Ginkgetin effectively mitigates collagen and AA-induced platelet activation via PLCγ2 but not cyclic nucleotide-dependent pathway in human.

Platelets assume a pivotal role in the cardiovascular diseases (CVDs). Thus, targeting platelet activation is imperative for mitigating CVDs. Ginkgetin (GK), from Ginkgo biloba L, renowned for its anticancer and neuroprotective properties, remains unexplored concerning its impact on platelet activation, particularly in humans. In this investigation, we delved into the intricate mechanisms through which GK influences human platelets. At low concentrations (0.5-1 µM), GK exhibited robust inhibition of collagen and arachidonic acid (AA)-induced platelet aggregation. Intriguingly, thrombin and U46619 remained impervious to GK's influence. GK's modulatory effect extended to ATP release, P-selectin expression, intracellular calcium ([Ca2+ ]i) levels and thromboxane A2 formation. It significantly curtailed the activation of various signaling cascades, encompassing phospholipase Cγ2 (PLCγ2)/protein kinase C (PKC), phosphoinositide 3-kinase/Akt/glycogen synthase kinase-3ß and mitogen-activated protein kinases. GK's antiplatelet effect was not reversed by SQ22536 (an adenylate cyclase inhibitor) or ODQ (a guanylate cyclase inhibitor), and GK had no effect on the phosphorylation of vasodilator-stimulated phosphoproteinSer157 or Ser239 . Moreover, neither cyclic AMP nor cyclic GMP levels were significantly increased after GK treatment. In mouse studies, GK notably extended occlusion time in mesenteric vessels, while sparing bleeding time. In conclusion, GK's profound impact on platelet activation, achieved through inhibiting PLCγ2-PKC cascade, culminates in the suppression of downstream signaling and, ultimately, the inhibition of platelet aggregation. These findings underscore the promising therapeutic potential of GK in the CVDs.

Hydralazine combined with conventional therapy improved outcomes in severe systolic dysfunction and mitral regurgitation.

AIMS: Patients with heart failure (HF) and reduced left ventricular ejection fraction (LVEF) accompanied by significant mitral regurgitation (MR) had poor outcome. Several vasodilator trials showed neutral results. We aimed to investigate the effect of early up-titration of hydralazine combined with conventional treatment in acute HF with severe systolic dysfunction and significant MR. METHODS AND RESULTS: The study was open-labelled, one-to-one ratio randomized designed. Consecutively hospitalized patients with decompensated HF symptoms, LVEF < 35%, and MR more than moderate severity were enrolled after exclusion. All participants with inadequate preload should have intake promotion with/without fluid supply. Patients receiving evidence-based medications (EBMs) as conventional treatment served as the control. Hydralazine + conventional treatment group received up-titration of hydralazine at Days 1-5 of the index admission combined with EBMs and throughout the course of follow-up. The endpoints included cardiovascular (CV) death and HF rehospitalization. Totally, 408 patients were enrolled (203 in conventional treatment and 205 in hydralazine + conventional treatment). The mean follow-up period was 3.5 years. The mean dose of hydralazine was 191 mg at index admission and 264 mg at study end in hydralazine + conventional treatment group. Both groups did not significantly differ in prescription rates and dosages of EBMs (all P > 0.05) at study end. Side effects did not differ between the two groups. Finally, 51% (104 out of 203 cases) reached endpoints in conventional group and 34.6% (71 out of 205 cases) in hydralazine + conventional treatment group, which had a significant reduction in CV events (hazard ratio 0.613, 95% confidence interval 0.427-0.877, P < 0.001). In-hospital death during the index admission was significantly higher in conventional group (5.4% vs. 0.5%, respectively; P = 0.001). CONCLUSIONS: When administered without inadequate preload, combining early up-titration of hydralazine with EBMs improves outcome in patients with severe systolic dysfunction and significant MR, and it is safe and well tolerated.

The Effects of Different Types of Sleep Disorder on Colorectal Cancer: A Nationwide Population-Based Cohort Study.

