Noninvasive radiodiagnosis of left ventricular diastolic dysfunction in hypertensive patients

To define the informative value of Doppler studies in the early diagnosis of left ventricular (LV) diastolic dysfunction in patients with hypertensive disease (HD), the authors examined 74 patients with grade 1-2 HD, including 65 men and 9 women aged 43 to 63 years. All the patients underwent echocardiography (echoCG), Doppler echoCG (DechoCG), tissue DechoCG (TDechoCG), and treadmill. According to the echoCG LV mass index (LVMI), all the patients were divided into 2 groups: 1) 33 patients with increased LVMI and 2) 41 with normal LVMI. A control group consisted of 20 apparently healthy patients. Groups 1 and 2 showed a preponderance of patients with concentric LV hypertrophy (CLVH) and those with concentric LV remodeling, respectively. In accordance with DechoCG, the signs of primary LV diastolic dysfunction ((E/A = 0.8+/-0.1; IVRT = 103+/-15) were found only in Group 1 patients. TDechoCG displayed the signs of primary LV diastolic dysfunction in both groups (e' or =10 ratio, suggests elevated LV filling pressure as an early stage of diastolic dysfunction.     

Elevation of B-type natriuretic peptide is a sensitive marker of left ventricular diastolic dysfunction in patients with maintenance haemodialysis

Objective: To determine the clinical value of B-type natriuretic peptide (BNP) in diagnosing left ventricular diastolic dysfunction (LVDD) associated with maintenance haemodialysis (MHD) population.

Methods: Plasma BNP was determined in 59 MHD patients with normal ejection fraction. The ratio of early to late annular velocity (E’/A’) was determined by tissue Doppler imaging as a parameter of diastolic function.

Results: LVDD occurred in 66% of the patients. Receiver-operating characteristic curve analyses identified a cut-off of 353.6 pg ml^?1 as the one with the highest sensitivity and specificity for detecting LVDD.

Conclusions: Plasma BNP may serve as a potential biomarker in diagnosing LVDD in MHD patients with normal systolic function.     

Alogliptin prevents diastolic dysfunction and preserves left ventricular mitochondrial function in diabetic rabbits

Background

There are increasing evidence that left ventricle diastolic dysfunction is the initial functional alteration in the diabetic myocardium. In this study, we hypothesized that alogliptin prevents diastolic dysfunction and preserves left ventricular mitochondrial function and structure in diabetic rabbits.

Methods

A total of 30 rabbits were randomized into control group (CON, n?=?10), alloxan-induced diabetic group (DM, n?=?10) and alogliptin-treated (12.5 mg/kd/day for 12 weeks) diabetic group (DM-A, n?=?10). Echocardiographic and hemodynamic studies were performed in vivo. Mitochondrial morphology, respiratory function, membrane potential and reactive oxygen species (ROS) generation rate of left ventricular tissue were assessed. The serum concentrations of glucagon-like peptide-1, insulin, inflammatory and oxidative stress markers were measured. Protein expression of TGF-β1, NF-κB p65 and mitochondrial biogenesis related proteins were determined by Western blotting.

Results

DM rabbits exhibited left ventricular hypertrophy, left atrial dilation, increased E/e′ ratio and normal left ventricular ejection fraction. Elevated left ventricular end diastolic pressure combined with decreased maximal decreasing rate of left intraventricular pressure (??dp/dtmax) were observed. Alogliptin alleviated ventricular hypertrophy, interstitial fibrosis and diastolic dysfunction in diabetic rabbits. These changes were associated with decreased mitochondrial ROS production rate, prevented mitochondrial membrane depolarization and improved mitochondrial swelling. It also improved mitochondrial biogenesis by PGC-1α/NRF1/Tfam signaling pathway.

Conclusions

The DPP-4 inhibitor alogliptin prevents cardiac diastolic dysfunction by inhibiting ventricular remodeling, explicable by improved mitochondrial function and increased mitochondrial biogenesis.

