scholarly journals Cardiac matrix metalloproteinase-2 expression independently induces marked ventricular remodeling and systolic dysfunction

2007 ◽  
Vol 292 (4) ◽  
pp. H1847-H1860 ◽  
Author(s):  
Marina R. Bergman ◽  
John R. Teerlink ◽  
Rajeev Mahimkar ◽  
Luyi Li ◽  
Bo-Qing Zhu ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Matrix Metalloproteinase ◽  
Ventricular Remodeling ◽  
Systolic Function ◽  
Systolic Dysfunction ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Matrix Metalloproteinase 2 ◽  
Membrane Type ◽  
Volume Relation

Although enhanced cardiac matrix metalloproteinase (MMP)-2 synthesis has been associated with ventricular remodeling and failure, whether MMP-2 expression is a direct mediator of this process is unknown. We generated transgenic mice expressing active MMP-2 driven by the α-myosin heavy chain promoter. At 4 mo MMP-2 transgenic hearts demonstrated expression of the MMP-2 transgene, myocyte hypertrophy, breakdown of Z-band registration, lysis of myofilaments, disruption of sarcomere and mitochondrial architecture, and cardiac fibroblast proliferation. Hearts from 8-mo-old transgenic mice displayed extensive myocyte disorganization and dropout with replacement fibrosis and perivascular fibrosis. Older transgenic mice also exhibited a massive increase in cardiac MMP-2 expression, representing recruitment of endogenous MMP-2 synthesis, with associated expression of MMP-9 and membrane type 1 MMP. Increases in diastolic [control (C) 33 ± 3 vs. MMP 51 ± 12 μl; P = 0.003] and systolic (C 7 ± 2 vs. MMP 28 ± 14 μl; P = 0.003) left ventricular (LV) volumes and relatively preserved stroke volume (C 26 ± 4 vs. MMP 23 ± 3 μl; P = 0.16) resulted in markedly decreased LV ejection fraction (C 78 ± 7% vs. MMP 48 ± 16%; P = 0.0006). Markedly impaired systolic function in the MMP transgenic mice was demonstrated in the reduced preload-adjusted maximal power (C 240 ± 84 vs. MMP 78 ± 49 mW/μl2; P = 0.0003) and decreased end-systolic pressure-volume relation (C 7.5 ± 1.5 vs. MMP 4.7 ± 2.0; P = 0.016). Expression of active MMP-2 is sufficient to induce severe ventricular remodeling and systolic dysfunction in the absence of superimposed injury.

Cardiac dilatation and pump dysfunction without intrinsic myocardial systolic failure following chronic β-adrenoreceptor activation

2007 ◽  
Vol 292 (4) ◽  
pp. H1898-H1905 ◽  
Author(s):  
Oleg E. Osadchii ◽  
Gavin R. Norton ◽  
Richard McKechnie ◽  
Dawn Deftereos ◽  
Angela J. Woodiwiss
Keyword(s):  
Diastolic Pressure ◽  
Systolic Function ◽  
Isolated Heart ◽  
Systolic Dysfunction ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Pump Failure ◽  
Volume Relation ◽  
The Impact ◽  
Fractional Shortening

There is no direct evidence to indicate that pump dysfunction in a dilated chamber reflects the impact of chamber dilatation rather than the degree of intrinsic systolic failure resulting from myocardial damage. In the present study, we explored the relative roles of intrinsic myocardial systolic dysfunction and chamber dilatation as mediators of left ventricular (LV) pump dysfunction. Administration of isoproterenol, a β-adrenoreceptor agonist, for 3 mo to rats (0.1 mg·kg−1·day−1) resulted in LV pump dysfunction as evidenced by a reduced LV endocardial fractional shortening (echocardiography) and a decrease in the slope of the LV systolic pressure-volume relation (isolated heart preparations). Although chronic β-adrenoreceptor activation induced cardiomyocyte damage (deoxynucleotidyl transferase-mediated dUTP nick-end labeling) as well as β1- and β2-adrenoreceptor inotropic downregulation (attenuated contractile responses to dobutamine and salbutamol), these changes failed to translate into alterations in intrinsic myocardial contractility. Indeed, LV midwall fractional shortening (echocardiography) and the slope of the LV systolic stress-strain relation (isolated heart preparations) were unchanged. A normal intrinsic myocardial systolic function, despite the presence of cardiomyocyte damage and β-adrenoreceptor inotropic downregulation, was ascribed to marked increases in myocardial norepinephrine release, to upregulation of α-adrenoreceptor-mediated contractile effects as determined by phenylephrine responsiveness, and to compensatory LV hypertrophy. LV pump failure was attributed to LV dilatation, as evidenced by increased LV internal dimensions (echocardiography), and a right shift and increased volume intercept of the LV diastolic pressure-volume relation. In conclusion, chronic sympathetic stimulation, despite reducing β-adrenoreceptor-mediated inotropic responses and promoting myocyte apoptosis, may nevertheless induce pump dysfunction primarily through LV dilatation, rather than intrinsic myocardial systolic failure.

