Efficacy and safety of rivaroxaban in extreme elderly patients with atrial fibrillation: Analysis of the Shikoku Rivaroxaban Registry Trial (SRRT).

BACKGROUND: The Shikoku Rivaroxaban Registry Trial (SRRT) is a retrospective survey of the use of rivaroxaban for stroke prevention in elderly patients in Shikoku, Japan. METHODS: The SRRT enrolled 1339 patients from 8 hospitals. Patients were divided into two groups according to their age, the extreme elderly group (453 patients aged ≧80 years) and the control group (886 patients aged <80 years). RESULTS: In the extreme elderly group, 41.5% of the patients had low body weight (<50kg) and 65.1% had abnormal renal function (creatinine clearance <50ml/min). The mean CHADS2, CHA2DS2-VASc, and HAS BLED scores were 2.7, 4.4, and 2.3, respectively. There were 333 (73.5%) patients who met the dosing criteria, and of these patients, 81.2% received rivaroxaban 10mg daily. Thromboembolic events occurred in 4 patients (0.94%/person year) and intracranial hemorrhage occurred in 4 patients (0.89%/person year). The incidence of these events was not significantly different from the control group. In addition, all patients with cerebral infarction had been treated with a smaller dose of rivaroxaban than recommended by the dosing criteria, suggesting that dosing criteria should be adhered to. CONCLUSION: These results suggest that rivaroxaban is effective and safe in extreme elderly patients with atrial fibrillation.

Role of epidermal growth factor receptor and endoplasmic reticulum stress in vascular remodeling induced by angiotensin II.

The mechanisms by which angiotensin II (AngII) elevates blood pressure and enhances end-organ damage seem to be distinct. However, the signal transduction cascade by which AngII specifically mediates vascular remodeling such as medial hypertrophy and perivascular fibrosis remains incomplete. We have previously shown that AngII-induced epidermal growth factor receptor (EGFR) transactivation is mediated by disintegrin and metalloproteinase domain 17 (ADAM17), and that this signaling is required for vascular smooth muscle cell hypertrophy but not for contractile signaling in response to AngII. Recent studies have implicated endoplasmic reticulum (ER) stress in hypertension. Interestingly, EGFR is capable of inducing ER stress. The aim of this study was to test the hypothesis that activation of EGFR and ER stress are critical components required for vascular remodeling but not hypertension induced by AngII. Mice were infused with AngII for 2 weeks with or without treatment of EGFR inhibitor, erlotinib, or ER chaperone, 4-phenylbutyrate. AngII infusion induced vascular medial hypertrophy in the heart, kidney and aorta, and perivascular fibrosis in heart and kidney, cardiac hypertrophy, and hypertension. Treatment with erlotinib as well as 4-phenylbutyrate attenuated vascular remodeling and cardiac hypertrophy but not hypertension. In addition, AngII infusion enhanced ADAM17 expression, EGFR activation, and ER/oxidative stress in the vasculature, which were diminished in both erlotinib-treated and 4-phenylbutyrate-treated mice. ADAM17 induction and EGFR activation by AngII in vascular cells were also prevented by inhibition of EGFR or ER stress. In conclusion, AngII induces vascular remodeling by EGFR activation and ER stress via a signaling mechanism involving ADAM17 induction independent of hypertension.

Epidermal growth factor receptor inhibitor protects against abdominal aortic aneurysm in a mouse model.

Angiotensin II (Ang II) has been implicated in the development of abdominal aortic aneurysm (AAA). In vascular smooth muscle cells (VSMC), Ang II activates epidermal growth factor receptor (EGFR) mediating growth promotion. We hypothesized that inhibition of EGFR prevents Ang II-dependent AAA. C57BL/6 mice were co-treated with Ang II and ß-aminopropionitrile (BAPN) to induce AAA with or without treatment with EGFR inhibitor, erlotinib. Without erlotinib, 64.3% of mice were dead due to aortic rupture. All surviving mice had AAA associated with EGFR activation. Erlotinib-treated mice did not die and developed far fewer AAA. The maximum diameters of abdominal aortas were significantly shorter with erlotinib treatment. In contrast, both erlotinib-treated and non-treated mice developed hypertension. The erlotinib treatment of abdominal aorta was associated with lack of EGFR activation, endoplasmic reticulum (ER) stress, oxidative stress, interleukin-6 induction and matrix deposition. EGFR activation in AAA was also observed in humans. In conclusion, EGFR inhibition appears to protect mice from AAA formation induced by Ang II plus BAPN. The mechanism seems to involve suppression of vascular EGFR and ER stress.