The impact of sleep disorders (SDs), particularly sleep apnea (SA), on the development of colorectal cancer (CRC) has been the subject of significant research. However, the potential contribution of other SDs to the incidence of CRC remains unexplored. The objective of this study was to examine the effects of SDs on the risk of developing CRC. This study assessed CRC risk among individuals diagnosed with SDs compared with age- and sex-matched unaffected individuals. A longitudinal, nationwide, population-based cohort study was conducted using data from the Taiwan National Health Insurance Research Database (NHIRD) encompassing 177,707 individuals diagnosed with SDs and 177,707 matched controls. Cox proportional hazard regression analysis was used to determine the relative increased risk of CRC in individuals with SDs and specific subgroups of SDs. The CRC incidences were 1.32-fold higher (95% CI 1.23-1.42) in the overall SD cohort, 1.17-fold higher (95% CI 0.82-1.68) in the SA cohort, 1.42-fold higher (95% CI 1.31-1.55) in the insomnia cohort, 1.27-fold higher (95% CI 1.17-1.38) in the sleep disturbance cohort, and 1.00-fold higher (95% CI 0.77-1.29) in the other SD cohort, after adjusting for age, sex, and comorbidities.

Early predicting improvement of severe systolic heart failure by left atrial volume.

Left atrium (LA) modulates left ventricle (LV) filling and cardiac performance. We aimed to assess the effect of heart failure (HF) therapy on LA and LV function, and the relationship between LA/LV improvement and clinical outcome in acute HF with reduced LV ejection fraction (LVEF). Totally, 224 hospitalized patients with acute HF and LVEF < 35% were enrolled and underwent echocardiography. They all received maximal tolerable doses of evidence-based medications. Patients received echocardiographic measurements at each visit including stroke volume, LVEF, LA minimal/maximal volume (LAVmin/LAVmax), LA expansion index, and tissue Doppler parameters. The threshold of LV functional improvement was LVEF > 45% ever occurred before study end. During the mean follow-up of 6.3 years, 62 cases improved well, mean LVEF 49 ± 5% at study end. The reduction of LV filling pressure occurring as early as 2 weeks later, LV systolic function improvement took longer (> 1 month). The reductions in LAVmin and LAVmax between initial stabilization and 2 weeks after HF treatment (Initial-2 W) and the increase of LA expansion index (Initial-2 W) were associated independently with LVEF improvement (p 0.002, 0.006, and 0.007, respectively). The best predictor of LVEF improvement was LAVmin reduction (Initial-2 W) > 5 ml with 77% sensitivity, 76% specificity. Cox proportional hazard regression analyses for cardiovascular events revealed LVEF improvement reduced 74% of events (hazard ratio 0.264, 95% CI 0.192-0.607, p < 0.0001); and LA expansion index (per 1% increase) reduced 14% of events (hazard ratio 0.862, 95% CI 0.771-0.959, p < 0.0001). The early reduction of LAV (Initial-2 W), especially LAVmin, is a powerful early predictor of LVEF improvement. Its occurrence reduces cardiovascular events significantly. ClinicalTrials.gov number: NCT01307722.

Glabridin, a Bioactive Flavonoid from Licorice, Effectively Inhibits Platelet Activation in Humans and Mice.

Platelets are crucial for hemostasis and arterial thrombosis, which may lead to severe cardiovascular diseases (CVDs). Thus, therapeutic agents must be developed to prevent pathological platelet activation. Glabridin, a major bioalkaloid extracted from licorice root, improves metabolic abnormalities (i.e., obesity and diabetes) and protects against CVDs and neuronal disorders. To the best of our knowledge, no studies have focused on glabridin's effects on platelet activation. Therefore, we investigated these effects in humans and mice. Glabridin exhibited the highest inhibitory effects on collagen-stimulated platelet aggregation and moderate effects on arachidonic-acid-stimulated activation; however, no effects were observed for any other agonists (e.g., thrombin or U46619). Glabridin evidently reduced P-selectin expression, ATP release, and intracellular Ca2+ ([Ca2+]i) mobilization and thromboxane A2 formation; it further reduced the activation of phospholipase C (PLC)γ2/protein kinase C (PKC), phosphoinositide 3-kinase (PI3K)/Akt/glycogen synthase kinase-3ß (GSK3ß), mitogen-activated protein kinase (MAPK), and NF-κB. In mice, glabridin reduced the mortality rate caused by acute pulmonary thromboembolism without altering bleeding time. Thus, glabridin effectively inhibits the PLCγ2/PKC cascade and prevents the activation of the PI3K/Akt/GSK3ß and MAPK pathways; this leads to a reduction in [Ca2+]i mobilization, which eventually inhibits platelet aggregation. Therefore, glabridin may be a promising therapeutic agent for thromboembolic disorders.

