Association between left ventricular diastolic dysfunction and severity of chronic obstructive pulmonary disease

OBJECTIVES: ,,,,,The prevalence of electrocardiographic and echocardiographic abnormalities in chronic obstructive pulmonary disease according to disease severity has not yet been established. The aim of this study was to assess the prevalence of electrocardiographic and echocardiographic abnormalities in chronic obstructive pulmonary disease patients according to disease severity. ,,,, ,,,, ,,,,,METHODS: ,,,,,The study included 25 mild/moderate chronic obstructive pulmonary disease patients and 25 severe/very severe chronic obstructive pulmonary disease patients. All participants underwent clinical evaluation, spirometry and electrocardiography/echocardiography. ,,,, ,,,, ,,,,,RESULTS: ,,,,,Electrocardiography and echocardiography showed Q-wave alterations and segmental contractility in five (10%) patients. The most frequent echocardiographic finding was mild left diastolic dysfunction (88%), independent of chronic obstructive pulmonary disease stage. The proportion of right ventricular overload (p<0.05) and blockage of the anterosuperior division of the left bundle branch were higher in patients with greater obstruction. In an echocardiographic analysis, mild/moderate chronic obstructive pulmonary disease patients showed more abnormalities in segmental contractility (p<0.05), whereas severe/very severe chronic obstructive pulmonary disease patients showed a higher prevalence of right ventricular overload (p<0.05), increased right cardiac chamber (p<0.05) and higher values of E-wave deceleration time (p<0.05). Age, sex, systemic arterial hypertension, C-reactive protein and disease were included as independent variables in a multiple linear regression; only disease severity was predictive of the E-wave deceleration time [r2 = 0.26, p = 0.01]. ,,,, ,,,, ,,,,,CONCLUSION: ,,,,,Chronic obstructive pulmonary disease patients have a high prevalence of left ventricular diastolic dysfunction, which is associated with disease severity. Because of this association, it is important to exclude decompensated heart failure during chronic obstructive pulmonary disease exacerbation.

Characteristics of left ventricular diastolic dysfunction in the community: an echocardiographic survey

Objective: To determine the prevalence and predictors of left ventricular (LV) diastolic dysfunction in older adults. Design, setting and participants: A cross-sectional survey of 1275 randomly selected residents of Canberra, aged 60 to 86 years (mean age 69.4; 50% men), conducted between February 2002 and June 2003. Main outcome measures: Prevalence of LV diastolic dysfunction as characterised by comprehensive Doppler echocardiography. Results: The prevalence of any diastolic dysfunction was 34.7% (95% CI 32.1% to 37.4%) and that of moderate to severe diastolic dysfunction was 7.3% (95% CI 5.9% to 8.9%). Of subjects with moderate to severe diastolic dysfunction, 77.4% had an LV ejection fraction (EF) > 50% and 76.3% were in a preclinical stage of disease. Predictors of diastolic dysfunction were higher age (p < 0.0001), reduced EF (p < 0.0001), obesity (p < 0.0001) and a history of hypertension (p < 0.0001), diabetes (p = 0.02) and myocardial infarction (p = 0.003). Moderate to severe diastolic dysfunction with normal EF, although predominantly preclinical, was independently associated with increased LV mass (p < 0.0001), left atrial volume (p < 0.0001), and circulating amino-terminal pro-B-type natriuretic peptide concentrations (p < 0.0001), and with decreased quality of life (p < 0.005). Conclusion: Diastolic dysfunction is common in the community and often unaccompanied by overt congestive heart failure. Despite the lack of symptoms, advanced diastolic dysfunction with normal EF is associated with reduced quality of life and structural abnormalities that reflect increased cardiovascular risk.

