Increase In Left Ventricular Contractility Research Articles

Physical exercise is essential for increasing ventricular contractility in hypertensive rats treated with losartan.

The treatment of hypertensive patients with losartan is very common. Despite the reduction in blood pressure, its effects on cardiac contractility and sympathetic autonomic drive are still controversial. In turn, aerobic physical training (APT) also presents an important therapeutic option, providing significant improvements in cardiovascular autonomic control, however little is known about its effects on cardiac contractility, especially when associated with losartan. Therefore, we investigated in spontaneously hypertensive rats (SHR) the effects of losartan and APT on cardiac hemodynamics and functionality, with emphasis on autonomic tonic balance and cardiac contractility. Sixty-four SHR (18 weeks old) were divided into four groups (N = 16): vehicle; vehicle submitted to APT through swimming for 12 weeks; treated with losartan (5 mg·kg-1·d-1) for 12 weeks; and treated with losartan associated with APT. The groups were submitted to cardiac morphological and functional analysis by echocardiography; double blockade of cardiac autonomic receptors with atropine and propranolol; and coronary bed reactivity and left ventricular contractility analyses by the Langendorff technique. APT improved functional parameters and autonomic balance by reducing sympathetic drive and/or increasing vagal drive. In contrast, it promoted a concentric remodeling of the left ventricle (LV). Treatment with losartan reduced sympathetic autonomic drive and cardiac morphological parameters, but there were no significant gains in cardiac functionality and contractility. When combined, the concentric remodeling of the LV to APT was abolished and gains in cardiac functionality and contractility were observed. Our findings suggest that the effects of losartan and APT are complementary and should be applied together in the treatment of hypertension. In spontaneously hypertensive rats, the combination of aerobic physical training with losartan treatment was crucial to greater blood pressure reductions and an increase in left ventricular contractility. Furthermore, losartan treatment prevented the concentric left ventricular remodeling caused by aerobic physical training.

Large scale genome-wide association analyses identify novel genetic loci and mechanisms in hypertrophic cardiomyopathy

Abstract Background Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality with both monogenic and polygenic components. Prior genome-wide association studies (GWAS) identified few genomic loci and disease genes due to limited sample size. Purpose To discover novel genetic loci, genes and mechanisms implicated in HCM using a large scale GWAS and multi-trait analysis of GWAS (MTAG). Methods and results We performed the largest HCM GWAS meta-analysis and MTAG to date including 5,900 HCM cases, 68,359 controls, and 36,083 UK Biobank (UKB) participants with cardiac magnetic resonance (CMR) imaging. We estimated the heritability of HCM attributable to common genetic variation (h2SNP) to be 0.25±0.02 using genome-based restricted maximum likelihood (GREML), with higher h2SNP in non-sarcomeric (0.29±0.02) compared to sarcomeric HCM (0.16±0.04). We identified a total of 70 loci (50 novel) associated with HCM (Figure 1), and 62 loci (32 novel) associated with relevant left ventricular (LV) structural or functional traits. Amongst the common variant HCM loci, we identify a novel HCM disease gene, SVIL, which encodes the actin-binding protein supervillin. We performed rare variant burden analysis including 1,845 clinically-diagnosed unrelated HCM cases and 37,481 controls and demonstrated a 10.5-fold (95% CI: 4.1-26.8; P=0.0000002) excess burden of SVIL loss of function (LoF) variants in HCM cases. Two-sample mendelian randomization analyses using LV contractility as exposure and obstructive (oHCM) and non-obstructive HCM (nHCM) as outcomes support a causal role of increased LV contractility in both oHCM and nHCM (Figure 2), suggesting common disease mechanisms and anticipating shared response to therapy. Conclusion We identify 50 novel genomic loci associated with HCM. Our data suggest that LoF variants in SVIL are a cause of HCM, and that increased contractility mediate both nHCM and oHCM. Taken together, the findings significantly increase our understanding of the genetic basis and molecular mechanisms of HCM, with potential implications for disease management.Figure 1Figure 2

Novel multi-site, multi-point biventricular pacing configuration: acute haemodynamic benefit