     

Modeling left ventricular diastolic dysfunction: classification and key indicators

Background

Mathematical modeling can be employed to overcome the practical difficulty of isolating the mechanisms responsible for clinical heart failure in the setting of normal left ventricular ejection fraction (HFNEF). In a human cardiovascular respiratory system (H-CRS) model we introduce three cases of left ventricular diastolic dysfunction (LVDD): (1) impaired left ventricular active relaxation (IR-type); (2) increased passive stiffness (restrictive or R-type); and (3) the combination of both (pseudo-normal or PN-type), to produce HFNEF. The effects of increasing systolic contractility are also considered. Model results showing ensuing heart failure and mechanisms involved are reported.

Methods

We employ our previously described H-CRS model with modified pulmonary compliances to better mimic normal pulmonary blood distribution. IR-type is modeled by changing the activation function of the left ventricle (LV), and R-type by increasing diastolic stiffness of the LV wall and septum. A 5^th-order Cash-Karp Runge-Kutta numerical integration method solves the model differential equations.

Results

IR-type and R-type decrease LV stroke volume, cardiac output, ejection fraction (EF), and mean systemic arterial pressure. Heart rate, pulmonary pressures, pulmonary volumes, and pulmonary and systemic arterial-venous O₂ and CO₂ differences increase. IR-type decreases, but R-type increases the mitral E/A ratio. PN-type produces the well-described, pseudo-normal mitral inflow pattern. All three types of LVDD reduce right ventricular (RV) and LV EF, but the latter remains normal or near normal. Simulations show reduced EF is partly restored by an accompanying increase in systolic stiffness, a compensatory mechanism that may lead clinicians to miss the presence of HF if they only consider LVEF and other indices of LV function. Simulations using the H-CRS model indicate that changes in RV function might well be diagnostic. This study also highlights the importance of septal mechanics in LVDD.

Conclusion

The model demonstrates that abnormal LV diastolic performance alone can result in decreased LV and RV systolic performance, not previously appreciated, and contribute to the clinical syndrome of HF. Furthermore, alterations of RV diastolic performance are present and may be a hallmark of LV diastolic parameter changes that can be used for better clinical recognition of LV diastolic heart disease.     

Increased levels of C-type natriuretic peptide in patients with idiopathic left ventricular dysfunction

C-type natriuretic peptide (CNP) is expressed in the vascular endothelium. It is not known whether CNP is specifically increased in patients with idiopathic left ventricular systolic dysfunction (ILVDys) with or without overt heart failure, and whether in these patients it is related with indicators of myocardial and/or endothelial/microvascular impairment. We determined plasma CNP levels in 51 ILVDys and in 60 controls. We observed a significant increase in patients with (7.0+/-0.9 pg/ml) or without (6.1+/-0.53 pg/ml) overt heart failure (p<0.001) in respect to controls (2.5+/-0.12 pg/ml). CNP was significantly correlated with LVEF (p<0.001), end-diastolic dimension (p<0.05), ANP (p<0.001) and BNP (p<0.001), interleukin-6 (p<0.001), total cholesterol (p<0.05), low-density lipoprotein (p=0.05), ratio total cholesterol/ high-density lipoprotein (p=0.05) and, in a subgroup of patients, with abnormal vasodilating capacity of the coronary microcirculation. In conclusion, CNP is activated in patients with LV dysfunction but without coronary artery disease, independently of the presence of overt heart failure and in tune with the extent of myocardial functional involvement. In these patients CNP is also related with both systemic and coronary indicators of endothelial/microvascular damage.     

