Common matrix metalloproteinase 2 gene haplotypes may modulate left ventricular remodelling in hypertensive patients

Matrix metalloproteinases (MMPs) are involved in cardiac remodelling. We examined whether MMP-2 genetic polymorphisms are associated with hypertension and left ventricular (LV) remodelling in hypertensive patients. We studied 160 hypertensive patients and 123 healthy controls. Echocardiography was performed in all patients and the C-1306T (rs243865) and C-735T (rs 2285053) MMP-2 polymorphisms were analysed. Haplo.stats analysis was used to evaluate whether MMP-2 haplotypes are associated with hypertension and with extremes in LV mass index (LVMI). Multiple linear regression analysis was performed to assess whether MMP-2 genotypes or haplotypes affect LVMI and other echocardiography parameters. The C-1306T 'CC' genotype was associated with reduced LVMI and LV end-diastolic diameter (EDD) (P=0.0365 and P=0.0438, respectively). The haplotype 'C, C' was associated with reduced LVMI and EDD (P=0.0278 and P=0.0322, respectively). The comparison of upper and lower extremes of the LVMI phenotype showed that the 'C, C' haplotype was more common in the lower LVMI group (P=0.0060), whereas the 'T, C' haplotype was more common in the higher quartile of LVMI (P=0.0187), and this haplotype was associated with increased risk of higher LVMI values (odds ratio=3.5121, 95% confidence interval 1.3193-9.3494). The findings suggest that MMP-2 polymorphisms affect hypertension-induced LV remodelling. Journal of Human Hypertension (2012) 26, 171-177; doi:10.1038/jhh.2011.8; published online 10 February 2011

A simple voltage/mass index increases the suspicion of amyloidotic cardiomyopathy: an electrocardiographic and echocardiographic study of 767 patients with increased left ventricular wall thickness due to different causes

Background-Amyloidotic cardiomyopathy (AC) can mimic true left ventricular hypertrophy (LVH), including hypertrophic cardiomyopathy (HCM) and hypertensive heart disease (HHD). We assessed the diagnostic value of combined electrocardiographic/echocardiographic indexes to identify AC among patients with increased echocardiographic LV wall thickness due to either different etiologies of amyloidosis or HCM or HHD. Method-First, we studied 469 consecutive patients: 262 with biopsy/genetically proven AC (with either AL or transthyretin (TTR)-related amyloidosis); 106 with HCM; 101 with HHD. We compared the diagnostic performance of: low QRS voltage, symmetric LVH, low QRS voltage plus interventricular septal thickness >1.98 cm, Sokolow index divided by the cross-sectional area of LV wall, Sokolow index divided by body surface area indexed LV mass (LVMI), Sokolow index divided by LV wall thickness, Sokolow index divided by (LV wall/height^2.7); peripheral QRS score divided by LVMI, Peripheral QRS score divided by LV wall thickness, Peripheral QRS score divided by LV wall thickness indexed to height^2.7, total QRS score divided by LVMI, total QRS score divided by LV wall thickness; total QRS score divided by (LV wall/height^2.7). We tested each criterion, separately in males and females, in the following settings: AC vs. HCM+HHD; AC vs. HCM; AL vs. HCM+HHD; AL vs. HCM; TTR vs. HCM+HHD; TTR vs. HCM. Results-Low QRS voltage showed high specificity but low sensitivity for the identification of AC. All the combined indexes had a higher diagnostic accuracy, being total QRS score divided by LV wall thickness or by LVMI associated with the best performances and the largest areas under the ROC curve. These results were validated in 298 consecutive patients with AC, HCM or HHD. Conclusions-In patients with increased LV wall thickness, a combined ECG/ echocardiogram analysis provides accurate indexes to non-invasively identify AC. Total QRS score divided by LVMI or LV wall thickness offers the best diagnostic performance.

