BOLA (BolA Family Member 3) Deficiency Controls Endothelial Metabolism and Glycine Homeostasis in Pulmonary Hypertension.

BACKGROUND: Deficiencies of iron-sulfur (Fe-S) clusters, metal complexes that control redox state and mitochondrial metabolism, have been linked to pulmonary hypertension (PH), a deadly vascular disease with poorly defined molecular origins. BOLA3 (BolA Family Member 3) regulates Fe-S biogenesis, and mutations in BOLA3 result in multiple mitochondrial dysfunction syndrome, a fatal disorder associated with PH. The mechanistic role of BOLA3 in PH remains undefined. METHODS: In vitro assessment of BOLA3 regulation and gain- and loss-of-function assays were performed in human pulmonary artery endothelial cells using siRNA and lentiviral vectors expressing the mitochondrial isoform of BOLA3. Polymeric nanoparticle 7C1 was used for lung endothelium-specific delivery of BOLA3 siRNA oligonucleotides in mice. Overexpression of pulmonary vascular BOLA3 was performed by orotracheal transgene delivery of adeno-associated virus in mouse models of PH. RESULTS: In cultured hypoxic pulmonary artery endothelial cells, lung from human patients with Group 1 and 3 PH, and multiple rodent models of PH, endothelial BOLA3 expression was downregulated, which involved hypoxia inducible factor-2α-dependent transcriptional repression via histone deacetylase 1-mediated histone deacetylation. In vitro gain- and loss-of-function studies demonstrated that BOLA3 regulated Fe-S integrity, thus modulating lipoate-containing 2-oxoacid dehydrogenases with consequent control over glycolysis and mitochondrial respiration. In contexts of siRNA knockdown and naturally occurring human genetic mutation, cellular BOLA3 deficiency downregulated the glycine cleavage system protein H, thus bolstering intracellular glycine content. In the setting of these alterations of oxidative metabolism and glycine levels, BOLA3 deficiency increased endothelial proliferation, survival, and vasoconstriction while decreasing angiogenic potential. In vivo, pharmacological knockdown of endothelial BOLA3 and targeted overexpression of BOLA3 in mice demonstrated that BOLA3 deficiency promotes histological and hemodynamic manifestations of PH. Notably, the therapeutic effects of BOLA3 expression were reversed by exogenous glycine supplementation. CONCLUSIONS: BOLA3 acts as a crucial lynchpin connecting Fe-S-dependent oxidative respiration and glycine homeostasis with endothelial metabolic reprogramming critical to PH pathogenesis. These results provide a molecular explanation for the clinical associations linking PH with hyperglycinemic syndromes and mitochondrial disorders. These findings also identify novel metabolic targets, including those involved in epigenetics, Fe-S biogenesis, and glycine biology, for diagnostic and therapeutic development.

Echocardiography Tips in the Emergency Room.

The emergency room is a principal entrance for the initial management of patients with acute heart failure. Echocardiography may be performed by cardiologists and noncardiologists in the emergency room. Echocardiographic studies require effective technical skills and precise diagnostic knowledge. This article contributes to physicians in the emergency room, general practitioners in training, and medical staff who engage in emergency medicine. This article emphasized the role of echocardiography in light of pathophysiology of acute heart failure in the emergency room and refining the clinical workflow by integrating conventional and innovative knowledge for the initial management of acute heart failure.

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.

Effective blood hemoglobin level to predict prognosis in heart failure with preserved left ventricular ejection fraction: results of the Japanese heart failure syndrome with preserved ejection fraction registry.

High prevalence of anemia in heart failure with preserved left ventricular ejection fraction (HFpEF) has been reported. However, little is known about the association of anemia and gender with prognosis in HFpEF patients. In addition, effective blood hemoglobin (Hb) level for prognosis in HFpEF patients remains largely unknown. In this study, we investigated the association between anemia, gender, and prognosis in 535 HFpEF patients enrolled in Japanese heart failure syndrome with preserved ejection fraction registry. Furthermore, we assessed effective blood Hb level to predict prognosis in HFpEF patients. According to the World Health Organization criteria, the prevalence rate of anemia on admission was about 70% in both male and female HFpEF patients. Kaplan-Meier analysis for all-cause mortality demonstrated that anemic patients had poor prognosis compared with non-anemic patients in both male and female HFpEF patients. Interestingly, multivariate analysis revealed that blood Hb level at discharge was an independent predictor of all-cause mortality in both male and female HFpEF patients. According to survival classification and regression tree analysis, blood Hb level at discharge of 9.4 g/dL for male and 12.3 g/dL for female was more accurate cutoff value to predict all-cause mortality in HFpEF patients. Anemia was implicated in poor prognosis in both male and female HFpEF patients. In particular, blood Hb level at discharge was an independent predictor of all-cause mortality in both male and female HFpEF patients. Effective cutoff value of blood Hb level at discharge to predict all-cause mortality was lower in male than in female HFpEF patients.