Computational modeling of left heart diastolic function: examination of ventricular dysfunction

A computational model that accounts for blood-tissue interaction under physiological flow conditions was developed and applied to a thin-walled model of the left heart. This model consisted of the left ventricle, left atrium, and pulmonary vein flow. The input functions for the model included the pulmonary vein driving pressure and time-dependent relationship for changes in chamber tissue properties during the simulation. The Immersed Boundary Method was used for the interaction of the tissue and blood in response to fluid forces and changes in tissue pathophysiology, and the fluid mass and momentum conservation equations were solved using Patankar's Semi-Implicit Method for Pressure Linked Equations (SIMPLE). This model was used to examine the flow fields in the left heart under abnormal diastolic conditions of delayed ventricular relaxation, delayed ventricular relaxation with increased ventricular stiffness, and delayed ventricular relaxation with an increased atrial contraction. The results obtained from the left heart model were compared to clinically observed diastolic flow conditions, and to the results from simulations of normal diastolic function in this model [1]. Cases involving impairment of diastolic function were modeled with changes to the input functions for fiber relaxation/contraction of the chambers. The three cases of diastolic dysfunction investigated agreed with the changes in diastolic flow fields seen clinically. The effect of delayed relaxation was to decrease the early filling magnitude, and this decrease was larger when the stiffness of the ventricle was increased. Also, increasing the contraction of the atrium during atrial systole resulted in a higher late filling velocity and atrial pressure. The results show that dysfunction can be modeled by changing the relationships for fiber resting-length and/or stiffness. This provides confidence in future modeling of disease, especially changes to chamber properties to examine the effect of local dysfunction on global flow fields.     

Brain natriuretic peptide and left ventricular dysfunction in chagasic cardiomyopathy

Global left ventricular (LV) systolic dysfunction is the strongest predictor of morbidity and mortality in Chagas disease. Echocardiography is considered the gold standard for the detection of LV dysfunction, but not always available in endemic areas where chagasic cardiomyopathy is most common. Brain natriuretic peptide (BNP) is a neurohormone that has been recently described as a simple and inexpensive diagnostic and prognostic marker for patients with congestive heart failure. Chagasic patients (n = 63) and non-infected healthy individuals (n = 18) were recruited prospectively and underwent complete clinical examination, echocardiography and 24-h Holter monitoring. BNP was measured from thawed plasma samples using the Triage BNP test. We observed high levels of BNP in association with depression of LV ejection fraction, with increase of LV end-diastolic diameter and with LV premature complexes. An elevated concentration of BNP, defined as a concentration of 60 pg/ml or more, had a sensitivity of 91.7%, specificity of 82.8%, positive predictive value of 52.4%, and negative predictive value of 98% for detecting LV dysfunction (LV ejection fraction < 40%).BNP measurement using a simple, relatively inexpensive and rapid test has a promising role in identifying LV dysfunction associated with chagasic cardiomyopathy. Equally important, patients with Trypanosoma cruzi infection who have low levels of BNP level in plasma have a very low likelihood of severe cardiac involvement, and echocardiography is probably not necessary.     

T-lymphocytes mediate left ventricular fibrillar collagen cross-linking and diastolic dysfunction in mice

Aberrant concentrations of cardiac extracellular matrix (ECM) fibrillar collagen cross-linking have been proposed to be an underlying cause of cardiac diastolic dysfunction however the role of the adaptive immune system in this process has yet to be investigated. Fibrillar collagen cross-linking is a product of the enzymatic activities of lysyl oxidase (LOX and LOXL-3) released by the cardiac fibroblast and possibly cardiac myocytes. Our hypothesis is that stimulation of the TH1 lymphocytes activates lysyl oxidase mediated ECM cross-linking and thereby alters left ventricular function. Three-month old C57BL/J female mice were treated with selective TH1 lymphocyte inducers — T-cell receptor Vβ peptides (TCR). After 6 weeks, candidate gene expression, tissue enzymatic activity, ECM composition, and left ventricular mechanics were quantified. Lymphocyte gene expression and cytokine assay revealed TH1 immune polarization with TCR administration which was associated with a 2.6-fold and 3.1-fold increase of LOX and LOXL3 gene expression, respectively, and a 55% increase in cardiac LOX enzymatic activity. The ECM cross-linked fibrillar collagen increased by 95% when compared with the control. Concurrently, there was a 33% increased ventricular stiffness, decreased cardiac output, and normal ejection fraction. These data implicate the TH1 lymphocyte in the pathogenesis of diastolic dysfunction which has potential clinical application in the pathogenesis of diastolic heart failure.     

