of cardioplegia used: Group 1 (n=74) was designated as the BC group, and Group 2 (n=49) was designated as the DNC group. The groups were compared in terms of aortic cross-clamp duration, cardiopulmonary bypass (CPB) duration, need for defibrillation during weaning from CPB, positive inotrope requirement, intra-aortic balloon pump requirement, postoperative troponin-I levels, postoperative atrial fibrillation occurence, postoperative prolonged ventilation, development of postoperative neurologic complications, need for reintervention due to postoperative bleeding, postoperative transfusion requirement, and EF values at one month after the operation. There was no significant difference between the two groups in the terms of aortic cross-clamp and CPB duration (p=0.955 vs. p=0.816). Additionally, there was no significant difference in the need for intra-aortic balloon pump usage between the two groups (p=0.105). Dopamine and dobutamine usage were significantly lower in Group 2 (p=0.04 and p=0.05, respectively). The intraoperative requirement for defibrillation was significantly lower in Group 2 (p=0.01). In addition, troponin levels at 12 h postoperatively were significantly lower in Group 2 (p=0.03). The incidence of postoperative atrial fibrillation was significantly lower in Group 2 (p=0.02). Moreover, there was no significant difference in EF values at one month after the operation (p=0.08). In patients who underwent CABG with reduced EF, modified DNC provided myocardial protection comparable to classic BC. Additionally, the need for intraoperative defibrillation and postoperative inotropic agents, as well as the incidence of postoperative atrial fibrillation, were lower in patients operated with DNC.

Cardiac-Sympathetic Contractility and Neural Alpha-Band Power: Cross-Modal Collaboration during Approach-Avoidance Conflict.

As evidence mounts that the cardiac-sympathetic nervous system reacts to challenging cognitive settings, we ask if these responses are epiphenomenal companions or if there is evidence suggesting a more intertwined role of this system with cognitive function. Healthy male and female human participants performed an approach-avoidance paradigm, trading off monetary reward for painful electric shock, while we recorded simultaneous electroencephalographic and cardiac-sympathetic signals. Participants were reward sensitive but also experienced approach-avoidance "conflict" when the subjective appeal of the reward was near equivalent to the revulsion of the cost. Drift-diffusion model parameters suggested that participants managed conflict in part by integrating larger volumes of evidence into choices (wider decision boundaries). Late alpha-band (neural) dynamics were consistent with widening decision boundaries serving to combat reward sensitivity and spread attention more fairly to all dimensions of available information. Independently, wider boundaries were also associated with cardiac "contractility" (an index of sympathetically mediated positive inotropy). We also saw evidence of conflict-specific "collaboration" between the neural and cardiac-sympathetic signals. In states of high conflict, the alignment (i.e., product) of alpha dynamics and contractility were associated with a further widening of the boundary, independent of either signal's singular association. Cross-trial coherence analyses provided additional evidence that the autonomic systems controlling cardiac-sympathetics might influence the assessment of information streams during conflict by disrupting or overriding reward processing. We conclude that cardiac-sympathetic control might play a critical role, in collaboration with cognitive processes, during the approach-avoidance conflict in humans.

Developmental Changes in the Excitation-Contraction Mechanisms of the Ventricular Myocardium and Their Sympathetic Regulation in Small Experimental Animals.

The developmental changes in the excitation-contraction mechanisms of the ventricular myocardium of small animals (guinea pig, rat, mouse) and their sympathetic regulation will be summarized. The action potential duration monotonically decreases during pre- and postnatal development in the rat and mouse, while in the guinea pig it decreases during the fetal stage but turns into an increase just before birth. Such changes can be attributed to changes in the repolarizing potassium currents. The T-tubule and the sarcoplasmic reticulum are scarcely present in the fetal cardiomyocyte, but increase during postnatal development. This causes a developmental shift in the Ca2+ handling from a sarcolemma-dependent mechanism to a sarcoplasmic reticulum-dependent mechanism. The sensitivity for beta-adrenoceptor-mediated positive inotropy decreases during early postnatal development, which parallels the increase in sympathetic nerve innervation. The alpha-adrenoceptor-mediated inotropy in the mouse changes from positive in the neonate to negative in the adult. This can be explained by the change in the excitation-contraction mechanism mentioned above. The shortening of the action potential duration enhances trans-sarcolemmal Ca2+ extrusion by the Na+-Ca2+ exchanger. The sarcoplasmic reticulum-dependent mechanism of contraction in the adult allows Na+-Ca2+ exchanger activity to cause negative inotropy, a mechanism not observed in neonatal myocardium. Such developmental studies would provide clues towards a more comprehensive understanding of cardiac function.

