Distinctive left ventricular-arterial and right ventricular-pulmonary arterial coupling observed in patients with heart failure and a higher left ventricular ejection fraction range.

AIMS: Higher left ventricular (LV) ejection fraction (EF) is related to unfavourable prognosis in patients with heart failure (HF) with preserved ejection fraction (HFpEF). The cause of this finding needs to be haemodynamically explained. Thus, we investigated this crucial issue from the perspective of LV-arterial (A) and right ventricular (RV)-pulmonary arterial (PA) coupling. METHODS AND RESULTS: Study patients were derived from our prospective cohort study of patients hospitalized due to acute decompensated HF and LVEF > 40%. We divided the 255 patients into three groups: HF with mildly reduced EF (HFmrEF), HFpEF with 50% ≤ LVEF < 60%, and HFpEF with LVEF ≥ 60%. We compared LV end-systolic elastance (Ees), effective arterial elastance (Ea), and Ees/Ea as a representative of LV-A coupling among groups and compared the ratio of tricuspid annular plane excursion to peak pulmonary arterial systolic pressure (TAPSE/PASP) as a representative of RV-PA coupling. All-cause death and readmission due to HF-free survival was worse in the group with a higher LVEF range. Ees/Ea was greater in HFpEF patients with LVEF ≥ 60% (2.12 ± 0.57) than in those with 50% ≤ LVEF < 60% (1.20 ± 0.14) and those with HFmrEF (0.82 ± 0.09) (P < 0.001). PASP was increased in the groups with higher LVEF; however, TAPSE/PASP did not differ among groups (n = 168, P = 0.17). In a multivariate Cox proportional hazard model, TAPSE/PASP but not PASP was significantly related to event-free survival independent of LVEF. CONCLUSION: HFpEF patients with higher LVEF have unfavourable prognosis and distinctive LV-A coupling: Ees/Ea is elevated up to 2.0 or more. Impaired RV-PA coupling also worsens prognosis in such patients. CLINICAL TRIAL REGISTRATION: URL: https://www.umin.ac.jp/ctr/index.htm Unique identifier: UMIN000017725.

The differences between conventional lead, thin lead, and leadless pacemakers regarding effects on tricuspid regurgitation in the early phase.

PURPOSE: Trans-venous pacemaker leads are associated with worsening of tricuspid regurgitation (TR) after pacemaker implantation (PMI) in some cases. Recently, leadless pacemakers and thin ventricular pacemaker leads without a stylet lumen have become popular. However, the differences in the effects of these leads on TR are unclear. We investigated differences in the changes in TR in the early phase after PMI in patients with conventional leads, thin leads, and leadless pacemakers. METHODS: We enrolled 65 patients who underwent PMI (32 males, 79 ± 8 years), including 48 with trans-venous PMI (29 with conventional 6.0-Fr leads and 19 with 4.1-Fr thin leads) and 17 with leadless pacemakers. Transthoracic echocardiography was performed before and 1 month after PMI for assessment of conventional echocardiographic parameters and severity of TR by quantitative assessment. RESULTS: Atrial fibrillation was the most frequent indication for PMI in patients with leadless pacemakers (p = 0.015). In the before and 1 month after PMI comparison, left ventricular ejection fraction decreased after PMI only in the conventional lead group (p = 0.022). The TR effective regurgitant orifice area (EROA) decreased post PMI in the leadless (p = 0.002) and thin lead groups (p = 0.001), but not in the conventional lead group (p = 0.596). The change in TR EROA was greater in the leadless and thin lead groups as compared with the conventional lead group (p < 0.05). CONCLUSION: The decrease in TR EROA in the early phase after PMI differed according to the type of pacemaker lead. The thin lead might be beneficial for reduction of TR after PMI.

Unfavourable outcomes in patients with heart failure with higher preserved left ventricular ejection fraction.