Specific circulating microRNAs display dose-dependent responses to variable intensity and duration of endurance exercise.

Circulating microRNAs (c-miRNAs), plasma-based noncoding RNAs that control posttranscriptional gene expression, mediate processes that underlie phenotypical plasticity to exercise. The relationship and biological relevance between c-miRNA expression and variable dose exercise exposure remains uncertain. We hypothesized that certain c-miRNAs respond to changes in exercise intensity and/or duration in a dose-dependent fashion. Muscle release of such c-miRNAs may then deplete intracellular stores, thus facilitating gene reprogramming and exercise adaptation. To address these hypotheses, healthy men participated in variable intensity ( n = 12, 30 × 1 min at 6, 7, and 8 miles/h, order randomized) and variable duration ( n = 14, 7 × 1 mile/h for 30, 60, and 90 min, order randomized) treadmill-running protocols. Muscle-enriched c-miRNAs (i.e., miRNA-1 and miRNA-133a) and others with known relevance to exercise were measured before and after exercise. c-miRNA responses followed three profiles: 1) nonresponsive (miRNA-21 and miRNA-210), 2) responsive to exercise at some threshold but without dose dependence (miRNA-24 and miRNA-146a), and 3) responsive to exercise with dose dependence to increasing intensity (miRNA-1) or duration (miRNA-133a and miRNA-222). We also studied aerobic exercise-trained mice, comparing control, low-intensity (0.5 km/h), or high-intensity (1 km/h) treadmill-running protocols over 4 wk. In high- but not low-intensity-trained mice, we found increased plasma c-miR-133a along with decreased intracellular miRNA-133a and increased serum response factor, a known miR-133a target gene, in muscle. Characterization of c-miRNAs that are dose responsive to exercise in humans and mice supports the notion that they directly mediate physiological adaptation to exercise, potentially through depletion of intracellular stores of muscle-specific miRNAs. NEW & NOTEWORTHY In this study of humans and mice, we define circulating microRNAs in plasma that are dose responsive to exercise. Our data support the notion that these microRNAs mediate physiological adaptation to exercise potentially through depletion of intracellular stores of muscle-specific microRNAs and releasing their inhibitory effects on target gene expression.

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.

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.

Long-term effects of L- and N-type calcium channel blocker on uric acid levels and left atrial volume in hypertensive patients.

Left ventricular (LV) diastolic dysfunction is associated with hypertension and hyperuricemia. However, it is not clear whether the L- and N-type calcium channel blocker will improve LV diastolic dysfunction through the reduction of uric acid. The aim of this study was to investigate the effects of anti-hypertensive therapy, the L- and N-type calcium channel blocker, cilnidipine or the L-type calcium channel blocker, amlodipine, on left atrial reverse remodeling and uric acid in hypertensive patients. We studied 62 patients with untreated hypertension, randomly assigned to cilnidipine or amlodipine for 48 weeks. LV diastolic function was assessed with the left atrial volume index (LAVI), mitral early diastolic wave (E), tissue Doppler early diastolic velocity (E') and the ratio (E/E'). Serum uric acid levels were measured before and after treatment. After treatment, systolic and diastolic blood pressures equally dropped in both groups. LAVI, E/E', heart rate and uric acid levels decreased at 48 weeks in the cilnidipine group but not in the amlodipine group. The % change from baseline to 48 weeks in LAVI, E wave, E/E' and uric acid levels were significantly lower in the cilnidipine group than in the amlodipine group. Larger %-drop in uric acid levels were associated with larger %-reduction of LAVI (p < 0.01). L- and N-type calcium channel blocker but not L-type calcium channel blocker may improve LV diastolic function in hypertensive patients, at least partially through the decrease in uric acid levels.

