Efficacy and safety of the dual L- and T-type calcium channel blocker, ACT-280778: a proof-of-concept study in patients with mild-to-moderate essential hypertension.

ACT-280778 is an oral, non-dihydropyridine, dual L-/T-type calcium channel blocker. This phase 2a, double-blind, randomized, placebo- and active-controlled study investigated the efficacy and safety of 10 mg ACT-280778. Patients with mild-to-moderate essential hypertension received once-daily placebo (n=53), ACT-280778 10 mg (n=52) or amlodipine 10 mg (n=54) for 4 weeks. The primary end point was the change from baseline to week 4 in placebo-adjusted mean trough sitting diastolic blood pressure (SiDBP) with ACT-280778. Tolerability was assessed by recording treatment-emergent adverse events (TEAEs). Baseline clinical characteristics were similar across groups. No significant difference was observed at week 4 in mean trough SiDBP between placebo (-9.9 (95% confidence limit (CL) -12.7, -7.0) mm Hg) and ACT-280778 (-9.5 (-12.4, -6.5) mm Hg; P=0.86); amlodipine reduced mean trough SiDBP by -16.8 (-19.0, -14.5) mm Hg, confirming assay validity. Change in mean PR interval at week 4 (pre-dose) differed between placebo (-1.0 (95% CL -4.4, 2.3) ms) and ACT-280778 (6.5 (3.5, 9.6) ms); amlodipine did not increase PR interval (1.1 (-1.6, 3.9) ms).Treatment-emergent adverse events (TEAE) frequency was 32.1% (placebo), 32.7% (ACT-280778) and 33.3% (amlodipine). The most common TEAEs were headache, peripheral edema, hypertension and second-degree atrioventricular block. ACT-280778 (10 mg) did not lower blood pressure in mild-to-moderate hypertension.

Surgical reconstruction for unilateral iliac artery lesions in patients younger than 50 years.

BACKGROUND: To evaluate safety, short and long-term graft patency, clinical success rates, and factors associated with patency, limb salvage and mortality after surgical reconstruction in patients younger than 50 years of age who had undergone unilateral iliac artery bypass surgery. PATIENTS AND METHODS: From January 2000 to January 2010, 65 consecutive reconstructive vascular operations were performed in 22 women and 43 men of age < 50 years with unilateral iliac atherosclerotic lesions and claudication or chronic limb ischemia. All patients were followed at 1, 3, 6, and 12 months after surgery and every 6 months thereafter. RESULTS: There was in-hospital vascular graft thrombosis in four (6.1 %) patients. No in-hospital deaths occurred. Median follow-up was 49.6 ± 33 months. Primary patency rates at 1-, 3-, 5-, and 10-year were 92.2 %, 85.6 %, 73.6 %, and 56.5 %, respectively. Seven patients passed away during follow-up of which four patients due to coronary artery disease, two patients due to cerebrovascular disease and one patient due to malignancy. Limb salvage rate after 1-, 3-, 5-, and 10-year follow-up was 100 %, 100 %, 96.3 %, and 91.2 %, respectively. Cox regression analysis including age, sex, risk factors for vascular disease, indication for treatment, preoperative ABI, lesion length, graft diameter and type of pre-procedural lesion (stenosis/occlusion), showed that only age (beta - 0.281, expected beta 0.755, p = 0.007) and presence of diabetes mellitus during index surgery (beta - 1.292, expected beta 0.275, p = 0.026) were found to be significant predictors of diminishing graft patency during the follow-up. Presence of diabetes mellitus during index surgery (beta - 1.246, expected beta 0.291, p = 0.034) was the only variable predicting mortality. CONCLUSIONS: Surgical treatment for unilateral iliac lesions in patients with premature atherosclerosis is a safe procedure with a low operative risk and acceptable long-term results. Diabetes mellitus and age at index surgery are predictive for low graft patency. Presence of diabetes is associated with decreased long-term survival.

[Alternative arterial cannulation site in acute aortic dissections].