Influence of left ventricular relaxation on the pressure half time of aortic regurgitation

BACKGROUND The severity of aortic regurgitation can be estimated using pressure half time (PHT) of the aortic regurgitation flow velocity, but the correlation between regurgitant fraction and PHT is weak. AIM To test the hypothesis that the association between PHT and regurgitant fraction is substantially influenced by left ventricular relaxation. METHODS In 63 patients with aortic regurgitation, subdivided into a group without (n = 22) and a group with (n = 41) left ventricular hypertrophy, regurgitant fraction was calculated using the difference between right and left ventricular cardiac outputs. Left ventricular relaxation was assessed using the early to late diastolic Doppler tissue velocity ratio of the mitral annulus (E/ADTI), the E/A ratio of mitral inflow (E/AM), and the E deceleration time (E-DT). Left ventricular hypertrophy was assessed using the M mode derived left ventricular mass index. RESULTS The overall correlation between regurgitant fraction and PHT was weak (r = 0.36, p < 0.005). In patients without left ventricular hypertrophy, there was a significant correlation between regurgitant fraction and PHT (r = 0.62, p < 0.005), but not in patients with left ventricular hypertrophy. In patients with a left ventricular relaxation abnormality (defined as E/ADTI< 1, E/AM< age corrected lower limit, E-DT >/= 220 ms), no associations between regurgitant fraction and PHT were found, whereas in patients without left ventricular relaxation abnormalities, the regurgitant fraction to PHT relations were significant (normal E/AM: r = 0.57, p = 0.02; E-DT< 220 ms: r = 0.50, p < 0.001; E/ADTI < 1: r = 0.57, p = 0.02). CONCLUSIONS Only normal left ventricular relaxation allows a significant decay of PHT with increasing aortic regurgitation severity. In abnormal relaxation, which is usually present in left ventricular hypertrophy, wide variation in prolonged backward left ventricular filling may cause dissociation between the regurgitant fraction and PHT. Thus the PHT method should only be used in the absence of left ventricular relaxation abnormalities.

Reversal of myocyte hypertrophy by ventricular unloading: cardiac improvement without adrenergic receptor up-regulation and relocalization.

In previous studies, we found that the improved contractile ability of cardiac myocytes from patients who have had left ventricular assist device (LVAD) support was due to a number of beneficial changes, most notably in calcium handling (increased sarcoplasmic reticulum calcium binding and uptake), improved integrity of cell membranes due to phospholipid reconstruction (reduced lysophospholipid content), and an upregulation of adrenoreceptors (increased adrenoreceptor numbers). However, in the case presented here, there was no increase in adrenoreceptor number, which is something that we usually find in core tissue at the time of LVAD removal or organ transplantation; also, there was no homogeneous postassist device receptor distribution. However, the patient was well maintained for 10 months following LVAD implantation, until a donor organ was available, regardless of the lack of adrenoreceptor improvement. We conclude from these studies that cardiac recovery is the result of the initiation of multiple repair mechanisms, and that the lack of expected changes, in this case increased adrenoreceptors, is not always an accurate indicator of anticipated outcome. We suggest that interventions and strategies have to consider multiple, beneficial changes due to unloading and target a number of biochemical and structural areas to produce improvement, even if not all of these improvements occur.

Alterations of left ventricular myocardial characteristics associated with obesity

Background-Obesity is associated with heart failure, but an effect of weight, independent of comorbidities, on cardiac structure and function is not well established. We sought whether body mass index (BMI) and insulin levels were associated with subclinical myocardial disturbances. Methods and Results-Transthoracic echocardiography, myocardial Doppler-derived systolic (sm) and early diastolic velocity ( em), strain and strain rate imaging and tissue characterization with cyclic variation (CVIB), and calibrated integrated backscatter (cIB) were obtained in 109 overweight or obese subjects and 33 referents (BMI35) and the referent patients (P

Matrix Metalloproteinases And Left Ventricular Function And Structure In Spinal Cord Injured Subjects.