Endothelial NADPH oxidase-2 promotes interstitial cardiac fibrosis and diastolic dysfunction through proinflammatory effects and endothelial-mesenchymal transition

Objectives: This study sought to investigate the effect of endothelial dysfunction on the development of cardiac hypertrophy and fibrosis.
Background: Endothelial dysfunction accompanies cardiac hypertrophy and fibrosis, but its contribution to these conditions is unclear. Increased nicotinamide adenine dinucleotide phosphate oxidase-2 (NOX2) activation causes endothelial dysfunction.
Methods: Transgenic mice with endothelial-specific NOX2 overexpression (TG mice) and wild-type littermates received long-term angiotensin II (AngII) infusion (1.1 mg/kg/day, 2 weeks) to induce hypertrophy and fibrosis.
Results: TG mice had systolic hypertension and hypertrophy similar to those seen in wild-type mice but developed greater cardiac fibrosis and evidence of isolated left ventricular diastolic dysfunction (p < 0.05). TG myocardium had more inflammatory cells and VCAM-1-positive vessels than did wild-type myocardium after AngII treatment (both p < 0.05). TG microvascular endothelial cells (ECs) treated with AngII recruited 2-fold more leukocytes than did wild-type ECs in an in vitro adhesion assay (p < 0.05). However, inflammatory cell NOX2 per se was not essential for the profibrotic effects of AngII. TG showed a higher level of endothelial-mesenchymal transition (EMT) than did wild-type mice after AngII infusion. In cultured ECs treated with AngII, NOX2 enhanced EMT as assessed by the relative expression of fibroblast versus endothelial-specific markers.
Conclusions: AngII-induced endothelial NOX2 activation has profound profibrotic effects in the heart in vivo that lead to a diastolic dysfunction phenotype. Endothelial NOX2 enhances EMT and has proinflammatory effects. This may be an important mechanism underlying cardiac fibrosis and diastolic dysfunction during increased renin-angiotensin activation.

Endothelial NADPH oxidase-2 promotes interstitial cardiac fibrosis and diastolic dysfunction through proinflammatory effects and endothelial-mesenchymal transition

OBJECTIVES: This study sought to investigate the effect of endothelial dysfunction on the development of cardiac hypertrophy and fibrosis. BACKGROUND: Endothelial dysfunction accompanies cardiac hypertrophy and fibrosis, but its contribution to these conditions is unclear. Increased nicotinamide adenine dinucleotide phosphate oxidase-2 (NOX2) activation causes endothelial dysfunction. METHODS: Transgenic mice with endothelial-specific NOX2 overexpression (TG mice) and wild-type littermates received long-term angiotensin II (AngII) infusion (1.1 mg/kg/day, 2 weeks) to induce hypertrophy and fibrosis. RESULTS: TG mice had systolic hypertension and hypertrophy similar to those seen in wild-type mice but developed greater cardiac fibrosis and evidence of isolated left ventricular diastolic dysfunction (p < 0.05). TG myocardium had more inflammatory cells and VCAM-1-positive vessels than did wild-type myocardium after AngII treatment (both p < 0.05). TG microvascular endothelial cells (ECs) treated with AngII recruited 2-fold more leukocytes than did wild-type ECs in an in vitro adhesion assay (p < 0.05). However, inflammatory cell NOX2 per se was not essential for the profibrotic effects of AngII. TG showed a higher level of endothelial-mesenchymal transition (EMT) than did wild-type mice after AngII infusion. In cultured ECs treated with AngII, NOX2 enhanced EMT as assessed by the relative expression of fibroblast versus endothelial-specific markers. CONCLUSIONS: AngII-induced endothelial NOX2 activation has profound profibrotic effects in the heart in vivo that lead to a diastolic dysfunction phenotype. Endothelial NOX2 enhances EMT and has proinflammatory effects. This may be an important mechanism underlying cardiac fibrosis and diastolic dysfunction during increased renin-angiotensin activation.

Can emerging biomarkers of myocardial remodelling identify asymptomatic hypertensive patients at risk for diastolic dysfunction and diastolic heart failure?

AIMS: Hypertension is one of the main drivers of the heart failure (HF) epidemic. The aims of this study were to profile fibro-inflammatory biomarkers across stages of the hypertensive heart disease (HHD) spectrum and to examine whether particular biochemical profiles in asymptomatic patients identify a higher risk of evolution to HF.