Sub-clinical left ventricular diastolic dysfunction in early stage of chronic obstructive pulmonary disease

Sub-clinical cardiac dysfunction may be significantly associated with chronic obstructive pulmonary disease (COPD) with a different degree of severity. In a cross-sectional design we aimed to evaluate the frequency of left ventricular diastolic dysfunction (LVdd) and its correlation with lung function, pulmonary arterial pressure and systemic inflammation in a selected population of COPD at an early stage of their disease. Fifty-five COPD patients with no clinical signs of cardiovascular dysfunction were recruited and compared to 40 matched healthy controls. All the subjects underwent pulmonary function testing, doppler echocardiography, and interleukin-6 blood sampling. Presence of LVdd was defined according to the significant change in both the ratio between early and late diastolic transmitral flow velocity (E/A ratio), isovolumetric relaxation time (IVRT), and deceleration time (DT). The frequency of LVdd was higher in the COPD group (70.9 percent) compared to controls (27.5 percent). In these patients decreased E/A ratio, and prolonged IVRT and DT clearly pointed to left ventricular filling impairment, a condition we found to be especially severe in those patients suffering from lung static hyperinflation as expressed by inspiratory-to-total lung capacity ratio (IC/TLC) <0.25. Circulating levels of interleukin-6 were also higher among COPD patients compared to controls. The results of the present study suggest that subclinical left ventricular filling impairment is frequently found in COPD patients at the earlier stage of the disease even in the absence of any other cardiovascular dysfunction. Doppler echocardiography may help the early identification of LVdd in COPD patients.     

Alveolar hypoxia induces left ventricular diastolic dysfunction and reduces phosphorylation of phospholamban in mice

Chronic obstructive pulmonary disease (COPD) may lead to pulmonary hypertension (PH) and reduced function of the right ventricle (RV). However, COPD patients may also develop left ventricular (LV) diastolic dysfunction. We hypothesized that alveolar hypoxia induces LV diastolic dysfunction and changes in proteins governing Ca(2+) removal from cytosol during diastole. Mice exposed to 10% oxygen for 1, 2, or 4 wk were compared with controls. Cardiac hemodynamics were assessed with Doppler echocardiography and a microtransducer catheter under general anesthesia. The pulmonary artery blood flow acceleration time was shorter and RV pressure was higher after 4 wk of hypoxia compared with controls (both P < 0.05). In the RV and LV, 4 wk of hypoxia induced a prolongation of the time constant of isovolumic pressure decay (51% RV, 43% LV) and a reduction in the maximum rate of decline in pressure compared with control (42% RV, 42% LV, all P < 0.05), indicating impaired relaxation and diastolic dysfunction. Alveolar hypoxia induced a 38%, 47%, and 27% reduction in Ser16-phosphorylated phospholamban (PLB) in the RV after 1, 2, and 4 wk of hypoxia, respectively, and at the same time points, Ser16-phosphorylated PLB in the LV was downregulated by 32%, 34%, and 25% (all P < 0.05). The amounts of PLB and sarco(endo)plasmic reticulum Ca(2+) ATPase (SERCA2a) were not changed. In conclusion, chronic alveolar hypoxia induces hypophosphorylation of PLB at Ser16, which might be a mechanism for impaired relaxation and diastolic dysfunction in both the RV and LV.     

Myeloperoxidase,a possible biomarker for the early diagnosis of cardiac diastolic dysfunction with preserved ejection fraction

The current study was conducted on a sample of 91 patients diagnosed with diastolic dysfunction (DD) with preserved systolic function caused by a painful chronic ischaemic cardiopathy – angina pectoris stable at the effort. The diagnosis was established following anamnesis, electrocardiogram, and echocardiography. Myeloperoxidase (MPO) serum levels were assessed in all patients and then these values were correlated with some of the echocardiography parameters that proved the mentioned diagnosis.

In conclusion, the execution of this investigation triad (electrocardiogram, echocardiography, and MPO) allows:

• Stratifying the patients depending on the disease risk by early detecting of any possible DD with preserved systolic function.

