Very short-term blood pressure variability by pulse transit time-based measurements during night-time predicts future cardiovascular events in patients with ischemic heart disease.

Blood pressure (BP) variability (BPV) is associated with an increased risk of cardiovascular events, independent of absolute BP values. However, the predictive significance of very short-term BPV, occurring within seconds or minutes, in patients with ischemic heart disease (IHD) has yet to be established. This prospective study involved 206 consecutive hospitalized patients with IHD (mean age 67.6 years, 78.2% male) who underwent pulse transit time (PTT)-based continuous BP recording during the night-time. Very short-term BPV was assessed by standard deviation (SD), coefficient of variation (CV), and variation independent of mean (VIM) of PTT-BP. Clinical outcome data were collected. When the patients were categorized into two groups according to the median value of very short-term BPV, Kaplan-Meier analysis revealed that patients with elevated SD, CV, and VIM of systolic and diastolic PTT-BP were associated with lower event-free survival rates from the composite cardiovascular events including cardiac deaths, worsening heart failure cases, nonfatal myocardial infarctions, unplanned revascularizations, and strokes over a median follow-up of 797 days. In a multivariate Cox proportional hazards analysis adjusting for confounding variables, each parameter as a continuous variable was independently associated with adverse events. Incorporating very short-term BPV into basic models had a significant impact on risk reclassification and integrated discrimination for cardiovascular outcomes. In conclusion, the identification of patients with elevated very short-term BPV during the night-time through a PTT-driven approach helps stratify the future risk in IHD patients.

Impact of Cardio-Ankle Vascular Index on Future Cancer in Patients With Coronary Artery Disease.

Background: Cardiovascular risk factors are associated with increased risk of future cancer. However, the relationship between quantitative parameters of atherosclerosis and future cancer risk is unclear. Methods and Results: A total of 1,057 consecutive patients with coronary artery disease was divided into 2 groups according to the cutoff value of the cardio-ankle vascular index (CAVI) derived by receiver operating characteristic curve analysis: low CAVI group (CAVI <8.82; n=487), and high CAVI group (CAVI ≥8.82; n=570). Patients in the high CAVI group were older and had a higher prevalence of diabetes, chronic kidney disease, anemia and history of stroke compared with patients in the low CAVI group. There were 141 new cancers during the follow-up period. The cumulative incidence of new cancer was significantly higher in the high CAVI group than in the low CAVI group (P=0.001). In a multivariate Cox proportional hazard analysis, high CAVI was found to be an independent predictor of new cancer diagnosis (hazard ratio 1.62; 95% confidence interval 1.11-2.36; P=0.012). In the analysis of individual cancer types, high CAVI was associated with lung cancer (hazard ratio 2.85; 95% confidence interval 1.01-8.07; P=0.049). Conclusions: High CAVI was associated with the risk of future cancer in patients with coronary artery disease.

Reduced Fetuin-A Levels Are Associated With Exercise Intolerance and Predict the Risk of Adverse Outcomes in Patients With Heart Failure: The Role of Cardiac-Hepatic-Peripheral Interaction.

BACKGROUND: Exercise intolerance in heart failure arises from multifactorial pathophysiological mechanisms. Hepatokines, liver-synthesized molecules, regulate systemic metabolisms in peripheral tissues. We previously identified the hepatokine fetuin-A as being linked to liver hypoperfusion in heart failure. Here, we investigated the role of fetuin-A in connecting cardiac-hepatic-peripheral interaction. METHODS AND RESULTS: We conducted a prospective study involving 202 consecutive hospitalized patients (mean age, 56.8 years; 76.2% men) with heart failure who underwent cardiopulmonary exercise testing. We measured the serum concentration of fetuin-A by ELISA. Correlation analysis revealed a negative association between fetuin-A levels and the ratio of minimum minute ventilation to carbon dioxide production, its slope, and a tendency toward a positive correlation with peak oxygen uptake. Patients with impaired exercise tolerance exhibited lower fetuin-A levels. During a median follow-up of 1045 days, 18.3% experienced cardiac events, including 4 cardiac deaths and 33 cases of worsening heart failure. Classification and regression tree analysis identified a high-risk subgroup with lower fetuin-A (<24.3 mg/L) and impaired exercise tolerance (peak oxygen uptake<14.2 mL/kg per min). Kaplan-Meier analysis revealed that this subgroup had the highest risk of cardiac events. In a multivariable Cox proportional hazard model, the combination of lower fetuin-A and exercise intolerance was independently associated with increased risks of cardiac events. CONCLUSIONS: Reduced circulating fetuin-A levels were associated with exercise intolerance in heart failure patients. Fetuin-A could emerge as a target implicated in exercise capacity connecting cardiac-hepatic-peripheral interaction and as a valuable biomarker for predicting prognosis when combined with peak oxygen uptake.

