Hyperhomocysteinemia leads to adverse cardiac remodeling in hypertensive rats

2002 ◽  
Vol 283 (6) ◽  
pp. H2567-H2574 ◽  
Author(s):  
Jacob Joseph ◽  
Abeer Washington ◽  
Lija Joseph ◽  
Laura Koehler ◽  
Louis M. Fink ◽  
...  

Hyperhomocysteinemia (Hhe), linked to cardiovascular disease by epidemiological studies, may be an important factor in adverse cardiac remodeling in hypertension. Specifically, convergence of myocardial and vascular alterations promoted by Hhe and hypertension may exacerbate cardiac remodeling and myocardial dysfunction. We studied male spontaneously hypertensive rats fed one of three diets: control, intermediate Hhe inducing, or severe Hhe inducing. After 10 wk of dietary intervention, cardiac function was assessed in vitro, and cardiac and coronary arteriolar remodeling were monitored by histomorphometric, immunohistochemical, and biochemical techniques. Results showed that Hhe induced diastolic dysfunction, as characterized by the diastolic pressure-volume curve, without significant changes in baseline systolic function. Perivascular collagen levels were increased by Hhe, and there was an increase in left ventricular hydroxyproline levels. Myocyte size was not affected. Coronary arteriolar wall thickness increased with Hhe due to smooth muscle hyperplasia. Mast cells increased in parallel with Hhe and collagen accumulation. In summary, 10 wk of Hhe caused coronary arteriolar remodeling, myocardial collagen deposition, and diastolic dysfunction in hypertensive rats.

1998 ◽  
Vol 274 (6) ◽  
pp. H2100-H2109 ◽  
Author(s):  
Masao Tayama ◽  
Steven B. Solomon ◽  
Stanton A. Glantz

The diastolic pressure-volume curve shifts upward during demand ischemia, most likely because of changes in Ca2+ dynamics within the sarcomere. It is possible that agents that affect Na+/Ca2+exchange, such as lidocaine, a class 1b-type Na+-channel blocker that decreases intracellular Na+, could affect the diastolic pressure-volume relationship because of indirect effects on intracellular Ca2+. Lidocaine is a drug widely used to treat arrhythmias in patients with myocardial ischemia. We studied the effects of lidocaine on diastolic dysfunction associated with demand ischemia. We compared diastolic (as represented by the shift in the diastolic pressure-volume relationship) and systolic function during demand ischemia before and after lidocaine injection. We created demand ischemia in pigs before and after administering lidocaine (5 mg/kg) in eight open-pericardium anesthetized pigs. Demand ischemia was induced by constricting the left anterior descending coronary artery and then pacing at 1.5–1.8 times the baseline heart rate for 1.5–3 min. Hemodynamics were recorded during baseline, demand ischemia, baseline after lidocaine injection, and demand ischemia after lidocaine. Lidocaine did not affect systolic function or the time constant of isovolumic relaxation, but it increased the upward shift of the diastolic pressure-volume curve during demand ischemia compared with the increase that occurred before lidocaine was administered. This result suggests that lidocaine could aggravate diastolic dysfunction in patients with ischemic heart disease.


2006 ◽  
Vol 290 (3) ◽  
pp. H1064-H1070 ◽  
Author(s):  
Shinsuke Kido ◽  
Naoyuki Hasebe ◽  
Yoshinao Ishii ◽  
Kenjiro Kikuchi

The aim of this study was to investigate what factor determines tachycardia-induced secretion of atrial and brain natriuretic peptides (ANP and BNP, respectively) in patients with hypertrophic cardiomyopathy (HCM). HCM patients with normal left ventricular (LV) systolic function and intact coronary artery ( n = 22) underwent rapid atrial pacing test. The cardiac secretion of ANP and BNP and the lactate extraction ratio (LER) were evaluated by using blood samples from the coronary sinus and aorta. LV end-diastolic pressure (LVEDP) and the time constant of LV relaxation of tau were measured by a catheter-tip transducer. These parameters were compared with normal controls ( n = 8). HCM patients were divided into obstructive (HOCM) and nonobstructive (HNCM) groups. The cardiac secretion of ANP was significantly increased by rapid pacing in HOCM from 384 ± 101 to 1,268 ± 334 pg/ml ( P < 0.05); however, it was not significant in control and HNCM groups. In contrast, the cardiac secretion of BNP was fairly constant and rather significantly decreased in HCM ( P < 0.01). The cardiac ANP secretion was significantly correlated with changes in LER ( r = −0.57, P < 0.01) and tau ( r = 0.73, P < 0.001) in HCM patients. Tachycardia potentiates the cardiac secretion of ANP, not BNP, in patients with HCM, particularly when it induces myocardial ischemia and LV diastolic dysfunction.


