Recovery from heart failure: structural and functional analysis in a canine model

1988 ◽  
Vol 66 (12) ◽  
pp. 1505-1512 ◽  
Author(s):  
Robert J. Howard ◽  
Terrance P. Stopps ◽  
Gordon W. Moe ◽  
Avrum Gotlieb ◽  
Paul W. Armstrong
Keyword(s):  
Heart Failure ◽  
Severe Heart Failure ◽  
Canine Model ◽  
Left Ventricular ◽  
Rapid Improvement ◽  
Cross Sectional ◽  
Developing Heart ◽  
Histologic Abnormality ◽  
Dimensional Echocardiography ◽  
Heart Failure Model

Chronic, rapid ventricular pacing produces congestive heart failure in the dog. Using echocardiography, the features of developing heart failure were analysed and the capacity of this model for recovery was assessed once pacing had been discontinued. Fifteen dogs were studied; nine were paced at 250 beats/min (bpm) to severe heart failure (5.0 ± 1.8 weeks) and six served as sham controls. In the paced animals at severe heart failure, two-dimensional echocardiography demonstrated a significant increase in diastolic cross-sectional cardiac area (from 11 ± 3 to16 ± 2 cm2, p < 0.05), associated with a marked fall in area ejection fraction (54 ± 8 to 21 ± 8%, p < 0.05), and significant left ventricular wall thinning (from 6.0 ± 0.7to4.7 ± 0.9 mm, p < 0.05). In addition, significant increases in heart rate (77 ± 7 to 126 ± 13 bpm, sinus rhythm; p < 0.05), respiratory rate (41 ± 13 to 80 ± 20 cycles/min, p < 0.05), and body weight (21 ± 1 to 24 ± 3 kg, p < 0.05) were noted. Serum sodium fell (146 ± 3 to 140 ± 8 mmol/L, p < 0.05), while blood urea nitrogen (6 ± 2 to 10 ± 2 mmol/L, p < 0.05) and creatinine (86 ± 12 to 101 ± 15 mmol/d, p < 0.05) increased. Recovery was characterized by rapid improvement such that all measured parameters normalized by 1 week, except for cross-sectional cardiac area which remained dilated up to 4 weeks (14 ± 3 cm2, p < 0.05 versus control). Necropsy data obtained from paced dogs after 4 weeks of recovery demonstrated cardiac hypertrophy when compared with sham controls (9.4 ± 1.2 versus 7.7 ± 0.9 g/kg, p < 0.05), but no histologic abnormality was revealed under light microscopy. Left ventricular norepinephrine levels were similar to those of sham controls (617 ± 323 versus 676 ± 177 ng/g wet weight, not significant). The rapid recovery of ventricular systolic performance demonstrated in this heart failure model suggests that reversible substrate depletion is the mechanism responsible. Despite this recovery, there is persistent diastolic enlargement of the left ventricle indicating that structural remodeling has taken place.

Cardiac mitofusin-1 is declined in non-responding patients with idiopathic dilated cardiomyopathy

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
Y Hsiao ◽  
I Shimizu ◽  
T Wakasugi ◽  
S Jiao ◽  
T Watanabe ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Heart Failure ◽  
Ventricular Myocytes ◽  
Severe Heart Failure ◽  
Left Ventricular ◽  
Neonatal Rat ◽  
Heart Failure Patients ◽  
Underlying Mechanisms ◽  
Neonatal Rat Ventricular Myocytes ◽  
Mitofusin 1