The association between left ventricular twisting motion and mechanical dyssynchrony: a three-dimensional speckle tracking study.

Left ventricular (LV) dyssynchrony is a causal factor in LV dysfunction and thought to be associated with LV twisting motion. We tested whether three-dimensional speckle tracking (3DT) can be used to evaluate the relationship between LV twisting motion and dyssynchrony. We examined 25 patients with sick sinus syndrome who had received dual chamber pacemakers. The acute effects of ventricular pacing on LV wall motion after the switch from atrial to ventricular pacing were assessed. LV twisting motion and dyssynchrony during each pacing mode were measured using 3DT. LV dyssynchrony was calculated from the time to the minimum peak systolic area strain of 16 LV imaging segments. Ventricular pacing increased LV dyssynchrony and decreased twist and torsion. A significant correlation was observed between changes in LV dyssynchrony and changes in torsion (r = -0.65, p < 0.01). Evaluation of LV twisting motion can potentially be used for diagnosing LV dyssynchrony.

Hemodynamic response to sildenafil in patients with decompensated congestive heart failure can be predicted by deceleration time of transmitral flow.

AIM: How sildenafil acutely provides hemodynamic alterations in patients with decompensated congestive heart failure remains unknown. The aim of this study was to investigate whether myocardial and/or hemodynamic conditions affect hemodynamic response to sildenafil in patients with decompensated heart failure. METHODS AND RESULTS: Twenty-five consecutive patients with decompensated congestive heart failure were enrolled. The patients underwent echocardiography before and 1 hour after a single oral administration of sildenafil (20 mg). Sildenafil decreased pulmonary vascular resistance by 24% (P < 0.05), and increased left ventricular (LV) time-velocity integral by 17% (P < 0.05). Alteration of the ratio of peak velocity of early LV filling to early diastolic myocardial velocity (E/E'), an indicator of LV filling pressure, following administration of sildenafil, negatively associated with the deceleration time of early filling wave (DcT) at baseline. Patients with baseline DcT ≥ 200 milliseconds (n = 11) exhibited E/E' increase, whereas patients with baseline DcT <200 milliseconds (n = 14) exhibited E/E' decrease. CONCLUSIONS: Administration of sildenafil elevated LV filling pressure in decompensated heart failure patients with shortened deceleration time of early diastolic transmitral flow.

Does Left Atrial Appendage Morphology Influence Left Atrial Appendage Flow Velocity?

BACKGROUND: The shape of the left atrial appendage (LAA) might affect thrombus formation. The chicken wing-type LAA (CW) has been reported as unlikely to influence stroke events in atrial fibrillation (AF) patients, so we investigated whether LAA shapes could influence LAA function. METHODS AND RESULTS: We studied 102 patients (64 men, age 65±9 years) who underwent transthoracic echocardiography, transesophageal echocardiography (TEE), and cardiac computed tomography prior to catheter ablation (CA) for AF. LAA morphology were classified into 2 types: (1) CW: LAA with a bend in its shape and (2) non-CW type (NCW): LAA without any bends. All patients were classified into these groups using a cutoff value of LAA flow velocity (LAAFV). Patients with LAAFV <35 cm/s were classified as the low LAAFV group (Low FV, n=37). The patients with LAAFV >35 cm/s were classified as normal LAAFV group (Normal FV, n=65). The NCW type was detected in 25/102 patients (25%). In multivariate analysis, the patients with Low FV were associated with NCW type (P=0.0429, odds ratio [OR] 9.664, 95% confidence interval [CI] 1.075-86.900) and higher B-type natriuretic peptide (BNP) (P=0.0350, OR 1.012 for each 1 pg/ml increase in BNP, 95% CI 1.001-1.022). CONCLUSIONS: The NCW-type LAA and higher BNP were associated with lower LAAFV. One reason for the frequent cardiogenic stroke in patients with the NCW-type LAA may be the lower LAAFV.

Use of proton pump inhibitors is associated with anemia in cardiovascular outpatients.