Apelin-13 administration allows for norepinephrine sparing in a rat model of cecal ligation and puncture-induced septic shock

BackgroundInfusion of exogenous catecholamines (i.e., norepinephrine [NE] and dobutamine) is a recommended treatment for septic shock with myocardial dysfunction. However, sustained catecholamine infusion is linked to cardiac toxicity and impaired responsiveness. Several pre-clinical and clinical studies have investigated the use of alternative vasopressors in the treatment of septic shock, with limited benefits and generally no effect on mortality. Apelin-13 (APL-13) is an endogenous positive inotrope and vasoactive peptide and has been demonstrated cardioprotective with vasomodulator and sparing life effects in animal models of septic shock. A primary objective of this study was to evaluate the NE-sparing effect of APL-13 infusion in an experimental sepsis-induced hypotension.MethodsFor this goal, sepsis was induced by cecal ligation and puncture (CLP) in male rats and the arterial blood pressure (BP) monitored continuously via a carotid catheter. Monitoring, fluid resuscitation and experimental treatments were performed on conscious animals. Based on pilot assays, normal saline fluid resuscitation (2.5 mL/Kg/h) was initiated 3 h post-CLP and maintained up to the endpoint. Thus, titrated doses of NE, with or without fixed-doses of APL-13 or the apelin receptor antagonist F13A co-infusion were started when 20% decrease of systolic BP (SBP) from baseline was achieved, to restore SBP values ≥ 115 ± 1.5 mmHg (baseline average ± SEM).ResultsA reduction in mean NE dose was observed with APL-13 but not F13A co-infusion at pre-determined treatment time of 4.5 ± 0.5 h (17.37 ± 1.74 µg/Kg/h [APL-13] vs. 25.64 ± 2.61 µg/Kg/h [Control NE] vs. 28.60 ± 4.79 µg/Kg/min [F13A], P = 0.0491). A 60% decrease in NE infusion rate over time was observed with APL-13 co-infusion, (p = 0.008 vs NE alone), while F13A co-infusion increased the NE infusion rate over time by 218% (p = 0.003 vs NE + APL-13). Associated improvements in cardiac function are likely mediated by (i) enhanced left ventricular end-diastolic volume (0.18 ± 0.02 mL [Control NE] vs. 0.30 ± 0.03 mL [APL-13], P = 0.0051), stroke volume (0.11 ± 0.01 mL [Control NE] vs. 0.21 ± 0.01 mL [APL-13], P < 0.001) and cardiac output (67.57 ± 8.63 mL/min [Control NE] vs. 112.20 ± 8.53 mL/min [APL-13], P = 0.0036), and (ii) a reduced effective arterial elastance (920.6 ± 81.4 mmHg/mL/min [Control NE] vs. 497.633.44 mmHg/mL/min. [APL-13], P = 0.0002). APL-13 administration was also associated with a decrease in lactate levels compared to animals only receiving NE (7.08 ± 0.40 [Control NE] vs. 4.78 ± 0.60 [APL-13], P < 0.01).ConclusionAPL-13 exhibits NE-sparing benefits in the treatment of sepsis-induced shock, potentially reducing deleterious effects of prolonged exogenous catecholamine administration.

Abstract Or103: Troponin I Serine 150 Phosphorylation as a Novel Cardiac Inotrope Without Detrimental Effects

Heart failure with systolic dysfunction is characterized by insufficient contractility. Standards of care for heart failure treat symptoms, however there are currently no approved therapies to increase contractility to directly improve the ability of the heart to pump blood. Previously tested positive inotropes increased heart function through mechanisms that increased intracellular calcium. Unfortunately, these early inotropes were associated with detrimental effects and worsened outcomes and therefore are not approved for long-term use. There remains a need for an alternative mechanism to increase contractility without increasing intracellular calcium. We previously demonstrated that phosphorylation of the inhibitory subunit of the troponin complex, troponin I (TnI) at serine residue 150 (S150) increases force development in ex vivo muscle by increasing calcium sensitivity. Increasing the sensitivity of the myofilament to calcium is an alternative mechanism to increase contractility without increasing intracellular calcium. We therefore hypothesize that increasing TnI-S150 phosphorylation in vivo would improve systolic function without harmful effects. To determine the effects of TnI-S150 phosphorylation in vivo , we generated a phosphorylation-mimetic mouse with TnI-S150 mutated to aspartic acid (TnI-pS150). Structural and functional measurements derived from echocardiography and hemodynamics demonstrate that TnI-pS150 mice have increased cardiac systolic function and contractility in vivo . We confirm that the mechanism for increasing in vivo function is through increased myofilament calcium sensitivity. Detrimental effects commonly observed with the use of inotropes (e.g. hypertrophy, hypertension, severe diastolic dysfunction, increased arrythmia susceptibility, increased mortality) were not observed in TnI-pS150 mice. Additionally, we did not observe any adverse long-term detrimental effects on cardiac structure and function in aged TnI-pS150 mice. These results support the phosphorylation of TnI-S150 as a novel signaling mechanism to increase systolic function without detrimental effects and is therefore a novel target for systolic heart failure therapies.

