Plasma Globotriaosylsphingosine and α-Galactosidase A Activity as a Combined Screening Biomarker for Fabry Disease in a Large Japanese Cohort.

Fabry disease is an X-linked disorder of α-galactosidase A (GLA) deficiency. Our previous interim analysis (1 July 2014 to 31 December 2015) revealed plasma globotriaosylsphingosine as a promising primary screening biomarker for Fabry disease probands. Herein, we report the final results, including patients enrolled from 1 January to 31 December 2016 for evaluating the potential of plasma globotriaosylsphingosine and GLA activity as a combined screening marker. We screened 5691 patients (3439 males) referred from 237 Japanese specialty clinics based on clinical findings suggestive of Fabry disease using plasma globotriaosylsphingosine and GLA activity as primary screening markers, and GLA variant status as a secondary screening marker. Of the 14 males who tested positive in the globotriaosylsphingosine screen (≥2.0 ng/mL), 11 with low GLA activity (<4.0 nmol/h/mL) displayed GLA variants (four classic, seven late-onset) and one with normal GLA activity and no pathogenic variant displayed lamellar bodies in affected organs, indicating late-onset biopsy-proven Fabry disease. Of the 19 females who tested positive in the globotriaosylsphingosine screen, eight with low GLA activity displayed GLA variants (six classic, two late-onset) and five with normal GLA activity displayed a GLA variant (one classic) and no pathogenic variant (four late-onset biopsy-proven). The combination of plasma globotriaosylsphingosine and GLA activity can be a primary screening biomarker for classic, late-onset, and late-onset biopsy-proven Fabry disease probands.

Coronary flow velocity pattern assessed noninvasively by transthoracic color Doppler echocardiography serves as a predictor of adverse cardiac events and left ventricular remodeling in patients with acute myocardial infarction.

BACKGROUND: Quantitative assessment of microvascular injury is possible in patients with reperfused anterior myocardial infarction by invasive method. Coronary flow velocity patterns can also be assessed by transthoracic color Doppler echocardiography (TTCDE). OBJECTIVES: The purpose of this study was to determine whether the coronary flow velocity pattern assessed by TTCDE serves as a predictor of adverse cardiac events and left ventricular remodeling. METHODS: The study population consisted of 64 consecutive patients. We could analyze coronary flow velocity patterns by TTCDE in 59 of 64 patients (92%) after coronary intervention. The patients were followed up for the occurrence of complications and underwent serial measurement of left ventricular volumes. RESULTS: In patients with a short deceleration time of diastolic flow velocity, the frequency of adverse cardiac events and left ventricular remodeling was higher. CONCLUSION: It is possible to predict clinical outcome by assessing coronary flow velocity pattern by TTCDE.

Transthoracic Doppler echocardiographic assessment of coronary flow velocity pattern in patient with acute myocardial infarction implies progression of myocardial damage.

BACKGROUND: Coronary flow velocity (CFV) pattern with a rapid deceleration time of diastolic flow velocity and small average systolic peak velocity immediately after reperfusion implies poor wall-motion recovery in patients with acute myocardial infarction. Microvascular injury has been demonstrated to progress after coronary reperfusion. The purpose of this study was to assess whether CFV 1 day after reperfusion (day 1) may reflect accurately the degree of myocardial damage. METHODS: In the left anterior descending coronary artery in 29 patients with anterior acute myocardial infarction, CFV was measured immediately and 1 day after recanalization using transthoracic Doppler echocardiography, respectively. Regional wall motion was estimated as anterior wall-motion score index (AWMSI) by echocardiography before recanalization and 1 month after the onset of acute myocardial infarction. RESULTS: Although significant correlation was observed among deceleration time of diastolic flow velocity, average systolic peak velocity, and average peak velocity immediately after reperfusion and 1-month AWMSI (r = -0.62, P < .001; r = -0.61, P < .001; and r = -0.55, P < .01, respectively), much better correlation was demonstrated between those at day 1 and 1-month AWMSI (r = -0.72, P < .0001; r = -0.68, P < .0001; and r = -0.60, P < .001, respectively). Deceleration time of diastolic flow velocity, average systolic peak velocity, and average peak velocity in poor wall-motion recovery group (1-month AWMSI > 2.0, n = 14) were significantly smaller (P < .01, P < .05, and P < .05, respectively) at day 1 compared with those immediately after reperfusion. CONCLUSIONS: CFV pattern assessed by transthoracic Doppler echocardiography at day 1 provides the degree of myocardial damage much more accurately than that immediately after reperfusion. These results may suggest that myocardial damage progresses after reperfusion.

Left atrial volume and the risk of paroxysmal atrial fibrillation in patients with hypertrophic cardiomyopathy.