INTRODUCTION: Acute aortic dissection is an urgent surgical disease. Often, due to hemodynamic instability, that is an indication for emergent surgical intervention. Majority of surgeons uses Femoral or Axillary artery as arterial inflow site forextracorporal circulation. Both approaches have disadvantages that potentially may cause devastating complications. Some of them have been described in literature such as inadequate flow on heart-lung machine, retrograde dissection and malperfusion syndrome. AIM OF STUDY: Aim of study is to show, that by using transventricular cannulation we are eliminating all technical problems and lowering peroperative morbidity and mortality. METHOD: Between 1996-2006 at Institute for Cardiovascular Disease "Dedinje" 107 patients were operated for acute ascending aortic dissection Femoral artery was used for arterial cannulation in 91 patients. Last 16 patients were operated by using transventricular approach to establish extracorporeal circulation. We used retrograde cerebral perfusion in 21 cases at the beginning of our experience. RESULTS: In group of patients where transapical cannulation was used, no neurological incidents were noticed. We didn't have any other problems related to extracorporeal circulation or placement of arterial cannula. Is this series we had only one death case. Patient passed away on eight postoperative day due to multiorgan insufficiency. CONCLUSION: Transapical cannulation is very simple and safe method for quick establishment of extracorporeal circulation. It always gives patient sufficient antegrade, physiological flow on heart-lung machine. This is the way to minimize possibility of malperfusion syndrome and to significantly diminish risk of neurological complication. By using this method all negative effects of other cannulation sites will be avoided.

Head-to-head comparison of indices of left ventricular contractile reserve assessed by high-dose dobutamine stress echocardiography in idiopathic dilated cardiomyopathy: five-year follow up.

OBJECTIVE: To compare head to head the indices of left ventricular contractile reserve assessed by high-dose dobutamine in the five-year prognosis of patients with idiopathic dilated cardiomyopathy. DESIGN AND SETTING: Prospective study in a tertiary care centre. PATIENTS: 63 consecutive patients with idiopathic dilated cardiomyopathy. INTERVENTIONS: High-dose dobutamine stress echocardiography was performed in progressive stages lasting 5 min each. Wall motion score index, ejection fraction, cardiac power output and end systolic pressure to volume ratio were evaluated as indices of left ventricular contractility. MAIN OUTCOME MEASURE: Five-year cardiac mortality. RESULTS: During the follow up of 59 patients, 27 (45.8%) died of cardiac causes. According to Kaplan-Meier and receiver operating characteristic analyses all indices of contractile reserve differentiated patients with respect to cardiac death. Wall motion score index achieved the best separation (log rank 21.75, p < 0.0001, area under the curve 0.84), followed by change in ejection fraction (log rank 11.25, p = 0.0008, area under the curve 0.79), end systolic pressure to volume ratio (log rank 14.32, p = 0.0002, area under the curve 0.75) and cardiac power output (log rank 9.84, p = 0.0017, area under the curve 0.71). Cox's regression model identified wall motion score index as the only independent predictor of cardiac death. CONCLUSIONS: These data show that all examined indices of left ventricular contractile reserve are predictive of five-year prognosis, but change in wall motion score index may have the greatest prognostic potential.

Prognostic significance of the dobutamine echocardiography test in idiopathic dilated cardiomyopathy.

Dobutamine stress echo provides potentially useful information on idiopathic dilated cardiomyopathy (IDC). From February 1, 1997, to October 1, 1999, 186 patients (131 men and 55 women, mean age 56 +/- 12 years) with IDC, ejection fraction <35%, and angiographically normal coronary arteries were studied by high-dose (up to 40 micro/kg/min) dobutamine echo in 6 centers, all quality controlled for stress echo reading. In all patients, wall motion score index (WMSI) (from 1 = normal to 4 = dyskinetic in a 16- segment model of the left ventricle) was evaluated by echo at baseline and peak dobutamine. One hundred eighty-four patients were followed up (mean 15 +/- 13 months) and only cardiac death was considered as an end point. There were 29 cardiac deaths. Significant parameters for survival prediction at univariate analysis are: DeltaWMSI (chi-square 20.1; p <0.0000), New York Heart Association (NYHA) class (chi-square 17.57; p <0.0000), rest ejection fraction (chi-square 10.41; p = 0.0013), angiotensin-converting enzyme inhibitors (chi-square 8.23; p = 0.0041), and hypertension (chi-square 8.08, p = 0.0045). In the multivariate stepwise analysis only DeltaWMSI and NYHA were independent predictors of outcome (DeltaWMSI = hazard ratio 0.02, p < 0.0000; NYHA class = hazard ratio 3.83, p < 0.0000). Kaplan-Meier survival estimates showed a better outcome for patients with a large inotropic response (DeltaWMSI > or =0.44, a cutoff identified by receiver-operating characteristic curves analysis) than for those with a small or no myocardial inotropic response to dobutamine (93.6% vs 69.4%, p = 0.00033). Thus, in patients with IDC, an extensive contractile reserve identified by high-dose dobutamine stress echocardiography is associated with a better survival.