Subjects with spinal cord injury (SCI) exhibit impaired left ventricular (LV) diastolic function, which has been reported to be attenuated by regular physical activity. This study investigated the relationship between circulating matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) and echocardiographic parameters in SCI subjects and the role of physical activity in this regard. Forty-two men with SCI [19 sedentary (S-SCI) and 23 physically-active (PA-SCI)] were evaluated by clinical, anthropometric, laboratory, and echocardiographic analysis. Plasmatic pro-MMP-2, MMP-2, MMP-8, pro-MMP-9, MMP-9, TIMP-1 and TIMP-2 levels were determined by enzyme-linked immunosorbent assay and zymography. PA-SCI subjects presented lower pro-MMP-2 and pro-MMP-2/TIMP-2 levels and improved markers of LV diastolic function (lower E/Em and higher Em and E/A values) than S-SCI ones. Bivariate analysis showed that pro-MMP-2 correlated inversely with Em and directly with E/Em, while MMP-9 correlated directly with LV mass index and LV end-diastolic diameter in the whole sample. Following multiple regression analysis, pro-MMP-2, but not physical activity, remained associated with Em, while MMP-9 was associated with LV mass index in the whole sample. These findings suggest differing roles for MMPs in LV structure and function regulation and an interaction among pro-MMP-2, diastolic function and physical activity in SCI subjects.

Effects Of Pde Type 5 Inhibitors On Left Ventricular Diastolic Dysfunction In Resistant Hypertension.

Resistant hypertension (RHTN) is a multifactorial disease characterized by blood pressure (BP) levels above goal (140/90 mmHg) in spite of the concurrent use of three or more antihypertensive drugs of different classes. Moreover, it is well known that RHTN subjects have high prevalence of left ventricular diastolic dysfunction (LVDD), which leads to increased risk of heart failure progression. This review gathers data from studies evaluating the effects of phosphodiesterase-5 (PDE-5) inhibitors (administration of acute sildenafil and short-term tadalafil) on diastolic function, biochemical and hemodynamic parameters in patients with RHTN. Acute study with sildenafil treatment found that inhibition of PDE-5 improved hemodynamic parameters and diastolic relaxation. In addition, short-term study with the use of tadalafil demonstrated improvement of LVDD, cGMP and BNP-32 levels, regardless of BP reduction. No endothelial function changes were observed in the studies. The findings of acute and short-term studies revealed potential therapeutic effects of IPDE-5 drugs on LVDD in RHTN patients.A Hipertensão arterial resistente (HAR) é uma doença multifatorial caracterizada por níveis pressóricos acima das metas (140/90 mmHg), a despeito de tratamento farmacológico otimizado de 3 ou mais fármacos anti-hipertensivos de diferentes classes. Pacientes diagnosticados como hipertensos resistentes apresentam alta prevalência de disfunção diastólica do ventrículo esquerdo (DDVE) que proporciona risco aumentado para insuficiência cardíaca. Esta revisão reúne dados de estudos prévios avaliando os efeitos dos inibidores de fosfodiesterase-5 (PDE-5) (administração aguda de sildenafil e de curto prazo de tadalafil) na função diastólica e nos parâmetros bioquímicos e hemodinâmicos em pacientes com HAR. O estudo agudo com sildenafil demonstrou que a inibição da PDE-5 melhorou os parâmetros hemodinâmicos e de relaxamento diastólico. Além disso, o estudo curto prazo com o uso de tadalafil revelou melhora da DDVE e dos níveis de GMPc e BNP-32, independente de redução de pressão arterial. A função endotelial não apresentou alteração com ambos os tratamentos. Os resultados dos estudos agudo e de curto prazo sugerem efeitos terapêuticos potenciais dos fármacos inibidores da PDE-5 na disfunção diastólica em pacientes com HAR.

Evaluation of left ventricular diastolic echocardiographic parameters in healthy dogs by pulsed-wave Doppler

Left ventricular diastolic dysfunction plays an important role on heart failure progression. In order to obtain additional reference values of left ventricular diastolic parameters and investigate influence of common variables, peak E wave (peak E), peak A wave (peak A), E/A ratio (E/A), E wave deceleration time (EDT) and isovolumic relaxation time (IRVT) were studied in 40 clinically healthy dogs, by pulsed wave Doppler. The following values were obtained: peak E = 0.747 ± 0.117 m/s, peak A = 0.487 ± 0.062 m/s, E/A = 1.533 ± 0.198, EDT = 88.7 ± 9.2 ms and IRVT = 0.080 ± 0.009 s. Some parameters were influenced by heart rate (peak E, peak A and IRVT), by age (peak A and E/A) and by body weight (TRIV). Gender influence was absent. Values obtained can be used as reference for canine specimens but its interpretation should consider on the influence of related variables.

