Overexpression of GRK2 in vascular smooth muscle leads to inappropriate hypertension and acute heart failure as in clinical scenario 1.

Clinical scenario 1 (CS1) is acute heart failure (HF) characterized by transient systolic blood pressure (SBP) elevation and pulmonary congestion. Although it is managed by vasodilators, the molecular mechanism remains unclear. The sympathetic nervous system plays a key role in HF, and desensitization of cardiac ß-adrenergic receptor (AR) signaling due to G protein-coupled receptor kinase 2 (GRK2) upregulation is known. However, vascular ß-AR signaling that regulates cardiac afterload remains unelucidated in HF. We hypothesized that upregulation of vascular GRK2 leads to pathological conditions similar to CS1. GRK2 was overexpressed in vascular smooth muscle (VSM) of normal adult male mice by peritoneally injected adeno-associated viral vectors driven by the myosin heavy chain 11 promoter. Upregulation of GRK2 in VSM of GRK2 overexpressing mice augmented the absolute increase in SBP (+ 22.5 ± 4.3 mmHg vs. + 36.0 ± 4.0 mmHg, P < 0.01) and lung wet weight (4.28 ± 0.05 mg/g vs. 4.76 ± 0.15 mg/g, P < 0.01) by epinephrine as compared to those in control mice. Additionally, the expression of brain natriuretic peptide mRNA was doubled in GRK2 overexpressing mice as compared to that in control mice (P < 0.05). These findings were similar to CS1. GRK2 overexpression in VSM may cause inappropriate hypertension and HF, as in CS1.

Heart failure with preserved ejection fraction phenogroup classification using machine learning.

AIMS: Heart failure (HF) with preserved ejection fraction (HFpEF) is a complex syndrome with a poor prognosis. Phenotyping is required to identify subtype-dependent treatment strategies. Phenotypes of Japanese HFpEF patients are not fully elucidated, whose obesity is much less than Western patients. This study aimed to reveal model-based phenomapping using unsupervised machine learning (ML) for HFpEF in Japanese patients. METHODS AND RESULTS: We studied 365 patients with HFpEF (left ventricular ejection fraction >50%) as a derivation cohort from the Nara Registry and Analyses for Heart Failure (NARA-HF), which registered patients with hospitalization by acute decompensated HF. We used unsupervised ML with a variational Bayesian-Gaussian mixture model (VBGMM) with common clinical variables. We also performed hierarchical clustering on the derivation cohort. We adopted 230 patients in the Japanese Heart Failure Syndrome with Preserved Ejection Fraction Registry as the validation cohort for VBGMM. The primary endpoint was defined as all-cause death and HF readmission within 5 years. Supervised ML was performed on the composite cohort of derivation and validation. The optimal number of clusters was three because of the probable distribution of VBGMM and the minimum Bayesian information criterion, and we stratified HFpEF into three phenogroups. Phenogroup 1 (n = 125) was older (mean age 78.9 ± 9.1 years) and predominantly male (57.6%), with the worst kidney function (mean estimated glomerular filtration rate 28.5 ± 9.7 mL/min/1.73 m2 ) and a high incidence of atherosclerotic factor. Phenogroup 2 (n = 200) had older individuals (mean age 78.8 ± 9.7 years), the lowest body mass index (BMI; 22.78 ± 3.94), and the highest incidence of women (57.5%) and atrial fibrillation (56.5%). Phenogroup 3 (n = 40) was the youngest (mean age 63.5 ± 11.2) and predominantly male (63.5 ± 11.2), with the highest BMI (27.46 ± 5.85) and a high incidence of left ventricular hypertrophy. We characterized these three phenogroups as atherosclerosis and chronic kidney disease, atrial fibrillation, and younger and left ventricular hypertrophy groups, respectively. At the primary endpoint, Phenogroup 1 demonstrated the worst prognosis (Phenogroups 1-3: 72.0% vs. 58.5% vs. 45%, P = 0.0036). We also successfully classified a derivation cohort into three similar phenogroups using VBGMM. Hierarchical and supervised clustering successfully showed the reproducibility of the three phenogroups. CONCLUSIONS: ML could successfully stratify Japanese HFpEF patients into three phenogroups (atherosclerosis and chronic kidney disease, atrial fibrillation, and younger and left ventricular hypertrophy groups).

Transthyretin Amyloid Cardiomyopathy: Impact of Transthyretin Amyloid Deposition in Myocardium on Cardiac Morphology and Function.