Abstract Background/Introduction Mitochondria are dynamic regulators of cellular metabolism and homeostasis. The dysfunction of mitochondria has long been considered a major contributor to aging and age-related diseases. The prognosis of severe heart failure is still unacceptably poor and it is urgent to establish new therapies for this critical condition. Some patients with heart failure do not respond to established multidisciplinary treatment and they are classified as “non-responders”. The outcome is especially poor for non-responders, and underlying mechanisms are largely unknown. Purpose Studies indicate mitochondrial dysfunction has causal roles for metabolic remodeling in the failing heart, but underlying mechanisms remain to be explored. This study tried to elucidate the role of Mitofusin-1 in a failing heart. Methods We examined twenty-two heart failure patients who underwent endomyocardial biopsy of intraventricular septum. Patients were classified as non-responders when their left-ventricular (LV) ejection fraction did not show more than 10% improvement at remote phase after biopsy. Fourteen patients were classified as responders, and eight as non-responders. Electron microscopy, quantitative PCR, and immunofluorescence studies were performed to explore the biological processes or molecules involved in failure to respond. In addition to studies with cardiac tissue specific knockout mice, we also conducted functional in-vitro studies with neonatal rat ventricular myocytes. Results Twenty-two patients with IDCM who underwent endomyocardial biopsy were enrolled in this study, including 14 responders and 8 non-responders. Transmission electron microscopy (EM) showed a significant reduction in mitochondrial size in cardiomyocytes of non-responders compared to responders. Quantitative PCR revealed that transcript of mitochondrial fusion protein, Mitofusin-1, was significantly reduced in non-responders. Studies with neonatal rat ventricular myocytes (NRVMs) indicated that the beta-1 adrenergic receptor-mediated signaling pathway negatively regulates Mitofusin-1 expression. Suppression of Mitofusin-1 resulted in a significant reduction in mitochondrial respiration of NRVMs. We generated left ventricular pressure overload model with thoracic aortic constriction (TAC) in cardiac specific Mitofusin-1 knockout model (c-Mfn1 KO). Systolic function was reduced in c-Mfn1 KO mice, and EM study showed an increase in dysfunctional mitochondria in the KO group subjected to TAC. Conclusions Mitofusin-1 becomes a biomarker for non-responders with heart failure. In addition, our results suggest that therapies targeting mitochondrial dynamics and homeostasis would become next generation therapy for severe heart failure patients. Funding Acknowledgement Type of funding source: None

scholarly journals Three dimensional echocardiography documents haemodynamic improvement by biventricular pacing in patients with severe heart failure

Heart ◽  
2001 ◽  
Vol 85 (5) ◽  
pp. 514-520
Author(s):  
W Y Kim ◽  
P Søgaard ◽  
P T Mortensen ◽  
H Kjærulf Jensen ◽  
A Kirstein Pedersen ◽  
...  
Keyword(s):  
Heart Failure ◽  
Biventricular Pacing ◽  
Three Dimensional ◽  
Left Ventricular ◽  
Walking Distance ◽  
Short Term ◽  
Bundle Branch Block ◽  
Patients With Heart Failure ◽  
Dimensional Echocardiography ◽  
Three Dimensional Echocardiography

OBJECTIVESTo quantify the short term haemodynamic effects of biventricular pacing in patients with heart failure and left bundle branch block by using three dimensional echocardiography.DESIGNThree dimensional echocardiography was performed in 15 consecutive heart failure patients (New York Heart Association functional class III or IV) with an implanted biventricular pacing system. Six minute walk tests were performed to investigate the effect of biventricular pacing on exercise capacity. Data were acquired at sinus rhythm and after short term (2–7 days) biventricular pacing.RESULTSCompared with baseline values, biventricular pacing significantly reduced left ventricular end diastolic volume (EDV) by mean (SD) 4.0 (5.1)% (p < 0.01) and end systolic volume (ESV) by 5.6 (6.4)% (p < 0.02). Mitral regurgitant fraction was significantly reduced by 11 (12.1)% (p < 0.003) and forward stroke volume (FSV) increased by 13.9 (18.6)% (p < 0.02). Exercise capacity was significantly improved with biventricular pacing by 48.4 (43.3)% (p < 0.00001). Regression analyses showed that the percentage increase in FSV independently predicted percentage improvement in walking distance (r2 = 0.73, p < 0.0002). Both basal QRS duration and QRS narrowing predicted pacing efficacy, showing a significant correlation with %ΔEDV, %ΔESV, and %ΔFSV.CONCLUSIONSIn five of 15 consecutive patients with heart failure and left bundle branch block, biventricular pacing induced a more than 15% increase in FSV, which predicted a more than 25% increase in walking distance and was accompanied by an immediate reduction in left ventricular chamber size and mitral regurgitation.