METHODS AND RESULTS: This was a cross-sectional observational study involving a population of 275 stable hypertensive patients divided into two different cohorts: Group 1, asymptomatic hypertension (AH) (n= 94); Group 2, HF with preserved ejection fraction (n= 181). Asymptomatic hypertension patients were further subdivided according to left atrial volume index ≥34 mL/m(2) (n= 30) and <34 mL/m(2) (n= 64). Study assays involved inflammatory markers [interleukin 6 (IL6), interleukin 8 (IL8), monocyte chemoattractant protein 1 (MCP1), and tumour necrosis factor α], collagen 1 and 3 metabolic markers [carboxy-terminal propeptide of collagen 1, amino-terminal propeptide of collagen 1, amino-terminal propeptide of collagen 3 (PIIINP), and carboxy-terminal telopeptide of collagen 1 (CITP)], extra-cellular matrix turnover markers [matrix metalloproteinase 2 (MMP2), matrix metalloproteinase 9 (MMP9), and tissue inhibitor of metalloproteinase 1 (TIMP1)], and the brain natriuretic peptide. Data were adjusted for age, sex, systolic blood pressure, and creatinine. Heart failure with preserved ejection fraction was associated with an increased inflammatory signal (IL6, IL8, and MCP1), an increased fibrotic signal (PIIINP and CITP), and an increased matrix turnover signal (MMP2 and MMP9). Alterations in MMP and TIMP enzymes were found to be significant indicators of greater degrees of asymptomatic left ventricular diastolic dysfunction.

CONCLUSION: These data define varying fibro-inflammatory profiles throughout different stages of HHD. In particular, the observations on MMP9 and TIMP1 raise the possibility of earlier detection of those at risk of evolution to HF which may help focus effective preventative strategies.

Murine Models of Diastolic Dysfunction and Heart Failure With Preserved Ejection Fraction

Left ventricular diastolic dysfunction leads to heart failure with preserved ejection fraction, an increasingly prevalent condition largely driven by modern day lifestyle risk factors. As heart failure with preserved ejection fraction accounts for almost one-half of all patients with heart failure, appropriate nonhuman animal models are required to improve our understanding of the pathophysiology of this syndrome and to provide a platform for preclinical investigation of potential therapies. Hypertension, obesity, and diabetes are major risk factors for diastolic dysfunction and heart failure with preserved ejection fraction. This review focuses on murine models reflecting this disease continuum driven by the aforementioned common risk factors. We describe various models of diastolic dysfunction and highlight models of heart failure with preserved ejection fraction reported in the literature. Strengths and weaknesses of the different models are discussed to provide an aid to translational scientists when selecting an appropriate model. We also bring attention to the fact that heart failure with preserved ejection fraction is difficult to diagnose in animal models and that, therefore, there is a paucity of well described animal models of this increasingly important condition.

Patients with a hypertensive response to exercise have impaired systolic function without diastolic dysfunction or left ventricular hypertrophy

OBJECTIVES We sought to determine if a hypertensive response to exercise (HRE) is associated with myocardial changes consistent with early hypertensive heart disease. BACKGROUND An HRE predicts the development of chronic hypertension (HT) and may reflect a preclinical stage of HT. METHODS Patients with a normal left ventricular (LV) ejection fraction and a negative stress test were recruited into three matched groups: 41 patients (age 56 +/- 10 years) with HRE (210/105 mm Hg in men; > 190/105 in women), comprising 22 patients with (HT+) and 19 without resting hypertension (HT-); and 17 matched control subjects without HRE. Long-axis function was determined by measurement of the strain rate (SR), peak systolic strain, and cyclic variation (CV) of integrated backscatter in three apical views. RESULTS An HRE was not associated with significant differences in LV mass index. Exercise performance and diastolic function were reduced in HRE(HT+) patients, but similar in HRE(HT-) patients and controls. Systolic dysfunction (peak systolic strain, SR, and CV) was significantly reduced in HRE patients (p < 0.001 for all). These reductions were equally apparent in patients with and without a history of resting HT (p = NS) and were independent of LV mass index and blood pressure (p < 0.01). CONCLUSIONS An HRE is associated with subtle systolic dysfunction, even in the absence of resting HT. These changes occur before the development of LV hypertrophy or detectable diastolic dysfunction and likely represent early hypertensive heart disease. (C) 2004 by the American College of Cardiology Foundation.