2007 ◽  
Vol 293 (5) ◽  
pp. R1787-R1797 ◽  
Author(s):  
Véronique A. Lacombe ◽  
Serge Viatchenko-Karpinski ◽  
Dmitry Terentyev ◽  
Arun Sridhar ◽  
Sitaramesh Emani ◽  
...  

Isolated diastolic dysfunction is found in almost half of asymptomatic patients with well-controlled diabetes and may precede diastolic heart failure. However, mechanisms that underlie diastolic dysfunction during diabetes are not well understood. We tested the hypothesis that isolated diastolic dysfunction is associated with impaired myocardial Ca2+ handling during type 1 diabetes. Streptozotocin-induced diabetic rats were compared with age-matched placebo-treated rats. Global left ventricular myocardial performance and systolic function were preserved in diabetic animals. Diabetes-induced diastolic dysfunction was evident on Doppler flow imaging, based on the altered patterns of mitral inflow and pulmonary venous flows. In isolated ventricular myocytes, diabetes resulted in significant prolongation of action potential duration compared with controls, with afterdepolarizations occurring in diabetic myocytes ( P < 0.05). Sustained outward K+ current and peak outward component of the inward rectifier were reduced in diabetic myocytes, while transient outward current was increased. There was no significant change in L-type Ca2+ current; however, Ca2+ transient amplitude was reduced and transient decay was prolonged by 38% in diabetic compared with control myocytes ( P < 0.05). Sarcoplasmic reticulum Ca2+ load (estimated by measuring the integral of caffeine-evoked Na+-Ca2+ exchanger current and Ca2+ transient amplitudes) was reduced by ∼50% in diabetic myocytes ( P < 0.05). In permeabilized myocytes, Ca2+ spark amplitude and frequency were reduced by 34 and 20%, respectively, in diabetic compared with control myocytes ( P < 0.05). Sarco(endo)plasmic reticulum Ca2+-ATPase-2a protein levels were decreased during diabetes. These data suggest that in vitro impairment of Ca2+ reuptake during myocyte relaxation contributes to in vivo diastolic dysfunction, with preserved global systolic function, during diabetes.


2002 ◽  
Vol 102 (5) ◽  
pp. 515-522 ◽  
Author(s):  
Gabriel W. YIP ◽  
Yan ZHANG ◽  
Peggy Y. TAN ◽  
Mei WANG ◽  
Pik-Yuk HO ◽  
...  

Impaired long-axis motion is a sensitive marker of systolic myocardial dysfunction, but no data are available that relate long-axis changes in systole with those in diastole, particularly in subjects with diastolic dysfunction and a ‘normal’ left ventricular (LV) ejection fraction. A total of 311 subjects (including 105 normal healthy volunteers) aged 20-89 years with variable degrees of systolic function (LV ejection fraction range 0.15-0.84) and diastolic function were studied using tissue Doppler echocardiography and M-mode echocardiography to determine mean mitral annular amplitude and peak velocity in systole and early and late diastole. The LV systolic mitral annular amplitude (SLAX, where LAX is long-axis amplitude) and peak velocity (Sm) correlated well with the respective early diastolic components (ELAX and Em) and late diastolic (atrial) components (ALAX and Am). A non-linear equation fitted better than a linear relationship (non-linear model: SLAX against ELAX, r2 = 0.67; Sm against Em, r2 = 0.60; SLAX against ALAX and Sm against Am, r2 = 0.42). After adjusting for age, sex and heart rate, linear relationships of early diastolic (ELAX, r2 = 0.70; Em, r2 = 0.60) and late diastolic (ALAX, r2 = 0.61; Am, r2 = 0.64) long-axis amplitudes and velocities with the respective values for SLAX and Sm were found, even in those subjects with apparently ‘isolated’ diastolic dysfunction. Long-axis changes in systole or diastole did not correlate with Doppler mitral velocities. We conclude that ventricular long-axis changes in early diastole are closely related to systolic function, even in subjects with diastolic dysfunction. ‘Pure’ or isolated diastolic dysfunction is uncommon.


2005 ◽  
Vol 289 (2) ◽  
pp. H708-H714 ◽  
Author(s):  
Per Reidar Woldbæk ◽  
Jørn Bodvar Sande ◽  
Tævje Andreas Strømme ◽  
Per Kristian Lunde ◽  
Srdjan Djurovic ◽  
...  