BACKGROUND: Transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) is increasingly being recognized as a cause of left ventricular (LV) hypertrophy (LVH) and progressive heart failure in elderly patients. However, little is known about the cardiac morphology of ATTR-CM and the association between the degree of TTR amyloid deposition and cardiac dysfunction in these patients. METHODS: We studied 28 consecutive patients with ATTR-CM and analyzed the relationship between echocardiographic parameters and pathological features using endomyocardial biopsy samples. RESULTS: The cardiac geometries of patients with ATTR-CM were mainly classified as concentric LVH (96.4%). The relative wall thickness, a marker of LVH, tended to be positively correlated with the degree of non-cardiomyocyte area. The extent of TTR deposition was positively correlated with enlargement of the non-cardiomyocyte area, and these were positively correlated with LV diastolic dysfunction. Additionally, the extent of the area containing TTR was positively correlated with the percentage of cardiomyocyte nuclei stained for 8-hydroxy-2'deoxyguanosine, a marker of reactive oxygen species (ROS). ROS accumulation in cardiomyocytes was positively correlated with LV systolic dysfunction. CONCLUSION: Patients with ATTR-CM mainly displayed concentric LVH geometry. TTR amyloid deposition was associated with cardiac dysfunction via increased non-cardiomyocyte area and ROS accumulation in cardiomyocytes.

Prevalence of mitral annular calcification and its association with mitral valvular disease.

BACKGROUND: Mitral annular calcification (MAC) is increasingly observed in elderly population. The purpose of this study was to investigate incidence of MAC and its association with mitral valvular disease (MVD). METHODS: A total of 13,483 consecutive patients who underwent echocardiography were enrolled. MAC was defined as an echo-dense, shelf-like structure with an irregular, lumpy appearance involving the mitral valve annulus, with acoustic shadowing. Prevalence of MAC and its association with significant mitral stenosis (MS) or mitral regurgitation (MR) were studied. Significant (≥moderate) MS was defined as mean transmitral valvular pressure gradient > 5 mm Hg and significant MR was defined as ≥moderate MR based on quantitative or semi-quantitative Doppler methods. RESULTS: MAC was present in 1881 of 13,483 patients (14%). Patients with MAC (MAC group) was older and more female gender than those without MAC (non-MAC group). Significant MS was present in 2.2% of MAC and in .6% of the non-MAC group (p < 0.0001). Significant MR was present in 11.9% of MAC and in 5.0% of the non-MAC group (p < 0.0001). Co-existence of MAC and aortic valve replacement (AVR) was associated with increased prevalence of MVD (MS:11.4%, MR:17.2%, respectively). CONCLUSION: MAC was present in 14% of the patients and was associated with significant MVD. Co-existence of MAC and AVR may increase the risk of MVD.

Prognostic Value of Fractional Excretion of Urea Nitrogen at Discharge in Acute Decompensated Heart Failure.

Background Maintaining euvolemia is crucial for improving prognosis in acute decompensated heart failure (ADHF). Although fractional excretion of urea nitrogen (FEUN) is used as a body fluid volume index in patients with acute kidney injury, the clinical impact of FEUN in patients with ADHF remains unclear. This study aimed to investigate whether FEUN can determine the long-term prognosis in patients with ADHF. Methods and Results We retrospectively identified 466 patients with ADHF who had FEUN measured at discharge between April 2011 and December 2018. The primary endpoint was post-discharge all-cause death. Patients were divided into two groups according to a FEUN cut-off value of 35%, commonly used in pre-renal failure. The FEUN <35% (low-FEUN) group included 224 patients (48.1%), and the all-cause mortality rate for the total cohort was 37.1%. The log-rank test revealed that the low-FEUN group had a significantly higher rate of all-cause death compared to the FEUN equal to or greater than 35% (high-FEUN) group (P<0.001). Multivariate Cox proportional hazards model analysis revealed that low-FEUN was associated with post-discharge all-cause death, independently of other heart failure risk factors (hazard ratio, 1.467; 95% CI, 1.030-2.088, P=0.033). The risk of low-FEUN compared to high-FEUN in post-discharge all-cause death was consistent across all subgroups; however, the effects tended to be modified by renal function (threshold: 60 mL/min/1.73 m2, interaction P=0.069). Conclusions Our study suggests that FEUN may be a novel surrogate marker of volume status in patients with ADHF requiring diuretics.

AAV-mediated YAP expression in cardiac fibroblasts promotes inflammation and increases fibrosis.