Abstract We013: Modeling Sex and Stress using Induced Pluripotent Stem Cell Derived Cardiomyocytes

Despite causing 1 in 3 deaths worldwide, cardiovascular disease and the heart have only recently been studied in women. Contrary to previous belief, the female heart is not just a smaller replica of a male heart. Almost all heart diseases show sexual differences in risk, treatment, and symptoms. Even with these differences there is a lack of female models in animal and cellular studies. Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) are a powerful human model to test baseline and stressed sex differences at the cellular level. We hypothesized that using stressors that mimic disease conditions (drugs, substrate stiffness) in multiple male and female hiPSC-CMs will result in differential sex-based responses. We ran Traction Force Microscopy on 3 male (n = 424 cells, 3 batches) and 3 female (n = 318 cells, 3 batches) cell lines on 10 kPa polyacrylamide hydrogels. Male cells had 42% higher twitch force (p = 8.8E-6) with 25% higher contraction (p = 1.77E-5) and relaxation (p = 0.0006) velocities. However, female cells had a larger spread area (823 +/- 17.32 µm 2 vs. 756 +/- 21.64 µm 2 , p = 0.0018). To validate hiPSC-CMs as a model we compared preliminary RNA-seq to publicly available Heart Cell Atlas sc/snRNA-seq data sets of primary ventricular cardiomyocytes. They had similar differentially expressed genes (DEGs) as our hiPSC-CMs. Furthermore, DEGs had significantly enriched gene sets including a 25-fold enrichment in hypertrophic cardiomyopathy (FDR = 1.6E-7), 23-fold in dilated cardiomyopathy (FDR = 1.6E-7), and 16-fold in cardiac muscle contraction (FDR = 6.3E-4). We analyzed stiffness by differentiating and culturing hiPSC-CMs on 10 kPa and 100 kPa stiffness hydrogels. Our RNA-seq analysis at day 10 and 30 after differentiation found 7000 DEGs at 10 kPa while only 556 DEGs at 100 kPa. We looked hypercontractility caused stres and performed RNA-seq on day 60 wild type and hypercontractile mutant hiPSC-CMs. The wild type was dosed with positive inotrope levosimendan to induce hypercontractility while the hypercontractile mutant was dosed with negative inotrope verapamil to lower contractility. Hypercontractility had significant upregulation of the cellular response to stress including ER stress, stress-activated MAPK cascades, stress fibers, and cardiac muscle hypertrophy in response to stress. These differences can identify possible gene targets for preventing cardiovascular disease and inform personalized medicine.

Detection of contractility changes in the heart from arterial blood pressure data using symmetric Projection Attractor Reconstruction

The potential for unintended drug induced changes in cardiac contractility is a major concern in medicines development. Whilst direct left ventricular pressure (LVP) measurement is the gold standard for measuring cardiac contractility in vivo, it is resource intensive and poses a welfare burden on research animals. In contrast, arterial blood pressure (BP) measurement has fewer challenges. Symmetric Projection Attractor Reconstruction (SPAR) is a signal processing technique which transforms physiological time-series signals into a corresponding visual image ('attractor'), amplifying morphology changes within physiological waveforms. It was hypothesized that SPAR analysis of BP signals would provide a surrogate measure of cardiac contractility by specifically amplifying the maximum slope of the systolic upstroke. BP (abdominal aorta) signals obtained from beagle dogs, treated with positive and negative inotropes, were retrospectively analysed to identify signal features that correlated with the maximum upslope of the LVP signal from simultaneously acquired LVP recordings. SPAR transformation of BP signals quantified drug induced changes in the maximum slope of the systolic upstroke. We identified key SPAR metrics that provided >0.8 correlation with the LVP maximum upslope, outperforming the BP systolic upstroke alone. This was observed for all 4 different drugs, doses and time points evaluated across studies. Thus, we conclude that the SPAR measures derived from the BP signal could be used as a first pass in vivo screen to flag any risk of drug induced changes in cardiac contractility during the conduct of non-clinical medicines development, potentially reducing or replacing the need to perform direct left ventricular measurements.