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Supported by the research grant of the AZV (Ministry of Health of the Czech Republic) Background Biventricular pacing (BVP) using multiple left ventricular (LV) sites may augment the hemodynamic effect of cardiac resynchronisation therapy (CRT) by engaging a greater mass of the myocardium. Purpose To evaluate the acute hemodynamic effect of a novel multi-site, multi-point BVP configuration. Methods The study investigated 18 patients with idiopathic dilated cardiomyopathy and left bundle-branch block during implantation of a BVP device (age: 59 ± 14 years, female gender: 7 [39%], LVEF: 27 ± 6%, native QRS: 171 ± 16 ms). Conventional leads were placed in the right atrium (RA) and ventricle (RV), one quadripolar LV lead (Quartet, Abbott, Abbott Park, IL, USA) was positioned in the posterolateral and another one in lateral or anterolateral coronary vein. Individual bipoles of all leads were connected through a splitter to separate external cardiac stimulators. Hemodynamics was evaluated using a micromanometer-tipped catheter (Micro-Cath, Millar, Tx, USA) located in the LV during RA pacing above sinus rate and five atrio-ventricular sequential pacing configurations at the same rate: 1.) RA+RV, 2.) RA + RV + distal bipole of the LV lead with greater dP/dT („conventional BVP"), 3.) RA + RV + distal and proximal bipoles of the LV lead with greater dP/dT („single-lead multi-point BVP"), 4.) RA + RV + distal bipoles of both LV leads („two-lead multi-site BVP"), and 5.) sequentional pacing RA + RV + all bipoles of both LV leads interconnected to a mesh („maximum BVP"). Results Compared to RA pacing, LV dP/dT was significantly greater during all BVP pacing configurations (RA pacing: 1940 ± 507 mmHg/s vs. conventional BVP: 2431 ± 855 mmHg/s, single-lead multi-point BVP: 2539 ± 740 mmHg/s, two-lead multisite BVP: 2517 ± 836 mmHg/s, and "maximum BVP": 2685 ± 893 mmHg/s, all p<0.001, Figure 1), but not during RA-RV pacing (2014 ± 721 mmHg/s, p=0.12). In addition, dP/dT was significantly greater during "maximum BVP" compared to conventional BVP (p=0.05). Conclusion Compared to RA pacing and conventional BVP, the greatest increase in LV contractility was achieved with a novel multi-site, multi-point "maximum BVP" configuration. These preliminary findings provide a rationale for designing new approaches to CRT.

Chronic Vagal Nerve Stimulation Rescues Sympathetic Control of the Heart following Myocardial Infarction

Cardiac injury, such as myocardial infarction (MI), leads to neurohormonal activation and autonomic remodeling, resulting in reflexive sympathoexcitation and parasympathetic dysfunction, which further contribute to progression of disease. The purpose of this study was to determine whether chronic cervical vagal nerve stimulation (VNS) influences MI‐associated changes in cardiac sympathetic function. Yucatan minipigs were divided into control (n=6), chronic MI (n=7), and chronic MI + chronic VNS (n=8) groups. VNS therapy was delivered to the right cervical vagus nerve and systematically titrated to an optimal intensity based on heart rate dynamics (5Hz, 2.1±0.3mA, 250μs, 17.5% duty cycle) using telemetry in the conscious state. Chronic MI was created using percutaneous embolization of the left anterior descending coronary artery with polystyrene beads under fluoroscopy (Figure 1A). VNS therapy was started 2 days following MI, and the animals maintained for 6‐8 weeks. At terminal study, we evaluated hemodynamic responses to graded bilateral sympathetic chain stimulation (BSS). Left ventricular (LV) strips encompassing regions of scar, border zone, and normal myocardium were fixed in 10% formalin, embedded in paraffin, sectioned, and studied using Masson's trichrome stain (Figure 1B‐C). Structural changes at the peri‐infarct area were scored (0‐3) for myocyte morphology and presence of hypertrophy or myocytolysis. Animals with MI alone exhibited spontaneous ventricular arrhythmias, including two that experienced sudden cardiac death (Figure 1D). At terminal study, there were no significant differences in baseline systolic function among groups. Moderate (4Hz) and high (10Hz) intensity BSS increased LV contractility (dp/dtmax) in all groups (Figure 2A‐B); however, evoked changes were significantly reduced in the chronic MI compared to control or MI + VNS groups. While control animals displayed evidence of contractile reserve at 10Hz vs 4Hz (1297±266 mmHg/s, p=0.03), chronic MI animals did not (631.9±264 mmHg/s, p=0.11), which was improved with chronic VNS therapy (1027±160.6 mmHg/s, p<0.01, Figure 2C). Chronic VNS therapy also significantly reduced MI‐associated structural remodeling in the peri‐infarct area, including the degree of myocytolysis and dysmorphic myocytes (structural abnormality index 0.6±0.2 vs 1.8±0.2, p<0.01). Our findings suggest that chronic VNS ameliorates sympathetic functional remodeling following myocardial infarction and improves cardiac mechanical performance in response to simulated stress. Furthermore, chronic VNS reduces pathologic myocardial remodeling at the peri‐infarct zone, potentially stabilizing the resultant ventricular scar.

Extent and determinants of left ventricular reverse remodeling in patients with secondary mitral regurgitation undergoing MitraClip implantation.

BackgroundIn secondary MR, data on left ventricular (LV) remodeling after MitraClip procedure are rare, even this information may impact patient selection. This study investigated changes in LV structure and function by cardiovascular magnetic resonance (CMR) following MitraClip implantation for secondary mitral regurgitation (MR) in order to assess extent and predictors of LV reverse remodeling (LVRR).Methods and ResultsTwenty-nine patients underwent CMR imaging prior to and six months after MitraClip procedure. LVRR was defined by a decrease of LV end-diastolic volume index (LVEDVi) > 15% compared to baseline. According to the definition of LVRR, 34% of patients displayed LVRR at follow-up CMR. Baseline LV stroke volume index (LVSVi), LV ejection fraction (LVEF), LV circumferential strain and MR volume at baseline were predictors of LVRR at follow-up. At second CMR, we detected an improvement in hemodynamic status as illustrated by an increase in effective LVSVi (28 ± 8 ml/m2 vs. 33 ± 8 ml/m2; p = 0.053) and cardiac index (2.0 ± 0.5 vs. 2.3 ± 0.5 l/min; p = 0.016), while LVEF and LV strain parameters did not change (p > 0.05). Improvements in effective LVSVi were associated with the decrease of MR volume (r = 0.509; p = 0.018) and MR fraction (r = 0.629; p = 0.002) by MitraClip.ConclusionsTogether, MitraClip implantation is associated with LVRR in one third of patients. Baseline LV function and magnitude of MR are important predictors of LVRR. Improvement of hemodynamic status may be assessed by effective stroke volume index and correlates with the reduction of MR by MitraClip implantation, rather than an increase in LV contractility.