Elevated blood bicarbonate levels and long-term adverse outcomes in patients with chronic heart failure.

AIMS: The bicarbonate (HCO3 -) buffer system is crucial for maintaining acid-base homeostasis and blood pH. Recent studies showed that elevated serum HCO3 - levels serve as an indicator of the beneficial effects of acetazolamide in improving decongestion in acute heart failure. In this study, we sought to clarify the clinical relevance and prognostic impact of HCO3 - in chronic heart failure (CHF). METHODS: This cohort study enrolled 694 hospitalized patients with CHF (mean age 68.6 ± 14.6, 62% male) who underwent arterial blood sampling and exhibited neutral pH ranging from 7.35 to 7.45. We characterized the patients based on HCO3 - levels and followed them to register cardiac events. RESULTS: Among the patients, 17.3% (120 patients) had HCO3 - levels exceeding 26 mmol/L. Patients presenting HCO3 - > 26 mmol/L were more likely to use loop diuretics and had higher serum sodium and lower potassium levels, but left ventricular ejection fraction did not differ compared with those with HCO3 - between 22 and 26 (379 patients) or those with HCO3 - < 22 mmol/L (195 patients). During a median follow-up period of 1950 days, Kaplan-Meier analysis revealed that patients with HCO3 - > 26 mmol/L had the lowest event-free survival rate from either cardiac deaths or heart failure-related rehospitalization (P < 0.01 and 0.03, respectively). In the multivariable Cox model, the presence of HCO3 - > 26 mmol/L independently predicted increased risks of each cardiac event with a hazard ratio of 2.31 and 1.69 (P < 0.01 and 0.02, respectively), while HCO3 - < 22 mmol/L was not associated with these events (hazard ratios, 0.99 and 1.19; P = 0.98 and 0.43, respectively). CONCLUSIONS: Elevated blood HCO3 - levels may signify enhanced proximal nephron activation and loop diuretic resistance, leading to long-term adverse outcomes in patients with CHF, even within a normal pH range.

Prognostic Significance of Proteomics-Discovered Circulating Inflammatory Biomarkers in Patients With Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) ultimately leads to right ventricular failure and premature death. The identification of circulating biomarkers with prognostic utility is considered a priority. As chronic inflammation is recognized as key pathogenic driver, we sought to identify inflammation-related circulating proteins that add incremental value to current risk stratification models for long-term survival in patients with PAH. METHODS AND RESULTS: Plasma levels of 384 inflammatory proteins were measured with the proximity extension assay technology in patients with PAH (n=60) and controls with normal hemodynamics (n=28). Among these, 51 analytes were significantly overexpressed in the plasma of patients with PAH compared with controls. Cox proportional hazard analyses and C-statistics were performed to assess the prognostic value and the incremental prognostic value of differentially expressed proteins. A panel of 6 proteins (CRIM1 [cysteine rich transmembrane bone morphogenetic protein regulator 1], HGF [hepatocyte growth factor], FSTL3 [follistatin-like 3], PLAUR [plasminogen activator, urokinase receptor], CLSTN2 [calsyntenin 2], SPON1 [spondin 1]) were independently associated with death/lung transplantation at the time of PAH diagnosis after adjustment for the 2015 European Society of Cardiology/European Respiratory Society guidelines, the REVEAL (Registry to Evaluate Early and Long-Term PAH Disease Management) 2.0 risk scores, and the refined 4-strata risk assessment. CRIM1, PLAUR, FSTL3, and SPON1 showed incremental prognostic value on top of the predictive models. As determined by Western blot, FSTL3 and SPON1 were significantly upregulated in the right ventricle of patients with PAH and animal models (monocrotaline-injected and pulmonary artery banding-subjected rats). CONCLUSIONS: In addition to revealing new actors likely involved in cardiopulmonary remodeling in PAH, our screening identified promising circulating biomarkers to improve risk prediction in PAH, which should be externally confirmed.