• The use of the MPO increased circulating levels as a biomarker for diagnosis and risk due to the statistically significant correlation between those and the results of the other two aforementioned paraclinical investigation.

     

Left atrial strain - an early marker of left ventricular diastolic dysfunction in patients with hypertension and paroxysmal atrial fibrillation

Background

2D strain imaging of the left atrium (LA) is a new echocardiographic method which allows us to determine contractile, conduit and reservoir functions separately. This method is particularly useful when changes are subtle and not easily determined by traditional parameters, as it is in arterial hypertension and atrial fibrillation (AF). The aims of our study were: to determine LA contractile, conduit and reservoir function by 2D strain imaging in patients with mild arterial hypertension and paroxysmal AF; to assess LA contractile, conduit and reservoir functions’ relation with LV diastolic dysfunction (DD) parameters.

Methods

LA contractile, conduit and reservoir functions together with echocardiographic signs of LV DD were assessed in 63 patients with arterial hypertension and paroxysmal AF. Patients were grouped according to number of signs showing LV DD (annular e’ velocity: septal e’?<?7 cm/s, lateral e’?<?10 cm/s, average E/e’ ratio?>?14, LA volume index >?34 ml/m², peak tricuspid regurgitation velocity?>?2.8 m/s) present. Number of patients with 0 signs – 17, 1 sign – 26, 2 signs – 19. Contractile, conduit and reservoir functions were compared between the groups.

Results

Mean contractile, conduit and reservoir strains in all the patients were???14.14 (± 5.83) %, 15.98 (± 4.85) % and 31.03 (± 7.64) % respectively. Contractile strain did not differ between the groups. Conduit strain was higher in patients with 0 signs compared with other groups (p =?0.016 vs 1 sign of LV DD and p =?0.001 vs 2 signs of LV DD). Reservoir strain was higher in patients with 0 signs compared with other groups (p =?0.014 vs 1 sign of LV DD and p <?0.001 vs 2 signs of LV DD).

Conclusions

The patients with paroxysmal AF and primary arterial hypertension have decreased reservoir, conduit and pump LA functions even in the absence of echocardiographic signs of LV DD. With increasing number of parameters showing LV DD, LA conduit and reservoir functions decrease while contractile does not change. LA conduit and reservoir functions decrease earlier than the diagnosis of LV DD can be established according to the guidelines in patients with primary arterial hypertension and AF.

     

The onset of left ventricular diastolic dysfunction in SHR rats is not related to hypertrophy or hypertension

Left ventricular (LV) diastolic dysfunction, particularly relaxation abnormalities, are known to be associated with the development of LV hypertrophy (LVH). Preliminary human and animal studies suggested that early LV diastolic dysfunction may be revealed independently of LVH. However, whether LV diastolic dysfunction is compromised before the onset of hypertension and LVH remains unknown. We therefore evaluated LV diastolic function in spontaneously hypertensive rats (SHR) at different ages and tested whether LV diastolic dysfunction is associated with abnormal intracellular calcium homeostasis. LV systolic and diastolic functions were evaluated by invasive and echocardiographic methods in 3-week-old (without hypertension) and 5-week-old (with hypertension) SHR and Wistar-Kyoto control rats. Basal intracytoplasmic calcium and sarcoplasmic reticulum (SR) Ca(2+) contents were measured in cardiomyocytes using fura-2 AM. Sarco(endo)plasmic Ca(2+)-ATPase isoform 2a (SERCA 2a) and phospholamban (PLB) expressions were quantified by Western blot and quantitative RT-PCR techniques. LV relaxation dysfunction was observed in 3-week-old SHR rats before onset of hypertension and LVH. An increase in basal intracytoplasmic Ca(2+) and a decrease in SR Ca(2+) release were demonstrated in SHR. Decreased expression of SERCA 2a and Ser16 PLB (p16-PLB) protein levels was also observed in SHR rats, whereas mRNA expression was not decreased. For the first time, we have shown that LV myocardial dysfunction precedes hypertension in 3-week-old SHR rats. This LV myocardial dysfunction was associated with high diastolic [Ca(2+)](i) possibly due to decreased SERCA 2a and p16-PLB protein levels. Diastolic dysfunction may be a potential predictive marker of arterial hypertension in genetic hypertension syndromes.     