AIMS: Newly introduced drugs for heart failure (HF) have been reported to improve the prognosis of HF with preserved ejection fraction (HFpEF) in the lower range of left ventricular ejection fraction (LVEF). We hypothesized that a higher LVEF is related to an unfavourable prognosis in patients with HFpEF. METHODS AND RESULTS: We tested this hypothesis by analysing the data from a prospective multicentre cohort study in 255 patients admitted to the hospital due to decompensated HF (LVEF > 40% at discharge). The primary endpoint of this study was a composite outcome of all-cause death and readmission due to HF, and the secondary endpoint was readmission due to HF. LVEF and the mitral E/e' ratio were measured using echocardiography. In multicovariate parametric survival time analysis, LVEF [hazard ratio (HR) = 1.046 per 1% increase, P = 0.001], concurrent atrial fibrillation (AF) (HR = 3.203, P < 0.001), and E/e' (HR = 1.083 per 1.0 increase, P < 0.001) were significantly correlated with the primary endpoint. In addition to these covariates, angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) use was significantly correlated with the secondary endpoint (HR = 0.451, P = 0.008). Diagnostic performance plot analysis demonstrated that the discrimination threshold value for LVEF that could identify patients prone to reaching the primary endpoint was ≥57.2%. The prevalence of AF or E/e' ratio did not differ significantly between patients with LVEF ≥ 58% and with 40% < LVEF < 58%. CONCLUSION: A higher LVEF is independently related to poor prognosis in patients with HFpEF, in addition to concurrent AF and an elevated E/e' ratio. ACEI/ARB use, in contrast, was associated with improved prognosis, especially with regard to readmission due to HF. CLINICAL TRIAL REGISTRATION: https://www.umin.ac.jp/ctr/index.htm. UNIQUE IDENTIFIER: UMIN000017725.

Clinical utility of reticulocyte hemoglobin equivalent in patients with heart failure.

Anemia and iron deficiency (ID) are common in patients with heart failure (HF) and intravenous (IV) administration of iron to patients hospitalized for decompensated HF with ID improves outcome. The diagnosis of ID in routine practice is based on serum ferritin and transferrin saturation (TSAT) but both have limitations; alternatives should be considered. Reticulocyte hemoglobin equivalent (Ret-He) reflects iron content in reticulocytes but its clinical utility in patients with HF remains uncertain. We prospectively enrolled 142 patients hospitalized for decompensated HF. Sixty five percent had ID as defined in current international guidelines. Ret-He was directly correlated with serum iron and ferritin concentrations and with TSAT. There was a poor relationship between quartile of Ret-He and HF hospitalization or death but increases or decreases in Ret-He between admission and discharge were associated with a worse outcome. The clinical utility of Ret-He for identifying ID and predicting response to IV iron and prognosis for patients with HF requires further investigation.

Effect of Oral Qing-Dai Medication on Pulmonary Arterial Pressure Levels in Patients With Ulcerative Colitis.

BACKGROUND: Qing-Dai (QD) treatment of patients with ulcerative colitis (UC) sometimes causes pulmonary arterial hypertension (PAH). However, the relationship of QD treatment to pulmonary arterial systolic pressure (PASP) in patients with UC has not been clarified.Methods and Results:The 27 patients with UC who were screened for PAH by transthoracic echocardiography (TTE) and underwent repeat TTE at 1 year were analyzed in this prospective observational study. Mean age was 44.0 years old, and median follow-up duration was 392. During the follow-up, 21 patients continued QD treatment (continuous group) and 6 patients discontinued the treatment (discontinuous group). In all patients, no significant difference in PASP levels between baseline and at follow-up was observed (21.4 vs. 21.3 mmHg, P=0.802). Furthermore, the mean PASP of patients in the continuous group did not differ from baseline to follow-up (21.4 mmHg to 22.6 mmHg, P=0.212); however, in the discontinuous group mean PASP was significantly decreased (21.5 mmHg to 16.8 mmHg, P=0.005). Moreover, changes in PASP from baseline to follow-up differed between the continuous and discontinuous groups (+1.1 mmHg vs. -4.7 mmHg, P=0.004). In addition, multivariable analyses revealed that only the duration of oral QD at baseline affected the increase of PASP. CONCLUSIONS: In patients with UC, QD treatment may have an undesirable association with an increase in PASP.

Clinical Significance and Prognostic Value of Novel Echocardiographic Index for the Severity of Mitral Regurgitation.

Background: Recently, the left ventricular early inflow-outflow index (LVEIO), calculated by dividing mitral E-wave velocity by the left ventricular outflow velocity time integral, has been proposed as a simple method for evaluating mitral regurgitation (MR). This study determined the optimal LVEIO threshold to assess severe MR with different etiologies and assessed its prognostic value. Methods and Results: The records of 18,692 consecutive patients who underwent echocardiography were reviewed. MR was classified into 4 groups: Grade 0/1, no, trivial, or mild MR; Grade 2, moderate MR; Grade 3, moderate to severe MR; and Grade 4, severe MR. The mean (±SD) LVEIO of Grades 0/1, 2, 3, and 4 was 3.6±1.4, 6.0±2.5, 7.4±3.1, and 9.5±2.8, respectively. An optimal LVEIO threshold of 5.4 was determined to distinguish moderate to severe or severe MR from non-severe MR (sensitivity 84%, specificity 91%). Kaplan-Meier survival analysis revealed high mortality in the group with LVEIO ≥5.4 (P=0.009, hazard ratio 1.833). This was found only in primary MR when separate analyses were performed according to etiology. Multivariate analysis revealed that LVEIO was an independent predictor for all-cause death only in primary MR. Conclusions: Using appropriate thresholds, LVEIO is a simple and useful method to diagnose severe MR regardless of etiology. LVEIO can also be useful for predicting prognosis in primary MR.