A novel Doppler echocardiographic index integrating left and right ventricular function is superior to conventional indices for predicting adverse outcome of acute myocardial infarction.

The ratio of peak diastolic early velocity (E) of left ventricular (LV) inflow to peak diastolic longitudinal velocity (e') of the mitral annulus (E/e') is thought to reflect LV filling pressure, and tricuspid annulus velocity at systole (s'-T) is thought to reflect right ventricular function. However, it has not been reported on significance of the combined use of E/e' and (s'-T) to predict outcome of acute myocardial infarction (AMI). Over 21 months, beginning in January 2007, we enrolled 65 AMI patients who were measured hemodynamic and echocardiographic parameters by Swan-Ganz (SG) catheterization just after reperfusion therapy and echocardiography immediately after reperfusion therapy. Cardiac index (CI) and pulmonary capillary wedge pressure (PCWP) via SG catheter were measured, and routine echocardiographic indices, including E, e', E/e', and (s'-T) were determined. In addition, we defined the functional integrated bi-myocardial tissue Doppler (FIT) index as (s'-T)÷E/e'. The relationships between CI, PCWP, and echocardiographic indices were investigated, including FIT index. Moreover, we investigated whether FIT index could predict adverse cardiac events. FIT index was significantly associated with not only CI but also PCWP. In the Cox proportional hazards model, FIT index<1.0 was a significant predictor for adverse outcome of AMI after adjustment for age, Killip class, history of previous coronary revascularization, location of culprit lesion, and LV ejection fraction. The novel index defined as (s'-T)÷E/e' could be quite useful predictor of prognosis in AMI.

A novel Doppler echocardiographic score reflecting cardiac functional status can predict adverse outcome in acute myocardial infarction.

BACKGROUND: E/e' and s' are thought to reflect left ventricular diastolic and systolic function, respectively. However, there are no reports on the combined use of E/e' and s' in predicting the outcome in acute myocardial infarction (AMI). METHODS: For 20 months beginning in October 2006, we enrolled 65 AMI patients who had undergone Swan-Ganz (SG) catheterization and echocardiography just after reperfusion therapy. We measured the cardiac index (CI) and the pulmonary capillary wedge pressure (PCWP) via an SG catheter and determined routine echocardiographic indices, including transmitral flow velocity (E), mitral annulus velocities at systole (s') and early diastole (e'), and E/e'. In addition, we rounded off the values of s' (cm/s) and E/e' (ratio of cm/s to cm/s) to the nearest integer, and designated them the s'-score and E/e'-score, respectively. We also defined the cardiac status score as the s'-score subtracted from the E/e'-score. In Study 1, we investigated the relationships between hemodynamic parameters (CI and PCWP) and echocardiographic indices, including the cardiac status score. In Study 2, we excluded patients with Killip class ≥II, yielding a final study population of 55 patients in whom we investigated whether the cardiac status score could predict adverse cardiac events. RESULTS: Only the cardiac status score significantly correlated with both the PCWP and the CI. In the Cox proportional hazards model, significant predictors were the left ventricular ejection fraction (LVEF), estimated glomerular filtration rate (eGFR), and cardiac score ≥3.0. CONCLUSIONS: The novel score achieved in this study by subtracting the s'-score from the E/e'-score could be highly useful for predicting outcomes in AMI with Killip class I.

High E/e' disrupts the rapid lowering of blood glucose in response to exercise training.