Fibrosis is a hallmark of heart disease independent of etiology and is thought to contribute to impaired cardiac dysfunction and development of heart failure. However, the underlying mechanisms that regulate the differentiation of fibroblasts to myofibroblasts and fibrotic responses remain incompletely defined. As a result, effective treatments to mitigate excessive fibrosis are lacking. We recently demonstrated that the Hippo pathway effector Yes-associated protein (YAP) is an important mediator of myofibroblast differentiation and fibrosis in the infarcted heart. Yet, whether YAP activation in cardiac fibroblasts is sufficient to drive fibrosis, and how fibroblast YAP affects myocardial inflammation, a significant component of adverse cardiac remodeling, are largely unknown. In this study, we leveraged adeno-associated virus (AAV) to target cardiac fibroblasts and demonstrate that chronic YAP expression upregulated indices of fibrosis and inflammation in the absence of additional stress. YAP occupied the Ccl2 gene and promoted Ccl2 expression, which was associated with increased macrophage infiltration, pro-inflammatory cytokine expression, collagen deposition, and cardiac dysfunction in mice with cardiac fibroblast-targeted YAP overexpression. These results are consistent with other recent reports and extend our understanding of YAP function in modulating fibrotic and inflammatory responses in the heart.

Involvement of chronic inflammation via monocyte chemoattractant protein-1 in uraemic cardiomyopathy: a human biopsy study.

AIMS: Patients undergoing dialysis, even those without coronary artery disease or valvular abnormalities, sometimes present with reduced heart function, which resembles dilated cardiomyopathy (DCM). This condition is known as uraemic cardiomyopathy (UCM). The mechanisms of UCM development are not fully understood. Previous studies demonstrated that the balance between placental growth factor (PlGF) and fms-like tyrosine kinase-1 (Flt-1) is correlated with renal function, and PlGF/Flt-1 signalling is involved in the development of cardiovascular diseases in patients with chronic kidney disease. This study was conducted to evaluate the pathogenesis of UCM and clarify the differences in the mechanisms of UCM and DCM by using human endomyocardial biopsy and blood samples. METHODS AND RESULTS: The clinical and pathological features of 30 patients on dialysis with reduced cardiac function [left ventricular ejection fraction (LVEF) ≤50%] (UCM group; mean age: 58.5 ± 9.4 years and LVEF: 39.1 ± 7.2%), 196 DCM patients (DCM group; mean age: 62.7 ± 14.0 years and LVEF: 33.5 ± 8.8%) as controls with reduced cardiac function (LVEF ≤ 45%), and 21 patients as controls with normal cardiac function (control group; mean age: 56.2 ± 19.3 years and LVEF: 67.5 ± 6.7%) were analysed. The percentage of the interstitial fibrosis area in the UCM group was greater than that in the DCM group (P = 0.045). In UCM patients, the percentage of the interstitial fibrosis area was positively correlated with the duration of renal replacement therapy (P < 0.001). The number of infiltrated CD68-positive macrophages in the myocardium and expression of monocyte chemoattractant protein-1 (MCP-1) in cardiomyocytes were significantly greater in the UCM group than in the other groups (P < 0.001, respectively). Furthermore, while the serum level of soluble form of Flt-1, an endogenous inhibitor of PlGF, in the UCM group was lower compared with that in the DCM group (P < 0.001), the serum levels of PlGF and PlGF/soluble form of Flt-1 ratio and plasma level of MCP-1 in the UCM group were higher than those in the DCM group (P < 0.001, respectively). CONCLUSIONS: These results suggest that activated PlGF/Flt-1 signalling and subsequent macrophage-mediated chronic non-infectious inflammation via MCP-1 in the myocardium are involved in the pathogenesis of UCM.

Local Action of Neprilysin Exacerbates Pressure Overload Induced Cardiac Remodeling.

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Serum iron: a new predictor of adverse outcomes independently from serum hemoglobin levels in patients with acute decompensated heart failure.