Serial changes of L wave according to heart rates in a heart failure patient with persistent atrial fibrillation.

Mid-diastolic forward flow velocity of transmitral flow (L wave) is known as a marker of diastolic dysfunction and is occasionally observed in patients with fluid retention, low heart rate, and atrial fibrillation (AF). However, how hemodynamic condition affects L wave is still unknown. An 81-year-old woman who underwent implantation of a DDD pacemaker due to complete atrioventricular block 38 years previously suffered from congestive heart failure and was admitted to our hospital. At the time of admission, electrocardiogram showed new-onset AF resulting in mode switch to VVI, and echocardiography showed a giant L wave. At the mid-term of the treatment, AF was converted to sinus rhythm resulting in mode switch to DDD, and pacemaker check-up was performed at pre- and post-cardioversion. During the pacemaker check-ups, L wave was assessed in various pacing rates. As pacing rate was increased, L wave altered according to heart rates and disappeared at 85 bpm in VVI with AF, whereas at 75 bpm in DDD. Through the treatment, L wave got smaller as fluid retention was improved and finally disappeared at the time of discharge. This case suggests that L wave is highly variable and affected by fluid volume, heart rate, and heart rhythm. .

Prognostic Value of Time Interval Between Mitral and Tricuspid Valve Opening in Patients With Heart Failure.

BACKGROUND: We used dual Doppler echocardiography to measure the time interval between the mitral and tricuspid valve opening (MO-TO time), which we expected would reflect the balance between left and right ventricular hemodynamics. Methods and Results: We prospectively enrolled 60 patients with heart failure (HF) and sinus rhythm. The MO-TO time was measured in addition to routine echocardiography parameters, invasive hemodynamic parameters and plasma B-type natriuretic peptide (BNP) level in all patients. Patients were divided into 2 groups based on the MO-TO time: MOP (mitral opening preceding tricuspid opening), and TOP (tricuspid opening preceding mitral opening) groups. We followed up the predefined adverse outcomes (cardiovascular [CV] death and hospitalization due to worsening HF) for 1 year. Pulmonary artery wedge pressure (PAWP) and mean pulmonary artery pressure (mPAP) were higher in the MOP than in the TOP group (P<0.001; P<0.001, respectively). The probability of an adverse CV outcome was higher in the MOP than in the TOP group (log-rank test; P=0.002). Addition of MOP improved the predictive power of univariate predictors (mitral E/A ratio and BNP) in the bivariate Cox analysis (P=0.017, P=0.024, respectively). CONCLUSIONS: MOP reflects pulmonary hypertension caused by left heart disease and has prognostic value in predicting adverse CV events in patients with HF.

Correlates and Prognostic Values of Appearance of L Wave in Heart Failure Patients With Preserved vs. Reduced Ejection Fraction.

BACKGROUND: Mid-diastolic mitral forward flow (L wave) is occasionally detected in heart failure (HF), but its correlates and prognostic value are still unknown, particularly in light of the type of HF, that is, HF with preserved or with reduced ejection fraction (HFpEF, HFrEF). Methods and Results: Of 151 patients with HF, L wave was observed in 23 of 82 HFrEF patients and in 25 of 69 HFpEF patients. Mitral early diastolic velocity (E), the ratio of E to mitral annulus velocity, and left atrial volume index were greater in the patients with L wave than in those without L wave in both subsets. Left ventricular (LV) mass index and relative wall thickness were greater in the patients with L wave than in those without L wave in the HFpEF group, but there was no difference in either parameter in the HFrEF group. Prognosis was poorer in those with L wave than in those without L wave both in the HFrEF and HFpEF groups. CONCLUSIONS: Appearance of L wave is associated with the degree of LV diastolic dysfunction, but there was a difference in LV geometrical correlates of the appearance of L wave between the HFpEF and HFrEF groups. Detection of L wave is suggestive of poor prognosis independent of LVEF in HF.