BACKGROUND: Proton pump inhibitors (PPI) are frequently prescribed in combination with aspirin for preventing peptic ulcer in patients with atherosclerotic diseases. In contrast, long-term use of PPI has been suggested to be associated with iron or vitamin B12 deficiency. The effect of PPI on hemoglobin (Hb) concentration, however, has not been clarified in cardiovascular outpatients. METHODS AND RESULTS: We retrospectively investigated the clinical characteristics of 278 continuous outpatients who received blood test including complete blood count and serum creatinine concentration (mean age, 69.9 ± 10.8 years; male, 68.7%). The frequency of anemia was 51% in patients receiving PPI and 19% in those not receiving PPI (chi-squared test, P<0.001). On multivariate analysis female sex (P<0.001), peripheral artery disease (P=0.003), PPI (P=0.003), low white blood cell count (P=0.004), old age (P=0.007), and low estimated glomerular filtration rate (P=0.010) were independently associated with low Hb. Among these patients, we investigated the change in Hb after the initiation of PPI in 36 patients for whom data on Hb level within 1 year before and within 1 year after the initiation of PPI were available. Mean decrease in Hb after the initiation of PPI was 0.38 ± 0.87 g/dl (95% confidence interval: -0.67 to -0.09 g/dl). CONCLUSIONS: Use of PPI was associated with anemia in Japanese cardiovascular outpatients.

Elevated arterial stiffness and diastolic dysfunction in subclinical hypothyroidism.

BACKGROUND: Thyroid hormone is associated with arterial stiffness and left ventricular diastolic function in hypothyroid disease. The relationship of thyroid hormone level to cardio-ankle vascular index (CAVI) and left ventricular diastolic function, however, remains unclear in subjects with subclinical hypothyroidism. METHODS AND RESULTS: We conducted a cross-sectional study of 83 patients with untreated subclinical hypothyroidism and compared them with 83 randomly selected controls from health check-ups. Log N-terminal prohormone of brain natriuretic peptide (NT-proBNP), C-reactive protein (CRP), and arterial stiffness were measured. In addition, we measured early diastolic mitral annular velocity (E') in 43 participants with subclinical hypothyroidism and in 40 controls. When compared with the control group, patients with subclinical hypothyroidism had higher logNT-proBNP (1.9±0.5 vs. 1.7±0.3pg/ml, P<0.05), CRP (0.22±0.04 vs. 0.09±0.06mg/dl, P<0.05), and CAVI (8.8±1.7 vs. 7.8±1.4, P<0.001) and lower E' (5.8±1.7 vs. 7.5±2.1cm/s, P<0.001). CAVI was significantly associated with logNT-proBNP, CRP and E' in the subclinical hypothyroidism group. CONCLUSIONS: High logNT-proBNP was associated with a raised CAVI in patients with subclinical hypothyroidism. Subclinical hypothyroidism may be a risk factor for cardiovascular events related to arterial stiffening and left ventricular diastolic dysfunction.

Nuclear factor-κB-hypoxia-inducible factor-2 pathway in aortic valve stenosis.

BACKGROUND AND AIM OF THE STUDY: Valvular calcification is a prominent feature of aortic valve stenosis (AS), and calcified aortic valves share several features with bone tissue. Hypoxia-inducible factor-2 (HIF-2) is activated by nuclear factor-κB (NF-κB) and plays a critical role in an osteoblastic differentiation. The study aim was to determine whether the NF-κB-HIF-2 pathway is involved in the pathophysiology of calcified aortic valve disease. METHODS: A total of 50 specimens of aortic valve leaflets obtained from patients who had undergone aortic valve replacement for AS was examined. The aortic valve leaflets from 10 patients with annulo-aortic ectasia (AAE) served as controls. The stenotic valve leaflets were examined using immunohistochemistry to detect NF-κB, HIF-2α, vascular endothelial growth factor (VEGF), vascular endothelial cells, and collagen X. The calcification area was measured and any correlation between the calcification area and NF-κB-HIF-2 pathway was assessed. RESULTS: NF-κB and HIF-2α were expressed in the leaflets from patients with AS, but not in those from AAE controls. Both factors were expressed around massive calcified lesions, and HIF-2α was co-localized with NF-κB. VEGF, neoangiogenesis and collagen X were located in the area where HIF-2α was expressed, and correlated positively with HIF-2α expression. The calcification area correlated positively with collagen X expression. CONCLUSION: The NF-κB-HIF-2 pathway was expressed in calcified aortic valves and associated with an increased expression of VEGF and collagen X. This signaling pathway may play important roles in the pathophysiology of AS.