Paroxysmal atrial fibrillation (PAF) is a common complication of patients with hypertrophic cardiomyopathy, often leading to acute or progressive heart failure and cerebral infarction. We assessed the echocardiographic data of 141 consecutive patients with hypertrophic cardiomyopathy, with and without PAF. In all, 31 patients (22%) had a history of PAF with spontaneous conversion to in sinus rhythm. Left atrial volume and left atrial volume indexed to body surface area were significantly increased for patients with PAF compared with those without PAF. Maximum left atrial volume was the most sensitive and specific parameter for the occurrence of PAF in patients with hypertrophic cardiomyopathy.

Prognosis of retrograde dissection from the descending to the ascending aorta.

BACKGROUND: Natural history of aortic dissection (AD) with intimal tear in the descending or abdominal aorta and retrograde extension into the ascending aorta (retrograde AD) remains unknown. The purpose of this study was to elucidate medium-term prognosis of patients with retrograde AD. METHODS AND RESULTS: Study population consisted of 109 patients with acute type A AD. There were 27 patients (25%) with retrograde AD and 82 patients (75%) with intimal tear in the ascending aorta (antegrade AD). In antegrade AD patients, 60 patients underwent surgery and 22 patients were treated medically. In retrograde AD patients, 14 patients showed localized crescentic high attenuation area along the ascending aortic wall without enhancement in computed tomography. Transesophageal echocardiography revealed complete thrombosis of false lumen (FL) in the ascending aorta (retrograde thrombosed). The remaining 13 patients showed incomplete or no thrombosis (retrograde nonthrombosed). All retrograde nonthrombosed AD patients underwent surgery except for 1 patient with stroke, whereas all retrograde thrombosed AD patients were treated medically. In-hospital mortality rate of retrograde AD patients was significantly lower than that of antegrade AD patients (15% versus 38%, P=0.027). The survival rates in retrograde AD patients were all 85% at 1, 2, and 5 years, which were significantly higher than those of antegrade AD patients (63%, 62%, and 57%, respectively)(P=0.009). CONCLUSIONS: Patients with type A retrograde AD have better medium-term prognosis than patients with antegrade AD. Retrograde AD patients with thrombosed FL in the ascending aorta could be treated medically with timed surgical repair.

Long-term prognosis of patients with type B aortic intramural hematoma.

BACKGROUND: The long-term clinical course of patients with type B aortic intramural hematoma (IMH) and predictors for progression remains unknown. The difference of aortic pathology may have a different impact on clinical course compared with classic aortic dissection (AD). The purpose of this study was to investigate long-term clinical course and predictors of progression in patients with type B IMH. METHODS AND RESULTS: Clinical data were compared retrospectively between 53 patients with acute type B IMH (IMH group) and 57 patients with acute type B AD (AD group). All patients were treated initially with medical therapy. Two patients in IMH group and 14 patients in AD group underwent surgical repair because of aortic enlargement. The in-hospital mortality rate in IMH group was significantly lower than that in AD group (0% and 14%, P=0.006). Mean follow-up periods were 53+/-43 months, which revealed 3 and 5 late deaths, respectively. Eleven patients with IMH showed progression (development of aortic dissection or aortic enlargement) in follow-up imaging study. The actuarial survival rates in IMH group were 100%, 97%, and 97% at 1, 2, and 5 years, which were significantly higher than those in AD group (83%, 79%, and 79%) (P=0.009). Multivariate analysis identified age >70 years and new appearance of an ulcerlike projection as the strongest predictors of progression in patients with IMH. CONCLUSIONS: Patients with type B IMH have better long-term prognosis than patients with AD. Older age and appearance of an ulcerlike projection are predictive for progression in patients with type B IMH.

Noninvasive assessment of flow velocity and flow velocity reserve in the right gastroepiploic artery graft by transcutaneous Doppler echocardiography: comparison with an invasive technique.

BACKGROUND: The measurement of flow velocity (FV) in coronary artery bypass grafts using a Doppler guidewire has provided useful clinical and physiologic information. The recently developed transcutaneous Doppler echocardiography is a noninvasive technique to measure FV and FV reserve (FVR) in the right gastroepiploic artery (GEA) graft. The purpose of this study was to evaluate whether transcutaneous Doppler echocardiography accurately measures FV and FVR in the right GEA graft in a clinical setting. METHODS: In 33 patients who underwent graft angiography for the assessment of the right GEA graft, FV in the right GEA graft was measured by transcutaneous Doppler echocardiography under the guidance of color flow Doppler imaging at the time of examination using a Doppler guidewire. FV in the midportion of the right GEA graft was measured at baseline and during hyperemic conditions using both transcutaneous Doppler echocardiography and a Doppler guidewire. RESULTS: There were excellent correlations between the value of FV obtained by transcutaneous Doppler echocardiography and those obtained with the Doppler guidewire (averaged peak velocity: y = 0.95 x + 1.46, r = 0.98, standard error of the estimate [SEE] = 2.94 cm/s; averaged systolic peak velocity: y = 0.94 x + 1.18, r = 0.97, SEE = 3.15 cm/s; diastolic peak velocity: y = 0.97 x + 1.62, r = 0.98, SEE = 4.40 cm/s; averaged diastolic peak velocity: y = 0.95 x + 1.75, r = 0.98, SEE = 3.60 cm/s). The FVR as determined by transcutaneous Doppler echocardiography showed a good correlation with that determined using the Doppler guidewire method (y = 0.90 x + 0.21, r = 0.92, SEE = 0.31). CONCLUSIONS: Transcutaneous Doppler echocardiography proved to be an accurate noninvasive method to measure FV and FVR in the right GEA graft.