Interatrial septal motion as a novel index to predict left atrial pressure.

We investigated whether the interatrial septal (IAS) motion of each heartbeat which is observed by transesophageal echocardiography reflects left atrial pressure (LAP) in patients with atrial fibrillation (AF). We studied 100 patients (70 males, age 67 ± 9 years) who underwent catheter ablation for AF. The amplitude of IAS motion was measured using M-mode and averaged for five cardiac cycles. Left and right atrial pressures, the left to right atrial pressure gradient were directly measured during the catheter ablation. In patients with sinus rhythm during measurement, elevated mean LAP, larger maximum left to right atrial pressure gradient, and greater left atrial emptying fraction were associated with IAS motion. The optimal cut-off value of the IAS motion for predicting high LAP (mean LAP > 15 mmHg) was 8.5 mm (sensitivity 100%, specificity 70.1%) in patients with sinus rhythm during pressure measurement. In addition, all patients were divided into 6 groups based on rhythm during measurement and cutoff value of IAS motion. In patients with sinus rhythm during measurement, low IAS motion group had a highest prevalence of elevated LAP compared with high IAS motion group (64 vs. 0%, P < 0.0001). The amplitude of interatrial septal motion during sinus rhythm reflects left atrial pressure in patients with atrial fibrillation. Interatrial septal motion could be a new index to predict elevated left atrial pressure.

Prognostic value of diastolic wall strain in patients with chronic heart failure with reduced ejection fraction.

Left ventricular (LV) diastolic dysfunction plays a crucial role in heart failure with reduced ejection fraction (HFrEF). LV stiffness is a main component of diastolic function, but its role and prognostic value in HFrEF patients remains unclear. This study aimed to determine whether diastolic wall strain (DWS) as a noninvasive and simple marker of LV stiffness can predict the prognosis of HFrEF patients who were administrated chronic beta blockade enough. We enrolled 75 HFrEF patients who were administrated chronic beta blockade. We evaluated the echocardiographic parameters and plasma brain natriuretic peptide (BNP) before the induction of beta blockade and also obtained pulmonary artery wedge pressure (PAWP) from the right heart catheterization. DWS was obtained from standard M-mode echocardiography as follows: DWS = [(LV posterior wall thickness (LVPWT) at end-systole - LVPWT at end-diastole)/LVPWT] at end-systole. DWS did not correlate with other echocardiographic parameters and PAWP. We defined primary outcome as HF hospitalization or cardiovascular death and followed for 7 years. The incidence rate was higher in low DWS than high DWS patients (p = 0.04). Other echocardiographic parameters could not be significant predictors of HFrEF outcome under the condition of enough beta blocker therapy. In multivariate analysis, DWS was the independent contributor to the event-free time. Impaired LV stiffness evaluated with DWS was associated with worse outcome and DWS might be an independent prognostic factor in HFrEF patients with chronic beta blockade.

Recurrent coronary artery dissection of left main trunk initially presented with normal coronary angiography.

Although spontaneous coronary artery dissection (SCAD) is usually diagnosed by coronary angiography, diagnosis may be missed because of various presentations and imperfections of coronary angiography. We report a case of a 41-year-old female with pregnancy-related SCAD who presented with cardiac arrest. Initial coronary angiography was normal without intimal flap. Unexpectedly, 4 days after admission, SCAD in left main trunk was revealed with recurrent myocardial infarction. Intimal flap was sealed at the time of first angiography and this is an interesting point that made us report this case. SCAD is a rare but not negligible cause of not only acute myocardial infarction but also sudden cardiac arrest even if first coronary angiography is normal. .

Square-plate culture method allows detection of differential gene expression and screening of novel, region-specific genes in Aspergillus oryzae.

When grown on solid agar medium, the mycelium of a filamentous fungus, Aspergillus oryzae, forms three morphologically distinct regions: the tip (T), white (W), and basal (B) regions. In this study, we developed the square-plate culture method, a novel culture method that enabled the extraction of mRNA samples from the three regions and analyzed the differential gene expression of the A. oryzae mycelium in concert with the microarray technique. Expression of genes involved in protein synthesis was predominant in the T region; relative expression was, at most, six times higher in the T region compared to the other regions. Genes encoding hypothetical proteins were expressed at high levels in the W and B regions. In addition, genes coding transporters/permeases were predominantly transcribed in the B region. By analyzing the expression patterns of genes in the three regions, we demonstrated the dynamic changes in the regulation of gene expression that occur along the mycelium of filamentous fungi. Consequently, our study established a method to analyze and screen for region-specific genes whose function may be essential for morphogenesis and differentiation in filamentous fungi and whose traits may be beneficial to the biotechnology industry.