Gestationally Administered RAS Modulators Reprogram Endotoxic Cardiovascular and Inflammatory Profiles in Adult Offspring of Preeclamptic Rats

Preeclampsia (PE) adversely programs fetal cardiovascular integrity and amplifies cardiovascular dysfunction induced by endotoxemia in adult offspring of preeclamptic mothers. Here, we asked if such aggravated endotoxic insult could be nullified by modulators of the renin-angiotensin system (RAS). PE was induced by gestational administration of L-NAME, a nitric oxide synthase inhibitor. Adult male offspring of PE mothers treated gestationally with Ang 1-7 (Ang II-derived vasodilator), losartan (AT1 receptor antagonist), pioglitazone (RAS modulator), or combined losartan/pioglitazone, were instrumented with femoral indwelling catheters and challenged intravenously with a 5 mg/kg dose of lipopolysaccharides (LPS, 5 mg/kg). LPS caused significant increases in heart rate and decreases in blood pressure and spectral index of overall heart rate variability. These effects were similarly reduced by all drug therapies. In offspring born to Ang 1-7-treated dams, the spectral index of cardiac sympathovagal balance showed elevated sympathetic dominance in response to LPS. Further, pioglitazone and its combination with losartan were more effective than Ang 1-7 or losartan in depressing the LPS-evoked increases in left ventricular contractility (dP/dtmax). Immunohistochemical studies revealed that Ang1-7, but not losartan/pioglitazone, regimen abolished the exaggerated increases in TLR-4 expression caused by PE/LPS in heart tissues and neuronal circuits of brainstem rostral ventrolateral medulla. By contrast, ACE expression in the same two areas was reduced by losartan/pioglitazone but not Ang 1-7. Together, gestational fetal reprogramming of Ang II (depression) and Ang 1-7 (activation) arms of RAS effectively counterbalance worsened endotoxic cardiovascular and inflammatory profiles in adult offspring of PE rats.

Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect.

The heart muscle diseases hypertrophic (HCM) and dilated (DCM) cardiomyopathies are leading causes of sudden death and heart failure in young otherwise healthy individuals. We conducted genome-wide association studies (GWAS) and multi-trait analyses in HCM (1,733 cases), DCM (5,521 cases), and nine left ventricular (LV) traits in 19,260 UK Biobank participants with structurally normal hearts. We identified 16 loci associated with HCM, 13 with DCM, and 23 with LV traits. We show strong genetic correlations between LV traits and cardiomyopathies, with opposing effects in HCM and DCM. Two-sample Mendelian randomization supports a causal association linking increased contractility with HCM risk. A polygenic risk score (PRS) explains a significant portion of phenotypic variability in carriers of HCM-causing rare variants. Our findings thus provide evidence that PRS may account for variability in Mendelian diseases. More broadly, we provide insights into how genetic pathways may lead to distinct disorders through opposing genetic effects.

Abstract 16685: Shared Genetic Pathways Contribute to Risk of Hypertrophic and Dilated Cardiomyopathies With Opposite Directions of Effect

Introduction: Hypertrophic (HCM) and dilated (DCM) cardiomyopathies are leading causes of sudden death and heart failure requiring transplantation in young individuals. While some cases have a monogenic underlying cause, the majority remain unexplained. Objective: To better understand the contribution of common genetic variants in susceptibility and severity of cardiomyopathy. Methods: We conducted three genome-wide association studies (GWAS) and multi-trait analyses in European-ancestry individuals, including a HCM (1,733 cases) and DCM meta-analyses (5,521 cases), and a GWAS of 9 left ventricular (LV) traits in 19,260 healthy participants from the UK Biobank that underwent cardiac magnetic resonance imaging. We investigated genetic correlations between LV traits, HCM and DCM using LD score regression. We used two-sample mendelian randomization (MR) to assess the causal relationship of increased LV contractility with HCM risk. Lastly, we derived a polygenic risk score and assessed whether it modulates maximal LV wall thickness (maxLVWT) and clinical events in 368 sarcomeric mutation carriers, using linear and Cox mixed effects models, respectively. Results: We identified 16 genetic loci (15 novel) associated with HCM, 13 loci (7 novel) associated with DCM, and 23 loci associated with LV traits. We showed strong genetic correlations between LV volumes and contractility traits in the general population and cardiomyopathies, with opposing effects in HCM and DCM. Using MR, we demonstrated a causal association linking increased LV contractility with HCM risk and estimated that each unit (1%) increase in LV ejection fraction increases the risk of HCM by 37% (95% CI 10%-69%, P=0.004). Lastly, a polygenic risk score (PRS HCM ) derived from the HCM GWAS was associated with maxLVWT (P=0.0001) and clinical events (P=0.009) in carriers of HCM-causing rare variants. Conclusion: Our findings highlight the contribution of common genetic variants in susceptibility for HCM and DCM, and in severity in sarcomeric mutation carriers. Our data also point to increased LV contractility as an important mechanism of HCM independently of sarcomere activating rare variants, and highlight the potential clinical relevance of PRS for risk stratification in HCM.