scholarly journals Cross sectional study estimating prevalence of heart failure and left ventricular systolic dysfunction in community patients at risk

Heart ◽  
2001 ◽  
Vol 86 (2) ◽  
pp. 172-178 ◽  
Author(s):  
O W Nielsen ◽  
J Hilden ◽  
C T Larsen ◽  
J F Hansen
Keyword(s):  
Heart Failure ◽  
Primary Care ◽  
General Practice ◽  
Heart Disease ◽  
Left Ventricular Systolic Dysfunction ◽  
Systolic Dysfunction ◽  
Left Ventricular ◽  
Ventricular Systolic Dysfunction ◽  
Cross Sectional ◽  
General Practices

OBJECTIVETo examine a general practice population to measure the prevalence of signs and symptoms of heart failure (SSHF) and left ventricular systolic dysfunction (LVSD).DESIGNCross sectional screening study in three general practices followed by echocardiography.SETTING AND PATIENTSAll patients ⩾ 50 years in two general practices and ⩾ 40 years in one general practice were screened by case record reviews and questionnaires (n = 2158), to identify subjects with some evidence of heart disease. Among these, subjects were sought who had SSHF (n = 115). Of 357 subjects with evidence of heart disease, 252 were eligible for examination, and 126 underwent further cardiological assessment, including 43 with SSHF.MAIN OUTCOME MEASURESPrevalence of SSHF as defined by a modified Boston index, LVSD defined as an indirectly measured left ventricular ejection fraction ⩽ 0.45, and numbers of subjects needing an echocardiogram to detect one case with LVSD.RESULTSSSHF afflicted 0.5% of quadragenarians and rose to 11.7% of octogenarians. Two thirds were handled in primary care only. At ⩾ 50 years of age 6.4% had SSHF, 2.9% had LVSD, and 1.9% (95% confidence interval 1.3% to 2.5%) had both. To detect one case with LVSD in primary care, 14 patients with evidence of heart disease without SSHF and 5.5 patients with SSHF had to be examined.CONCLUSIONSSHF is extremely prevalent in the community, especially in primary care, but more than two thirds do not have LVSD. The number of subjects with some evidence of heart disease needing an echocardiogram to detect one case of LVSD is 14.

The effect of oestrogen withdrawal on cardiac Ca2+ regulation and the influence of GPER1

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
A.J Francis ◽  
J.M Firth ◽  
N Islam ◽  
J Gorelik ◽  
K.T MacLeod
Keyword(s):  
Heart Failure ◽  
Structural Integrity ◽  
Left Ventricular ◽  
Funding Source ◽  
Hormonal Changes ◽  
Ion Conductance ◽  
Developing Heart ◽  
Rapid Stimulation ◽  
Post Menopausal