Placental senescence pathophysiology is shared between peripartum cardiomyopathy and preeclampsia in mouse and human.

Peripartum cardiomyopathy (PPCM) is an idiopathic form of pregnancy-induced heart failure associated with preeclampsia. Circulating factors in late pregnancy are thought to contribute to both diseases, suggesting a common underlying pathophysiological process. However, what drives this process remains unclear. Using serum proteomics, we identified the senescence-associated secretory phenotype (SASP), a marker of cellular senescence associated with biological aging, as the most highly up-regulated pathway in young women with PPCM or preeclampsia. Placentas from women with preeclampsia displayed multiple markers of amplified senescence and tissue aging, as well as overall increased gene expression of 28 circulating proteins that contributed to SASP pathway enrichment in serum samples from patients with preeclampsia or PPCM. The most highly expressed placental SASP factor, activin A, was associated with cardiac dysfunction or heart failure severity in women with preeclampsia or PPCM. In a murine model of PPCM induced by cardiomyocyte-specific deletion of the gene encoding peroxisome proliferator-activated receptor γ coactivator-1α, inhibiting activin A signaling in the early postpartum period with a monoclonal antibody to the activin type II receptor improved heart function. In addition, attenuating placental senescence with the senolytic compound fisetin in late pregnancy improved cardiac function in these animals. These findings link senescence biology to cardiac dysfunction in pregnancy and help to elucidate the pathogenesis underlying cardiovascular diseases of pregnancy.

Platypnea-Orthodeoxia: An Effective Diagnostic Tool for Hepatopulmonary Syndrome With Chronic Obstructive Pulmonary Disease.

Hepatopulmonary syndrome (HPS) shows progressive dyspnea resulting from intrapulmonary atrioventricular shunts in liver cirrhosis. The comorbidity of chronic lung disease often hampers the diagnosis of progressive dyspnea in patients with HPS. Therefore, a comprehensive approach to the determination of dyspnea is required. Here, this case report shows that a patient with chronic obstructive pulmonary disease (COPD) and alcoholic liver cirrhosis was diagnosed with HPS after admission due to worsening dyspnea. Although COPD exacerbation was initially suspected because of the long history of smoking, physical examinations, laboratory findings, and imaging data, dyspnea remained after recovery from worsening respiratory failure. HPS was suspected due to the absence of increased CO2 levels and the presence of platypnea-orthodeoxia. We diagnosed the intrapulmonary arteriovenous shunt with microbubble-contrast echocardiography and technetium-99m macroaggregated albumin scintigraphy. Therefore, this case highlighted that HPS rather than COPD was suspected of hypoxemia associated with repositioning for the differential diagnosis of dyspnea.

The Prognostic Value of Right Atrial Strain Imaging in Patients with Precapillary Pulmonary Hypertension.

BACKGROUND: Right ventricular (RV) failure in patients with pulmonary hypertension (PH) is associated with unfavorable clinical events and a poor prognosis. Elevation of right atrial (RA) pressure is established as a marker for RV failure. However, the additive prognostic value of RA mechanical function is unclear. METHODS: The authors tested the hypothesis that RA function by strain echocardiography has prognostic usefulness by studying 165 consecutive patients with precapillary PH defined invasively: mean pulmonary artery pressure ≥ 25 mm Hg and pulmonary capillary wedge pressure < 15 mm Hg. Speckle-tracking strain analyses of the right atrium and right ventricle were performed, along with routine measures. Peak RA strain values from six segments using generic speckle-tracking software were averaged to RA peak longitudinal strain, representing RA global reservoir function. The primary end point was all-cause mortality during 5 years of follow-up. RA strain was similarly analyzed in a control group of 16 normal subjects for comparison. RESULTS: There were 151 patients with PH (mean age, 55 ± 16 years; 73% women; mean World Health Organization functional class, 2.6 ± 0.6), after 14 exclusions (three with atrial septal defects and 11 with left ventricular ejection fractions < 50%). RA strain measurement was feasible in 93% of patients and RV strain measurement in 88%. RA peak longitudinal strain was significantly reduced in patients with PH compared with control subjects, as expected (P < .001). During 5-year follow-up, 73 patients (48%) died. Patients with RA peak strain in the lowest quartile (<25%) had a significant risk for death (P = .006), even after correcting for confounding variables. RA strain was independently associated with survival in multivariate analysis (P = .039) and had additive prognostic value to RV strain (log-rank P = .01) in subgroup analysis. CONCLUSIONS: RA peak longitudinal strain had additive prognostic usefulness to other clinical measures, including RV strain, RA area, and RA pressure, in patients with PH. RA mechanical function by strain imaging has potential for clinical applications in patients with PH.