Systolic pulmonary regurgitation affects the outcome of patients with severe systolic heart failure.

AIMS: Little is known of the impact of systolic pulmonary regurgitation (PR) on acute decompensated heart failure (HF). We assessed the prevalence and prognostic significance of systolic PR in patients with severe HF. METHODS AND RESULTS: According to recent 10 year echocardiographic database of E-Da Hospital, 533 patients admitted for first systolic heart failure (HF) and left ventricular ejection fraction <35% were under investigation. Systolic PR was defined as the presence of pulmonary backward flow persistent after QRS in electrocardiogram. Isovolumic contraction/relaxation time and myocardial performance index were derived by tissue Doppler imaging. Right ventricular (RV) function was assessed by RV fractional area change. Estimated pulmonary vascular resistance (PVR) was assessed by the ratio of peak tricuspid regurgitation velocity to the RV outflow tract time-velocity integral. The factors associated with systolic PR were assessed by multivariate logistic regression. Cox proportional regression analyses were used to estimate the impact of cardiovascular events including HF rehospitalization and cardiovascular death. For estimated prevalence of 5480 control subjects, echocardiographic screens in those with normal left ventricular ejection fraction were performed. Of 533 systolic HF cases, 143 (26.8%) had systolic PR during indexed hospitalization. Among 143 cases, 86% systolic PR disappeared during late follow-up. In control subjects, 0.3% (18/5480) had systolic PR. Systolic PR correlated to RV dysfunction, estimated PVR, E/e', sign of low cardiac output, and pulmonary oedema. Systolic PR was associated independently with further cardiovascular events (hazard ratio 2.266, 95% confidence interval 1.682-3.089, P < 0.0001) including cardiovascular death and HF rehospitalization. CONCLUSIONS: Systolic PR is not uncommon in systolic HF and is associated with high PVR and RV dysfunction. Systolic PR significantly impacts cardiovascular outcome.

Malnutrition Affects the Outcomes of Patients with Low-Output Heart Failure and Congestion.

BACKGROUND: This study aimed to investigate the relationship between malnutrition and outcomes in patients with decompensated severe systolic heart failure (HF) focusing on clinical presentations and medication use. METHODS: This study prospectively enrolled 108 patients admitted for severe systolic HF with a left ventricular (LV) ejection fraction < 35%, low cardiac output, and high LV filling pressure. Five patients died during the index hospitalization, and the remaining 103 patients were followed up for 2 years. The primary endpoints were HF rehospitalization and all-cause mortality. Nutritional risk index (NRI) was calculated as (1.519 × serum albumin, g/L) + (41.7 × body weight/ideal body weight). RESULTS: Forty-four patients reached the study endpoints. An NRI ≤ 93 predicted events. The NRI ≤ 93 group had higher pulmonary artery systolic pressure, more edema over dependent parts, longer hospital stay, and more primary endpoints compared to the NRI > 93 group. The NRI ≤ 93 group received fewer evidence-based medications and more loop diuretics compared to the NRI > 93 group. NRI was an independent predictor of cardiovascular events [hazard ratio 0.902; 95% confidence interval (CI) 0.814-0.982 per 1 point increase; p = 0.012]. Low NRI was associated with a significantly higher use of loop diuretics [odds ratio (OR) 2.75; 95% CI 1.046-5.647; p = 0.004] and significantly lower use of beta blockers (OR 0.541; 95% CI 0.319-0.988; p = 0.002). CONCLUSIONS: Malnutrition assessed using the NRI was associated with cardiovascular events in the patients with severe systolic HF with low cardiac output and high LV filling pressure. Low NRI was associated with more diuretic and less beta blocker use.

Risk of nasopharyngeal carcinoma in patients with chronic rhinosinusitis: A nationwide propensity score matched study in Taiwan.