Pioglitazone reduces neointimal tissue proliferation after coronary stent implantation in patients with type 2 diabetes mellitus: an intravascular ultrasound scanning study.

BACKGROUND: It has been reported that pioglitazone reduces neointimal hyperplasia after balloon-induced vascular injury in an experimental model. METHODS: To determine whether pioglitazone reduces neointimal tissue proliferation after coronary stent implantation in patients with type 2 diabetes mellitus, we studied 44 stented lesions in 44 patients with diabetes mellitus who underwent successful coronary stent implantation. Study patients were randomized into 2 groups: the pioglitazone group (23 patients with 23 lesions) and the control group (21 patients with 21 lesions). All patients underwent serial quantitative coronary angiography and serial intravascular ultrasound scanning studies. With a motorized pullback system, multiple image slices within the stent were obtained at every 1 mm. The stent area and lumen area were measured, and the neointimal area was calculated. Measurements were averaged over the number of selected image slices. The neointimal index was calculated as the averaged neointimal area divided by the averaged stent area multiplied by 100 (%). RESULTS: After 6 months of treatment, angiographic in-stent restenosis (17% vs 43%, respectively, P =.0994) and target lesion revascularization (13% vs 38%, respectively, P =.0835) were less frequent in the pioglitazone group than the control group; however, these differences did not reach significance. The intravascular ultrasound scanning study demonstrated that the neointimal index in the pioglitazone group was significantly smaller than that in the control group (28% +/- 9% vs 48% +/- 15%, respectively, P <.0001). CONCLUSION: A serial intravascular ultrasound scanning assessment demonstrated that pioglitazone reduces neointimal tissue proliferation after coronary stent implantation in patients with type 2 diabetes mellitus.

Potentiality of double liposomes containing salmon calcitonin as an oral dosage form.

The hypocalcemic effects of salmon calcitonin (SCT) after oral administration in rats by means of SCT-loading double liposomes (DL) which consist of liposomes containing small liposomes were investigated. SCT-loading DL consisted of four types of the inner liposomes such as neutral liposomes (NL) and cationic charged liposomes (CL) prepared using Coatsome, and neutral (VET) and cationic charged (c-VET) liposomes prepared using a mechanochemical method and sizing to 100 nm by the extrusion procedure were prepared. DL could be prepared by a combination of mechanochemical and glass-beads methods at a high efficiency. DL produced the increase in bioavailability in all groups treated with SCT-loading liposomes except for c-VET. The bioavailability of VET-DL was not significantly different but the greatest among the samples used in this study regardless of the similar size of NL-DL and CL-DL, and was approx. 6.8-fold higher than that of SCT solution when taken orally. The group treated with c-VET showed the strongest hypocalcemic effects among the inner liposomes examined (P>0.05). Therefore, it is speculated that not only the size of liposomes but also the cationic charge plays an important role in the intestinal absorption of DL. These findings suggested the utility of DL as an oral dosage form of SCT.

In vitro characteristics of liposomes and double liposomes prepared using a novel glass beads method.

A novel preparative method for liposomes and double liposomes (DL) using glass beads was superior to a glass-filter method developed previously. Lipid dissolved in chloroform was poured into a kjeldahl flask with glass beads (BZ-04, 0.350-0.500 mm phi; BZ-3, 2.794-3.962 mm phi; or BZ-6, 5.613-6.680 mm phi), and the organic solvent was evaporated. The lipid layer that formed on the glass beads was hydrated with 1.5 ml of the suspension of inner liposomes at a temperature above the phase transition temperature of the lipids employed, and was agitated vigorously. Erythrosine (ER) was used as a model drug. The size of liposomes prepared by the glass beads method depended on the size of the glass beads. The size of the liposomes became smaller as glass beads with a smaller size were used. A high encapsulation efficiency was observed when glass bead blends consisting of two different sizes were used. Large sizes (BZ-3/BZ-6) had a tendency to show high encapsulation efficiency and size also played an important role in the formation of liposomes. DL formation inhibited the release of ER and DL formative efficiency was markedly improved by means of the glass beads method. These findings suggested that the glass beads method developed in this study conferred a high drug loading and a high DL formation on liposomes compared with ordinary methods.

