Dapagliflozin Influences Ventricular Hemodynamics and Exercise-Induced Pulmonary Hypertension in Type 2 Diabetes Patients　- A Randomized Controlled Trial.

BACKGROUND: This prospective randomized multicenter open-label trial evaluated whether sodium-glucose cotransporter-2 inhibitor (SGLT2-i) improves left ventricular (LV) pump function and suppresses elevation of LV filling pressure (LVFP) and right ventricular systolic pressure (RVSP) during exercise in type 2 diabetes mellitus (T2DM) patients.Methods and Results:Based on HbA1c and LV ejection fraction, 78 patients with poorly controlled T2DM were randomly assigned to D-group (dapagliflozin 5 mg/day add-on) or C-group (conventional therapy add-on). Physical examination, home and office blood pressure examination, blood tests, and echocardiography at rest and during ergometer exercise were performed at baseline and at 1.5 and 6 months after treatment. The primary endpoint was defined as the change in RVSP (mmHg) between baseline and 6-month follow up. The secondary endpoints were changes in LVFP (ratio), stroke volume index (SVi; mL/m2), and cardiac index (CI; L/min/m2). Both RVSP and LVFP during exercise significantly decreased from baseline to 6 months after starting treatment in the D-group (P<0.001). No changes to either parameter was observed in the C-group. The SVi and CI did not improve in either group. Both home and office blood pressure significantly decreased in the D-group. Decreases in HbA1c were somewhat greater in the C-group. CONCLUSIONS: Dapagliflozin significantly improved RVSP and LVFP during exercise in patients with T2DM and cardiovascular risk, which may contribute to favorable effects on heart failure.

Impact of depression on masked hypertension and variability in home blood pressure in treated hypertensive patients.

This study was conducted to determine the effects of depression and/or insomnia on masked hypertension (MHT) compared with other types of HT and on variability in home-measured blood pressure (HBP) and clinic BP (CBP). Three hundred and twenty-eight hypertensives (132 women) aged 68±10 years were classified into four BP types: controlled HT (CHT), white-coat HT, MHT and sustained HT (SHT), based on CBP (140/90 mm Hg) and morning HBP (135/85 mm Hg) measurements. A score of ⩾16 on the Center for Epidemiologic Studies Depression Scale (CES-D) was defined as depression. The mean values and s.d. of BP were calculated from measurements taken during the 14 consecutive days just before the CES-D evaluation. Compared with the CHT group, the risk of depression was 2.77-fold higher in the SHT group and even higher in the MHT group (7.02-fold). The association between depression and MHT was augmented in the presence of insomnia and was somewhat stronger in women. A HBP variability index defined as s.d./mean BPs in both morning and night time was significantly higher in MHT than in the other BP types, whereas that of CBP was not. Both morning and night-time HBP variability were significantly higher in depressive patients than in non-depressives. These suggest that depression is associated with MHT and that increases both morning and night-time HBP variability but not CBP variability. Physicians should be mindful of mental stresses such as depression in their hypertensive patients when forming strategies to control BP over the diurnal cycle.

Reversible T-wave inversions and neurogenic myocardial stunning in a patient with recurrent stress-induced cardiomyopathy.

A 72-year-old female was diagnosed as a stress-induced cardiomyopathy from apical ballooning pattern of left ventricular dysfunction without coronary artery stenosis after the mental stress. ECG showed the transient T-wave inversions after the ST-segment elevations. By the mental stress after 1 year, she showed a transient dysfunction with similar ECG changes again. T-wave inversions recovered earlier, and cardiac sympathetic dysfunction showed a lighter response corresponding to the less severe dysfunction than those after the first onset. Wellens' ECG pattern was associated with the degree of neurogenic myocardial stunning with sympathetic hyperinnervation caused by mental stress.

Anxiety disorder is associated with nocturnal and early morning hypertension with or without morning surge: ambulatory blood pressure monitoring.