Although increased levels of circulating interleukin (IL)-18 have been demonstrated in patients with cardiovascular diseases, the functional consequences of chronically increased circulating IL-18 with respect to myocardial function have not been defined. Thus we aimed to examine the effects of chronic IL-18 exposure on left ventricular (LV) function in healthy mice. Moreover, to clarify whether IL-18 has direct effects on the cardiomyocyte, we examined effects of IL-18 on cardiomyocytes in vitro. After 7 days of daily intraperitoneal injections of 0.5 μg IL-18 in healthy mice, a 40% ( P < 0.05) reduction in the LV maximal positive derivative, a 25% ( P < 0.05) reduction in the LV maximal rate of pressure decay, and a 2.8-fold ( P < 0.001) increase in the LV end-diastolic pressure were measured, consistent with myocardial dysfunction. Furthermore, we measured a 75% ( P < 0.05) reduction in β-adrenergic responsiveness to isoproterenol. IL-18 induced myocardial hypertrophy, and there was a 2.9-fold increase ( P < 0.05) in atrial natriuretic peptide mRNA expression in the LV myocardium. In vitro examinations of isolated adult rat cardiomyocytes being stimulated with IL-18 (0.1 μg/ml) exhibited an increase in peak Ca2+ transients ( P < 0.05) and in diastolic Ca2+ concentrations ( P < 0.05). In conclusion, this study shows that daily administration of IL-18 in healthy mice causes LV myocardial dysfunction and blunted β-adrenergic responsiveness to isoproterenol. A direct effect of IL-18 on the cardiomyocyte in vitro was demonstrated, suggesting that IL-18 reduces the responsiveness of the myofilaments to Ca2+. Finally, induction of myocardial hypertrophy by IL-18 indicates a role for this cytokine in myocardial remodeling.


2003 ◽  
Vol 285 (2) ◽  
pp. H679-H686 ◽  
Author(s):  
Jacob Joseph ◽  
Lija Joseph ◽  
Nawal S. Shekhawat ◽  
Sulochana Devi ◽  
Junru Wang ◽  
...  

A recent report indicated that hyperhomocysteinemia (Hhe), in addition to its atherothrombotic effects, exacerbates the adverse cardiac remodeling seen in response to hypertension, a powerful stimulus for pathological ventricular hypertrophy. The present study was undertaken to determine whether Hhe has a direct effect on ventricular remodeling and function in the absence of other hypertrophic stimuli. Male Wistar-Kyoto rats were fed either an amino acid-defined control diet or an intermediate Hhe-inducing diet. After 10 wk of dietary treatment, rats were subjected to echocardiographic assessment of left ventricular (LV) dimensions and systolic function. Subsequently, blood was collected for plasma homocysteine measurements, and the rats were killed for histomorphometric and biochemical assessment of cardiac remodeling and for in vitro cardiac function studies. Significant LV hypertrophy was detected by echocardiographic measurements, and in vitro results showed hypertrophy with significantly increased myocyte size in the LV and right ventricle (RV). LV and RV remodeling was characterized by a disproportionate increase in perivascular and interstitial collagen, coronary arteriolar wall thickening, and myocardial mast cell infiltration. In vitro study of LV function demonstrated abnormal diastolic function secondary to decreased compliance because the rate of relaxation did not differ between groups. LV systolic function did not vary between groups in vitro. In summary, in the absence of other hypertrophic stimuli short-term intermediate Hhe caused pathological hypertrophy and remodeling of both ventricles with diastolic dysfunction of the LV. These results demonstrate that Hhe has direct adverse effects on cardiac structure and function, which may represent a novel direct link between Hhe and cardiovascular morbidity and mortality, independent of other risk factors.


2008 ◽  
Vol 294 (1) ◽  
pp. H372-H378 ◽  
Author(s):  
Gavin R. Norton ◽  
Demetri G. A. Veliotes ◽  
Oleg Osadchii ◽  
Angela J. Woodiwiss ◽  
D. Paul Thomas