Neutrophil Extracellular Traps in Myocardial Tissue Drive Cardiac Dysfunction and Adverse Outcomes in Patients With Heart Failure With Dilated Cardiomyopathy.

BACKGROUND: The immune systems and chronic inflammation are implicated in the pathogenesis of dilated cardiomyopathy (DCM) and heart failure. However, the significance of neutrophil extracellular traps (NETs) in heart failure remains to be elucidated. METHODS: We enrolled consecutive 62 patients with heart failure with idiopathic DCM who underwent endomyocardial biopsy. Biopsy specimens were subjected to fluorescent immunostaining to detect NETs, and clinical and outcome data were collected. Ex vivo and in vivo experiments were conducted. RESULTS: The numbers of NETs per myocardial tissue area and the proportion of NETs per neutrophil were significantly higher in patients with DCM compared with non-DCM control subjects without heart failure, and the numbers of NETs were negatively correlated with left ventricular ejection fraction. Patients with DCM with NETs (n=32) showed lower left ventricular ejection fraction and higher BNP (B-type natriuretic peptide) than those without NETs (n=30). In a multivariable Cox proportional hazard model, the presence of NETs was independently associated with an increased risk of adverse cardiac events in patients with DCM. To understand specific underlying mechanisms, extracellular flux analysis in ex vivo revealed that NETs-containing conditioned medium from wild-type neutrophils or purified NET components led to impaired mitochondrial oxygen consumption of cardiomyocytes, while these effects were abolished when PAD4 (peptidyl arginine deiminase 4) in neutrophils was genetically ablated. In a murine model of pressure overload, NETs in myocardial tissue were predominantly detected in the acute phase and persisted throughout the ongoing stress. Four weeks after transverse aortic constriction, left ventricular ejection fraction was reduced in wild-type mice, whereas PAD4-deficient mice displayed preserved left ventricular ejection fraction without inducing NET formation. CONCLUSIONS: NETs in myocardial tissue contribute to cardiac dysfunction and adverse outcomes in patients with heart failure with DCM, potentially through mitochondrial dysfunction of cardiomyocytes.

Exploring Integrin α5ß1 as a Potential Therapeutic Target for Pulmonary Arterial Hypertension: Insights from Comprehensive Multicenter Preclinical Studies.

Pulmonary arterial hypertension (PAH) is characterized by obliterative vascular remodeling of the small pulmonary arteries (PA) and progressive increase in pulmonary vascular resistance (PVR) leading to right ventricular (RV) failure. Although several drugs are approved for the treatment of PAH, mortality remains high. Accumulating evidence supports a pathological function of integrins in vessel remodeling, which are gaining renewed interest as drug targets. However, their role in PAH remains largely unexplored. We found that the arginine-glycine-aspartate (RGD)-binding integrin α5ß1 is upregulated in PA endothelial cells (PAEC) and PA smooth muscle cells (PASMC) from PAH patients and remodeled PAs from animal models. Blockade of the integrin α5ß1 or depletion of the α5 subunit resulted in mitotic defects and inhibition of the pro-proliferative and apoptosis-resistant phenotype of PAH cells. Using a novel small molecule integrin inhibitor and neutralizing antibodies, we demonstrated that α5ß1 integrin blockade attenuates pulmonary vascular remodeling and improves hemodynamics and RV function in multiple preclinical models. Our results provide converging evidence to consider α5ß1 integrin inhibition as a promising therapy for pulmonary hypertension. One sentence summary: The α5ß1 integrin plays a crucial role in pulmonary vascular remodeling.

Collagen Triple Helix Repeat-Containing Protein 1 Is a Novel Biomarker of Right Ventricular Involvement in Pulmonary Hypertension.