BACKGROUND: Nocturnal and early morning hypertension are both significant risk factors for cardiovascular events. It remains unclear whether anxiety disorder affects nocturnal blood pressure (BP), early morning BP, or BP pattern in hypertensive patients. METHODS AND RESULTS: One hundred and twenty consecutive hypertensive outpatients (77 men and 43 women; mean age, 66±11 years) were divided into 2 groups based on Hospital Anxiety and Depression Scale (HADS) score: a control group (n=78; HADS ≤10) and an anxiety group (42 patients; HADS ≥11). Nocturnal BP, early morning BP, morning BP surge (defined as BP rise ≥50 mmHg), and BP pattern (extreme-dipper/dipper/non-dipper/riser) were measured on ambulatory BP monitoring. Clinical characteristics and BP were also evaluated at physician check-up. There was no significant difference between the 2 groups for BP check-up, but nocturnal and early morning BP were significantly higher in the anxiety group (142±16 mmHg and 152±21 mmHg) than in the control group (126±14 mmHg and 141±18 mmHg). With regard to patients with morning BP surge, nocturnal and early morning BP were also significantly higher in the anxiety group. The relative risk of existing anxiety disorders in riser-type hypertension was 4.48-fold higher (95% confidence interval: 1.58-12.74; P<0.005) than in dipper-type hypertension. CONCLUSIONS: Anxiety disorder is associated with nocturnal and early morning hypertension, and may be a risk factor for cardiovascular events.

Quantitative assessment of microcollateral recruitment during coronary occlusion using real-time intravenous myocardial contrast echocardiography.

BACKGROUND: Residual collateral-derived myocardial blood flow (MBF) (A x beta) is important to protect against myocardial ischemia after acute coronary occlusion. METHODS: Recruitment of microcollateral was assessed in 22 dogs with left circumflex coronary artery occlusion by analysis of MBF and regional wall thickening (WT) using real-time myocardial contrast echocardiography. RESULTS: Video intensity and WT at the center of risk area were significantly lower than those at the border of risk area. The video intensity, A value, beta value, and MBF correlated well with WT after left circumflex coronary artery occlusion. The WT of the area with above 25% of normal MBF was preserved and was higher than that at below 25%. However, the deterioration of WT was not distinguished according to A value. CONCLUSION: Real-time myocardial contrast echocardiography is a useful noninvasive method to evaluate collateral-derived MBF, which can be a reliable index of protection against myocardial ischemia.

Improved septal contraction and coronary flow velocity after cardiac resynchronization therapy elucidated by strain imaging and pulsed wave Doppler echocardiography.

OBJECTIVES: The effects of cardiac resynchronization therapy (CRT) with various atrioventricular conduction delay settings were investigated on cardiac hemodynamic changes involved in coronary flow velocity using color and pulsed wave Doppler modalities and myocardial regional contractility using a novel echocardiographic technique (strain imaging). METHODS: Seven patients with advanced heart failure (left ventricular ejection fraction < 35%) and left bundle branch block(QRS > or = 140 msec) were treated with CRT. Color and pulsed wave Doppler imaging were performed from the apical four-chamber view to examine the cardiac functions such as stroke volume, cardiac output, mitral regurgitant volume and coronary flow velocity. Strain imaging was performed to quantify the asynchrony of both intraventricular and interventricular time delay between the septum and left ventricular free wall (posterior wall) and to assess the regional contractile function. Wall motion was also evaluated. RESULTS: Intraventricular and interventricular asynchrony were improved from 173 +/- 18 to 60 +/- 6 msec, and 69 +/- 25 to 12 +/- 3 msec, respectively. Stroke volume (55.2 +/- 6.2 to 76.8 +/- 10.8 ml; 39% up), cardiac output (3.9 +/- 0.3 to 5.4 +/- 0.5 I/min; 38% up) and coronary flow velocity (24 +/- 3 to 36 +/- 5 cm/sec; 50% up) were greatly increased and mitral regurgitant volume (59.7 +/- 18.0 to 38.9 +/- 11.3 ml; 35% down)was clearly decreased. Septal wall shortening was greatly increased from 10.2 +/- 2.3% to 17.0 +/- 1.8% and septal wall motion (radial thickening)was also improved simultaneously. Atrioventricular interval settings influenced all above parameters. CONCLUSIONS: CRT improved the cardiac hemodynamics involved in coronary flow significantly due to both resynchronization of inter and intra asynchrony, and improvement of the regional myocardial contraction in patients with severe congestive heart failure and complete left bundle branch block.

Predicting prognosis based on the shape of the left ventricular cavity in dilated cardiomyopathy: analysis using rate of improvement in the circle index.