A Focus on the Pathophysiology of Adrenomedullin Expression: Endothelitis and Organ Damage in Severe Viral and Bacterial Infections.

Adrenomedullin (ADM) is a peptide hormone produced primarily in the adrenal glands, playing a crucial role in various physiological processes. As well as improving vascular integrity and decreasing vascular permeability, ADM acts as a vasodilator, positive inotrope, diuretic, natriuretic and bronchodilator, antagonizing angiotensin II by inhibiting aldosterone secretion. ADM also has antihypertrophic, anti-apoptotic, antifibrotic, antioxidant, angiogenic and immunoregulatory effects and antimicrobial properties. ADM expression is upregulated by hypoxia, inflammation-inducing cytokines, viral or bacterial substances, strength of shear stress, and leakage of blood vessels. These pathological conditions are established during systemic inflammation that can result from infections, surgery, trauma/accidents or burns. The ability to rapidly identify infections and the prognostic, predictive power makes it a valuable tool in severe viral and bacterial infections burdened by high incidence and mortality. This review sheds light on the pathophysiological processes that in severe viral or bacterial infections cause endothelitis up to the development of organ damage, the resulting increase in ADM levels dosed through its more stable peptide mid-regional proadrenomedullin (MR-proADM), the most significant studies that attest to its diagnostic and prognostic accuracy in highlighting the severity of viral or bacterial infections and appropriate therapeutic insights.

Cardiomyocyte-specific RXFP1 overexpression protects against pressure overload-induced cardiac dysfunction independently of relaxin

Heart failure (HF) prevalence is rising due to reduced early mortality and demographic change. Relaxin (RLN) mediates protective effects in the cardiovascular system through Relaxin-receptor 1 (RXFP1). Cardiac overexpression of RXFP1 with additional RLN supplementation attenuated HF in the pressure-overload transverse aortic constriction (TAC) model. Here, we hypothesized that robust transgenic RXFP1 overexpression in cardiomyocytes (CM) protects from TAC-induced HF even in the absence of RLN. Hence, transgenic mice with a CM-specific overexpression of human RXFP1 (hRXFP1tg) were generated. Receptor functionality was demonstrated by in vivo hemodynamics, where the administration of RLN induced positive inotropy strictly in hRXFP1tg. An increase in phospholamban-phosphorylation at serine 16 was identified as a molecular correlate. hRXFP1tg were protected from TAC without additional RLN administration, presenting not only less decline in systolic left ventricular (LV) function but also abrogated LV dilation and pulmonary congestion compared to WT mice. Molecularly, transgenic hearts exhibited not only a significantly attenuated fetal and fibrotic gene activation but also demonstrated less fibrotic tissue and CM hypertrophy in histological sections. These protective effects were evident in both sexes. Similar cardioprotective effects of hRXFP1tg were detectable in a RLN-knockout model, suggesting an alternative mechanism of receptor activation through intrinsic activity, alternative endogenous ligands or crosstalk with other receptors. In summary, CM-specific RXFP1 overexpression provides protection against TAC even in the absence of endogenous RLN. This suggests RXFP1 overexpression as a potential therapeutic approach for HF, offering baseline protection with optional RLN supplementation for specific activation.

Factors associated with non-fatal heart failure and atrial fibrillation or flutter within the first 30 days post COPD exacerbation: a nested case-control study