Abstract Background Post-menopausal women have an enhanced risk of developing heart failure, attributed to declining oestrogen levels during menopause. However, the signalling mechanisms remain undetermined. Purpose We aim to determine the role of G-protein coupled oestrogenic receptor 1 (GPER1) in intracellular Ca2+ regulation and the consequences of hormonal changes that may exacerbate the pathophysiology of heart failure. Methods Ovariectomy (OVx) (mimics menopausal hormone changes) or sham surgeries were conducted on female guinea pigs. Left ventricular cardiomyocytes were isolated 150-days post-operatively for experimental use. Cellular t-tubule network and structural integrity was measured using fluorescent di-8-ANEPPs staining and scanning ion conductance microscopy. GPER1 expression and localisation was measured by Western blot and immunostaining. The role of GPER1 activation was measured using selective agonist G-1 in electrophysiological and Ca2+-sensitive dye fluorescence experiments. Results Following oestrogen withdrawal, the t-tubule network density decreased by 13% and z-groove index reduced by 15%. GPER1 predominantly localised to the peri-nuclear endoplasmic reticulum and its expression increased by 32% in OVx. Action potential duration (APD) prolonged in OVx and following GPER1 activation, APD90 shortened by 11% and 25% in sham and OVx respectively. OVx cells had larger peak inward Ca2+ current (ICaL) (by 22%) and sarcoplasmic reticulum (SR) Ca2+ content (by 13%), compared with sham. While GPER1 activation had little effect on peak ICaL or SR content, it reduced Ca2+ transient amplitude (by 20%), SR fractional release (by 11%) in OVx cells. The frequency of occurrence of spontaneous Ca2+ waves evoked by periods of rapid stimulation reduced by 40% and wave-free survival time prolonged in OVx cells following GPER1 activation. Conclusions In the hearts of an animal species whose electrophysiology and intracellular Ca2+ regulation is akin to humans, we show that following oestrogen deficiency, the t-tubule network is down-regulated and becomes disorganised, GPER1 expression is increased and its activation induces negative inotropic responses in cardiomyocytes. This may limit the adverse changes to Ca2+ signalling reported in OVx that could be pro-arrhythmic and exacerbate the progression to heart failure. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): British Heart Foundation

Anaemia and heart failure

Open Medicine ◽  
2011 ◽  
Vol 6 (1) ◽  
pp. 11-25
Author(s):  
Enrico Vizzardi ◽  
Tania Bordonali ◽  
Elena Tanghetti ◽  
Marco Metra ◽  
Livio Cas
Keyword(s):  
Heart Failure ◽  
Ventricular Dysfunction ◽  
Severe Heart Failure ◽  
Left Ventricular ◽  
Favourable Effect ◽  
Heart Failure Trial ◽  
Patients With Heart Failure ◽  
Darbepoetin Alpha ◽  
Main Determinants ◽  
Independent Determinant

AbstractAnaemia is one of the most frequent co-morbidities in patients with heart failure. Its prevalence increases from 4% to7% in subjects with asymptomatic left ventricular dysfunction to >30% in patients with severe heart failure. Renal insufficiency, activation of inflammatory mediators and treatment with renin-angiotensin antagonists seem to be its main determinants. The results of many studies agree in providing evidence that anaemia is a powerful independent determinant of survival in patients with heart failure. However, the mechanisms of this relation are still not fully understood. Moreover a favourable effect of the correction of anaemia on prognosis has not yet been shown. Also In addition to this, controlled studies assessing its effects on exercise tolerance have yielded controversial results. Further research is needed to assess the effect of correcting anaemia in chronic heart failure (CHF) patients; ongoing reduction of events with RED-HF (Darbepoetin alpha in heart failure) trial will help define the role.

scholarly journals Linearity of the left ventricular end-systolic pressure-volume relation in patients with severe heart failure

1989 ◽  
Vol 14 (1) ◽  
pp. 127-134 ◽  
Author(s):  
Constantine N. Aroney ◽  
Howard C. Herrmann ◽  
Marc J. Semigran ◽  
G. William ◽  
Charles A. Boucher ◽  
...  
Keyword(s):  
Heart Failure ◽  
Severe Heart Failure ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Volume Relation

Synthesis and Biological Activity of the Pyridine-Hexacyclic-Steroid Derivative on a Heart Failure Model

2021 ◽  
Vol 21 ◽  
Author(s):  
Figueroa-Valverde Lauro ◽  
López-Ramos Maria ◽  
Díaz-Cedillo Francisco ◽  
Rosas-Nexticapa Marcela ◽  
Mateu-Armad Maria Virginia ◽  
...  
Keyword(s):  
Heart Failure ◽  
Biological Activity ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Ventricular Pressure ◽  
Pyridine Derivative ◽  
Dependent Manner ◽  
Inotropic Activity ◽  
Heart Failure Model ◽  
Chemical Strategies