AIMS: Chronic inflammation is linked to cancer. This study aims to evaluate the association between chronic rhinosinusitis (CRS) and nasopharyngeal carcinoma (NPC) through a Taiwanese nationwide database. METHODS: We used the National Health Insurance Research Database between January 1, 2003, and December 31, 2012. The starting date is either the date of the first clinical visit or the diagnosis of CRS. Patients were followed up until the first occurrence of target disease or the last date of medical record. Propensity score 1 to 2 matching was used to match pairs of patients with/without CRS. RESULTS: A total of 951 380 eligible patients were included in our study, with 36 210 patients diagnosed with CRS. After 1 to 2 propensity score matching, non-CRS cohort consisted of 69 258 patients and CRS cohort consisted of 34 629 patients. CRS was associated with the risk of developing NPC (adjusted OR = 2.23; 95% CI, 1.61-3.09). However, no significant association among CRS and NPC was observed in patients followed up for more than 1 year (adjusted OR = 1.16; 95% CI, 0.76-1.78). CONCLUSIONS: Patients with CRS diagnosis have relationship with developing NPC within 1 year of follow-up, but not for longer intervals. The short-term association may be due to reversed causation or biased diagnosis. Accordingly, the study suggests CRS a weak role for NPC.

Comparisons of Left Atrial Functional Parameters with Left Ventricular Diastolic Dysfunction in a Large Taiwanese Population with Normal Left Ventricular Ejection Fraction According to Age.

BACKGROUND: Recent studies have shown that left atrial (LA) volume is a sensitive morphophysiological indicator of the severity of LV dysfunction and may also be a useful index of cardiovascular risk. In this study, we performed comparisons among left atrial (LA) functional parameters for predicting age-related diastolic dysfunction. METHODS: Echocardiography was performed in 2248 healthy participants with a low possibility of heart disease according to the decennium of age, and reference values were established. Progressive diastolic dysfunction paralleled increasing age and could be well identified by traditional and advanced echocardiographic parameters, including mitral inflow pattern, tissue Doppler parameters, and LA volume. RESULTS: Regarding LA functional parameters analyzed based on the decennium of age, left atrial ejection fraction (LAEF) and emptying fraction could not represent aging diastolic dysfunction well, but LA expansion index ((Volmax - Volmin) × 100% / Volmin) could. Volmax indicated maximal LA volume and Volmin indicated minimal LA volume. In assessments of diastolic dysfunction with receiver operating characteristic curve analysis, the best cut-off value of LA expansion index was < 100%, with an area under the curve (AUC) of 0.86, sensitivity of 80%, and specificity of 74%. LAEF < 30% (AUC 0.76, sensitivity 67%, specificity 70%) and LA emptying fraction < 50% (AUC 0.80, sensitivity 72%, specificity 71%) were also useful but performed less well. CONCLUSIONS: Compared with other LA functional parameters, LA expansion index can well represent age-related diastolic dysfunction.

Utility of Left Atrial Expansion Index and Stroke Volume in Management of Chronic Systolic Heart Failure.

BACKGROUND: Titration of evidence-based medications, important for treating heart failure (HF), is often underdosed by symptom-guided treatment. The aim of this study was to investigate, using echocardiographic parameters, stroke volume and left ventricular (LV) filling pressure to guide up-titration of medications, increasing prognostic benefits. METHODS: A total of 765 patients with chronic HF and severely reduced LV ejection fractions (<35%), referred from 2008 to 2016, were prospectively studied. Echocardiographic guidance was performed in 149 patients. LV filling pressure was assessed by left atrial expansion index, and stroke volume was estimated from diameter and time-velocity integral in the LV outflow tract. Up-titration of evidence-based medications and adjustment for side effects or worsening clinical conditions according to those parameters were performed. Propensity score matching was used to match pairs of patients with (n = 110) or without (n = 110) echocardiographic guidance. End points were 4-year frequencies of HF hospitalization and all-cause mortality. RESULTS: During a mean follow-up time of 4.1 years, rates of adverse events were 58 (52.7%) with no echocardiographic guidance and 36 (32.7%) with echocardiographic guidance (P < .0001). Echocardiography provided effective guidance to reduce prescribing frequency and dose of diuretics and to promote evidence-based medication prescription. It reduced HF rehospitalization and all-cause mortality. By multivariate analysis, prognostic improvement was associated with up-titration of medications with echocardiographic guidance. CONCLUSIONS: There was a statistically significant difference in long-term prognosis between propensity score-matched pairs of patients with chronic severe HF with and without echocardiographic guidance. These findings need further validation in large prospective clinical trials.