Diastolic dysfunction is a manifestation of ventricular-vascular interaction in patients with type 2 diabetes mellitus

Vascular disease is accelerated in patients with Type 2 diabetes mellitus (T2DM). Since the systemic vasculature plays a pivotal role in myocardial loading, this study aimed to determine the effect of arterial characteristics on left ventricular (LV) morphology and function in patients with T2DM. Conventional echocardiography and tissue Doppler imaging were performed in 172 T2DM patients (95 men; aged 55±11y) with preserved ejection fraction (62±5%). Patients were stratified into groups based on LV geometric pattern (normal [n = 79], concentric remodeling [n = 33], concentric hypertrophy [n = 29], eccentric hypertrophy [n = 31]). Total arterial compliance (TAC) was recorded by simultaneous radial tonometry and aortic outflow pulsed wave Doppler. Arterial (brachial and carotid) structure and function were determined by standard ultrasound methods. There were no significant differences between the LV geometric groups in demographic or clinical parameters. The concentric hypertrophy group had significantly increased carotid artery diameter (6.0±0.7mm versus 6.5±0.7mm; p < 0.05) and stiffness (1912±1203 dynes/cm2mm versus 2976±2695 dynes/cm2mm×10−6; p < 0.05) compared to those with normal geometry. However, TAC did not differ between groups. LV diastolic function, as determined by the ratio of diastolic mitral inflow velocity to mitral annulus tissue velocity (E/E_), was significantly associated with carotid artery relative wall thickness and intima media thickness (p < 0.05). Moreover, E/E_ was independently predicted by carotid artery relative wall thickness (β = 22.9; p = 0.007). We conclude that structural characteristics of the carotid artery are associated with abnormal LV structure and function in patients with T2DM. The LV functional irregularities may be a downstream consequence of amplified pressure wave reflections effecting sub-optimal ventricular-vascular interaction.

Cardiomyopathy and Diastolic Dysfunction in the Embryo and Neonate of a Type 1 Diabetic Mouse Model

Objective: The purpose of this study was to examine the effect of maternal type 1 diabetes on the structure and function of the embryonic and neonatal mouse heart.

Methods: Type 1 diabetes was induced in female C57BL6/J mice using streptozotocin. Embryonic (n = 105) and neonatal hearts (n = 46) were examined using high-frequency ultrasound (US) and a cohort of E18.5 (n = 34) and 1-day-old pup hearts (n = 27) underwent histological examination.

Results: Global cardiac hypertrophy in late gestation (E18.5) was evident on US in the diabetic group compared to controls with increased interventricular septal (IVS) thickness (0.44 ± 0.08 mm vs 0.36 ± 0.08 mm, P < .05) and increased left ventricular wall thickness (0.38 ± 0.04 mm vs 0.29 mm ± 0.05, P < .01). Isovolumetric relaxation time was initially prolonged in the diabetic group but resolved by E18.5 to control values. Histological examination at E18.5 demonstrated increased transverse measurements (2.42 ± 0.72 mm/g vs 1.86 ± 0.55 mm/g, P < .05) and increased IVS thickness (0.64 ± 0.20 mm/g vs 0.43 ± 0.15 mm/g, P < .05) in diabetic embryos compared to control embryos.

Conclusion: Maternal hyperglycemia has severe effects on offspring with evidence of cardiac impairment and cardiac hypertrophy in the embryo. These effects persisted in the 1-day old but attenuated in the 1-week old suggesting cardiac remodeling after the hyperglycemic milieu of pregnancy is removed