BACKGROUND: Pulmonary hypertension leads to right ventricular failure, which is a major determinant of prognosis. Circulating biomarkers for right ventricular function are poorly explored in pulmonary hypertension. This study aimed to clarify the significance of collagen triple helix repeat-containing protein 1 (CTHRC1) as a biomarker of right ventricular failure in pulmonary hypertension. METHODS: A monocrotaline-induced pulmonary hypertension rat model was used to evaluate right ventricular CTHRC1 expression and its relationship with fibrosis. Next, human plasma CTHRC1 levels were measured in controls (n = 20), pulmonary arterial hypertension (n = 46), and patients with chronic thromboembolic pulmonary hypertension (CTEPH) (n = 64) before the first and after the final balloon pulmonary angioplasty. RESULTS: CTHRC1 expression was higher in the right ventricles of rats with monocrotaline-induced pulmonary hypertension than in those of controls. CTHRC1 was colocalized with vimentin and associated with fibrosis in the right ventricles. Plasma CTHRC1 levels were higher in human patients with pulmonary arterial hypertension (P = 0.006) and CTEPH (P = 0.011) than in controls. Plasma CTHRC levels were correlated with B-type natriuretic peptide (R = 0.355, P < 0.001), tricuspid lateral annular peak systolic velocity (R = -0.213, P = 0.029), and right ventricular fractional area change (R = -0.225, P = 0.017). Finally, plasma CTHRC1 levels were decreased after the final balloon pulmonary angioplasty (P < 0.001) in CTEPH. CONCLUSIONS: CTHRC1 can be a circulating biomarker associated with right ventricular function and fibrosis in pulmonary hypertension and might reflect the therapeutic efficacy of balloon pulmonary angioplasty in CTEPH.

Targeting N-Myristoylation Through NMT2 Prevents Cardiac Hypertrophy and Heart Failure.

Protein diversity can increase via N-myristoylation, adding myristic acid to an N-terminal glycine residue. In a murine model of pressure overload, knockdown of cardiac N-myristoyltransferase 2 (NMT2) by adeno-associated virus 9 exacerbated cardiac dysfunction, remodeling, and failure. Click chemistry-based quantitative chemical proteomics identified substrate proteins of N-myristoylation in cardiac myocytes. N-myristoylation of MARCKS regulated angiotensin II-induced cardiac pathological hypertrophy by preventing activations of Ca2+/calmodulin-dependent protein kinase II and histone deacetylase 4 and histone acetylation. Gene transfer of NMT2 to the heart reduced cardiac dysfunction and failure, suggesting targeting N-myristoylation through NMT2 could be a potential therapeutic approach for preventing cardiac remodeling and heart failure.

A Case of Giant Goiter Associated with Airway Stenosis Caused by Long-Term Intravenous Epoprostenol Therapy for Idiopathic Pulmonary Arterial Hypertension.

Idiopathic pulmonary arterial hypertension is a progressive and life-threatening disease with pulmonary vasculature remodeling, leading to right-sided heart failure. Epoprostenol (prostaglandin I2) is highly recommended for patients with severe pulmonary arterial hypertension (PAH) categorized by the World Health Organization as functional class III or IV. It has been reported that prostaglandin I2 analogs can cause thyroid gland swelling and abnormal thyroid function. A 34-year-old woman was diagnosed with idiopathic pulmonary arterial hypertension and started receiving continuous intravenous epoprostenol. Three years after starting epoprostenol, she began complaining of neck swelling and was diagnosed with Graves' disease. The patient's thyroid function was controlled by thiamazole and levothyroxine; nevertheless, her thyroid gland enlargement worsened as the epoprostenol dose was titrated. After 20 years, she developed respiratory failure with a giant goiter leading to airway stenosis, and she passed away. The pathological autopsy confirmed a massive goiter associated with hyperthyroidism and airway stenosis. We experienced a case of idiopathic pulmonary hypertension with a giant goiter and airway stenosis after long-term intravenous epoprostenol therapy.

Prognostic Role of Circulating LTBP-2 in Patients With Dilated Cardiomyopathy: A Novel Biomarker Reflecting Extracellular Matrix LTBP-2 Accumulation.