BACKGROUND: No relationship between the ratio of peak early velocity of left ventricular inflow to peak systolic longitudinal velocity of the mitral annulus velocity (E/e') and insulin resistance has yet been shown in patients with cardiac disease. We hypothesized that patients with high E/e' values would tend not to show the rapid blood glucose-lowering in response to exercise training characteristic of impaired glucose tolerance (IGT) or diabetes mellitus (DM) patients. METHODS: The subjects were continuous IGT/DM patients (n = 27) participating in cardiac rehabilitation. All patients' E/e' values were measured by echocardiography. The patients' blood glucose levels (mg/dl) were measured just before (pre-BS) and after (post-BS) exercise training. Post-BS was subtracted from pre-BS to obtain ΔBS, and the relationship between E/e' and ΔBS was investigated. RESULTS: E/e' correlated negatively with ΔBS. Moreover, E/e' was a significant predictor of ΔBS and as such was independent of hemoglobin A1c (HbA1c), pre-BS, and presence of atrial fibrillation on multivariate analysis. CONCLUSIONS: Patients with high E/e', indicating high left ventricular filling pressure, were unlikely to exhibit the rapid glucose-lowering response.

Preventive effect of renin-angiotensin system inhibitor on left atrial remodelling in patients with chronic atrial fibrillation: long-term echocardiographic study.

AIMS: Left atrium (LA) gradually enlarges with the time course of atrial fibrillation (AF). The aim of this study was to examine whether the renin-angiotensin system (RAS) inhibitor could prevent LA remodelling in patients with chronic AF. METHODS AND RESULTS: Forty-one patients with chronic non-valvular AF were enrolled and divided into the following two groups: the RAS group taking an RAS inhibitor and the non-RAS group not taking it. We compared echocardiographic parameters including LA volume at the beginning and the end of follow-up. Percent change of these parameters was calculated from the value at the end of follow-up divided by the value at the beginning of follow-up. An enlargement of LA volume index and a decrease in LA expansion fraction was significantly prevented in the RAS group. Administration of RAS inhibitors was significantly associated with the prevention of increasing LA volume in multivariate analysis. CONCLUSION: RAS inhibitors may prevent structural and functional degradation of LA in chronic non-valvular AF.

Relation of gender and interatrial dyssynchrony on tissue Doppler imaging to the prediction of the progression to chronic atrial fibrillation in patients with nonvalvular paroxysmal atrial fibrillation.

This prospective study aimed to identify the relation of gender and interatrial dyssynchrony on tissue Doppler imaging (TDI) to the prediction of the progression to chronic atrial fibrillation (CAF) in nonvalvular paroxysmal AF (PAF) patients. Nineteen consecutive men and 19 women with nonvalvular PAF were prospectively followed after echocardiography. We measured the interval of time from initiation of the P wave on the electrocardiogram until the beginning of the late diastolic TDI signal at the lateral border of the mitral (P-A'(M)) and the tricuspid annulus (P-A'(T)). Interatrial dyssynchrony was defined as the difference between the P-A'(M) and P-A'(T) intervals (A'(M)-A'(T)). The study endpoint was the onset of CAF (>6 months). Six men developed CAF during a follow-up of 32 +/- 26 months, and 3 women developed CAF during a follow-up of 25 +/- 19 months. Compared to those without CAF, the patients with CAF had significantly longer A'(M)- A'(T) intervals (men: 41 +/- 10 vs 27 +/- 12 ms, women: 64 +/- 4 vs 23 +/- 9 ms; P < 0.01) in both genders. Kaplan-Meier analysis, using cutoff values determined by analysis of receiver-operating characteristics curves, revealed that the progression to CAF was significantly observed more often when A'(M)-A'(T) interval was >34 ms in men and >43 ms in women. This prospective study suggests that nonvalvular PAF men and women with a high risk of developing CAF have "interatrial dyssynchrony" on atrial TDI, whose cutoff values are shorter and may affect the vulnerability of AF in men.

Diastolic flow velocity pattern of the left anterior descending coronary artery in hypertrophied heart, with special reference to the difference between hypertrophic cardiomyopathy and hypertensive left ventricular hypertrophy.