We explored whether the hypertensive heart is susceptible to myocardial dysfunction in viable noninfarcted tissue post-myocardial infarction (MI), the potential mechanisms thereof, and the impact of these changes on pump function. Six to seven months after the ligation of the left anterior descending coronary artery, left ventricular (LV) myocardial systolic function, as assessed from the percent shortening of the noninfarcted lateral wall segmental length determined over a range of filling pressures (ultrasonic transducers placed in the lateral wall in anaesthetized, open-chest, ventilated rats) and the percent thickening of the posterior wall (echocardiography), was reduced in infarcted spontaneous hypertensive rats (SHR-MI) ( P < 0.05) but not in normotensive Wistar-Kyoto (WKY-MI) animals compared with corresponding controls [SHR-sham operations (Sham) and WKY-Sham]. This change in the regional myocardial function in SHR-MI, but not in WKY-MI, occurred despite a similar degree of LV dilatation (increased LV end-diastolic dimensions and volume intercept of the LV end-diastolic pressure-volume relation) in SHR-MI and WKY-MI rats and a lack of difference in LV relative wall thinning, LV wall stress, apoptosis [terminal deoxynucleotidyl transferase biotin-dUTP nick-end labeling (TUNEL)], or necrosis (pathological score) between SHR-MI and WKY-MI rats. Although the change in regional myocardial function in the SHR-MI group was not associated with a greater reduction in baseline global LV chamber systolic function [end-systolic elastance (LV Ees) and endocardial fractional shortening determined in the absence of an adrenergic stimulus], in the presence of an isoproterenol challenge, noninfarct-zone LV systolic myocardial dysfunction manifested in a significant reduction in LV Ees in SHR-MI compared with WKY-MI and SHR and WKY-Sham rats ( P < 0.04). In conclusion, these data suggest that with chronic MI, the hypertensive heart is susceptible to the development of myocardial dysfunction, a change that cannot be attributed to excessive chamber dilatation, apoptosis, or necrosis, but which in turn contributes toward a reduced cardiac adrenergic inotropic reserve.


2006 ◽  
Vol 101 (1) ◽  
pp. 92-101 ◽  
Author(s):  
Leonid Shmuylovich ◽  
Sándor J. Kovács

Maximum elastance is an experimentally validated, load-independent systolic function index stemming from the time-varying elastance paradigm that decoupled extrinsic load from (intrinsic) contractility. Although Doppler echocardiography is the preferred method of diastolic function (DF) assessment, all echo-derived indexes are load dependent, and no invasive or noninvasive load-independent index of filling (LIIF) exists. In this study, we derived and experimentally validated a LIIF. We used a kinematic filling paradigm (the parameterized diastolic filling formalism) to predict and derive the (dimensionless) dynamic diastolic efficiency M, defined by the slope of the peak driving force [maximum driving force ( kx o) ∝ peak atrioventricular (AV) gradient] to maximum viscoelastic resistive force [peak resistive force ( cEpeak)] relation. To validate load independence, we analyzed E-waves recorded while load was varied via tilt table (head up, horizontal, and head down) in 16 healthy volunteers. For the group, linear regression of E-wave derived kx o vs. cEpeak yielded kx o = M ( cEpeak) + B, r2 = 0.98; where M = 1.27 ± 0.09 and B = 5.69 ± 1.70. Effects of diastolic dysfunction (DD) on M were assessed by analysis of preexisting simultaneous cath-echo data in six DD vs. five control subjects. Average M for the DD group ( M = 0.98 ± 0.07) was significantly lower than controls ( M = 1.17 ± 0.05, P < 0.001). We conclude that M is a LIIF because it uncouples intrinsic DF (i.e., the pressure-flow relation) from extrinsic load (left ventricular end-diastolic pressure). Larger M values imply better DF in that increasing AV pressure gradient results in relatively smaller increases in peak resistive losses ( cEpeak). Conversely, lower M implies that increasing AV gradient leads to larger increases in resistive losses. Further prospective validation characterizing M in well-defined pathological states is warranted.


2006 ◽  
Vol 291 (6) ◽  
pp. H3154-H3158 ◽  
Author(s):  
Robert M. Gill ◽  
Bonita D. Jones ◽  
Angela K. Corbly ◽  
Juan Wang ◽  
Julian C. Braz ◽  
...  

Left ventricular (LV) diastolic dysfunction is a fundamental impairment in congestive heart failure (CHF). This study examined LV diastolic function in the canine model of CHF induced by chronic coronary embolization (CCE). Dogs were implanted with coronary catheters (both left anterior descending and circumflex arteries) for CCE and instrumented for measurement of LV pressure and dimension. Heart failure was elicited by daily intracoronary injections of microspheres (1.2 million, 90- to 120-μm diameter) for 24 ± 4 days, resulting in significant depression of cardiac systolic function. After CCE, LV maximum negative change of pressure with time (dP/d tmin) decreased by 25 ± 2% ( P < 0.05) and LV isovolumic relaxation constant and duration increased by 19 ± 5% and 25 ± 6%, respectively (both P < 0.05), indicating an impairment of LV active relaxation, which was cardiac preload independent. LV passive viscoelastic properties were evaluated from the LV end-diastolic pressure (EDP)-volume (EDV) relationship (EDP = beα*EDV) during brief inferior vena caval occlusion and acute volume loading, while the chamber stiffness coefficient (α) increased by 62 ± 10% ( P < 0.05) and the stiffness constant ( k) increased by 66 ± 13% after CCE. The regional myocardial diastolic stiffness in LV anterior and posterior walls was increased by 70 ± 25% and 63 ± 24% (both P < 0.05), respectively, after CCE, associated with marked fibrosis, increase in collagen I and III, and enhancement of plasminogen activator inhibitor-1 (PAI-1) protein expression. Thus along with depressed LV systolic function there is significant impairment of LV diastolic relaxation and increase in chamber stiffness, with development of myocardial fibrosis and activation of PAI-1, in the canine model of CHF induced by CCE.