[Assessment of the clinical feasibility of OptiGo for hand-held echocardiography].

OBJECTIVES: Hand-held ultrasound devices are becoming available for clinical examination, but the accuracy and precision of such devices are unclear. This study compared the accuracy of a hand-held echo device to a standard echo system. METHODS: Twenty-two patients were examined with the OptiGo (Phillips Medial Systems) hand-held ultrasound system with a 2.5 MHz transducer and SONOS 5500 (Phillips Medial Systems) standard ultrasound system with a 2 to 4 MHz wideband transducer. Patients with cardiac arrhythmia and tachycardia were excluded. Image quality, chamber size (left ventricle, left atrium), global and regional left ventricular function, valve morphology and severity of valve regurgitation were assessed. RESULTS: There was good agreement between the two imaging devices for image quality (77.3%), left ventricular ejection fraction (90.5%), regional wall motion score (> 90%), valve morphology (> 90%), severity of valve regurgitation (> 81.0%) and there was good correlation and agreement for left ventricular and left atrial size. CONCLUSIONS: Although the OptiGo has limitations, the hand-held examination appropriately estimates global and regional left ventricular function, valve morphology, valve regurgitation and chamber size.

Coronary flow velocity pattern immediately after percutaneous coronary intervention as a predictor of complications and in-hospital survival after acute myocardial infarction.

BACKGROUND: Recently, it was reported that the degree of microvascular injury and left ventricular functional recovery during the chronic period can be predicted after treatment of the infarct-related artery based on the coronary flow velocity (CFV) pattern assessed using a Doppler guidewire. The aim of this prospective study was to examine whether the CFV pattern may predict complications and in-hospital survival after acute myocardial infarction (AMI). METHODS AND RESULTS: The study population consisted of 169 consecutive patients with a first anterior AMI successfully treated with percutaneous coronary intervention (PCI). We examined the CFV pattern immediately after PCI using a Doppler guidewire. In accordance with previous findings, we defined severe microvascular injury as a diastolic deceleration time < or =600 ms and the presence of systolic flow reversal. Patients were divided into two groups: those without severe microvascular injury (n=118; group 1) and those with severe microvascular injury (n=51; group 2). All of the patients who had cardiac rupture were in group 2. Congestive heart failure (CHF) was observed more frequently in group 2 than in group 1 (53% versus 8%, P<0.001). The in-hospital cardiac mortality rate was significantly higher in group 2 than in group 1 (18% versus 0%, P<0.001). Nine patients in group 2 died, 5 patients because of CHF and 4 patients because of cardiac rupture. CONCLUSIONS: These findings suggest that the CFV pattern is an accurate predictor of the presence or absence of complications and of in-hospital survival after AMI.

Effects of microvascular dysfunction on myocardial fractional flow reserve after percutaneous coronary intervention in patients with acute myocardial infarction.

Fractional flow reserve (FFR) has emerged as a lesion-specific index of the functional severity of coronary stenosis in patients with chronic coronary artery disease. As the coronary blood flow in acute myocardial infarction (AMI) patients with microvascular damage is restricted, the pressure drop across the stenosis during hyperemia may be smaller than expected. However, the effects of microvascular dysfunction on FFR in AMI patients remain undetermined. The study comprised 33 AMI patients who underwent coronary stenting within 12 hr of onset, and 15 patients with stable angina pectoris who underwent elective stenting. Assessment of the 48 lesions by means of intravascular ultrasound and pressure measurements after stenting showed that postinterventional FFR was higher in AMI than angina pectoris patients (0.95 +/- 0.04 vs. 0.90 +/- 0.04; P = 0.002), although there were no significant differences in intravascular ultrasound parameters. AMI patients were divided into two subgroups based on their postprocedural Thrombolysis on Myocardial Infarction (TIMI) flow grade (23 patients with TIMI 3 and 10 with TIMI 2). There were no differences in intravascular ultrasound parameters between the AMI subgroups, while FFR was greater in the patients with TIMI 2 than in those with TIMI 3 (0.98 +/- 0.02 vs. 0.93 +/- 0.05; P = 0.017). No significant correlation was found between FFR and intravascular ultrasound parameters in either AMI subgroup, while FFR of more than 0.94 was observed in all TIMI 2 cases independent of residual stenosis severity. We conclude that in patients with marked microvascular dysfunction, FFR may not be reliable for the assessment of coronary lesion severity and may underestimate coronary lesion severity.