Hyperglycemia can delay left ventricular dysfunction but not autonomic damage after myocardial infarction in rodents

Background: Although clinical diabetes mellitus is obviously a high risk factor for myocardial infarction (MI), in experimental studies disagreement exists about the sensitivity to ischemic injury of an infarcted myocardium. Recently, our group demonstrated that diabetic animals presented better cardiac function recovery and cellular resistance to ischemic injury than nondiabetics. In the present study, we evaluated the chronic effects of MI on left ventricular (LV) and autonomic functions in streptozotocin (STZ) diabetic rats. Methods: Male Wistar rats were divided into 4 groups: control (C, n = 15), diabetes (D, n = 16), MI (I, n = 21), and diabetes + MI (DI, n = 30). MI was induced 15 days after diabetes (STZ) induction. Ninety days after MI, LV and autonomic functions were evaluated (8 animals each group). Left ventricular homogenates were analyzed by Western blotting to evaluate the expression of calcium handling proteins. Results: MI area was similar in infarcted groups (similar to 43%). Ejection fraction and + dP/dt were reduced in I compared with DI. End-diastolic pressure was additionally increased in I compared with DI. Compared with DI, I had increased Na(+)-Ca(2+) exchange and phospholamban expression (164%) and decreased phosphorylated phospholamban at serine(16) (65%) and threonine(17) (70%) expression. Nevertheless, diabetic groups had greater autonomic dysfunction, observed by baroreflex sensitivity and pulse interval variability reductions. Consequently, the mortality rate was increased in DI compared with I, D, and C groups. Conclusions: LV dysfunction in diabetic animals was attenuated after 90 days of myocardial infarction and was associated with a better profile of calcium handling proteins. However, this positive adaptation was not able to reduce the mortality rate of DI animals, suggesting that autonomic dysfunction is associated with increased mortality in this group. Therefore, it is possible that the better cardiac function has been transitory, and the autonomic dysfunction, more prominent in diabetic group, may lead, in the future, to the cardiovascular damage.

Mock circulatory system for the evaluation of left ventricular assist devices, endoluminal prostheses, and vascular diseases

A new digital computer mock circulatory system has been developed in order to replicate the physiologic and pathophysiologic characteristics of the human cardiovascular system. The computer performs the acquisition of pressure, flow, and temperature in an open loop system. A computer program has been developed in Labview programing environment to evaluate all these physical parameters. The acquisition system was composed of pressure, flow, and temperature sensors and also signal conditioning modules. In this study, some results of flow, cardiac frequencies, pressures, and temperature were evaluated according to physiologic ventricular states. The results were compared with literature data. In further works, performance investigations will be conducted on a ventricular assist device and endoprosthesis. Also, this device should allow for evaluation of several kinds of vascular diseases.

Single Axis Controlled Hybrid Magnetic Bearing for Left Ventricular Assist Device: Hybrid Core and Closed Magnetic Circuit

In previous studies, we presented main strategies for suspending the rotor of a mixed-flow type (centrifugal and axial) ventricular assist device (VAD), originally presented by the Institute Dante Pazzanese of Cardiology (IDPC), Brazil. Magnetic suspension is achieved by the use of a magnetic bearing architecture in which the active control is executed in only one degree of freedom, in the axial direction of the rotor. Remaining degrees of freedom, excepting the rotation, are restricted only by the attraction force between pairs of permanent magnets. This study is part of a joint project in development by IDPC and Escola Politecnica of Sao Paulo University, Brazil. This article shows advances in that project, presenting two promising solutions for magnetic bearings. One solution uses hybrid cores as electromagnetic actuators, that is, cores that combine iron and permanent magnets. The other solution uses actuators, also of hybrid type, but with the magnetic circuit closed by an iron core. After preliminary analysis, a pump prototype has been developed for each solution and has been tested. For each prototype, a brushless DC motor has been developed as the rotor driver. Each solution was evaluated by in vitro experiments and guidelines are extracted for future improvements. Tests have shown good results and demonstrated that one solution is not isolated from the other. One complements the other for the development of a single-axis-controlled, hybrid-type magnetic bearing for a mixed-flow type VAD.