BACKGROUND: Dilated cardiomyopathy (DCM) is a life-threatening disease related to heart failure. Extracellular matrix proteins have an important role in the pathogenesis of DCM. Latent transforming growth factor beta-binding protein 2 (LTBP-2), a type of extracellular matrix protein, has not been investigated in DCM. METHODS: First, we compared plasma LTBP-2 levels in 131 patients with DCM who underwent endomyocardial biopsy and 44 controls who were matched for age and sex and had no cardiac abnormalities. Next, we performed immunohistochemistry for LTBP-2 on endomyocardial biopsy specimens and followed the DCM patients for ventricular assist device (VAD) implantation, cardiac death, and all-cause death. RESULTS: Patients with DCM had elevated plasma LTBP-2 levels compared with controls (P < 0.001). Plasma LTBP-2 levels were positively correlated with LTBP-2-positive fraction in the myocardium from the biopsy specimen. When patients with DCM were divided into 2 groups according to LTBP-2 levels, Kaplan-Meier analysis demonstrated that patients with high plasma LTBP-2 were associated with increased incidences of cardiac death/VAD and all-cause death/VAD. In addition, patients with high myocardial LTBP-2-positive fractions were associated with increased incidences of these adverse outcomes. Multivariable Cox proportional hazard analysis showed that plasma LTBP-2 and myocardial LTBP-2-positive fraction were independently associated with adverse outcomes. CONCLUSIONS: Circulating LTBP-2 can serve as a biomarker to predict adverse outcomes, reflecting extracellular matrix LTBP-2 accumulation in the myocardium in DCM.

Effects of continuous positive airway pressure on very short-term blood pressure variability associated with sleep-disordered breathing by pulse transit time-based blood pressure measurements.

BACKGROUND: Blood pressure (BP) variability (BPV) is a predictor of cardiovascular outcomes independently of BP absolute values. We previously reported that pulse transit time (PTT) enables monitoring beat-to-beat BP, identifying a strong relationship between the extent of very short-term BPV and the severity of sleep-disordered breathing (SDB). Here, we investigated the effects of continuous positive airway pressure (CPAP) on very short-term BPV. METHODS: We studied 66 patients (mean age 62 years old, 73% male) with newly diagnosed SDB who underwent full polysomnography on two consecutive days for diagnosis (baseline) and CPAP, together with PTT-driven BP continuous recording. PTT index was defined as the average number of acute transient rises in BP (≥12 mmHg) within 30 s/h. RESULTS: CPAP treatment effectively improved SDB parameters, and attenuated PTT-based BP absolute values during the night-time. Very short-term BPV that includes PTT index and standard deviation (SD) of systolic PTT-BP was significantly reduced by CPAP therapy. The changes in PTT index from baseline to CPAP were positively correlated with the changes in apnea-hypopnea index, obstructive apnea index (OAI), oxygen desaturation index, minimal SpO 2 , and mean SpO 2 . Multivariate regression analysis revealed that changes in OAI and minimal SpO 2 , as well as heart failure, were the independent factors in determining the reduction of PTT index following CPAP. CONCLUSION: PTT-driven BP monitoring discovered the favorable effects of CPAP on very short-term BPV associated with SDB events. Targeting very short-term BPV may be a novel approach to identifying individuals who experience greater benefits from CPAP.

G9a/GLP Targeting Ameliorates Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is characterized by progressive vascular remodeling of small pulmonary arteries (PAs) causing sustained elevation of PA pressure, right ventricular failure, and death. Similar to cancer cells, PA smooth muscle cells (PASMCs), which play a key role in pulmonary vascular remodeling, have adopted multiple mechanisms to sustain their survival and proliferation in the presence of stress. The histone methyltransferase G9a and its partner protein GLP (G9a-like protein) have been shown to exert oncogenic effects and to serve as a buffer against an exaggerated transcriptional response. Therefore, we hypothesized that upregulation of G9a and GLP in PAH plays a pivotal role in pulmonary vascular remodeling by maintaining the abnormal phenotype of PAH-PASMCs. We found that G9a is increased in PASMCs from patients with PAH as well as in remodeled PAs from animal models. Pharmacological inhibition of G9a/GLP activity using BIX01294 and UNC0642 significantly reduced the prosurvival and proproliferative potentials of cultured PAH-PASMCs. Using RNA sequencing, further exploration revealed that G9a/GLP promotes extracellular matrix production and affords protection against the negative effects of an overactive stress response. Finally, we found that therapeutic treatment with BIX01294 reduced pulmonary vascular remodeling and lowered mean PA pressure in fawn-hooded rats. Treatment of Sugen/hypoxia-challenged mice with BIX01294 also improved pulmonary hemodynamics and right ventricular function. In conclusion, these findings indicate that G9a/GLP inhibition may represent a new therapeutic approach in PAH.