2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1627.3-1628
Author(s):  
F. Adeline ◽  
X. Romand ◽  
M. Dalecky ◽  
A. Pfimlin ◽  
D. Wendling ◽  
...  

Background:Axial Spondyloarthritis (ax-SpA) displays an increased cardiovascular disease (CVD) risk compared with the general population. Although ischemic cardiac manifestations are well known, prevalence of non-ischemic manifestations such as myocardial dysfunction and valvulopathy is less clear.Objectives:To compare prevalence of myocardial dysfunction and valvulopathy by ultrasound in ax-SpA patients and versus healthy controls.Methods:Two investigators independently searched for studies indexed in PUBMED, Cochrane Library and EMBASE databases and published before January 17th 2020. The search was focused on ultrasound evaluation of myocardial function and valvulopathy, with two-dimensional, Doppler, tissue Doppler, and speckle tracking echocardiography. We included for meta-analysis all controlled studies including ax-SpA without previous cardiovascular disease. Data were pooled using appropriate random or fixed effects model.Results:Literature search retrieved of 186 abstracts. A total of 31 papers were included in the systematic review and 27 papers were analyzed in the meta-analysis (1,494 ax-SpA patients and 1,091 healthy controls). Studies displayed cross-sectional design and included ax-SpA without prevalent cardiovascular disease.Ax-SpA was defined according to the modified New York criteria (24 studies) followed or the ASAS criteria (2 studies). HLA B27+ positivity ranged from 51 to 100%, mean age ranged from 26.7 to 55.7 years, disease duration ranged from 3.2 to 23.3 years and mean BASDAI ranged from 1.24 to 5.6.Patients with ax-SpA displayed a lower diastolic function with a lower E/A ratio, a higher deceleration time, a higher isovolumetric relaxation time and a lower systolic function with a lower ejection fraction (figure 1). Left-ventricular end diastolic and systolic diameters were higher in ax-SpA patients with respectively mean difference 0.55 mm [CI95%; 0.19, 0.91] and 0.79 mm [CI95%; 0.40, 1.17]. We did not find any difference for left and posterior ventricular thickness, left atrial dimension, and left ventricular mass index.Figure 1.Systolic and diastolic dysfunction is slightly altered in ax-SpA patients compared to healthy individuals Diastolic dysfunction was assessed by (A) E/A ratio (m/s), (B) deceleration time (ms), (C) Isovolumetric relaxation time (ms) and (D) systolic function was assessed by ejection fraction (%).A total of 15 articles reported prevalence of valvulopathy in ax-SpA. Prevalence of mitral regurgitation and aortic regurgitation were similar in ax-SpA patients and healthy individuals: OR=1.13 [CI95% 0.76, 1.68] and OR=1.18 [CI95% 0.68, 2.04].Conclusion:Prevalence of valvulopathy was similar in ax-SpA and healthy individuals. Diastolic and systolic function seems to be slightly altered in ax-SpA compared to healthy controls. However, this difference is unlikely clinically relevant. Usefulness of systematic echography remains to be determined in future longitudinal studies.Disclosure of Interests:Fanny Adeline: None declared, Xavier Romand Consultant of: Xavier ROMAND has received honorarium fees from Abbvie, Mickael Dalecky Consultant of: Mickael DALECKY has received honorarium fees from Abbvie, Arnaud Pfimlin Consultant of: Arnaud PFIMLIN has received honorarium fees from Abbvie, Daniel Wendling: None declared, Philippe Gaudin Speakers bureau: Lilly, Pascal Claudepierre Speakers bureau: Janssen, Novartis, Lilly, Maxime Dougados Grant/research support from: AbbVie, Eli Lilly, Merck, Novartis, Pfizer and UCB Pharma, Consultant of: AbbVie, Eli Lilly, Merck, Novartis, Pfizer and UCB Pharma, Speakers bureau: AbbVie, Eli Lilly, Merck, Novartis, Pfizer and UCB Pharma, Athan Baillet Consultant of: Athan BAILLET has received honorarium fees from Abbvie for his participation as the coordinator of the systematic literature review


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