BACKGROUND: This study aimed to clarify the characteristics of diastolic flow velocity pattern of the left anterior descending coronary artery (LAD) in patients with left ventricular hypertrophy (LVH), and the difference in diastolic LAD flow velocity pattern between hypertensive LVH and hypertrophic cardiomyopathy (HCM). METHODS: The flow velocity pattern was recorded at the mid-portion of the LAD by high-frequency transthoracic Doppler echocardiography in 22 patients with HCM, 10 hypertensive patients with LVH [LVH(+)HT], and 9 hypertensive patients without LVH [LVH(-)HT]. The diastolic flow pattern was analyzed. Standard two-dimensional echocardiogram and apexcardiogram (ACG) were also recorded. RESULTS: The interventricular septal thickness (IVST) and the sum of the IVST and LV posterior wall thickness (PWT) (IVST + PWT) were greater in HCM than in HT (p < 0.01) patients. Early diastolic upstroke time (D-UT) of the LAD flow velocity wave was longest in HCM, and was longer in LVH(+)HT than in LVH(-)HT (p < 0.01) patients. Direct correlation was found between D-UT and IVST, IVST + PWT in patients with LVH(+)HT and LVH(-)HT (r = 0.80, 0.79, respectively; p < 0.01), but no correlation was found between these parameters in HCM. Late-diastolic step (LDS) formation of the LAD flow velocity wave was observed in 68% of HCM, 20% of LVH(+)HT, but none of the LVH(-)HT patients. The A wave ratio of ACG was higher in patients with LDS than in those without (p < 0.01). The LDS occurred coincidently with the A wave of ACG. CONCLUSIONS: The diastolic LAD flow velocity pattern in hypertrophied heart is characterized by slow acceleration and LDS formation, reflecting impaired relaxation and increased stiffness of the LV, respectively. These abnormalities correlate with the degree of hypertrophy in hypertensive heart, but do not correlate with that in HCM.

Prediction of transition to chronic atrial fibrillation in elderly patients with nonvalvular paroxysmal atrial fibrillation by transthoracic Doppler echocardiography.

BACKGROUND: It is well known that paroxysmal atrial fibrillation (PAF) often precedes the development of chronic atrial fibrillation (CAF). HYPOTHESIS: The purpose of this study was to determine prospectively whether transthoracic echocardiography is useful for the prediction of the transition to CAF in elderly patients with nonvalvular PAF. METHODS: Forty-two consecutive elderly patients (> or =65 years) with nonvalvular PAF were prospectively evaluated after undergoing transthoracic echocardiography. The study endpoint was the transition to CAF (AF; > or = 6 mo). RESULTS: During a follow-up period of 32 +/- 24 mo, 12 patients developed CAF. Patients with CAF had a significantly lower peak A velocity (A) and a higher E/A ratio of the transmitral inflow (TMF) such as a pseudonormalization pattern, and a lower peak atrial reversal wave velocity, higher peak diastolic wave velocity (D), and lower peak systolic/diastolic wave velocity ratio (S/D ratio) of the pulmonary venous flow (PVF). Kaplan-Meier analysis revealed that the transition to CAF was observed more often when A was < or = 70 cm/sec and E/A ratio was > or = 1.07 of TMF, and D was > or = 44 cm/sec and the S/D ratio was < or = 1.34 of PVF. All patients developed CAF when the E/A ratio was > or = 1.15 or the S/D ratio was < or = 0.75. CONCLUSIONS: This prospective study suggests that elderly patients at high risk for transition to CAF have a pseudonormalization pattern of TMF and a diastolic dominant pattern of PVF, and that transthoracic Doppler estimation of TMF and PVF may be useful in identifying elderly patients at high risk for the transition from nonvalvular PAF to CAF.

Transthoracic echocardiography during sinus rhythm identifies elderly patients with nonvalvular paroxysmal atrial fibrillation at high risk of cerebral infarction.

We performed transthoracic echocardiography during sinus rhythm in elderly nonvalvular paroxysmal atrial fibrillation (NV-PAF) patients (> or =65 years) with cerebral infarction and in patients without cerebral infarction. This study suggests that elderly NV-PAF patients at high risk for cerebral infarction seem to have a pseudonormalization pattern of transmitral inflow, and decreased atrial reversal flow of pulmonary venous flow, and increased left atrial volume.

