Left Ventricular Torsion in Hypertension and Hypertensive Heart Failure　- 3-Dimensional Speckle Tracking Echocardiography Assessment.

Background: Left ventricular (LV) torsion by contraction of inner and outer oblique muscles contributes to EF. Outer muscle plays a predominant role in torsion. We evaluated the impact of LV remodeling by hypertension (HTN) on torsion using 3-dimensional speckle tracking echocardiography (3D-STE). Methods and Results: LV strain, strain rate during systole (SR-S) and torsion at endocardium, mid-wall and epicardium were assessed on 3D-STE in 53 controls and 186 HTN patients. Torsion was defined as the difference between apical and basal rotation divided by long axis length. LVEF and strain, SR-S and torsion in all 3 layers in HTN without LV hypertrophy (LVH) were similar to those in controls. LV longitudinal strain at endocardium in HTN with LVH decreased, whereas LVEF was similar to that in controls and, which was associated with increased torsion at epicardium. Reduced LVEF in hypertensive HF was associated with reduced strain, SR-S and torsion in all layers and with LV dilation. On multivariate analysis, epicardial torsion was an independent determinant of LVEF. At epicardial torsion cut-off 0.41, the sensitivity and specificity for the identification of HFrEF were 88% and 68%. Conclusions: Torsion on 3D-STE may represent a compensatory mechanism to maintain LVEF despite reduced endocardial function, suggesting that the deterioration of torsion caused by insult to outer muscle and dilation may lead to HFrEF.

Non-Invasive Pulmonary Capillary Wedge Pressure Assessment on Speckle Tracking Echocardiography as a Predictor of New-Onset Non-Valvular Atrial Fibrillation　- Four-Year Prospective Study (NIPAF Study).

BACKGROUND: Although new-onset atrial fibrillation (AF) increases with ageing, the prediction of new-onset AF is complicated. We previously reported that pulmonary capillary wedge pressure (ePCWP) estimated by the combination of left atrial volume index (LAVI) and active left atrial emptying function (aLAEF) had a strong relationship with PCWP on catheterization (r=0.92): ePCWP=10.8-12.4×log (aLAEF/minimum LAVI). We sought to determine the usefulness of ePCWP to predict new-onset AF. Methods and Results: We measured LAVI, aLAEF and ePCWP on speckle tracking echocardiography (STE) in 566 consecutive elderly patients (72±6 years) without a history of AF. A total of 63 patients (73±6 years) developed electrocardiographically confirmed AF during a mean follow-up period of 50 months. Baseline aLAEF was significantly lower in patients with than without new-onset AF (17.9±6.5 vs. 28.2±7.5%), whereas ePCWP was significantly higher (14.8±3.7 vs. 10.3±3.1 mmHg). In multivariate logistic regression analysis, ePCWP and aLAEF were strong independent predictors of AF. Using ePCWP >13 mmHg or aLAEF ≤22% on univariate Cox regression analysis, the HR for new-onset AF were 3.53 (95% CI: 1.68-7.44, P<0.001) and 4.06 (95% CI: 1.90-8.65, P<0.001), respectively. By combining these 2 criteria (>13 mmHg and ≤22%), the HR increased to 11.84 (95% CI: 6.85-20.5, P<0.001). CONCLUSIONS: ePCWP and aLAEF measured on STE are useful predictors of new-onset AF. ePCWP provides added value for risk stratification of new-onset AF.

Antimalarial proteasome inhibitor reveals collateral sensitivity from intersubunit interactions and fitness cost of resistance.

We describe noncovalent, reversible asparagine ethylenediamine (AsnEDA) inhibitors of the Plasmodium falciparum proteasome (Pf20S) ß5 subunit that spare all active subunits of human constitutive and immuno-proteasomes. The compounds are active against erythrocytic, sexual, and liver-stage parasites, against parasites resistant to current antimalarials, and against P. falciparum strains from patients in Africa. The ß5 inhibitors synergize with a ß2 inhibitor in vitro and in mice and with artemisinin. P. falciparum selected for resistance to an AsnEDA ß5 inhibitor surprisingly harbored a point mutation in the noncatalytic ß6 subunit. The ß6 mutant was resistant to the species-selective Pf20S ß5 inhibitor but remained sensitive to the species-nonselective ß5 inhibitors bortezomib and carfilzomib. Moreover, resistance to the Pf20S ß5 inhibitor was accompanied by increased sensitivity to a Pf20S ß2 inhibitor. Finally, the ß5 inhibitor-resistant mutant had a fitness cost that was exacerbated by irradiation. Thus, used in combination, multistage-active inhibitors of the Pf20S ß5 and ß2 subunits afford synergistic antimalarial activity with a potential to delay the emergence of resistance to artemisinins and each other.