Sex-related differences in cardiac and myofilament function in rats with pressure-overload induced left ventricular hypertrophy

Abstract Introduction Recent findings indicate that sex is a major determinant of left ventricular (LV) structure in pressure overload (PO)-induced LV myocardial hypertrophy (LVH). However, data are scare regarding sex-related differences in LV function in case of PO-evoked LVH. Aim Hence, in the present study we aimed at comprehensively investigating sex-related functional differences on the global cardiac level and also on the myofilament level in PO-induced LVH. Method Abdominal aortic banding (AB) was carried out to induce chronic PO for 6 or 12 weeks in male and female rats. Age- and sex-matched sham-operated animals served as controls. The development of LVH was followed by serial echocardiography. The extent of cardiomyocyte hypertrophy and myocardial fibrosis were evaluated by histology. Cardiac function was assessed by pressure-volume analysis. Force measurement was carried out in permeabilized cardiomyocytes to compute myofilament function. Results At week 6, robust myocardial hypertrophy, concentric LV geometry and moderate interstitial fibrosis were detected in both male and female AB rats. This early stage of PO-induced LVH was associated with increased LV contractility (slope of end-systolic pressure-volume relationship [ESPVR, mmHg/μl]: 3.09±0.18 Male-AB-wk6 vs. 1.79±0.22 Male-Sham-wk6 P<0.05; 3.68±0.77 Female-AB-wk6 vs. 1.87±0.21 Female-Sham-wk6 P<0.05) and enhanced myofilament Ca2+ sensitivity in both sexes (pCa50: 5.86±0.01 Male-AB-wk6 vs. 5.73±0.02 Male-Sham-wk6 P<0.05; 5.94±0.03 Female-AB-wk6 vs. 5.73±0.01 Female-Sham-wk6 P<0.05). At week 6, the augmented LV contractility effectively counterbalanced the increased afterload in both male and female AB groups. Hence, ventricular-arterial coupling (VAC) was maintained and LV systolic function was preserved in the AB groups in both sexes. In contrast, at week 12, marked sex differences could be observed. At this later stage, LVH was characterized by eccentric remodeling and intensified collagen accumulation in male AB rats. The initial LV contractility augmentation (slope of ESPVR, mmHg/μl: 1.74±0.13 Male-AB-wk12 vs. 1.31±0.17 Male-Sham-wk12 n.s.) as well as the enhanced myofilament Ca2+ sensitivity (pCa50: 5.78±0.02 Male-AB-wk12 vs. 5.75±0.01 Male-Sham-wk12 n.s.) diminished, leading to impaired VAC and reduced LV systolic function. On the contrary, in female AB rats, cardiac contractility (ESPVR, mmHg/ μl: 3.97±0.50 Female-AB-wk12 vs. 2.08±0.17 Female-Sham-wk12 P<0.05) and myofilament Ca2+ sensitivity (pCa50:5.85±0.02 Female-AB-wk12 vs. 5.78±0.01 Female-Sham-wk12 P<0.05) remained increased, resulting in adequate VAC and preserved LV systolic function at late-stage of PO-induced LVH as well. Conclusion The initially augmented LV contractility and enhanced myofilament Ca2+ sensitivity declines in male but not in female AB rats at later time points. Hence, characteristically different alterations occur in LV systolic function between the two sexes in late-stage of PO-evoked LVH. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): NVKP_16-1-2016-0017.

Modulation of the acute defence reaction by eplerenone prevents cardiac disease progression in viral myocarditis.