HANP1/H1T2, a novel histone H1-like protein involved in nuclear formation and sperm fertility.

We cloned a testis-specific cDNA from mice that encodes a histone H1-like, haploid germ cell-specific nuclear protein designated HANP1/H1T2. The HANP1/H1T2 protein was specifically localized to the nuclei of murine spermatids during differentiation steps 5 to 13 but not to the nuclei of mature sperm. HANP1/H1T2 contains an arginine-serine-rich domain and an ATP/GTP binding site, and it binds to DNA, ATP, and protamine. To investigate the physiological role of HANP1/H1T2, we generated Hanp1/H1T2-disrupted mutant mice. Homozygous Hanp1/H1T2 mutant males were infertile, but females were fertile. Although a substantial number of sperm were recovered from the epididymides, their shape and function were abnormal. During sperm morphogenesis, the formation of nuclei was disturbed and protamine-1 and -2 were only weakly detectable in the nuclei. The chromatin packaging was aberrant, as demonstrated by electron microscopy and biochemical analysis. The mutant sperm exhibited deficient motility and were not competent to fertilize eggs under in vitro fertilization conditions; however, they were capable of fertilizing eggs via intracytoplasmic sperm injection that resulted in the birth of healthy progeny. Thus, we found that HANP1/H1T2 is essential for nuclear formation in functional spermatozoa and is specifically involved in the replacement of histones with protamines during spermiogenesis. At the time of submission of the manuscript, we found an independent publication by Martianov et al. (I. Martianov, S. Brancorsini, R. Catena, A. Gansmuller, N. Kotaja, M. Parvinen, P. Sassone-Corsi, and I. Davidson, Proc. Natl. Acad. Sci. USA 102:2808-2813, 2005) that reported similar results.

Effects of protein transport inhibitors on the distribution and secretion of the fusion protein RntA-EGFP in Aspergillus oryzae.

The distribution of the secreted protein ribonuclease T1 (RntA) fused with the enhanced green fluorescent protein (EGFP), RntA-EGFP, was visualized in hyphae of Aspergillus oryzae in the presence of a protein transport inhibitor, brefeldin A, cytochalasin A, or nocodazole. During treatment with the protein transport inhibitors, the distribution of RntA-EGFP changed and distinct patterns of fluorescence accumulation were observed. The addition of brefeldin A caused RntA-EGFP fluorescence to appear in reticular networks, and the disruption of the polymerization of actin filaments by cytochalasin A caused an increase in RntA-EGFP fluorescence intensity in the hyphae without accumulation in a specific cellular component. In contrast, RntA-EGFP fluorescence was distributed in different parts of a hypha during treatment with nocodazole, a compound that depolymerizes microtubules. In addition, quantitative analysis was performed using the RntA-EGFP visualization system to analyze the relative amount of RntA-EGFP secreted into the culture medium during treatment with the protein transport inhibitors.

In vivo visualization of the distribution of a secretory protein in Aspergillus oryzae hyphae using the RntA-EGFP fusion protein.

A fusion gene encoding ribonuclease T1-EGFP (rntA-egfp) was constructed and expressed to use it as a tool for studies on the secretory pathway in Aspergillus oryzae. The successful secretion of the intact RntA-EGFP fusion protein was detected by fluorescence measurement and Western analysis. With use of the RntA-EGFP system, we were able to see high fluorescence at hyphal tips and observe concentrated fluorescence at septa in basal cells during growth at optimal conditions. Cold or heat shock during growth caused the accumulation of EGFP fluorescence in vacuoles.

Use of stepwise subtraction to comprehensively isolate mouse genes whose transcription is up-regulated during spermiogenesis.

We report the isolation of 153 mouse genes whose expression is dramatically up-regulated during spermiogenesis. We used a novel variation of the subtractive hybridization technique called stepwise subtraction, wherein the subtraction process is systematically repeated in a stepwise manner. We named the genes thus identified as TISP genes (transcript induced in spermiogenesis). The transcription of 80 of these TISP genes is almost completely specific to the testis. This transcription is abruptly turned on after 17 days of age, when the mice enter puberty and spermiogenesis is initiated. Considering that the most advanced cells present at these stages of spermatogenesis are the spermatids, it is likely that we could isolate most of the spermatid-specific genes. DNA sequencing revealed that about half the TISP genes are novel and uncharacterized genes, confirming the utility of the stepwise subtraction approach for gene discovery.