Iron is an essential trace element in the body. However, in heart failure (HF), iron is only recognized as the cause of anemia. Actually, iron itself affects myocardial exercise tolerance and cardiac function via mitochondrial function. Therefore, it is necessary to clarify the pathological significance of iron in acute HF, irrespective of concomitant anemia. We investigated the impact of serum iron level at discharge on the prognosis of 615 patients emergently admitted with acute decompensated HF (ADHF). Patients were divided into two groups according to the median level of serum iron (62 µg/dL). The endpoint was the composite outcome, which included all-cause mortality and readmission for HF. During the mean follow-up period of 32.1 months, there were 333 events. Kaplan-Meier analysis showed that the incidence of the composite outcome was significantly higher in the Low iron group (P < 0.0001). In the multivariate analysis adjusted with factors including hemoglobin and ferritin levels, low serum iron was an independent predictor for the composite outcome (hazard ratio, 1.500; 95% confidence interval, 1.128-1.976; P = 0.0044). Low serum iron was an independent predictor of poor prognosis in ADHF, irrespective of hemoglobin or ferritin level, providing a new concept that iron may play a role in the pathophysiology of ADHF via non-hematopoietic roles.

"Hidden" takotsubo cardiomyopathy in cardiac care unit.

BACKGROUND: Takotsubo cardiomyopathy (TC) is characterized as a transient segmental cardiac dysfunction mimicking acute coronary syndrome triggered by emotional or physical stress. Although neurological disorders, infection, malignant diseases, trauma and surgery are known triggers for the development of TC, role of cardiac diseases as underlying conditions for the development of TC is uncertain. The aim of this study was to investigate incidence and clinical characteristics of TC among critically ill cardiac disease patients and to verify that TC may coexist with other cardiac diseases. METHODS: Between November, 2015 and September, 2017, 862 echocardiographic examinations were recorded from 413 patients who were admitted to the CCU. All echo images, electrocardiograms as well as medical records were reviewed. TC was diagnosed according to the modified Mayo criteria. RESULTS: Takotsubo cardiomyopathy was diagnosed in 29 of 413 patients (7%). TC was a primary diagnosis in 18 patients (group P) and the other 11 patients (group S) were not diagnosed as TC during the CCU stay. Primary diagnosis of these patients was acute myocardial infarction (n = 5), acute decompensated heart failure (two aortic stenosis, one cardiac amyloidosis, and two tachycardia induced cardiomyopathy), and ventricular tachycardia (n = 1). CONCLUSION: Takotsubo cardiomyopathy may develop in critically ill cardiac diseases but are often underdiagnosed. Careful echocardiographic examination is needed to unveil these "hidden" TC.

AST-120, an Oral Carbon Absorbent, Protects against the Progression of Atherosclerosis in a Mouse Chronic Renal Failure Model by Preserving sFlt-1 Expression Levels.

Soluble Flt-1 (sFlt-1), an endogenous antagonist of the proatherogenic cytokine placental growth factor, is decreased in chronic kidney disease (CKD), leading to atherosclerotic progression. In this study, we investigated the effect of AST-120, an oral carbon adsorbent which can remove uremic toxins, on sFlt-1 expression levels and atherosclerosis progression. Atherosclerotic apolipoprotein E-deficient mice underwent a 5/6 nephrectomy (5/6 NR) or a sham operation (sham) at 8 weeks of age and were then treated or not with oral AST-120 for 12 weeks. sFlt-1 expression levels and the degree of atherosclerosis were assessed at 22 weeks of age in each of the four groups (sham; n = 7, 5/6 NR; n = 10, sham + AST-120: n = 8, 5/6 NR + AST-120; n = 8). The expression levels of sFlt-1 mRNA in the kidney were significantly lower in the 5/6 NR group than in the sham group, but AST-120 treatment prevented this decrease in sFlt-1 levels. Similarly, the atherosclerotic plaque area of the thoracoabdominal aorta was significantly larger in the 5/6 NR group than in the sham group, and AST-120 treatment prevented this increase in atherosclerosis. AST-120 could, therefore, be used as a therapeutic to treat atherosclerosis in patients with CKD.

Prognostic Value of Urinary Neutrophil Gelatinase-Associated Lipocalin on the First Day of Admission for Adverse Events in Patients With Acute Decompensated Heart Failure.