Cardiac resynchronization therapy evaluated by myocardial scintigraphy with (99m)Tc-MIBI: changes in left ventricular uptake, dyssynchrony, and function

(99m)Tc-MIBI gated myocardial scintigraphy (GMS) evaluates myocyte integrity and perfusion, left ventricular (LV) dyssynchrony and function. Cardiac resynchronization therapy (CRT) may improve the clinical symptoms of heart failure (HF), but its benefits for LV function are less pronounced. We assessed whether changes in myocardial (99m)Tc-MIBI uptake after CRT are related to improvement in clinical symptoms, LV synchrony and performance, and whether GMS adds information for patient selection for CRT. A group of 30 patients with severe HF were prospectively studied before and 3 months after CRT. Variables analysed were HF functional class, QRS duration, LV ejection fraction (LVEF) by echocardiography, myocardial (99m)Tc-MIBI uptake, LV end-diastolic volume (EDV) and end-systolic volume (ESV), phase analysis LV dyssynchrony indices, and regional motion by GMS. After CRT, patients were divided into two groups according to improvement in LVEF: group 1 (12 patients) with increase in LVEF of 5 or more points, and group 2 (18 patients) without a significant increase. After CRT, both groups showed a significant improvement in HF functional class, reduced QRS width and increased septal wall (99m)Tc-MIBI uptake. Only group 1 showed favourable changes in EDV, ESV, LV dyssynchrony indices, and regional motion. Before CRT, EDV, and ESV were lower in group 1 than in group 2. Anterior and inferior wall (99m)Tc-MIBI uptakes were higher in group 1 than in group 2 (p < 0.05). EDV was the only independent predictor of an increase in LVEF (p=0.01). The optimal EDV cut-off point was 315 ml (sensitivity 89%, specificity 94%). The evaluation of EDV by GMS added information on patient selection for CRT. After CRT, LVEF increase occurred in hearts less dilated and with more normal (99m)Tc-MIBI uptake.

Reference Values of Tissue Doppler Imaging and Pulsed Doppler Echocardiography for Analysis of Left Ventricular Diastolic Function in Healthy Adults

To determine reference values for tissue Doppler imaging (TDI) and pulsed Doppler echocardiography for left ventricular diastolic function analysis in a healthy Brazilian adult population. Observations were based on a randomly selected healthy population from the city of Vitoria, Espirito Santo, Brazil. Healthy volunteers (n = 275, 61.7% women) without prior histories of cardiovascular disease underwent transthoracic echocardiography. We analyzed 175 individuals by TDI and evaluated mitral annulus E`- and A`-waves from the septum (S) and lateral wall (L) to calculate E`/A` ratios. Using pulsed Doppler echocardiography, we further analyzed the mitral E- and A-waves, E/A ratios, isovolumetric relaxation times (IRTs), and deceleration times (DTs) of 275 individuals. Pulsed Doppler mitral inflow mean values for men were as follows: E-wave: 71 +/- 16 cm/sec, A-wave: 68 +/- 15 cm/sec, IRT: 74.8 +/- 9.2 ms, DT: 206 +/- 32.3 ms, E/A ratio: 1.1 +/- 0.3. Pulsed Doppler mitral inflow mean values for women were as follows: E-wave: 76 +/- 17, A-wave: 69 +/- 14 cm/sec, IRT: 71.2 +/- 10.5 ms, DT: 197 +/- 33.3 ms, E/A ratio: 1.1 +/- 0.3. IRT and DT values were higher in men than in women (P = 0.04 and P = 0.007, respectively). TDI values in men were as follows: E`S: 11 +/- 3 cm/sec, A`S: 13 +/- 2 cm/sec, E`S/A`S: 0.89 +/- 0.2, E`L: 14 +/- 3 cm/sec, A`L: 14 +/- 2 cm/sec, E`L/A`L: 1.1 +/- 0.4. E-wave/ E`S ratio: 6.9 +/- 2.2; E-wave / E`L ratio: 4.9 +/- 1.7. In this study, we determined pulsed Doppler and TDI derived parameters for left ventricular diastolic function in a large sample of healthy Brazilian adults. (Echocardiography 2010;27:777-782).