AimsLeft ventricular (LV) dysfunction in viral myocarditis is attributed to myocardial inflammation and fibrosis, inducing acute and long‐time cardiac damage. Interventions are not established. On the basis of the link between inflammation, fibrosis, aldosterone, and extracellular matrix regulation, we aimed to investigate the effect of an early intervention with the mineralocorticoid receptor antagonist (MRA) eplerenone on cardiac remodelling in a murine model of persistent coxsackievirus B3 (CVB3)‐induced myocarditis.Methods and resultsSWR/J mice were infected with 5 × 104 plaque‐forming units of CVB3 (Nancy strain) and daily treated either with eplerenone (200 mg/kg body weight) or with placebo starting from Day 1. At Day 8 or 28 post infection, mice were haemodynamically characterized and subsequently sacrificed for immunohistological and molecular biology analyses. Eplerenone did not influence CVB3 load. Already at Day 8, 1.8‐fold (P < 0.05), 1.4‐fold (P < 0.05), 3.2‐fold (P < 0.01), and 2.1‐fold (P < 0.001) reduction in LV intercellular adhesion molecule 1 expression, presence of monocytes/macrophages, oxidative stress, and apoptosis, respectively, was observed in eplerenone‐treated vs. untreated CVB3‐infected mice. In vitro, eplerenone led to 1.4‐fold (P < 0.01) and 1.2‐fold (P < 0.01) less CVB3‐induced cardiomyocyte oxidative stress and apoptosis. Furthermore, collagen production was 1.1‐fold (P < 0.05) decreased in cardiac fibroblasts cultured with medium of eplerenone‐treated vs. untreated CVB3‐infected HL‐1 cardiomyocytes. These ameliorations were in vivo translated into prevention of cardiac fibrosis, as shown by 1.4‐fold (P < 0.01) and 2.1‐fold (P < 0.001) lower collagen content in the LV of eplerenone‐treated vs. untreated CVB3‐infected mice at Days 8 and 28, respectively. This resulted in an early and long‐lasting improvement of LV dimension and function, as indicated by reduced LV end‐systolic volume and end‐diastolic volume, and an increase in LV contractility (dP/dtmax) and LV relaxation (dP/dtmin), respectively (P < 0.05).ConclusionsEarly intervention with the MRA eplerenone modulates the acute host and defence reaction and prevents cardiac disease progression in experimental CVB3‐induced myocarditis without aggravation of viral load. The findings advocate for an initiation of therapy of viral myocarditis as early as possible, even before the onset of inflammation‐induced myocardial dysfunction. This may also have implications for coronavirus disease‐19 therapy.

CaMKII activity contributes to homeometric autoregulation of the heart: A novel mechanism for the Anrep effect.

The Anrep effect represents the alteration of left ventricular (LV) contractility to acutely enhanced afterload in a few seconds, thereby preserving stroke volume (SV) at constant preload. As a result of the missing preload stretch in our model, the Anrep effect differs from the slow force response and has a different mechanism. The Anrep effect demonstrated two different phases. First, the sudden increased afterload was momentary equilibrated by the enhanced LV contractility as a result of higher power strokes of strongly-bound myosin cross-bridges. Second, the slightly delayed recovery of SV is perhaps dependent on Ca2+ /calmodulin-dependent protein kinase II activation caused by oxidation and myofilament phosphorylation (cardiac myosin-binding protein-C, myosin light chain 2), maximizing the recruitment of available strongly-bound myosin cross-bridges. Short-lived oxidative stress might present a new facet of subcellular signalling with respect to cardiovascular regulation. Relevance for human physiology was demonstrated by echocardiography disclosing the Anrep effect in humans during handgrip exercise. The present study investigated whether oxidative stress and Ca2+ /calmodulin-dependent protein kinase II (CaMKII) activity are involved in triggering the Anrep effect. LV pressure-volume (PV) analyses of isolated, preload controlled working hearts were performed at two afterload levels (60 and 100mmHg) in C57BL/6N wild-type (WT) and CaMKII-double knockout mice (DKOCaMKII ). In snap-frozen WT hearts, force-pCa relationship, H2 O2 generation, CaMKII oxidation and phosphorylation of myofilament and Ca2+ handling proteins were assessed. Acutely raised afterload showed significantly increased wall stress, H2 O2 generation and LV contractility in the PV diagram with an initial decrease and recovery of stroke volume, whereas end-diastolic pressure and volume, as well as heart rate, remained constant. Afterload induced increase in LV contractility was blunted in DKOCaMKII -hearts. Force development of single WT cardiomyocytes was greater with elevated afterload at submaximal Ca2+ concentration and associated with increases in CaMKII oxidation and phosphorylation of cardiac-myosin binding protein-C, myosin light chain and Ca2+ handling proteins. CaMKII activity is involved in the regulation of the Anrep effect and associates with stimulation of oxidative stress, presumably starting a cascade of CaMKII oxidation with downstream phosphorylation of myofilament and Ca2+ handling proteins. These mechanisms improve LV inotropy and preserve stroke volume within few seconds.

Myofilament Ca2+ sensitivity correlates with left ventricular contractility during the progression of pressure overload-induced left ventricular myocardial hypertrophy in rats

AimHere we aimed at investigating the relation between left ventricular (LV) contractility and myofilament function during the development and progression of pressure overload (PO)-induced LV myocardial hypertrophy (LVH). MethodsAbdominal aortic banding (AB) was performed to induce PO in rats for 6, 12 and 18 weeks. Sham operated animals served as controls. Structural and molecular alterations were investigated by serial echocardiography, histology, quantitative real-time PCR and western blot. LV function was assessed by pressure-volume analysis. Force measurement was carried out in permeabilized cardiomyocytes. ResultsAB resulted in the development of pathological LVH as indicated by increased heart weight-to-tibial length ratio, LV mass index, cardiomyocyte diameter and fetal gene expression. These alterations were already present at early stage of LVH (AB-week6). Furthermore, at more advanced stages (AB-week12, AB-week18), myocardial fibrosis and chamber dilatation were also observed. From a hemodynamic point of view, the AB-wk6 group was associated with increased LV contractility, maintained ventriculo-arterial coupling (VAC) and preserved systolic function. In the same experimental group, increased myofilament Ca2+ sensitivity (pCa50) and hyperphosphorylation of cardiac troponin-I (cTnI) at Threonine-144 was detected. In contrast, in the AB-wk12 and AB-wk18 groups, the initial augmentation of LV contractility, as well as the increased myofilament Ca2+ sensitivity and cTnI (Threonine-144) hyperphosphorylation diminished, leading to impaired VAC and reduced systolic performance. Strong correlation was found between LV contractility parameters and myofilament Ca2+-sensitivity among the study groups. ConclusionChanges in myofilament Ca2+ sensitivity might underlie the alterations in LV contractility during the development and progression of PO-induced LVH.