Detection of common sequence variations of familial hypercholesterolemia in Taiwan using DNA mass spectrometry.

BACKGROUND: Familial hypercholesterolemia (FH) is a heterogeneous autosomal dominant disease. The genetic heterogeneity of FH requires low-cost, high-throughput, and rapid mutation detection technology to efficiently integrate genetic screening into clinical practice. OBJECTIVES: The aims of the study were to customize the MassARRAY assay to (1) establish an FH mutation assay panel, comprising known point mutations located on FH-causing genes and (2) test the feasibility of the assay for screening FH patients residing in Taiwan who fit the clinical criteria of FH diagnosis. METHODS: We designed a custom Agena iPLEX assay to detect 68 point mutations on FH-causing genes. First, the assay performance was verified by analyzing 180 previously sequenced subjects (120 with point mutations and 60 healthy controls), with the results being compared with those of Sanger DNA sequencing. Second, a blind study was carried out on 185 FH probands (44 definite FH and 141 probable/possible FH). RESULTS: In the first part of this study, only 1 discrepancy was found between the Agena iPLEX and Sanger sequencing genotyping results. In the blind study, a total of 62 probands with mutations were identified by both techniques. Five mutations were detected by Sanger sequencing assay only. The detection sensitivity and specificity rates of Agena iPLEX were 92.5% and 100%, respectively, in the blind study. The hands-on time for the Agena iPLEX assay was around 1 day. CONCLUSIONS: The custom-designed Agena iPLEX assay has high specificity and sensitivity for FH genetic screening. Considering its low cost, rapidity, and flexibility, the assay has great potential to be incorporated into FH screening in Taiwan.

Renal function decline predicted by left atrial expansion index in non-diabetic cohort with preserved systolic heart function.

AIMS: Since natriuretic peptide and troponin are associated with renal prognosis and left atrial (LA) parameters are indicators of subclinical cardiovascular abnormalities, this study investigated whether LA expansion index can predict renal decline. METHODS AND RESULTS: This study analysed 733 (69% male) non-diabetic patients with sinus rhythm, preserved systolic function, and estimated glomerular filtration rate (eGFR) higher than 60 mL/min/1.73 m2. In all patients, echocardiograms were performed and LA expansion index was calculated. Renal function was evaluated annually. The endpoint was a downhill trend in renal function with a final eGFR of <60 mL/min/1.73 m2. Rapid renal decline was defined as an annual decline in eGFR >3 mL/min/1.73 m2. The median follow-up time was 5.2 years, and 57 patients (7.8%) had renal function declines (19 had rapid renal declines, and 38 had incidental renal dysfunction). Events were associated with left ventricular mass index, LA expansion index, and heart failure during the follow-up period. The hazard ratio was 1.426 (95% confidence interval, 1.276-1.671; P < 0.0001) per 10% decrease in LA expansion index and was independently associated with an increased event rate. Compared with the highest quartile for the LA expansion index, the lowest quartile had a 9.7-fold risk of renal function decline in the unadjusted model and a 6.9-fold risk after adjusting for left ventricular mass index and heart failure during the follow-up period. CONCLUSIONS: Left atrial expansion index is a useful early indicator of renal function decline and may enable the possibility of early intervention to prevent renal function from worsening. CLINICALTRIALS. GOV NUMBER: NCT01171040.

Diastolic Heart Failure Predicted by Left Atrial Expansion Index in Patients with Severe Diastolic Dysfunction.