Abstract 5882: Myocardial Contractile Dysfunction in Heart Failure with Preserved Ejection Fraction

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Barry A Borlaug ◽  
Carolyn S Lam ◽  
Veronique Roger ◽  
Richard J Rodeheffer ◽  
Margaret M Redfield
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Myocardial Contractility ◽  
Ventricular Remodeling ◽  
Systolic Function ◽  
Systolic Dysfunction ◽  
Wall Stress ◽  
Left Ventricular ◽  
Preserved Ejection Fraction ◽  
Long Term Outcome

Background Patients with heart failure and preserved ejection fraction (HFpEF) have diastolic dysfunction, but are traditionally considered to have normal left ventricular (LV) systolic function. However, ventricular remodeling can result in preservation of EF despite abnormal myocardial contractility. Methods We performed echo-Doppler characterization of LV chamber and myocardial systolic properties in a population-based study, comparing patients with HFpEF (N=244) to healthy controls (CON, N=617), and hypertensives without HF (HTN, N=719), then examined long term outcome. Results All subjects had a normal EF (>50%). However, systolic chamber function, measured by wall stress-corrected endocardial fractional shortening (sc-eFS), was impaired in HFpEF (96±12%) compared to both CON (100±8%, p<0.0001) and HTN (108±11%, p<0.0001). Myocardial contractility, assessed by wall stress-corrected midwall shortening (sc-mFS), was also reduced in HFpEF (91±13%) compared to CON (100±10%, p<0.0001) and HTN (105±12%, p<0.0001). HTN had increased sc-eFS and sc-mFS compared with both HFpEF and CON (p<0.0001). In HFpEF, impaired sc-mFS was associated with increased mortality, independent of age (Figure ), while EF and sc- eFS were not. Conclusions Despite preservation of EF, unselected HFpEF patients from the community have significantly impaired systolic chamber function and depressed myocardial contractility. Abnormal myocardial contractility in HFpEF is associated with increased mortality. These data suggest that myocardial systolic dysfunction contributes to the pathophysiology of HFpEF and may represent a potential therapeutic target.

scholarly journals A dilated cardiomyopathy mutation blunts adrenergic response and induces contractile dysfunction under chronic angiotensin II stress

2015 ◽  
Vol 309 (11) ◽  
pp. H1936-H1946 ◽  
Author(s):  
Ross Wilkinson ◽  
Weihua Song ◽  
Natalia Smoktunowicz ◽  
Steven Marston
Keyword(s):  
Dilated Cardiomyopathy ◽  
Chronic Stress ◽  
Troponin I ◽  
Systolic Function ◽  
Systolic Dysfunction ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Mouse Heart ◽  
Relaxation Rates

We investigated cardiac contractility in the ACTC E361G transgenic mouse model of dilated cardiomyopathy (DCM). No differences in cardiac dimensions or systolic function were observed in young mice, whereas young adult mice exhibited only mild diastolic abnormalities. Dobutamine had an inotropic and lusitropic effect on the mouse heart. In papillary muscle at 37°C, dobutamine increased relaxation rates [∼50% increase of peak rate of force decline normalized to force (dF/dtmin/F), 25% reduction of time to 90% relaxation (t90) in nontransgenic (NTG) mice], but in the ACTC E361G mouse, dF/dtmin/F was increased 20–30%, and t90 was only reduced 10% at 10 Hz. Pressure-volume measurements showed increases in maximum rate of pressure decline and decreases in time constant of left ventricular pressure decay in the ACTC E361G mouse that were 25–30% of the changes in the NTG mouse, consistent with blunting of the lusitropic response. The inotropic effect of dobutamine was also blunted in ACTC E361G mice, and the dobutamine-stimulated increase in cardiac output (CO) was reduced from 2,100 to 900 μl/min. Mice were treated with high doses of ANG II for 4 wk. The chronic stress treatment evoked systolic dysfunction in ACTC E361G mice but not in NTG. There was a significant reduction in rates of pressure increase and decrease, as well as reduced end-systolic pressure and increased volume. Ejection fraction and CO were reduced in the ACTC E361G mouse, indicating DCM. In vitro DCM-causing mutations uncouple the relationship between Ca2+ sensitivity and troponin I phosphorylation. We conclude that this leads to the observed, reduced response to β1 agonists and reduced cardiac reserve that predisposes the heart to DCM under conditions of chronic stress.