Impact of tissue characteristics on luminal narrowing of mild angiographic coronary stenosis: assessment of integrated backscatter intravascular ultrasound.

Integrated backscatter intravascular ultrasound (IB-IVUS) is a useful method for analyzing coronary plaque tissue. We evaluated whether tissue composition determined using IB-IVUS is associated with the progression of stenosis in coronary angiography. Sixty-three nontarget coronary lesions in 63 patients with stable angina were evaluated using conventional IVUS and IB-IVUS. IB-IVUS images were analyzed at 1-mm intervals for a length of 10 mm. After calculating the relative areas of the tissue components using the IB-IVUS system, fibrous volume (FV) and lipid volume (LV) were calculated through integration of the slices, after which percentages of per-plaque volume (%FV/PV, %LV/PV) and per-vessel volume (%FV/VV, %LV/VV) were calculated. Progression of coronary stenosis was interpreted from the increase in percent diameter stenosis (%DS) from baseline to the follow-up period (6-9 months) using quantitative coronary angiography. %DS was 24.1 ± 12.8 % at baseline and 23.2 ± 13.7 % at follow-up. Using IB-IVUS, LV was 31.7 ± 10.5 mm(3), and %LV/PV and %LV/VV were 45.6 ± 10.3 % and 20.2 ± 6.0 %, respectively. FV, %FV/PV, and %FV/VV were 35.5 ± 12.1 mm(3), 52.1 ± 9.5 %, and 23.4 ± 7.1 %, respectively. The change in %DS was -0.88 ± 7.25 % and correlated closely with %LV/VV (r = 0.27, P = 0.03) on simple regression. Multivariate regression after adjustment for potentially confounding risk factors showed %LV/VV to be correlated independently with changes in %DS (r = 0.42, P = 0.02). Logistic regression analysis after adjusting for confounding coronary risk factors showed LV (odds ratio 1.08; 95 % confidence interval 1.01-1.16; P = 0.03) and %LV/VV (odds ratio 1.13; 95 % confidence interval 1.01-1.28; P = 0.03) to be independent predictors of the progression of angiographic coronary stenosis. Our findings suggest that angiographic luminal narrowing of the coronary artery is likely associated with tissue characteristics. IB-IVUS may provide information about the natural progression of luminal narrowing in coronary stenosis.

Comparison between integrated backscatter intravascular ultrasound and 64-slice multi-detector row computed tomography for tissue characterization and volumetric assessment of coronary plaques.

BACKGROUND: The purpose of this study was to determine the cut-off values of Hounsfield units (HU) for the discrimination of plaque components and to evaluate the feasibility of measurement of the volume of plaque components using multi-detector row computed tomography (MDCT). METHODS: Coronary lesions (125 lesions in 125 patients) were visualized by both integrated backscatter intravascular ultrasound (IB-IVUS) and 64-slice MDCT at the same site. The IB values were used as a gold standard to determine the cut off values of HU for the discrimination of plaque components. RESULTS: Plaques were classified as lipid pool (n =50), fibrosis (n =65) or calcification (n =35) by IB-IVUS. The HU of lipid pool, fibrosis and calcification were 18 ± 18 HU (-19 to 58 HU), 95 ± 24 HU (46 to 154 HU) and 378 ± 99 HU (188 to 605 HU), respectively. Using receiver operating characteristic curve analysis, a threshold of 50 HU was the optimal cutoff values to discriminate lipid pool from fibrosis. Lipid volume measured by MDCT was correlated with that measured by IB-IVUS (r =0.66, p <0.001), whereas fibrous volume was not (r =0.21, p =0.059). CONCLUSION: Lipid volume measured by MDCT was moderately correlated with that measured by IB-IVUS. MDCT may be useful for volumetric assessment of the lipid volume of coronary plaques, whereas the assessment of fibrosis volume was unstable.