BACKGROUND: Left atrial (LA) echocardiographic parameters are increasingly used to predict clinically relevant cardiovascular events. The study aims to evaluate the LA expansion index (LAEI) for predicting diastolic heart failure (HF) in patients with severe left ventricular (LV) diastolic dysfunction. METHODS: This prospective study enrolled 162 patients (65% male) with preserved LV systolic function and severe diastolic dysfunction (132 grade 2 patients, 30 grade 3 patients). All patients had sinus rhythm at enrollment. The LAEI was calculated as (Volmax - Volmin) x 100% / Volmin, where Volmax was defined as maximal LA volume and Volmin was defined as minimal volume. The endpoint was hospitalization for HF withp reserved LV ejection fraction (HFpEF). RESULTS: The median follow-up duration was 2.9 years. Fifty-four patients had cardiovascular events, including 41 diastolic and 8 systolic HF hospitalizations. In these 54 patients, 13 in-hospital deaths and 5 sudden out-of-hospital deaths occurred. Multivariate analyses revealed that HFpEF was associated with LAEI.and atrial fibrillation during follow-up. For predicting HFpEF, the LAEI had a hazard ratio of 1.197per 10% decrease. In patients who had HFpEF events, the LAEI significantly (P< 0.0001) decreased from 69±18% to 39±11% during hospitalization. Although the LAEI improved during follow-up (53±13%), it did not return to baseline. CONCLUSIONS: The LAEI predicts HFpEF in patients with severe diastolic dysfunction; it worsens during HFpEF events and partially recovers during followup.

Genetic diagnosis of familial hypercholesterolemia in Han Chinese.

Familial hypercholesterolemia (FH) is an inherited autosomal dominant disorder of lipoprotein metabolism resulting in elevated serum levels of low-density lipoprotein cholesterol (LDL-C), which lead to increased risk for premature cardiovascular disease. The recognized cause is mutations of the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin/kexin type 9 genes. This study reviewed the literature in Han Chinese to investigate the frequency and spectrum of mutations that are recognized by molecular genetics as causes of FH, the clinical characteristics, and mutation detection rates of FH. MEDLINE, EMBASE, BIOSIS, Wanfang, CNKI, and FH websites, were reviewed through December 2014. Sixty-six studies met inclusion criteria. Totally, 143 different LDLR mutations were identified, including 134 point mutations and 9 large rearrangements; functional characteristics of 46 point mutations were studied. The 5 most frequent mutations included APOB 10579C>T, LDLR 986G>A, 1747C>T, 1879G>A, and 268G>A. Most of these mutations were reported in Southeast China, Hong Kong, and Taiwan. DNA detection rates of heterozygous FH were 6.5% to 77.5%, depending on the inclusion criteria and chosen screening method. With the economic growth and Western-like diet patterns being adopted over the past decade in municipalities in mainland China and Taiwan, the mean pretreatment concentration of LDL-C is higher among heterozygous FH patients reported since 2005 than in patients reported before 2005 (231 vs 196 mg/dL, P < .001). This review of DNA data for Han Chinese patients with FH updates the frequency and spectrum of FH scenarios. Large-scale investigations are needed to determine the interactions between mutations and LDL-C level in relation to cardiovascular risk assessment and management.

Therapeutic Benefits of Induced Pluripotent Stem Cells in Monocrotaline-Induced Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is characterized by progressive increases in vascular resistance and the remodeling of pulmonary arteries. The accumulation of inflammatory cells in the lung and elevated levels of inflammatory cytokines in the bloodstream suggest that inflammation may play a role in PAH. In this study, the benefits of induced pluripotent stem cells (iPSCs) and iPSC-conditioned medium (iPSC CM) were explored in monocrotaline (MCT)-induced PAH rats. We demonstrated that both iPSCs and iPSC CM significantly reduced the right ventricular systolic pressure and ameliorated the hypertrophy of the right ventricle in MCT-induced PAH rats in models of both disease prevention and disease reversal. In the prevention of MCT-induced PAH, iPSC-based therapy led to the decreased accumulation of inflammatory cells and down-regulated the expression of the IL-1ß, IL-6, IL-12α, IL-12ß, IL-23 and IFNγ genes in lung specimens, which implied that iPSC-based therapy may be involved in the regulation of inflammation. NF-κB signaling is essential to the inflammatory cascade, which is activated via the phosphorylation of the NF-κB molecule. Using the chemical inhibitor specifically blocked the phosphorylation of NF-κB, and in vitro assays of cultured human M1 macrophages implied that the anti-inflammation effect of iPSC-based therapy may contribute to the disturbance of NF-κB activation. Here, we showed that iPSC-based therapy could restore the hemodynamic function of right ventricle with benefits for preventing the ongoing inflammation in the lungs of MCT-induced PAH rats by regulating NF-κB phosphorylation.