PURPOSE: To elucidate the relation between a quantitative measure of the shape of the left ventricular cavity, cardiac function, and prognosis in patients with dilated cardiomyopathy (DCM). METHODS: The hearts of 20 healthy individuals and 18 patients with DCM were evaluated. Participants were aged 48.5 ± 5.0 years. On the basis of end-systolic four-chamber view echocardiograms, the endocardium of the left ventricle was traced and the resulting curve was segmented using 100 points. A line tangential to the curve was then drawn at each point, and the angle between two adjacent tangential lines was calculated. The deviation of these angles was designated as the circle index. The circle index and hemodynamic findings in patients with DCM were compared, and the rate of improvement in the circle index in these cases of DCM was determined. These patients were then placed into one of two groups: group R (11 patients), those with improvement rates of 10% or higher at time of discharge; and group NR (seven patients), those with rates less than 10%. Diuretic (furosemide) use, New York Heart Association (NYHA) classification, and readmission rate for the two groups were compared 2 years after discharge. RESULTS: The circle index was 2.7 ± 0.9 in the DCM group and 17.5 ± 4.2 in the healthy group (P < 0.01). The circle index in the DCM group was correlated with pulmonary capillary wedge pressure (r(2) = 0.42). Use of furosemide was unchanged in group R 2 years after discharge, but had increased for all patients in group NR. All cases in group R were classified as NYHA I 2 years after discharge. In group NR, in contrast, although all cases were classified as NYHA I at discharge, five of seven cases had deteriorated to NYHA III-IV 2 years later and were readmitted to hospital. CONCLUSION: There appears to be a quantifiable correlation between the circularity of the left ventricular cavity and the circle index. This suggests that rate of improvement after treatment for heart failure could predict prognosis in patients with DCM.

Contractile reserve, thallium-201 reverse redistribution and mismatch between perfusion and metabolism in reperfused infarct-related myocardium with delayed and incomplete functional recovery.

We investigated simultaneously the correlations between dobutamine-induced contractile reserve (CC), thallium-201 reverse redistribution (RR) and a mismatch between perfusion and metabolism (MM) to the magnitude of functional recovery. In 32 patients with coronary angioplasty early after infarction, echocardiography was performed at low-dose dobutamine stress within 1 week and at resting state at 1 month. Thallium-201/iodine-123 beta-methyl-iodophenyl pentadecanoic acid (BMIPP) dual-isotope single photon emission tomography was performed at 1 month. Wall motion and the uptake of each tracer were scored as 0 to 2 in the infarct-related segments, and CC, RR, and MM were evaluated in the infarct-related segments. In 71 akinetic or dyskinetic segments before reperfusion, the initial thallium-201 uptake and initial BMIPP uptake scores and the 4 hour redistribution thallium-201 uptake scores were less severe in the group with complete functional recovery (group A), followed by the group with incomplete recovery (group B) and then the group with no recovery (group C) (each P < 0.0001). CC was the greatest in group A, followed by group B, and then group C (76.2% in 16/21, 60% in 15/25, 36% in 9/25, P = 0.0212). RR and MM were greater in group B (52% in 13 and 64% in 16) than in groups A and C (19% in 4 and 8% in 2, 33.3% in 7 and 24% in 6, P = 0.0013 and P = 0.0113). The intensity of functional damage reflects perfusion and metabolism, but the delayed and incomplete functional recovery after reperfusion may be closely related to RR, MM, and CC.

Usefulness of simultaneous evaluations of contractile reserve, perfusion, and metabolism during dobutamine stress for predicting wall motion reversibility (myocardial stunning) after successful PTCA.

The optimal diagnostic approaches using contractile reserve, perfusion, and free fatty acid metabolism together for identifying myocardial stunning after reperfusion have not been clarified in the clinical setting. We investigated the usefulness of simultaneous evaluation of these parameters during myocardial stunning to predict the functional recovery in infarct-related myocardium after reperfusion. In 43 patients (60.7 +/- 10.4 years) with successful coronary angioplasty early after a first myocardial infarction, low-dose (5 to 10 microg/kg/min) dobutamine stress thallium-201/iodine-123 beta-methyl-iodophenyl pentadecanoic acid (BMIPP) dual-isotope single photon emission computed tomography was performed with echocardiography in the acute phase within 1 week after reperfusion. Regional wall motion and the uptake of each tracer were obtained simultaneously in the infarct-related segments. In 93 segments with dyssynergy in the acute phase after reperfusion, the sensitivity, specificity, and accuracy using contractile reserve for predicting the final functional recovery in the chronic phase more than 3 months after PTCA were 81.3%, 67.2%, and 72%, respectively. More accurate predictions were obtained by simultaneous measurements of thallium-201 and BMIPP uptakes (93.8%, 66.7%, and 79.4%, respectively). The final functional recovery in the stunned myocardium after early reperfusion following acute myocardial infarction was predicted more accurately by simultaneous evaluation of these parameters at dobutamine stress testing.