BACKGROUND: Urinary neutrophil gelatinase-associated lipocalin (U-NGAL) is an early predictor of acute kidney injury and adverse events in various diseases; however, in acute decompensated heart failure patients, its significance remains poorly understood. This study aimed to investigate the prognostic value of U-NGAL on the first day of admission for the occurrence of acute kidney injury and long-term outcomes in acute decompensated heart failure patients. METHODS AND RESULTS: We studied 260 acute decompensated heart failure patients admitted to our department between 2011 and 2014 by measuring U-NGAL in 24-hour urine samples collected on the first day of admission. Primary end points were all-cause death, cardiovascular death, and heart failure admission. Patients were divided into 2 groups according to their median U-NGAL levels (32.5 µg/gCr). The high-U-NGAL group had a significantly higher occurrence of acute kidney injury during hospitalization than the low-U-NGAL group (P=0.0012). Kaplan-Meier analysis revealed that the high-U-NGAL group exhibited a worse prognosis than the low-U-NGAL group in all-cause death (hazard ratio 2.07; 95%CI 1.38-3.12, P=0.0004), cardiovascular death (hazard ratio 2.29; 95%CI 1.28-4.24, P=0.0052), and heart failure admission (hazard ratio 1.77; 95%CI 1.13-2.77, P=0.0119). The addition of U-NGAL to the estimated glomerular filtration rate significantly improved the predictive accuracy of all-cause mortality (P=0.0083). CONCLUSIONS: In acute decompensated heart failure patients, an elevated U-NGAL level on the first day of admission was related to the development of clinical acute kidney injury and independently associated with poor prognosis.

Suppressed Production of Soluble Fms-Like Tyrosine Kinase-1 Contributes to Myocardial Remodeling and Heart Failure.

Soluble fms-like tyrosine kinase-1 (sFlt-1), an endogenous inhibitor of vascular endothelial growth factor and placental growth factor, is involved in the pathogenesis of cardiovascular disease. However, the significance of sFlt-1 in heart failure has not been fully elucidated. We found that sFlt-1 is decreased in renal failure and serves as a key molecule in atherosclerosis. In this study, we aimed to investigate the role of the decreased sFlt-1 production in heart failure, using sFlt-1 knockout mice. sFlt-1 knockout mice and wild-type mice were subjected to transverse aortic constriction and evaluated after 7 days. The sFlt-1 knockout mice had significantly higher mortality (52% versus 15%; P=0.0002) attributable to heart failure and showed greater cardiac hypertrophy (heart weight to body weight ratio, 8.95±0.45 mg/g in sFlt-1 knockout mice versus 6.60±0.32 mg/g in wild-type mice; P<0.0001) and cardiac dysfunction, which was accompanied by a significant increase in macrophage infiltration and cardiac fibrosis, than wild-type mice after transverse aortic constriction. An anti-placental growth factor-neutralizing antibody prevented pressure overload-induced cardiac hypertrophy, fibrosis, and cardiac dysfunction. Moreover, monocyte chemoattractant protein-1 expression was significantly increased in the hypertrophied hearts of sFlt-1 knockout mice compared with wild-type mice. Monocyte chemoattractant protein-1 inhibition with neutralizing antibody ameliorated maladaptive cardiac remodeling in sFlt-1 knockout mice after transverse aortic constriction. In conclusion, decreased sFlt-1 production plays a key role in the aggravation of cardiac hypertrophy and heart failure through upregulation of monocyte chemoattractant protein-1 expression in pressure-overloaded heart.

Major non-cardiac surgery is a risk factor for rapid hemodynamic progression of non-rheumatic aortic stenosis.

BACKGROUND: Inflammatory processes are suggested to play a pathogenic role in the development and progression of non-rheumatic aortic stenosis (AS). Major surgery causes an inflammatory reaction. With the increasing prevalence of non-rheumatic AS, the number of affected patients undergoing major surgery increases. We hypothesized that major non-cardiac surgery (MNCS) could accelerate the progression of non-rheumatic AS. METHODS AND RESULTS: We enrolled 218 consecutive patients with non-rheumatic AS who underwent transthoracic echocardiography (TTE) at least twice more than 6 months apart. Study patients were divided into the MNCS group and the non-MNCS group. The MNCS group consisted of patients who underwent MNCS during the TTE follow-up interval. At baseline, peak pressure gradient across the aortic valve (AVG) was similar between the groups. Also baseline clinical characteristics and TTE follow-up interval were similar. The annual rate of peak AVG increase was much higher in the MNCS group than in the non-MNCS group. The proportion of patients with rapid hemodynamic progression was much higher in the MNCS group than in the non-MNCS group. Multiple logistic regression analysis showed that MNCS was an independent predictor of rapid hemodynamic progression of non-rheumatic AS. CONCLUSIONS: The present study indicates for the first time that MNCS is associated with the rapid progression of non-rheumatic AS.

Three different morphologies of inferior vena cava thrombosis: case reports.

Inferior vena cava (IVC) thrombosis is a rare but significant complication in hospitalized patients. However, relevant information regarding IVC thrombosis, especially on its morphology, remains scarce. We present three cases of IVC thrombosis, with each showing a different morphology: mural, floating, and small polyp-like thrombus.