Anemia has an impact on prognosis in heart failure with preserved ejection fraction with mild chronic kidney disease.

BACKGROUND: Anemia and chronic kidney disease (CKD) are common in patients with heart failure with preserved left ventricular fraction (HFpEF). However, it is entirely unknown about the impact of anemia on prognosis in HFpEF patients with CKD. In this study, we investigated the impact of anemia on prognosis and the optimal hemoglobin (Hb) levels to predict prognosis in HFpEF patients with CKD. METHODS AND RESULTS: We prospectively examined 523 consecutive HFpEF patients enrolled in Japanese heart failure syndrome with preserved ejection fraction registry. CKD was defined as an estimated glomerular filtration rate (eGFR) of <60 mL /min/1.73 m2. The prevalence rate of anemia was 78% in HFpEF patients with CKD by using the World Health Organization criteria. Kaplan-Meier analysis for all-cause mortality and heart failure rehospitalization demonstrated that anemic patients had poor prognosis compared with non-anemic patients in HFpEF patients with CKD, but not those without CKD. According to the degree of CKD, anemia affected prognosis in HFpEF patients with mild CKD (45 ≤ eGFR < 60), but not those with moderate to severe CKD (15 ≤ eGFR < 45). Additionally, multivariate analysis revealed that anemia and Hb levels were independent predictors of composite outcomes in HFpEF patients with mild CKD, but not those with moderate to severe CKD. Finally, survival classification and regression tree analysis showed that the optimal Hb levels to predict composite outcomes were 10.7 g/dL in those with mild CKD. CONCLUSIONS: Anemia has an impact on prognosis in HFpEF patients, especially among those with mild CKD.

Neurocardiac Injury Assessed by Strain Imaging Is Associated With In-Hospital Mortality in Patients With Subarachnoid Hemorrhage.

OBJECTIVES: This study sought to test the hypothesis that speckle tracking strain echocardiography can quantify neurocardiac injuries in patients with aneurysmal subarachnoid hemorrhage (SAH), which is associated with worse clinical outcome. BACKGROUND: SAH may be a life-threatening disease associated with variable degrees of neurocardiac injury. Strain imaging has the potential to detect subtle myocardial dysfunction which is additive to conventional measurements. METHODS: A total of 255 consecutive patients were prospectively enrolled with acute SAH, who were admitted to the intensive care unit with echocardiography studies within 72 h. Left ventricular (LV) and right ventricular (RV) strains were acquired from standard apical views. Abnormal LV global longitudinal strain (GLS) and RV free-wall strain were pre-defined as <17% and <23% (absolute values), respectively. RESULTS: Performing LV GLS was feasible in 221 patients (89%) 53 ± 10 years of age, 71% female, after excluding those with previous cardiac disease. Abnormal LV GLS findings were observed in 53 patients (24%) and were associated with worse clinical severity, including a Hunt-Hess grade >3 (34% vs. 15%; p = 0.005) and biomarker evidence of neurocardiac injury and higher troponin values (1.50 [interquartile range (IQR): 0.01 to 3.87] vs. 0.01 [IQR: 0.01 to 0.22] ng/ml; p < 0.001). A reverse Takotsubo pattern of segmental strain was observed in 49% of patients (apical sparing and reduced basal strain). Importantly, LV GLS was more strongly associated with in-hospital mortality than left ventricular ejection fraction (LVEF), even after adjusting for clinical severity (odds ratio [OR]: 3.11; 95% confidence interval [CI]: 1.12 to 8.63; p = 0.029). RV strain was measured in 159 subjects (72%); abnormal RV strain was added to LV GLS for predicting in-hospital mortality (p = 0.007). CONCLUSIONS: Neurocardiac injury can be detected by LV GLS and RV strain in patients with acute SAH. LV GLS was significantly associated with in-hospital mortality. RV strain, when available, added prognostic value to LV GLS. Abnormal myocardial strain is a marker for increased risk of in-hospital mortality in SAH and has clinical prognostic utility.