Preinfarction angina prevents left ventricular remodeling in patients treated with thrombolysis for myocardial infarction.

BACKGROUND: It has been shown that preinfarction angina may have beneficial effects on infarct size and mortality. However, there are no studies that have serially assessed the impact of preinfarction angina on left ventricular (LV) function in a large series of patients. HYPOTHESIS: The study was undertaken to determine whether preinfarction angina (within 7 days before infarction) influences LV remodeling. METHODS: In all, 119 consecutive patients with acute myocardial infarction were serially evaluated by 2-dimensional echocardiography (on Days 1, 2, 3, and 7; at 3 and 6 weeks; and at 3, 6, and 12 months following infarction). Left ventricular volumes were determined using Simpson's biplane formula and normalized for body surface area. Wall motion score index and sphericity index were calculated for each study. Coronary angiography was performed before discharge. RESULTS: Preinfarction angina was detected in 39 of 119 patients. Initial echocardiographic and clinical data as well as the incidence of patent infarct-related artery and collaterals were similar for patients with and without preinfarction angina. In the subset of thrombolysed patients, patients with preinfarction angina showed decrease of LV end-diastolic and end-systolic volumes during the follow-up period (p = 0.033 and p = 0.001, respectively), and improvement of wall motion score index (p < 0.001) and ejection fraction occurred (p = 0.001), without changing of LV shape (p > 0.05); in addition, patients with preinfarction angina had smaller LV volumes and higher ejection fraction than did those without angina, from 3 weeks onward. These favorable effects were not detected in patients not treated with thrombolysis. CONCLUSIONS: These data indicate that preinfarction angina has an inhibiting effect on long-term LV remodeling in patients who underwent thrombolysis for first acute myocardial infarction. It appears that preinfarction angina has no impact on infarct size and early postinfarction LV function.

Myocardial fibrosis assessment by semiquantitative, point-counting and computer-based methods in patients with heart muscle disease: a comparative study.

AIMS: No study has directly compared different histomorphometric methods of quantification of myocardial fibrosis. Therefore we compared the results of semiquantitative, point-counting and computer-based methods in the assessement of myocardial fibrosis in a consecutive series of endomyocardial biopsy samples from patients with heart muscle disease. METHODS AND RESULTS: Histological samples (at least three per patient) were obtained by endomyocardial biopsy from 11 patients with focal myocarditis and from 24 ambulatory patients with idiopathic dilated cardiomyopathy, or during surgery in 10 patients who underwent partial left ventriculectomy. Samples were cut and stained with Masson-trichrome for better contrast. From each sample, a representative field was digitized, and the amount of fibrosis was assessed by semiquantitative scoring, by point-counting, and by computer-based software. Semiquantitative scoring correlated with both point-counting (Spearman's r = 0.69, P < 0.0001) and computer-based (Spearman's r = 0.83, P < 0.0001) methods. There was also a good correlation between point-counting and computer-based methods (r = 0.71, P < 0.0001). However, when compared with the point-counting method, the computer-based method overestimated percent fibrosis by 3.0 +/- 6.7% (P = 0.004). This overestimation correlated with the mean percent fibrosis (r = 0.38, P = 0.014). CONCLUSIONS: Our data show good correlations between the three methods of myocardial fibrosis assessment. However, systematic differences between them emphasize that this should be taken into consideration when comparing results of the studies using different methods of fibrosis assessment.

Single-day loading dose of oral amiodarone for the prevention of new-onset atrial fibrillation after coronary artery bypass surgery.