Left Atrial Expansion Index Predicts Left Ventricular Filling Pressure and Adverse Events in Acute Heart Failure With Severe Left Ventricular Dysfunction.

BACKGROUND: The power of left atrial (LA) parameters for predicting left ventricular (LV) filling pressure and adverse events in acute heart failure (HF) with severe LV dysfunction, either sinus rhythm or atrial fibrillation (AF), is not fully understood. METHODS AND RESULTS: Echocardiography was performed in 141 patients with acute decompensated congestive HF and LV ejection fraction <35%, including 42 with permanent AF. The LA expansion index was calculated as (Volmax - Volmin) × 100%/Volmin, where Volmax was defined as maximal and Volmin as minimal LA volume. Of 141 patients, invasive LV filling pressures within 12 hours of LA expansion index measurement were available in 109. The end points were 3-year frequencies of HF hospitalization and all-cause mortality. Over a median follow-up of 3.1 years, 74 participants (52.5%) reached the end points (sinus vs AF group: 48.5% vs 61.9%, respectively; P = .047). Multivariate analysis revealed that adverse events of both groups were only independently associated with age and LA expansion index. Rates of adverse events were proportional to LA expansion index. There was a good logarithmic relationship between LA expansion index and LV filling pressure, regardless of presence or absence of AF. CONCLUSIONS: LV filling pressure can be estimated well by LA expansion index, with or without AF. The LA expansion index predicts adverse events in HF patients with severe systolic dysfunction. (ClinicalTrials.gov number: NCT01307722).

Genetic Diagnosis via Whole Exome Sequencing in Taiwanese Patients with Hypertriglyceridemia.

AIM: Whole exome sequencing (WES) is a recently developed method for discovering rare mutations associated with hereditary disorders. However, the feasibility and utilization of this method in identifying familial hypertriglyceridemia is not well known. The purpose of the study was to identify the genetic locus that causes hypertriglyceridemia and assess its prevalence in Taiwanese subjects with hypertriglyceridemia. METHODS: We performed WES among two individuals with hypertriglyceridemia and one control subject in an index family (22 members). Based on the WES findings, we extended the study to genotype 65 unrelated adult index patients with a fasting serum triglyceride level of ＞ 500 mg/dL and 125 normal controls using polymerase chain reaction. RESULTS: Using WES alignment, variant calling and annotation, 15 presumptive causal variants were initially identified, including 13 cases by the autosomal dominant model and two cases by the autosomal recessive model. Only APOA5 c.553 G ＞ T (rs2075291), resulting in the amino acid mutation Gly185Cys, co-segregated well with hypertriglyceridemia in terms of autosomal recessive inheritance (homozygote TT: mean triglyceride level: 1,071 mg/dL vs non TT (GT and GG): mean triglyceride level: 118 mg/dL; p ＜ 0.001) in the index family. In the unrelated cohorts, the frequency of the TT genotype of rs2075291 was 12.3% in the hypertriglyceridemic group; however, no TT genotype was found in the control group. CONCLUSIONS: Our results demonstrate that WES is feasible for identifying the genetic locus that causes hypertriglyceridemia. The TT genotype of APOA5 c.553G ＞ T acts as an important indicator of hypertriglyceridemia in patients in Taiwan.

Detection of mutations in symptomatic patients with hypertrophic cardiomyopathy in Taiwan.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a common genetic cardiac disorder associated with sudden death, heart failure, and stroke. The aim of the present study was to evaluate the prevalence and types of mutations in symptomatic patients with HCM in Taiwan. METHODS: Thirty-eight HCM index patients (mean age 60±16 years) underwent systematic mutation screening of eight sarcomeric genes: ß-myosin heavy chain (MYH7), myosin-binding protein C (MYBPC3), troponin T (TNNT2), troponin I (TNNI3), myosin ventricular regulatory light chain 2 (MYL2), myosin ventricular essential light chain 1 (MYL3), α-tropomyosin (TPM1), and cardiac α-actin (ACTC), using direct DNA sequencing. In silico programs predicted damaging amino acids. In the positive families, genotype-phenotype correlation studies were done. RESULTS: Overall, 13 mutations were identified in 13 index patients (34.2%). The three most frequently mutated genes were MYH7, MYBPC3, and TNNT2. One patient carried double mutations. Five mutations (MYH7 R147S; MYBPC3 R597Q; MYBPC3 W1007R; TNNI3 E124Q; MYL3 R63C) were novel; all were missense mutations. Analysis using in silico tools showed near consensus to classify these five novel mutations as pathological. Family pedigree analysis showed the presence of cosegregation in at least two affected members in each proband family, but incomplete penetrance in young family members with a positive genotype. CONCLUSIONS: We identified 13 HCM pedigrees, including 5 carrying novel mutations and 1 with a double mutation. The three most commonly mutated genes were MYH7, MYBPC3, and TNNT2. These results, together with genetic counseling, could lead to earlier diagnosis and better management of family members at risk of HCM.