Background: Several drugs with inotropic activity have been synthesized; however, there is very little information on biological activity exerted by steroid derivatives in the cardiovascular system. Objective: The aim of this research was to prepare a steroid-pyridine derivative to evaluate the effect it exerts on left ventricular pressure and characterize its molecular interaction. Methods: The first stage was carried out through the synthesis of a steroid-pyridine derivative using some chemical strategies. The second stage involved the evaluation of the biological activity of the steroid-pyridine derivative on left ventricular pressure using a model of heart failure in the absence or presence of the drugs, such as flutamide, tamoxifen, prazosin, metoprolol, indomethacin, and nifedipine. Results: The results showed that steroid-pyridine derivative increased left ventricular pressure in a dose-dependent manner (0.001-100 nM); however, this phenomenon was significantly inhibited only by nifedipine at a dose of 1 nM. These results indicate that positive inotropic activity produced by the steroid-pyridine derivative was via calcium channel activation. Furthermore, the biological activity exerted by the steroid-pyridine derivative on the left ventricle produces changes in cAMP concentration. Conclusion: It is noteworthy that positive inotropic activity produced by this steroid-pyridine derivative involves a different molecular mechanism compared to other positive inotropic drugs. Therefore, this steroid could be a good candidate for the treatment of heart failure.

scholarly journals Levosimendan treatment of severe acute congestive heart failure refractory to dobutamine/milrinone in children

2011 ◽  
Vol 68 (11) ◽  
pp. 979-984
Author(s):  
Sergej Prijic ◽  
Sanja Rakic ◽  
Ljubica Nikolic ◽  
Bosiljka Jovicic ◽  
Mila Stajevic ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Myocardial Contractility ◽  
Severe Heart Failure ◽  
Oxygen Demand ◽  
Left Ventricular ◽  
Myocardial Oxygen Demand ◽  
Univentricular Heart ◽  
Dilatative Cardiomyopathy ◽  
Hemodynamic Improvement

Introduction. Levosimendan is a novel positive inotropic agent which, improves myocardial contractility through its calcium-sensitizing action, without causing an increase in myocardial oxygen demand. Also, by opening ATP-sensitive potassium channels, it causes vasodilatation with the reduction in both afterload and preload. Because of the long halflife, its effects last for up 7 to 9 days after 24-hour infusion. Case report. We presented three patients 2, 15 and 17 years old. All the patients had severe acute deterioration of the previously diagnosed chronic heart failure (dilatative cardiomyopathy; univentricular heart with bidirectional Glenn anastomosis and restrictive bulboventricular foramen; bacterial endocarditis on artificial aortic valve with severe stenosis and regurgitation). Signs and symptoms of severe heart failure, cardiomegaly (cardio-thoracic index 0.65) and left ventricular dilatation (end-diastolic diameter z-score 2.6; 4.1 and 4.0) were confirmed on admission. Also, myocardial contractility was poor with ejection fraction (EF - 27%, 25%, 35%), fractional shortening (FS - 13%, 11%, 15%) and stroke volume (SV - 40, 60, 72 mL/m2). The treatment with standard intravenous inotropic agents resulted in no improvement but in clinical deterioration. Thus, standard intravenous inotropic support was stopped and levosimendan treatment was introduced. All the patients received a continuous 24-h infusion 0.1 ?g/kg/min of levosimendan. In a single patient an initial loading dose of 11 ?g/kg over 10 min was administrated, too. Levosimendan treatment resulted in both clinical and echocardiography improvement with the improved EF (42%, 34%, 44%), FS (21%, 16%, 22%) and SV (59, 82, 93 mL/m2). Hemodynamic improvement was registered too, with the reduction in heart rate in all the treated patients from 134-138 bpm before, to less than 120 bpm after the treatment. These parameters were followed by the normalization of lactate levels. Nevertheless, left ventricular end-diastolic diameter did not change after the levosimendan treatment. Conclusion. Our initial experience demonstrates that administration of levosimendan in patients with severe chronic heart failure not responsive to standard intravenous inotropic treatment might result in a significant clinical and hemodynamic improvement and that, in selected patients, it might be life saving. According to our best knowledge patients presented are the first pediatric patients treated with levosimendan in our country.

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