BACKGROUND: Various regimens have been proposed for the prevention of postoperative atrial fibrillation, including the use of intravenous and oral amiodarone. The purpose of this study was to determine the effectiveness of a single-day loading dose of oral amiodarone in prophylaxis of atrial fibrillation during the 7 days after coronary artery bypass surgery. METHODS: We conducted a double-blind, randomized, placebo-controlled study encompassing 315 consecutive patients who underwent coronary artery bypass surgery. They received either amiodarone (159 patients) or placebo (156 patients). Therapy consisted of a single oral loading dose of 1200 mg of amiodarone 1 day before surgery, followed by the maintenance dose of 200 mg daily during the next 7 days. Only episodes of atrial fibrillation lasting more than 1 hour or associated with hemodynamic compromise were taken into consideration. RESULTS: Overall, the incidence of atrial fibrillation was similar in patients who received amiodarone (31/159, 19.5%) and placebo (33/156, 21.2%) (P = .78). However, amiodarone reduced the incidence of atrial fibrillation in elderly patients (age > or = 60 years): it occurred in 20 of 75 (26.7%) patients on amiodarone and in 28 of 65 (43.1%) patients in the placebo group (P = .05). There were no differences between the study groups regarding the postoperative intrahospital morbidity and mortality and the duration of hospital stay. CONCLUSIONS: A single-day loading dose of oral amiodarone (1200 mg) does not prevent postoperative atrial fibrillation in a general population of patients undergoing coronary artery bypass surgery. However, it appears that this regimen reduces the occurrence of postoperative atrial fibrillation in elderly patients.

Short early filling deceleration time on day 1 after acute myocardial infarction is associated with short and long term left ventricular remodelling.

OBJECTIVE: To assess the relations between early filling deceleration time, left ventricular remodelling, and cardiac mortality in an unselected group of postinfarction patients. DESIGN AND PATIENTS: Prospective evaluation of 131 consecutive patients with first acute myocardial infarction. Echocardiography was performed on day 1, day 2, day 3, day 7, at three and six weeks, and at three, six, and 12 months after infarction. According to deceleration time on day 1, patients were divided into groups with short (< 150 ms) and normal deceleration time (>/= 150 ms). SETTING: Tertiary care centre. RESULTS: Patients with a short deceleration time had higher end systolic and end diastolic volume indices and a higher wall motion score index, but a lower ejection fraction, in the year after infarction. These patients also showed a significant increase in end diastolic (p < 0.001) and end systolic volume indices (p = 0.007) during the follow up period, while ejection fraction and wall motion score index remained unchanged. In the group with normal deceleration time, end diastolic volume index increased (p < 0.001) but end systolic volume index did not change; in addition, the ejection fraction increased (p = 0.002) and the wall motion score index decreased (p < 0.001). One year and five year survival analysis showed greater cardiac mortality in patients with a short deceleration time (p = 0.04 and p = 0.02, respectively). In a Cox model, which included initial ejection fraction, infarct location, and infarct size, deceleration time on day 1 was the only significant predictor of five year mortality. CONCLUSIONS: A short deceleration time on day 1 after acute myocardial infarction can identify patients who are likely to undergo left ventricular remodelling in the following year. These patients have a higher one year and five year cardiac mortality.

Functional capacity late after partial left ventriculectomy: relation to ventricular geometry and performance.

OBJECTIVES: While partial left ventriculectomy (PLV) may improve functional status, the duration and determinants of this improvement are poorly known. This study sought to assess the relationship between left ventricular (LV) shape and function and functional status in late survivors after PLV for non-ischemic dilated cardiomyopathy (DCM). METHODS: We assessed the relations between LV shape and function and functional status in 17 consecutive patients who survived >12 months after PLV for non-ischemic DCM. Invasive diagnostic studies were performed before, early after, at mid-term after, and late after PLV. According to their functional status after >12 months of follow-up, patients were divided into responders (n=10) or non-responders (n=7). RESULTS: After PLV, the LV systolic major-to-minor axis ratio was higher in responders at early, mid-, and late follow-up (P=0.003, P=0.008 and P=0.04, respectively). LV circumferential end-diastolic stress decreased early after PLV, but increased afterwards in non-responders only (P=0.049). LV ejection fraction was similar in the two groups at baseline, and at early and mid-follow-up, but was lower in non-responders at late follow-up (P=0.006). However, LV end-diastolic and end-systolic volumes, and LV end-systolic circumferential stress showed no difference between the two groups. CONCLUSIONS: It appears that poor functional capacity in late post-PLV survivors is related to postoperative LV geometry.

Association of Killip class on admission and left ventricular dilatation after myocardial infarction: a closer look into an old clinical classification.