BackgroundAn immediate, temporal risk of heart failure and arrhythmias after a Chronic Obstructive Pulmonary Disease (COPD) exacerbation has been demonstrated, particularly in the first month post-exacerbation. However, the clinical profile of patients who develop heart failure (HF) or atrial fibrillation/flutter (AF) following exacerbation is unclear. Therefore we examined factors associated with people being hospitalized for HF or AF, respectively, following a COPD exacerbation.MethodsWe conducted two nested case-control studies, using primary care electronic healthcare records from the Clinical Practice Research Datalink Aurum linked to Hospital Episode Statistics, Office for National Statistics for mortality, and socioeconomic data (2014-2020). Cases had hospitalization for HF or AF within 30 days of a COPD exacerbation, with controls matched by GP practice (HF 2:1;AF 3:1). We used conditional logistic regression to explore demographic and clinical factors associated with HF and AF hospitalization.ResultsOdds of HF hospitalization (1,569 cases, 3,138 controls) increased with age, type II diabetes, obesity, HF and arrhythmia history, exacerbation severity (hospitalization), most cardiovascular medications, GOLD airflow obstruction, MRC dyspnea score, and chronic kidney disease. Strongest associations were for severe exacerbations (adjusted odds ratio (aOR)=6.25, 95%CI 5.10-7.66), prior HF (aOR=2.57, 95%CI 1.73-3.83), age≥80 years (aOR=2.41, 95%CI 1.88-3.09), and prior diuretics prescription (aOR=2.81, 95%CI 2.29-3.45).Odds of AF hospitalization (841 cases, 2,523 controls) increased with age, male sex, severe exacerbation, arrhythmia and pulmonary hypertension history and most cardiovascular medications. Strongest associations were for severe exacerbations (aOR=5.78, 95%CI 4.45-7.50), age≥80 years (aOR=3.15, 95%CI 2.26-4.40), arrhythmia (aOR=3.55, 95%CI 2.53-4.98), pulmonary hypertension (aOR=3.05, 95%CI 1.21-7.68), and prescription of anticoagulants (aOR=3.81, 95%CI 2.57-5.64), positive inotropes (aOR=2.29, 95%CI 1.41-3.74) and anti-arrhythmic drugs (aOR=2.14, 95%CI 1.10-4.15).ConclusionsCardiopulmonary factors were associated with hospitalization for HF in the 30 days following a COPD exacerbation, while only cardiovascular-related factors and exacerbation severity were associated with AF hospitalization. Understanding factors will help target people for prevention.

Tricuspid repair: short and long-term results of suture annuloplasty techniques and rigid and flexible ring annuloplasty techniques

BackgroundFunctional tricuspid regurgitation may arise from left heart valve diseases or other factors. If not addressed concurrently with primary surgical intervention, it may contribute to increased morbidity and mortality rates during the postoperative period. This study investigates the impact of various repair techniques on crucial factors such as systolic pulmonary artery pressure (SPAP), tricuspid valve regurgitation, and New York Heart Association (NYHA) functional capacity class in the postoperative period.Materials and methodsFrom April 2007 to June 2013, 379 adults underwent open-heart surgery for functional tricuspid regurgitation. Patients were categorized into four groups: Group 1 (156) with De Vega suture annuloplasty, Group 2 (60) with Kay suture annuloplasty, Group 3 (122) with Flexible Duran ring annuloplasty, and Group 4 (41) with Semi-Rigid Carpentier-Edwards ring annuloplasty. Demographic, clinical, operative, and postoperative data were recorded over a mean follow-up of 35.6 ± 19.1 months. Postoperative SPAP values, tricuspid regurgitation grades, and NYHA functional capacity classes were compared among the groups.ResultsNo statistically significant differences were observed among the groups regarding age, gender, preoperative disease diagnoses, history of previous cardiac operations, or echocardiographic characteristics such as preoperative ejection fraction, SPAP, and tricuspid regurgitation. Hospital and intensive care unit length of stay and postoperative complications also showed no significant differences. However, patients in Group 3 exhibited longer Cardio-Pulmonary Bypass duration, cross-clamp duration, and higher positive inotrope requirements. While the mortality rate within the first 30 days was higher in Group 1 compared to the other groups (p: 0.011), overall mortality rates did not significantly differ among the groups. Significant regression in functional tricuspid regurgitation and a notable decrease in SPAP values were observed in patients from Group 3 and Group 4 (p: 0.001). Additionally, patients in Group 3 and Group 4 showed a more significant reduction in NYHA functional capacity classification during the postoperative period (p: 0.001).ConclusionAmong the repair techniques, ring annuloplasty demonstrated superiority in reducing SPAP, regressing tricuspid regurgitation, and improving NYHA functional capacity in functional tricuspid regurgitation repairs.