Significance of low-dose dobutamine stress echocardiography for the prediction of the long-term prognosis for patients with acute myocardial infarction.

OBJECTIVES: Detection of stunned myocardium using low-dose dobutamine stress echocardiography is a good predictor of improvement of cardiac function in patients with acute myocardial infarction during short hospital stays. The present study evaluated the detection of stunned myocardium as a predictor of the long-term prognosis for patients with acute myocardial infarction. METHODS: One hundred and two patients (83 males, 19 females, mean age 61.5 years) with initial myocardial infarction underwent successful reperfusion therapy (direct percutaneous transluminal coronary angioplasty or stent) in the acute stage. Within 7 days, low-dose dobutamine was administered by intravenous drip and improvement of wall motion of the infarct area was evaluated by echocardiography. The patients were divided into two groups, the viable group that showed one grade or more improvement (61 patients), and the non-viable group that showed no improvement (41 patients). These groups were compared to determine the differences in clinical findings such as remodeling of the left ventricle measured by two-dimensional echocardiography, physical work capacity during serial multi-step exercise testing, and the prognosis. RESULTS: The viable group showed greater improvement in hemodynamics and wall motion of the infarct areas than the non-viable group. After discharge, the physical work capacity was significantly increased and there was no recognizable enlargement of the left ventricle in the viable group. No sudden cardiac death or heart failure occurred in the viable group, in contrast to incidences of 6% and 9%, respectively, in the non-viable group. Unstable angina and nonfatal re-infarction occurred more frequently in the viable group. CONCLUSIONS: The presence of stunned myocardium is a predictor of the prognosis for patients with acute myocardial infarction.

[Is blood squeezed out from the microcirculation soon after coronary occlusion?: real time myocardial contrast echocardiographic study].

BACKGROUND AND OBJECTIVES: The fate of blood trapped inside the myocardial microvessels after complete occlusion of the coronary artery has not been elucidated. Blood may be squeezed out by residual contraction even after coronary occlusion. The microcirculation was examined soon after coronary occlusion by real-time contrast echocardiography. METHODS: Myocardial opacification in the short-axis view was examined during infusion of FS69 (Optison) using the Coherent Contrast Imaging method(SIEMENS Sequoia 512) in 17 open chest dogs. The left circumflex coronary artery was completely ligated for 15 sec and the video intensity (256 gray level) of the risk area was measured at end-systole of every 3 beats before and after ligation. Temporal deterioration of the wall motion was evaluated, defined as normokinesis, mild hypokinesis and severe hypokinesis, and akinesis. Changes in the video intensity during each stage of wall motion abnormalities were examined. RESULTS: The video intensity of the risk area decreased significantly after coronary occlusion. Wall motion of the risk area deteriorated gradually after ligation, in which mild hypokinesis, severe hypokinesis and akinesis developed consecutively at 2.8 +/- 0.5, 5.4 +/- 0.5 and 7.8 +/- 0.8 sec after coronary ligation, respectively. The changes in video intensity during each stage of the wall motion abnormalities were small and not statistically significant, irrespective of severity of wall motion abnormalities. CONCLUSIONS: These findings suggest that the blood remains in the vascular bed immediately after the coronary occlusion and is not squeezed out even if wall motion of the risk area continues.

Multi-focus setting improves the heterogeneity of myocardial opacification in intravenous contrast echocardiography.

OBJECTIVES: Myocardial contrast echocardiography observes heterogeneous opacification between regions near and far from the transducer depending on the depth of the focus point. The efficacy of the multi-focus setting was investigated for the improvement of this heterogeneous opacification of the myocardium in myocardial contrast echocardiography. METHODS: Myocardial contrast echocardiography was performed in five closed-chest dogs using triggered (every fourth cardiac cycle) second harmonic technology (1.8/3.6 MHz) following intravenous injection of 0.1 ml of Optison. The short-axis view of the left ventricle was recorded and baseline subtracted video intensity (peak intensity) was calculated in the anterior, septal and posterior left ventricular walls to evaluate myocardial opacification. Three different single foci at near (2 cm), middle (4 cm), and far (6 cm) points were examined, as well as the multi-focus setting combining the near and far foci. RESULTS: Using any single focus point, the peak intensities of segments far from the focus points were decreased and heterogeneous myocardial opacification was observed. Only the multi-focus setting demonstrated absence of differences in peak intensities between each segment with sufficient myocardial opacification of all segments. CONCLUSIONS: The multi-focus setting may be advantageous for improving the heterogeneity of myocardial opacification in myocardial contrast echocardiography.