Clonal hematopoiesis and cardiovascular diseases: role of JAK2V617F.

Bone marrow-derived hematopoietic and immune cells play important roles in the onset and progression of cardiovascular diseases. Recent genetic analyses have discovered that clonal expansion of bone marrow hematopoietic stem/progenitor cells carrying somatic gene mutations is common and is increasing with age in healthy individuals who do not show any hematologic disorders, termed as clonal hematopoiesis. It is emergingly recognized that clonal hematopoiesis is a significant risk factor for cardiovascular diseases rather than a cumulative incidence risk of blood cancers. JAK2V617F, a gain-of-function mutation, has been identified as one of the most important mutations in clonal hematopoiesis as well as the most frequent driver mutation in myeloproliferative neoplasms. Hematopoietic cell clones harboring JAK2V617F are causally associated with the pathogenesis of cardiovascular diseases. Here, we will review the key of JAK2V617F-mediated clonal hematopoiesis including identification, prevalence, and biological impacts, linking to cardiovascular diseases and the related mechanisms. Clonal hematopoiesis with JAK2V617F may be a novel therapeutic target for cardiovascular diseases, connected to precision medicines by detecting its presence.

Transcriptional profiling unveils molecular subgroups of adaptive and maladaptive right ventricular remodeling in pulmonary hypertension.

Right ventricular (RV) function is critical to prognosis in all forms of pulmonary hypertension. Here we perform molecular phenotyping of RV remodeling by transcriptome analysis of RV tissue obtained from 40 individuals, and two animal models of RV dysfunction of both sexes. Our unsupervised clustering analysis identified 'early' and 'late' subgroups within compensated and decompensated states, characterized by the expression of distinct signaling pathways, while fatty acid metabolism and estrogen response appeared to underlie sex-specific differences in RV adaptation. The circulating levels of several extracellular matrix proteins deregulated in decompensated RV subgroups were assessed in two independent cohorts of individuals with pulmonary arterial hypertension, revealing that NID1, C1QTNF1 and CRTAC1 predicted the development of a maladaptive RV state, as defined by magnetic resonance imaging parameters, and were associated with worse clinical outcomes. Our study provides a resource for subphenotyping RV states, identifying state-specific biomarkers, and potential therapeutic targets for RV dysfunction.

Utility of a novel wearable electrode embedded in an undershirt for electrocardiogram monitoring and detection of arrhythmias.

BACKGROUND: A 12-lead electrocardiogram (ECG) and Holter ECG have been established as gold standards for detection of arrhythmias. Recently, wearable ECG monitoring devices have been available. Our purpose of the present study was to investigate whether a novel wearable electrode embedded in an undershirt is useful for ECG monitoring and detection of arrhythmias. METHODS: We studied 31 consecutive hospitalized patients who underwent catheter ablation of tachyarrhythmias. Patients equipped a wearable electrode and a lead CM5 of Holter ECG simultaneously, and total heart beats, maximum heart rate (HR), mean HR, minimum HR, detections of arrhythmias, such as atrial fibrillation, non-sustained ventricular tachycardia, and premature ventricular contractions (Lown's grade >II), were compared between the two methods using a Holter ECG analysis software. RESULTS: Median recording time of ECG by wearable electrodes was 12.6 hours. Strong correlations between the two methods were observed in total heart beats (R = 0.999, P <0.001), maximum HR (R = 0.997, P <0.001), mean HR (R = 0.999, P <0.001), minimum HR (R = 0.989, P <0.001) and QRS duration (R = 0.900, P <0.001). Bland-Altman analysis showed excellent concordance between each parameter measured by two methods. In addition, the detection of atrial fibrillation (nine events), non-sustained ventricular tachycardia (two events), and premature ventricular contractions of Lown's grade >II (five events) were concordant in two methods. In addition, there were no significant difference in parameters of time-domain and frequency-domain analyses of heart rate variability between the two methods. CONCLUSIONS: The usefulness of a novel electrode embedded in an undershirt is equivalent to that of a Holter ECG in monitoring the ECG and detection of arrythmias.

DNA Damage Induced by Radiation Exposure from Cardiac Catheterization.