Clinical significance of anterior mitral leaflet fibrillation in patients with nonvalvular atrial fibrillation: comparison with blood flow and wall motion of the left atrial appendage.

BACKGROUND AND PURPOSE: Diastolic fibrillation of the anterior mitral leaflet (AML) is seen in patients with atrial fibrillation (AF). However, its clinical significance has been unclear. On the other hand, reduced blood flow velocity in the left atrial appendage (LAA) may be associated with LA thrombus formation. In this study, we investigate the relationship between the flow velocity and the wall motion velocity of the LAA and diastolic fibrillation of the AML in patients with nonvalvular AF. METHODS: We performed transthoracic echocardiography (TTE) in 45 consecutive patients with chronic nonvalvular AF. The LAA flow velocity was measured by pulsed Doppler echocardiography with the sample volume positioned at the center of the LAA. The LAA wall motion velocity was measured by pulsed Doppler tissue imaging (DTI) with the sample volume at the medial wall of the LAA. The AML fibrillation velocity was measured by pulsed DTI with the sample volume at the AML tip. RESULTS: The AML fibrillation velocity could be measured in 44 patients (97.8%), and the LAA flow and wall motion velocities were measurable in 35 (77.8%) and 42 (93.3%) patients, respectively. The AML fibrillation velocity had a range from 4 to 21 cm/s and showed significant positive correlation with the LAA flow velocity (r = 0.82, P < 0.001) and the wall motion velocity (r = 0.80, P < 0.001) of the LAA. An AML fibrillation velocity of ≤7 cm/s predicted patients having a tendency to LA thrombus formation (LAA flow velocity ≤20 cm/s) with high sensitivity (87.5%) and specificity (88.9%). CONCLUSION: The AML fibrillation velocity seems to be a viable substitute for the LAA flow velocity in the detection of flow stagnation in the LA.

Isolated congenital left ventricular diverticulum in an elderly patient that was identified because of an incidental finding during a complete medical checkup.

Congenital left ventricular diverticulum is a rare cardiac malformation in an elderly patient. It frequently is associated with other cardiac or non-cardiac congenital malformations. We present an asymptomatic elderly patient, evaluated because of an incidental finding of a left ventricular anatomic change on chest computed tomography during a complete medical checkup. The diagnosis of isolated congenital left ventricular diverticulum was confirmed by echocardiography and cardiac catheterization. With the general use of a complete medical checkup, the incidental findings of patients with isolated congenital left ventricular diverticulum might increase, which might allow for a valid estimation of the morbidity and mortality of these patients.

Gender differences in short-term effects of atorvastatin on lipid profile, fibrinolytic parameters, and endothelial function.

BACKGROUND AND AIM: Little is known about the impact of gender on short-term effects of atorvastatin. We investigated the gender differences in the short-term lipid-lowering and pleiotropic effects of atorvastatin therapy. METHODS AND RESULTS: Seventy-two consecutive patients including 48 women with primary hypercholesterolemia, were assigned prospectively to treatment with atorvastatin (10mg/day) for 3 months. We measured fasting lipid concentrations, thiobarbituric acid reactive substances (TBARS) as marker of lipid peroxide, fibrinolytic parameters, and endothelial function by flow-mediated vasodilation of the brachial artery (FMD), at baseline and after 3 months of therapy. We assessed the impact of gender on temporal differences in these parameters. In men, atorvastatin decreased total, low-density lipoprotein (LDL), and small, dense LDL-cholesterol concentrations, and increased FMD after 3 months. In women, atorvastatin decreased TBARS, triglyceride, and total, LDL, small, dense LDL, and remnant-like lipoprotein particle-cholesterol concentrations, and increased FMD after 3 months. Fibrinolytic parameters did not change significantly in either men or women. With respect to the percent change in those parameters after 3 months, TBARS (-17.6+/-12.4 vs. -0.4+/-18.8%, p<0.01) and small, dense LDL-cholesterol (-96.7+/-8.3 vs. -68.6+/-29.7%, p<0.01) decreased to a greater degree in women, although the relative changes in other parameters were similar between men and women. CONCLUSIONS: We found gender differences in some of the lipid altering changes, including TBARS and small, dense LDL-cholesterol concentrations, after short-term atorvastatin therapy, which were greater in women. However, short-term atorvastatin therapy may be beneficial in improving endothelial function equally in both men and women.