Inducing positive inotropy in human iPSC-derived cardiac muscle by gene editing-based activation of the cardiac α-myosin heavy chain

Human induced pluripotent stem cells and their differentiation into cardiac myocytes (hiPSC-CMs) provides a unique and valuable platform for studies of cardiac muscle structure–function. This includes studies centered on disease etiology, drug development, and for potential clinical applications in heart regeneration/repair. Ultimately, for these applications to achieve success, a thorough assessment and physiological advancement of the structure and function of hiPSC-CMs is required. HiPSC-CMs are well noted for their immature and sub-physiological cardiac muscle state, and this represents a major hurdle for the field. To address this roadblock, we have developed a hiPSC-CMs (β-MHC dominant) experimental platform focused on directed physiological enhancement of the sarcomere, the functional unit of cardiac muscle. We focus here on the myosin heavy chain (MyHC) protein isoform profile, the molecular motor of the heart, which is essential to cardiac physiological performance. We hypothesized that inducing increased expression of α-MyHC in β-MyHC dominant hiPSC-CMs would enhance contractile performance of hiPSC-CMs. To test this hypothesis, we used gene editing with an inducible α-MyHC expression cassette into isogeneic hiPSC-CMs, and separately by gene transfer, and then investigated the direct effects of increased α-MyHC expression on hiPSC-CMs contractility and relaxation function. Data show improved cardiac functional parameters in hiPSC-CMs induced with α-MyHC. Positive inotropy and relaxation was evident in comparison to β-MyHC dominant isogenic controls both at baseline and during pacing induced stress. This approach should facilitate studies of hiPSC-CMs disease modeling and drug screening, as well as advancing fundamental aspects of cardiac function parameters for the optimization of future cardiac regeneration, repair and re-muscularization applications.

FRESH™ 3D bioprinted cardiac tissue, a bioengineered platform for in vitro pharmacology.

There is critical need for a predictive model of human cardiac physiology in drug development to assess compound effects on human tissues. In vitro two-dimensional monolayer cultures of cardiomyocytes provide biochemical and cellular readouts, and in vivo animal models provide information on systemic cardiovascular response. However, there remains a significant gap in these models due to their incomplete recapitulation of adult human cardiovascular physiology. Recent efforts in developing in vitro models from engineered heart tissues have demonstrated potential for bridging this gap using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in three-dimensional tissue structure. Here, we advance this paradigm by implementing FRESH™ 3D bioprinting to build human cardiac tissues in a medium throughput, well-plate format with controlled tissue architecture, tailored cellular composition, and native-like physiological function, specifically in its drug response. We combined hiPSC-CMs, endothelial cells, and fibroblasts in a cellular bioink and FRESH™ 3D bioprinted this mixture in the format of a thin tissue strip stabilized on a tissue fixture. We show that cardiac tissues could be fabricated directly in a 24-well plate format were composed of dense and highly aligned hiPSC-CMs at >600 million cells/mL and, within 14 days, demonstrated reproducible calcium transients and a fast conduction velocity of ∼16 cm/s. Interrogation of these cardiac tissues with the β-adrenergic receptor agonist isoproterenol showed responses consistent with positive chronotropy and inotropy. Treatment with calcium channel blocker verapamil demonstrated responses expected of hiPSC-CM derived cardiac tissues. These results confirm that FRESH™ 3D bioprinted cardiac tissues represent an in vitro platform that provides data on human physiological response.

Evolving targets for heart failure: the journey so far

The treatment of heart failure has included vasodilators, positive inotropes and most successfully neurohormonal blockade. Recent research has looked at metabolic and immune modulatory approaches, and implantable, mainly electrical devices. The near future in pharmacological research for heart failure remains focused on classic methodologies and small molecules, but despite significant improvements we still know relatively little of the complex interactions in heart failure, particularly for heart failure with preserved ejection fraction. Pharmacotherapy will in future be combined with advances in biotechnology, nanotechnology and devices and a digital revolution will help us to monitor patients at a distance, using wireless devices. Heart failure research has achieved much over the last 4 decades, but the pace of innovation and research has not abated and future advances in this disabling condition are indeed likely.

Evolving targets for heart failure: the journey so far

The treatment of heart failure has included vasodilators, positive inotropes and most successfully neurohormonal blockade. Recent research has looked at metabolic and immune modulatory approaches, and implantable, mainly electrical devices. The near future in pharmacological research for heart failure remains focused on classic methodologies and small molecules, but despite significant improvements we still know relatively little of the complex interactions in heart failure, particularly for heart failure with preserved ejection fraction. Pharmacotherapy will in future be combined with advances in biotechnology, nanotechnology and devices and a digital revolution will help us to monitor patients at a distance, using wireless devices. Heart failure research has achieved much over the last 4 decades, but the pace of innovation and research has not abated and future advances in this disabling condition are indeed likely.