Three days of chronic intermittent hypoxia is sufficient to induce β1‐adrenoceptor dependent increases in left ventricular contractility

Chronic intermittent Hypoxia (CIH) is the primary pathological feature of obstructive sleep apnea, manifesting sympathetic nervous system hyperactivity and hypertension. Modest durations of CIH exposure have been shown to increase cardiac output that may contribute to the hypertensive state. Prolonged CIH exposures induce heart failure. We sought to determine if increases in cardiac work develop before the CIH‐induced hypertensive phenotype is established.Male Wistar rats were exposed to repetitive cycles of hypoxia (FiO2=0.05 nadir; 90 seconds) and normoxia (FiO2=0.21; 210 seconds) for eight hours per day for three days (CIH; n=6). Sham animals (n=7) were constantly exposed to room air and the same environmental cues. Assessment of cardiovascular parameters was performed under urethane anesthesia (1.5 g/kg i.p.). Data are presented as mean±SD (sham vs CIH) and were analysed using unpaired Student's t‐tests. P&lt;0.05 was taken as significant.Systolic blood pressure (p=0.439), mean arterial pressure (p=0.267) and heart rate (p=0.149) were all unaffected by three days of CIH exposure. In addition, plasma adrenaline (p=0.294) and noradrenaline (p=0.155) concentrations were not elevated in CIH exposed animals compared with sham controls. However, at baseline, left ventricular contractility (dP/dtMAX) was significantly increased in CIH exposed animals compared with sham animals (12320 ± 2725 vs 15300 ± 2002 mmHg/s; p=0.025). Interestingly, β1‐adrenoceptor inhibition with atenolol (5 mg/kg; i.v.) provided greater inhibition of left ventricular contractility in CIH animals compared with sham animals (−4747 ± 2080 vs −7604 ± 1298 mmHg/s; p=0.014), reducing dP/dtMAX to equivalent levels. Systolic blood pressure (p=0.735) and heart rate (p=0.25) responses to atenolol were similar in sham and CIH animals. Sympathetic ganglion blockade with hexamethonium (25 mg/kg; i.v.) produced equivalent responses in CIH and sham animals for measured cardiovascular parameters (p&gt;0.05).This study suggests that global sympathetic hyperactivity has not yet developed in this three‐day model of CIH, as evidenced by catecholamine concentrations, blood pressure and heart rate, which are equivalent with sham animals. Nevertheless, three days of CIH exposure is sufficient to increase cardiac work. We hypothesize that through this mechanism the heart drives development of the hypertensive phenotype in the early stages of CIH, as opposed to sympathetically‐mediated peripheral vasoconstriction.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Heme oxygenase byproducts variably influences myocardial and autonomic dysfunctions induced by the cyclosporine/diclofenac regimen in female rats

We recently reported that exposure to cyclosporine (CSA) plus diclofenac causes hypertension and impairs left ventricular (LV) and cardiac autonomic functions in female rats. Here, we tested the hypothesis that these effects could be mitigated by facilitated heme oxygenase (HO) signaling. Experiments were performed in female rats to assess the effects of 10-day treatment with CSA (25 mg/kg/day)/diclofenac (1 mg/kg/day) regimen on cardiovascular functions in absence and presence of maneuvers that upregulate HO or its enzymatic products. The CSA/diclofenac-induced hypertension and impairment in cardiac sympathovagal balance (i.e. reduced low-frequency/high-frequency spectral ratio) were blunted upon concurrent treatment with hemin (HO-1 inducer), tricarbonyldichlororuthenium (II) dimer (CORM-2, carbon monoxide-releasing molecule), or bilirubin. While none of the latter treatments affected the CSA/diclofenac-evoked decrease in isovolumic relaxation constant (Tau, a measure of diastolic function), the increased LV contractility (dP/dtmax) and attenuated reflex bradycardia in CSA/diclofenac-treated rats was abolished by bilirubin only. Paradoxically, the CSA/diclofenac-evoked attenuation in reflex tachycardia was improved in presence of hemin or CORM-2, but not bilirubin. The favorable hemin effects were abrogated after inhibition of HO (ZnPP) or nitric oxide synthase (NOS, l-NAME). These finding highlights NOS-dependent modulatory roles for HO and its enzymatic products in improving the worsened cardiovascular profile in CSA/diclofenac-treated female rats.

Noninvasive evaluation of left ventricular elastance according to pressure-volume curves modeling in arterial hypertension.