Comparisons of short- and intermediate-term effects of pitavastatin versus atorvastatin on lipid profiles, fibrinolytic parameter, and endothelial function.

We compared short- and intermediate-term effects on lipid profiles, fibrinolytic parameter, and endothelial function between pitavastatin and atorvastatin. Short-term improvement of endothelial function was superior with pitavastatin compared to atorvastatin therapy. Pitavastatin could be a potentially better therapeutic choice for lipid-lowering and early alterations in endothelial function. Our study provides an important basis on which further trials involving larger numbers of patients may be studied prospectively.

QT-interval dispersion in type 2 diabetic and non-diabetic patients with post-myocardial infarction.

BACKGROUND AND AIMS: QT-interval dispersion (QTD), which reflects spatial ventricular repolarization inhomogeneity, has been reported to increase and to have a prognostic value in patients with either myocardial infarction or diabetes. Our aim was to compare increases in QTD in type 2 diabetic and non-diabetic patients following post-myocardial infarction (post-MI). We also compared QTD in type 2 diabetic patients with post-MI treated with insulin, sulfonylurea, or diet alone. METHODS AND RESULTS: We determined the rate corrected QT-interval (QTc) dispersion (QTcD) in 178 consecutive post-MI patients, including 48 type 2 diabetic and 130 non-diabetic patients. The QTcD, measured with software (QTD-1), was defined as the difference in the minimum and maximum QTc in any of the 12 standard electrocardiographic leads. There were no significant differences in age, gender, left ventricular end-diastolic diameter, ejection fraction, or minimum QTc between type 2 diabetic and non-diabetic patients with post-MI. Compared with post-MI patients without diabetes, those with type 2 diabetes had higher maximum QTc (481+/-37 vs. 459+/-43ms, P<0.05) and QTcD (67+/-18 vs. 58+/-16ms, P<0.05). Among type 2 diabetic patients with post-MI treated with insulin, sulfonylurea, or diet alone, the QTcD (81+/-18 vs. 64+/-16 vs. 62+/-17ms, P<0.05, respectively) was significantly greater and the R-R interval was shorter in the insulin therapy group. CONCLUSIONS: Type 2 diabetes is associated with an additional increase in the QTD in post-MI patients. This additional increase in spatial repolarization inhomogeneity might be implicated in the increased mortality risk in post-MI patients with type 2 diabetes. These findings were thought to be more striking in the insulin therapy group.

[Age-related changes in cardiac performance index (TEI index) with special reference to the difference between the ventricles].

OBJECTIVES: The TEI index is a clinically useful parameter of combined systolic and diastolic cardiac performance, but age-related changes of this index remain unclear. This study investigated age-related changes in the TEI index and the differences between the ventricles. METHODS: Ninety-nine healthy subjects aged 14 to 89 years were studied using pulsed Doppler echocardiography. The isovolumic contraction time(ICT), isovolumic relaxation time(IRT), and ejection time (ET) of both ventricles were measured from the recordings of the ventricular inflow or outflow velocities and the electrocardiogram, and the TEI index of both ventricles was calculated as (ICT + IRT) /ET. RESULTS: IRT and TEI index correlated directly with age in both ventricles, and the correlations of these parameters were better in the left ventricle than in the right ventricle. ICT and ET showed no correlation with age in both ventricles. In the left ventricle, TEI index showed a normal value (< 0.47) in all subjects aged less than 50 years, but showed an abnormal value (> or = 0.47) in 3 of 29 subjects (10%) in the sixth and seventh decades, and in 6 of 25 subjects (24%) in the eighth and ninth decades. In contrast, no subjects had an abnormal value of TEI index (> or = 0.37) in the right ventricle. CONCLUSIONS: TEI index shows an age-related increase predominantly in the left ventricle, probably due to prolongation of IRT reflecting the relaxation abnormality of the ventricle. The effect of aging must be considered in the clinical application of TEI index.