Almost 40% of medical radiation exposure is related to cardiac imaging or intervention. However, the biological effects of low-dose radiation from medical imaging remain largely unknown. This study aimed to evaluate the effects of ionized radiation from cardiac catheterization on genomic DNA integrity and inflammatory cytokines in patients and operators.Peripheral mononuclear cells (MNCs) were isolated from patients (n = 51) and operators (n = 35) before and after coronary angiography and/or percutaneous coronary intervention. The expression of γH2AX, a marker for DNA double-strand breaks, was measured by immunofluorescence. Dicentric chromosomes (DICs), a form of chromosome aberrations, were assayed using a fluorescent in situ hybridization technique.In the patient MNCs, the numbers of γH2AX foci and DICs increased after cardiac catheterization by 4.5 ± 9.4-fold and 71 ± 122%, respectively (P < 0.05 for both). The mRNA expressions of interleukin (IL)-1α, IL-1ß, leukemia inhibitory factor, and caspase-1 were significantly increased by radiation exposure from cardiac catheterization. The increase in IL-1ß was significantly correlated with that of γH2AX, but not with the dose area product. In the operators, neither γH2AX foci nor the DIC level was changed, but IL-1ß mRNA was significantly increased. The protein expression of IκBα was significantly decreased in both groups.DNA damage was increased in the MNCs of patients, but not of operators, who underwent cardiac catheterization. Inflammatory cytokines were increased in both the patients and operators, presumably through NF-κB activation. Further efforts to reduce radiation exposure from cardiac catheterization are necessary for both patients and operators.

PARP1-PKM2 Axis Mediates Right Ventricular Failure Associated With Pulmonary Arterial Hypertension.

The authors show that increased poly(adenosine diphosphate-ribose) polymerase 1 (PARP1) and pyruvate kinase muscle isozyme 2 (PKM2) expression is a common feature of a decompensated right ventricle in patients with pulmonary arterial hypertension and animal models. The authors find in vitro that overactivated PARP1 promotes cardiomyocyte dysfunction by favoring PKM2 expression and nuclear function, glycolytic gene expression, activation of nuclear factor κB-dependent proinflammatory factors. Pharmacologic and genetic inhibition of PARP1 or enforced tetramerization of PKM2 attenuates maladaptive remodeling improving right ventricular (RV) function in multiple rodent models. Taken together, these data implicate the PARP1/PKM2 axis as a critical driver of maladaptive RV remodeling and a new promising target to directly sustain RV function in patients with pulmonary arterial hypertension.

Myocardial T-Lymphocytes as a Prognostic Risk-Stratifying Marker of Dilated Cardiomyopathy　- Results of the Multicenter Registry to Investigate Inflammatory Cell Infiltration in Dilated Cardiomyopathy in Tissues of Endomyocardial Biopsy (INDICATE Study).

BACKGROUND: Dilated cardiomyopathy (DCM) associated with inflammation is diagnosed by endomyocardial biopsy; patients with this have a poorer prognosis than patients without inflammation. To date, standard diagnostic criteria have not been established.Methods and Results: This study analyzed clinical records and endomyocardial biopsy samples of 261 patients with DCM (201 males, median left ventricular ejection fraction; 28%) from 8 institutions in a multicenter retrospective study. Based on the European Society of Cardiology criteria and CD3 (T-lymphocytes) and CD68 (macrophages) immunohistochemistry, 48% of patients were categorized as having inflammatory DCM. For risk-stratification, we divided patients into 3 groups using Akaike Information Criterion/log-rank tests, which can determine multiple cut-off points: CD3+-Low, <13/mm2(n=178, 68%); CD3+-Moderate, 13-24/mm2(n=58, 22%); and CD3+-High, ≥24/mm2(n=25, 10%). The survival curves for cardiac death or left ventricular assist device implantation differed significantly among the 3 groups (10-year survival rates: CD3+-Low: 83.4%; CD3+-Moderate: 68.4%; CD3+-High: 21.1%; Log-rank P<0.001). Multivariate Cox analysis revealed CD3+count as a potent independent predictive factor for survival (fully adjusted hazard ratio: CD3+-High: 5.70, P<0.001; CD3+-Moderate: 2.64, P<0.01). CD3+-High was also associated with poor left ventricular functional and morphological recovery at short-term follow up. CONCLUSIONS: Myocardial CD3+T-lymphocyte infiltration has a significant prognostic impact in DCM and a 3-tiered risk-stratification model could be helpful to refine patient categorization.