P6 Characterisation of right heart dysfunction in left ventricular systolic failure

2020 ◽  
Vol 41 (Supplement_1) ◽  
Author(s):  
H H L Chen ◽  
C H Gan ◽  
D Makarious ◽  
C H Ng ◽  
A Bhat ◽  
...  
Keyword(s):  
Systolic Function ◽  
Systolic Dysfunction ◽  
Systolic Pressure ◽  
Disease Process ◽  
Left Ventricular ◽  
Pulmonary Artery Systolic Pressure ◽  
P Value ◽  
Basal Diameter ◽  
Lv Dysfunction ◽  
Rv Function

Abstract Funding Acknowledgements Nil Background Left and right ventricular (RV) function is proposed to be intimately linked. Reduced systolic ventricular interaction in patients with reduced global left ventricular (LV) performance is hypothesised to result in a reduction in RV contractile performance, even if the RV is not directly involved in the disease process. Concurrent RV and LV dysfunction is known to carry a poorer prognosis. However, the incidence of RV structural change and systolic dysfunction in patients with LV dysfunction in patients in a clinical setting is not well characterised. Purpose To determine the prevalence of RV systolic impairment in patients with LV systolic impairment from non-ischaemic cardiomyopathy (NICM); and to characterise the relationship between LV and RV systolic function using echocardiographic parameters. Methods 86 consecutive patients with stable heart failure with reduced ejection fraction secondary to NICM without valvular, congenital, and pulmonary disease were recruited. All patients underwent a comprehensive transthoracic echocardiogram and were stratified into tertiles based on LVEF (mild: 40-49%, moderate: 30-39%, severe: &lt;30%). RV function was characterised using standard and novel measures. 2D RV free wall peak systolic strain (RV FWS) was measured using vendor independent software (TomTec Image Arena, Germany v4.6).  Results Of the mild, moderate and severe groups (mean age 58 ± 34, 36% men): mean LVEF (%) was 46 ± 6, 35 ± 6, 22 ± 10 ; mean pulmonary artery systolic pressure (mmHg) was 28 ± 24, 34 ± 31, 38 ± 24; 26%, 79%, 74% had mild or moderate pulmonary hypertension respectively. 33% had RV impairment based on TAPSE of &lt;1.6cm; 48% had RV impairment based on RVS’ of &lt;10cm/s; and 65% had RV impairment based on a FAC of &lt;35%.  Conclusion Whilst there is a concurrent increase in the prevalence of RV impairment with severity of LV systolic impairment, interestingly not all patients with LV dysfunction had RV dysfunction. The presence of RV dysfunction is greatest when measured using FAC and RV FWS. Routine screening of RV dysfunction in patients with HFrEF secondary to NICM may help identify patients with poorer prognosis, who could benefit with more intensive follow up and treatment. LVEF 40-49% (n = 31) LVEF 30-39% (n = 28) LVEF &lt; 30% (n = 27) ONE WAY ANOVA Significance (P value) Mean RV Basal Diameter (cm) 4.1 ± 1.3 3.7 ± 1.6 3.6 ± 1.5 0.51 Mean TAPSE (cm) 2.1 ± 0.8 1.9 ± 1.0 1.7 ± 1.1 0.49 Mean RVS" (cm/s) 11 ± 5 11 ± 6 9 ± 6 0.24 Mean FAC (%) 44 ± 20 29 ± 21 17 ± 13 0.000 Mean RV FWS (%) -27.4 ± 14.4 -17.2 ± 11.6 -7.9 ± 6 0.000

Long-term cardiovascular effects of neonatal dexamethasone treatment: hemodynamic follow-up by left ventricular pressure-volume loops in rats

2008 ◽  
Vol 104 (2) ◽  
pp. 446-450 ◽  
Author(s):  
Miriam P. Bal ◽  
Willem B. de Vries ◽  
Matthijs F. M. van Oosterhout ◽  
Jan Baan ◽  
Ernst E. van der Wall ◽  
...  
Keyword(s):  
Side Effects ◽  
Systolic Function ◽  
Systolic Dysfunction ◽  
Systolic Pressure ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Long Term Effects ◽  
Dexamethasone Treatment ◽  
Large Patient