BACKGROUND: Early identification of patients in whom left ventricular dilatation is likely to occur may have important therapeutic implications. Thus the purpose of this study was to evaluate the relation between Killip class on admission and subsequent left ventricular dilatation after acute myocardial infarction. METHODS AND RESULTS: We serially evaluated 129 consecutive patients by two-dimensional and Doppler echocardiography on days 1, 2, 3, and 7, at 3 and 6 weeks, and at 3, 6, and 12 months after infarction. Killip class on admission >1 was found in 29 of 129 (22.5%) patients, and they had significantly higher end-systolic and end-diastolic volume indexes and wall motion score index from day 1 onward compared with patients with Killip class 1, whereas ejection fraction was lower during the follow-up period in these patients. Patients with Killip class >1 showed the progressive increase of end-diastolic (68.2 +/- 2.99 to 88.0 +/- 7.55 ml/m2, p = 0.001) and end-systolic volume indexes (43.9 +/- 2.67 to 56.3 +/- 6. 18 ml/m2, p = 0.004) during the follow-up period, whereas ejection fraction and wall motion score index remained unchanged. In patients with Killip class 1, end-systolic volume index did not change (30.8 +/- 1.06 to 33.8 +/- 2.15 ml/m2, p = 0.064), ejection fraction increased (49.3% +/- 0.99% to 51.8% +/- 1.17%, p = 0.027), and wall motion score index decreased (1.50 +/- 0.03 to 1.35 +/- 0.04, p < 0. 001). End-systolic volume index was the major independent correlate of Killip class, followed by history of diabetes and peak creatine kinase level. No association was found between Doppler indexes of diastolic filling and Killip class on admission. CONCLUSIONS: Killip class >1 on admission is associated with both acute and long-term left ventricular dilatation. On the other hand, Killip class 1 is associated with favorable left ventricular functional indices, and it appears that left ventricular function in these patients may improve over time. Initial end-systolic volume index but not ejection fraction is the major correlate of Killip class.

[Relation of the pressure-volume loop and mechanical energy properties of the left ventricle]. / Odnos pritisak-zapremina i mehanoenergetiske odlike leve komore srca.

New biomechanical models of the left ventricle, as well as recent technological breakthroughs, allowed a wider use of pressure/volume loop in the assessment of mechano-energetic properties of the left ventricle. The most widely used parameter derived from the pressure/volume loop is end-systolic elastance, which reflects the left ventricular contractility. Additionally, pressure/volume loop has been proved to be useful in the assessment of left ventricular diastolic function. More complex parameters of left ventricular mechanisms, such as stroke work and potential energy, can be studied by plotting pressure/volume loop and lines depicting end-systolic and end-diastolic pressure/volume relations. Similarly, the ratio of the area contained in the pressure/volume loop, that is stroke work, and the level of myocardial oxygen consumption can be used in the assessment of the efficiency by which the left ventricle converts chemical energy into mechanical energy. In conclusion, the use of pressure/volume loop and its relationship to myocardial oxygen consumption can be very effective in the analysis of cardiovascular performance in various settings.

Pericardial effusion after streptokinase for acute myocardial infarction: an echocardiographic 1-year follow-up study.

Since the reported incidence of pericardial effusion following thrombolysis is highly variable, we have evaluated 80 consecutive patients with first acute myocardial infarction treated with streptokinase. Two-dimensional echocardiographic studies were performed on days 1, 2, 3, and 7, at 3 and 6 weeks, and 3, 6, and 12 months following acute myocardial infarction. Throughout the study, pericardial effusion was found in 7 of 80 (8.75%) patients, being small in 5 patients, moderate in 1, and large in 1 patient. No clinical, angiographic, or echocardiographic variable was associated with pericardial effusion formation. The incidence of pericardial effusion found in our study is almost three times lower than in other echocardiographic studies on pericardial effusion in thrombolysed patients. Whether this differences results from the beneficial effects of streptokinase is not clear.

Isolated mitral regurgitation complicating relapsing polychondritis.

The reported incidence of mitral regurgitation in relapsing polychondritis ranges from 2 to 3% and is associated with aortic regurgitation. There are no reports that mitral regurgitation can be an isolated cardiac complication of relapsing polychondritis. This case report demonstrates that partial chordal rupture and consequent severe mitral regurgitation can be the only features of cardiac involvement in relapsing polychondritis.