Tissue characterization of coronary plaques and assessment of thickness of fibrous cap using integrated backscatter intravascular ultrasound. Comparison with histology and optical coherence tomography.

BACKGROUND: The purpose of this study was to develop a new online integrated backscatter intravascular ultrasound (IB-IVUS) system and to validate its ability to measure fibrous cap thickness by comparing IB-IVUS images with those from optical coherence tomography (OCT). METHODS AND RESULTS: Images were acquired from 125 segments of 26 coronary arteries obtained at autopsy from 11 cadavers. In the training study (n=30), 242 regions-of-interest on color-coded maps were compared with histology. In the validation study, 95 cross-sections were diagnosed by IB-IVUS and histology. In 24 patients with stable angina, 28 arterial cross-sections were imaged by IB-IVUS and OCT in vivo. In the training study, cutoff values of 39 decibels (dB) and 17dB were the optimal predictors of lipid pool/fibrosis and fibrosis/calcification, respectively, with 38-MHz mode; 42dB and 20dB, respectively, with 43-MHz mode. In the validation study, IB classified the fibrous, lipid-rich and fibrocalcific components with an accuracy of 92%, 91% and 95%, respectively. Agreement between the histological and IB-IVUS diagnoses was excellent (Cohen's κ=0.83). There was a correlation between the fibrous cap thickness measured by IB-IVUS and OCT (r=0.74, P<0.001). CONCLUSIONS: The IB-IVUS system with improved resolution provides high diagnostic accuracy for the analysis of the tissue characteristics of coronary plaques, and enables estimation of the thickness of the fibrous cap in the clinical setting.

J-SAP study 1-2: outcomes of patients with stable high-risk coronary artery disease receiving medical-preceding therapy in Japan.

BACKGROUND: Stable coronary artery disease (CAD) is classified into 2 types: high-risk (ie, 3-vessel disease, left main trunk lesions, or ostial lesions of the left anterior descending (LAD)) and low-risk (1- or 2-vessel disease other than ostial lesions of the LAD). Generally, the former is treated with coronary artery bypass grafting-preceding therapy (CABG), but not medical-preceding therapy (Medical); however, this is based on evidence from 30 years ago or more and does not reflect the recent progression of Medical and CABG. In addition, a randomized study has not been performed in Japan. METHODS AND RESULTS: In high-risk CAD, the long-term outcomes of 77 Medical patients and age-, sex-, coronary-lesion-, symptom- and risk-factor-matched 99 CABG patients were surveyed over 3 years (mean: 3.4 years) starting in 2000 at 37 nationwide hospitals. The incidences of cardiac death and cardiac death+non-fatal acute coronary syndrome (9.1% and 11.7% in Medical, and 2.0% and 3.0% in CABG, respectively) were significantly higher and the improvement in clinical symptoms was significantly lower in Medical than CABG. CONCLUSIONS: CABG is recommended in patients with high-risk CAD from the view of long-term prognosis; however, it should be remembered that the long-term outcome in Medical has considerably improved.

Outcomes of patients with stable low-risk coronary artery disease receiving medical- and PCI-preceding therapies in Japan: J-SAP study 1-1.