The PPARGC1A Gly482Ser polymorphism is associated with left ventricular diastolic dysfunction in men

Background

The objective was to explore the relationship between left ventricular ejection fraction (LVEF) assessed during hospitalization for acute myocardial infarction (MI) and later health-related quality of life (HRQoL).

Methods

We used multivariable linear regression to assess the relationship between LVEF and HRQoL in 256 MI patients who responded to the Kansas City Cardiomyopathy Questionnaire (KCCQ), the EQ-5D Index, and the EuroQol Visual Analogue Scale (EQ-VAS) 2.5 years after the index MI.

Results

167 patients had normal LVEF (>50%), 56 intermediate (40%–50%), and 33 reduced (<40%). The mean (SD) KCCQ clinical summary scores were 85 (18), 75 (22), and 68 (21) (p <0.001) in the three groups, respectively. The corresponding EQ-5D Index scores were 0.83 (0.18), 0.72 (0.27), and 0.76 (0.14) (p = 0.005) and EQ-VAS scores were 72 (18), 65 (21), and 57 (20) (p = 0.001). In multivariable linear regression analysis age ≥ 70 years, known chronic obstructive pulmonary disease (COPD), subsequent MI, intermediate LVEF, and reduced LVEF were independent determinants for reduced KCCQ clinical summary score. Female sex, medication for angina pectoris at discharge, and intermediate LVEF were independent determinants for reduced EQ-5D Index score. Age ≥ 70 years, COPD, and reduced LVEF were associated with reduced EQ-VAS score.

Conclusion

LVEF measured during hospitalization for MI was a determinant for HRQoL 2.5 years later.     

A possible role for mitochondrial dysfunction in migraine

Migraine is a common neurological disorder characterised by debilitating head pain and an assortment of additional symptoms which can include nausea, emesis, photophobia, phonophobia and occasionally visual sensory disturbances. Migraine is a complex disease caused by an interplay between predisposing genetic variants and environmental factors. It affects approximately 12?% of studied Caucasian populations with affected individuals being predominantly female. Genes involved in neurological, vascular or hormonal pathways have all been implicated in predisposition towards developing migraine. All of these are nuclear encoded genes, but given the role of mitochondria in a number of neurological disorders and in energy production it is possible that mitochondrial variants may play a role in the pathogenesis of this disease. Mitochondrial DNA has been a useful tool for studying population genetics and human genetic diseases due to the clear inheritance shown through successive generations. Given the clear gender bias found in migraine patients it may be important to investigate X-linked inheritance and mitochondrial-related variants in this disorder. This paper explores the possibility that mitochondrial DNA changes may play a role in migraine. Few variants in the mitochondrial genome have so far been investigated in migraine and new studies should be aimed towards investigating the role of mitochondrial DNA in this common disorder.     

Adaptation of passive rat left ventricle in diastolic dysfunction.

This article deals with providing a theoretical explanation for quantitative changes in the geometry, the opening angle and the deformation parameters of the rat ventricular wall during adaptation of the passive left ventricle in diastolic dysfunction. A large deformation theory is applied to analyse transmural stress and strain distribution in the left ventricular wall considering it to be made of homogeneous, incompressible, transversely isotropic, non-linear elastic material. The basic assumptions made for computing stress distributions are that the average circumferential stress and strain for the adaptive ventricle is equal to the average circumferential stress and strain in the normotensive ventricle, respectively.All the relevant parameters, such as opening angle, twist per unit length, axial extension, internal and external radii and others, in the stress-free, unloaded and loaded states of normotensive, hypertensive and adaptive left ventricle are determined. The circumferential stress and strain distribution through the ventricular wall are also computed. Our analysis predicts that during adaptation, wall thickness and wall mass of the ventricle increase. These results are consistent with experimental findings and are the indications of initiation of congestive heart failure.