End-systolic left ventricular (LV) elastance (Ees) has been previously calculated and validated invasively using LV pressure-volume (P-V) loops. Noninvasive methods have been proposed, but clinical application remains complex. The aims of the present study were to 1) estimate Ees according to modeling of the LV P-V curve during ejection ("ejection P-V curve" method) and validate our method with existing published LV P-V loop data and 2) test the clinical applicability of noninvasively detecting a difference in Ees between normotensive and hypertensive subjects. On the basis of the ejection P-V curve and a linear relationship between elastance and time during ejection, we used a nonlinear least-squares method to fit the pressure waveform. We then computed the slope and intercept of time-varying elastance as well as the volume intercept (V0). As a validation, 22 P-V loops obtained from previous invasive studies were digitized and analyzed using the ejection P-V curve method. To test clinical applicability, ejection P-V curves were obtained from 33 hypertensive subjects and 32 normotensive subjects with carotid tonometry and real-time three-dimensional echocardiography during the same procedure. A good univariate relationship (r2 = 0.92, P < 0.005) and good limits of agreement were found between the invasive calculation of Ees and our new proposed ejection P-V curve method. In hypertensive patients, an increase in arterial elastance (Ea) was compensated by a parallel increase in Ees without change in Ea/Ees In addition, the clinical reproducibility of our method was similar to that of another noninvasive method. In conclusion, Ees and V0 can be estimated noninvasively from modeling of the P-V curve during ejection. This approach was found to be reproducible and sensitive enough to detect an expected increase in LV contractility in hypertensive patients. Because of its noninvasive nature, this methodology may have clinical implications in various disease states.NEW & NOTEWORTHY The use of real-time three-dimensional echocardiography-derived left ventricular volumes in conjunction with carotid tonometry was found to be reproducible and sensitive enough to detect expected differences in left ventricular elastance in arterial hypertension. Because of its noninvasive nature, this methodology may have clinical implications in various disease states.

Cardiac myosin binding protein C, adrenergic stimulation and cardiac contractility

Myosin binding protein C remained a perplexing although integral component of the sarcomeric thick filament until the discovery that genetic defects in its corresponding gene is a frequent cause of hypertrophic cardiomyopathy. Basic science investigation subsequently revealed that it is one of the most potent regulators of cardiac contractility. Phosphorylation of its N-terminus upon adrenergic stimulation, causes increased order in myosin heads as well as increased ATPase activity, Fmax and Ca2+-sensitivity of contraction, while its dephosphorylation upon cholinergic stimulation or during low flow ischaemia leads to changes in the sarcomeric thick filament that diminish interaction between myosin heads and actin. This dynamic flux in phosphorylation upon adrenergic stimulation is not only crucial to normal cardiac function and structure, but also vital for protection against ischaemic injury. Genetically-driven deficiency or inadequacy in cMyBPC leads to severe cardiac dysfunction and structural changes, including cardiac hypertrophy and dilation, and particularly attenuates the adaptive increase in left ventricular contractility that follows on β-adrenergic stimulation or pressure overload, resulting in decreased systolic function, and reduced cardiac output.

Saxagliptin and Tadalafil Differentially Alter Cyclic Guanosine Monophosphate (cGMP) Signaling and Left Ventricular Function in Aortic-Banded Mini-Swine.

BackgroundCyclic guanosine monophosphate‐protein kinase G‐phosphodiesterase 5 signaling may be disturbed in heart failure (HF) with preserved ejection fraction, contributing to cardiac remodeling and dysfunction. The purpose of this study was to manipulate cyclic guanosine monophosphate signaling using the dipeptidyl‐peptidase 4 inhibitor saxagliptin and phosphodiesterase 5 inhibitor tadalafil. We hypothesized that preservation of cyclic guanosine monophosphate cGMP signaling would attenuate pathological cardiac remodeling and improve left ventricular (LV) function.Methods and ResultsWe assessed LV hypertrophy and function at the organ and cellular level in aortic‐banded pigs. Concentric hypertrophy was equal in all groups, but LV collagen deposition was increased in only HF animals. Prevention of fibrotic remodeling by saxagliptin and tadalafil was correlated with neuropeptide Y plasma levels. Saxagliptin better preserved integrated LV systolic and diastolic function by maintaining normal LV chamber volumes and contractility (end‐systolic pressure‐volume relationship, preload recruitable SW) while preventing changes to early/late diastolic longitudinal strain rate. Function was similar to the HF group in tadalafil‐treated animals including increased LV contractility, reduced chamber volume, and decreased longitudinal, circumferential, and radial mechanics. Saxagliptin and tadalafil prevented a negative cardiomyocyte shortening‐frequency relationship observed in HF animals. Saxagliptin increased phosphodiesterase 5 activity while tadalafil increased cyclic guanosine monophosphate levels; however, neither drug increased downstream PKG activity. Early mitochondrial dysfunction, evident as decreased calcium‐retention capacity and Complex II‐dependent respiratory control, was present in both HF and tadalafil‐treated animals.ConclusionsBoth saxagliptin and tadalafil prevented increased LV collagen deposition in a manner related to the attenuation of increased plasma neuropeptide Y levels. Saxagliptin appears superior for treating heart failure with preserved ejection fraction, considering its comprehensive effects on integrated LV systolic and diastolic function.