BACKGROUND: Stable coronary artery disease (CAD) is classified into 2 types: high-risk (ie, 3-vessel disease, left main trunk lesions, or ostial lesions of the left anterior descending (LAD)) and low-risk (1- or 2-vessel disease other than ostial lesions of the LAD), which comprise the majority of CAD patients. According to ACC/AHA/ACP-ASIM guidelines for low-risk CAD, anti-anginal agents should be initially administered to control attacks, then coronary intervention should be considered when medical therapy is not effective (medical-preceding therapy: M). In Japan, however, the initial treatment is generally percutaneous coronary intervention (PCI) combined with medical therapy (PCI-preceding therapy: P). METHODS AND RESULTS: In the present study the long-term outcomes of 190 M patients and 192 matched P patients at 34 nationwide hospitals were surveyed over 3 years (mean: 3.4 years) starting in 2000. Age, gender, initial severity of anginal symptoms, number of lesion vessels, risk factors and prescriptions were similar between the 2 groups. During the 3.4-year follow-up, additional PCI or coronary artery bypass grafting was required in 9.4% of the M group and in 33.2% of the P group. The rates of cardiac death were similar (1.6% in M and 2.6% in P). The overall rate of cardiac death and acute coronary syndrome was 2.1% in M and 4.7% in P, but the difference was not significant. The grade of anginal symptoms 12 months later was well improved in both M (1.6+/-1.4 to 0.6+/-0.9) and P (1.7+/-1.4 to 0.3+/-0.7) and there was no significant difference. Averaged annual medical cost was lower in M than in P (4.4-fold lower in the first year and 3.1-fold by the next year). CONCLUSIONS: The present study suggests that M and P for Japanese low-risk CAD may have a similar effect on long-term prognosis, but M is cheaper.

Assessment of vulnerable plaques causing acute coronary syndrome using integrated backscatter intravascular ultrasound.

OBJECTIVES: This study aims to define tissue characteristics of vulnerable plaques before acute coronary syndrome (ACS) by use of integrated backscatter intravascular ultrasound (IB-IVUS). BACKGROUND: Tissue characterization of coronary plaques is possible with the use of IB-IVUS. METHODS: The subjects were 140 patients with angina pectoris, and we selected 160 coronary lesions without significant stenosis for evaluation. Ultrasound signals were obtained by an IVUS system using a 40-MHz catheter. RESULTS: At the follow-up (30 +/- 7 months), 12 plaques caused ACS after the initial IVUS examination. Ten of the 12 plaques had IVUS parameters recorded at baseline. These 10 plaques were classified as vulnerable plaques (VP), and the other plaques were classified as stable plaques (SP; n = 143). There was no significant difference of vessel area, lumen area, and plaque area between VP and SP. However, plaque burden (60 +/- 9% vs. 52 +/- 9%; p = 0.014), eccentricity (0.70 +/- 0.10 vs. 0.55 +/- 0.17; p = 0.013), remodeling index (1.30 +/- 0.08 vs. 1.16 +/- 0.16; p = 0.006) and percentage lipid area (72 +/- 10% vs. 50 +/- 16%; p < 0.0001) were greater in VP than in SP. Percentage fibrous area (23 +/- 6% vs. 47 +/- 14%; p < 0.0001) was smaller in VP than in SP. The sensitivities, specificities, and positive predictive values of percentage fibrous area (90%, 96%, and 69%, respectively) and percentage lipid area (80%, 90%, and 42%, respectively) for classifying VP were evaluated. CONCLUSIONS: Tissue characteristics of VP before ACS were different from those of SP. This suggests that VP and SP as classified by IB-IVUS are useful in predicting ACS.

Assessment of arterial medial characteristics in human carotid arteries using integrated backscatter ultrasound and its histological implications.

Recently, ultrasound tissue characterization of the carotid arteries with an integrated backscatter (IB) analysis was shown to identify a high-risk group of atherosclerosis. To clarify whether IB ultrasound is useful in assessing arterial sclerosis as well as stiffness beta and whether IB values reflect the histological structure, we measured IB values of common carotid media in 52 subjects without coronary risk factors and in 10 patients with systemic sclerosis (SSc) in the clinical studies and 12 patients in the histological studies with a Philips Medical Systems Sonos 5500. IB values were correlated with age (r=0.69, P<0.0001), intima-media thickness (r=0.72, P<0.0001) and stiffness beta (r=0.80, P<0.0001) in the control subjects. IB values and stiffness beta in the SSc group were greater than in an age- and sex-matched control group (IB values: 9.6+/-2.7dB versus 16.1+/-1.8dB; stiffness beta: 11.5+/-4.5 versus 20.6+/-5.6, P<0.01). IB values of the media were correlated with the elastic fragmentation index (r=0.63, P=0.029) and the collagen fiber index (r=0.59, P=0.046). Measurements of IB values of carotid media are useful for non-invasively evaluating arterial sclerosis.