Dexamethasone is clinically applied in preterm infants to treat or prevent chronic lung disease. However, concern has emerged about adverse side effects. The cardiovascular short-term side effects of neonatal dexamethasone treatment are well documented, but long-term consequences are unknown. Previous studies showed suppressed mitosis during dexamethasone treatment, leading to reduced ventricular weight, depressed systolic function, and compensatory dilatation in prepubertal rats. In addition, recent data indicated a reduced life expectancy. Therefore, we investigated the long-term effects of neonatal dexamethasone treatment on cardiovascular function. Neonatal rats were treated with dexamethasone or received saline. Cardiac function was determined in 8-, 50-, and 80-wk-old animals, representing young adult, middle-aged, and elderly stages. A pressure-conductance catheter was introduced into the left ventricle to measure pressure-volume loops. Subsequently, the hearts were collected for histological examination. Our results showed reduced ventricular and body weights in dexamethasone-treated rats at 8 and 80 wk, but not at 50 wk. Cardiac output and diastolic function were unchanged, but systolic function was depressed at 50 and 80 wk, evidenced by reduced ejection fractions and rightward shifts of the end-systolic pressure-volume relationships. We concluded that previously demonstrated early adverse effects of neonatal dexamethasone treatment are transient but that reduced ventricular weight and systolic dysfunction become manifest again in elderly rats. Presumably, cellular hypertrophy initially compensates for the dexamethasone treatment-induced lower number of cardiomyocytes, but this mechanism falls short at a later stage, leading to systolic dysfunction. If applicable to humans, cardiac screening of a relatively large patient group to enable secondary prevention may be indicated.

scholarly journals Central and obstructive apneas prevalence in heart failure with reduced, mid-range and preserved ejection fraction

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
C Borrelli ◽  
P Sciarrone ◽  
F Gentile ◽  
N Ghionzoli ◽  
G Mirizzi ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Left Ventricular Systolic Dysfunction ◽  
Systolic Function ◽  
Systolic Dysfunction ◽  
Cardiopulmonary Exercise Testing ◽  
Left Ventricular ◽  
Apnea Hypopnea Index ◽  
Preserved Ejection Fraction ◽  
2D Echocardiography

Abstract Background Central apneas (CA) and obstructive apneas (OA) are highly prevalent in heart failure (HF) both with reduced and preserved systolic function. However, a comprehensive evaluation of apnea prevalence across HF according to ejection fraction (i.e HF with patients with reduced, mid-range and preserved ejection fraction- HFrEf, HFmrEF and HFpEF, respectively) throughout the 24 hours has never been done before. Materials and methods 700 HF patients were prospectively enrolled and then divided according to left ventricular EF (408 HFrEF, 117 HFmrEF, 175 HFpEF). All patients underwent a thorough evaluation including: 2D echocardiography; 24-h Holter-ECG monitoring; cardiopulmonary exercise testing; neuro-hormonal assessment and 24-h cardiorespiratory monitoring. Results In the whole population, prevalence of normal breathing (NB), CA and OA at daytime was 40%, 51%, and 9%, respectively, while at nighttime 15%, 55%, and 30%, respectively. When stratified according to left ventricular EF, CA prevalence decreased from HFrEF to HFmrEF and HFpEF: (daytime CA: 57% vs. 43% vs. 42%, respectively, p=0.001; nighttime CA: 66% vs. 48% vs. 34%, respectively, p&lt;0.0001), while OA prevalence increased (daytime OA: 5% vs. 8% vs. 18%, respectively, p&lt;0.0001; nighttime OA: 20 vs. 29 vs. 53%, respectively, p&lt;0.0001). When assessing moderte-severe apneas, defined with an apnea/hypopnea index &gt;15 events/hour, prevalence of CA was again higher in HFrEF than HFmrEF and HFpEF both at daytime (daytime moderate-severe CA: 28% vs. 19% and 23%, respectively, p&lt;0.05) and at nighttime (nighttime moderate-severe CA: 50% vs. 39% and 28%, respectively, p&lt;0.05). Conversely, moderate-severe OA decreased from HFrEF to HFmrEF to HFpEF both at daytime (daytime moderate-severe OA: 1% vs. 3% and 8%, respectively, p&lt;0.05) and nighttime (noghttime moderate-severe OA: 10% vs. 11% and 30%, respectively, p&lt;0.05). Conclusions Daytime and nighttime apneas, both central and obstructive in nature, are highly prevalent in HF regardless of EF. Across the whole spectrum of HF, CA prevalence increases and OA decreases as left ventricular systolic dysfunction progresses, both during daytime and nighttime. Funding Acknowledgement Type of funding source: None

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
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