Improved arterial-ventricular coupling in metabolic syndrome after exercise training: a pilot study.

The metabolic syndrome (MetS) is associated with threefold increased risk of cardiovascular (CV) morbidity and mortality, which is partly due to a blunted CV reserve capacity, reflected by a reduced peak exercise left ventricular (LV) contractility and aerobic capacity and a blunted peak arterial-ventricular coupling. To date, no study has examined whether aerobic exercise training in MetS can reverse peak exercise CV dysfunction. Furthermore, examining how exercise training alters CV function in a group of individuals with MetS before the development of diabetes and/or overt CV disease can provide insights into whether some of the pathophysiological CV changes can be delayed/reversed, lowering their CV risk. The objective of this study was to examine the effects of 8 wk of aerobic exercise training in individuals with MetS on resting and peak exercise CV function. Twenty participants with MetS underwent either 8 wk of aerobic exercise training (MetS-ExT, n = 10) or remained sedentary (MetS-NonT, n = 10) during this period. Resting and peak exercise CV function was characterized using Doppler echocardiography and gas exchange. Exercise training did not alter resting LV diastolic or systolic function and arterial-ventricular coupling in MetS. In contrast, at peak exercise, an increase in LV contractility (40%, P < 0.01), cardiac output (28%, P < 0.05), and aerobic capacity (20%, P < 0.01), but a reduction in vascular resistance (30%, P < 0.05) and arterial-ventricular coupling (27%, P < 0.01), were noted in the MetS-ExT but not in the MetS-NonT group. Furthermore, an improvement in lifetime risk score was also noted in the MetS-ExT group. These findings have clinical importance because they provide insight that some of the pathophysiological changes associated with MetS can be improved and can lower the risk of CV disease.

Pulmonary hypertension and the right ventricle in hypoxia

Hypoxia causes pulmonary vasoconstriction. Regional hypoxic vasoconstriction improves the matching of perfusion to alveolar ventilation. Global hypoxic vasoconstriction increases right ventricular afterload. The hypoxic pulmonary pressor response is universal in mammals and in birds, but with considerable interspecies and interindividual variability. Chronic hypoxia induces pulmonary hypertension in proportion to initial vasoconstriction. Prolonged hypoxic exposure is also associated with an increase in red blood cell mass, which aggravates pulmonary hypertension by an increase in blood viscosity. Hypoxic pulmonary hypertension in humans is usually mild to moderate, but pulmonary vascular pressure-flow relationships are steep, which corresponds to a substantial afterload on the right ventricle during exercise. A partial recovery of 10-25% of the hypoxia-induced decrease in maximal oxygen uptake has been reported with intake-specific pulmonary vasodilating interventions. Hypoxia has been reported to decrease myocardial fibre contractility in vitro. However, the acutely hypoxic right ventricle remains able to preserve the coupling of its contractility to increased afterload in intact animals. Echocardiographic studies of the right ventricle in healthy hypoxic human subjects show altered diastolic function, but systolic function that is preserved or even increased acutely and slightly depressed chronically. These findings are more pronounced in patients with chronic mountain sickness. Their clinical significance remains incompletely understood. Almost no imaging studies of right ventricular function have been reported in a minority of subjects who develop severe pulmonary hypertension and clinical right ventricular failure in hypoxia. No imaging studies of right ventricular function during hypoxic exercise in normal subjects are yet available. Thus, while it is plausible that the right ventricle limits exercise capacity in hypoxia, this still needs to be firmly established.

Effect of Epivascular Cardiac Autonomic Nerve Stimulation on Cardiac Function

The cardiac plexus contains sympathetic and parasympathetic cardiac nerves. Our goal was to assess the hemodynamic and functional effects of stimulating the cardiac autonomic nervous system (CANS) at the epivascular surfaces of the cardiac plexus. Although CANS therapy to modulate cardiovascular function has drawn widespread interest, research has focused only on stimulating parasympathetic or sympathetic nerves, not both at once. Using general anesthesia and an open-chest surgical procedure, 12 dogs received epivascular stimulation of the cardiac plexus. A bipolar electrode was placed between the right pulmonary artery (PA) and the ascending aorta, with the stimulation frequency/pulse width held constant (20 Hz/4 ms) and the voltage varied (10-50 V). Left ventricular (LV) pressure-volume loops and hemodynamic data were recorded with and without stimulation. In all dogs, aortic and LV systolic pressures, maximum rate of change of LV pressure, and LV stroke work increased (p<0.0001), as did cardiac output (2.9±1.0-0.4±1.0 L/min; p=0.001), end-systolic elastance (1.2±0.4-1.5±0.5 mm Hg/mL; p=0.0001), preload recruitable stroke work (30.1±11.0-39.3±7.8 mm Hg; p=0.003), and LV ejection fraction (p=0.012). Systemic vascular resistance increased slightly (p=0.04), and pulmonary vascular resistance decreased (p=0.01). Mean heart rate and pulmonary arterial, central venous, and left atrial pressures remained unchanged (p>0.1). In contrast to inotropic drugs, epivascular CANS stimulation induced a significant and selective increase in LV contractility with no increase in heart rate.