Myocardial Tissue Doppler Imaging Detects Right Ventricular Dysfunction after Percutaneous Angioplasty of Dysfunctional Hemodialysis Access in Uremic Patients.

BACKGROUND: Right ventricular dysfunction has been observed in uremic patients receiving percutaneous transluminal angioplasty (PTA). This prospective study focuses on the impact of tissue Doppler imaging echocardiographic parameters on assessing right ventricle function in uremic patients post PTA of dysfunctional hemodialysis access. METHODS: Sixty uremic patients were divided into two groups by angiographic findings: an occlusive group (26 patients) and a stenotic group (34 patients). All uremic patients underwent routine echocardiography with tissue Doppler imaging both before and immediately following PTA to assess the right ventricular (RV) function and pulmonary artery systolic pressure (PASP). The right ventricular (RV) myocardial performance index (MPI) was obtained during tissue Doppler imaging over the lateral tricuspid annulus. The M index was measured and defined as the peak early diastolic mitral inflow velocity divided by the RV MPI. The RV MPI, RV isovolumic relaxation time (IVRT) and M-index were used to evaluate RV function post-PTA. RESULTS: Immediately following PTA, PASP (31.6 ± 11.3 mmHg versus 42.6 ± 12.0 mmHg, p = 0.001), RV MPI (0.46 ± 0.08 versus 0.62 ± 0.13, p < 0.001) and IVRT (75.1 ± 12.9 versus 98.4 ± 27.7 ms, p < 0.001) increased significantly in the occlusive group. However, PASP and RV function did not change significantly in the stenotic group. In 42.3% patients from the occlusive group, the M-index fell below 112 and RV MPI rose above 0.55 post-PTA; this occurred in only 8.8% of the stenotic group. CONCLUSIONS: This prospective study demonstrated that there was a higher incidence of RV dysfunction in uremic patients with elevated PASP with totally occluded hemodialysis access than those with stenotic access post-PTA. KEY WORDS: Myocardial performance index; Percutaneous transluminal angioplasty; Pulmonary hypertension; Tissue Doppler image; Uremic.

Left atrial expansion index predicts atrial fibrillation in dyspnea.

BACKGROUND: The left atrial (LA) expansion index for predicting atrial fibrillation (AF) in a relatively low-risk cohort is not fully understood. METHODS AND RESULTS: In this prospective study of 2,200 dypnea patients, the LA expansion index was calculated as (Volmax-Volmin)×100%/Volmin, where Volmax was defined as maximum LA volume and Volmin was defined as minimum volume. The endpoints were 2-year frequency of AF, including both paroxysmal and persistent. Of the 180 participants (8.2%) who had AF attacks over a median follow-up of 2.7 years, 90 (4.1%) had at least 1 episode of persistent AF. Compared to patients with paroxysmal AF, those with persistent AF had a much lower LA expansion index (100±59% vs. 44±24%). LA expansion index was associated exponentially with the incidence of persistent AF. Independent predictors of AF included age, renal function impairment, pulmonary artery systolic pressure, and LA expansion index. Persistent AF, however, had significant independent associations only with prior heart failure, renal function impairment, diastolic dysfunction, and LA expansion index (odds ratio, 0.970; 95% confidence interval: 0.959-0.981 per 1% increase, P<0.0001). Compared to other parameters, LA expansion index <61.4% was the best cut-off point to predict persistent AF. CONCLUSIONS: The LA expansion index is associated with the presence of AF, and a reduced LA expansion index has a strong association with persistent AF.