Evaluation of multimeric tyrosine-O-sulfate as a cytoprotectant in an in vivo model of acute myocardial infarction in pigs.

OBJECTIVES: Intracoronary administration of glycosaminoglycan analogs, including the complement inhibitor dextran sulfate, attenuates myocardial ischemia/reperfusion injury (I/R injury). However, dextran sulfate has a distinct anticoagulatory effect, possibly limiting its use in specific situations in vivo. We therefore developed multimeric tyrosine sulfate (sTyr-PAA), a novel, minimally anticoagulatory, fully synthetic non-carbohydrate-containing polyacrylamide conjugate, for in vivo testing in an acute closed-chest porcine model of acute myocardial infarction. METHODS: Following balloon occlusion of the left anterior descending artery just after the first diagonal branch (60-minute ischemia), sTyr-PAA (approx. 10 mg/kg bodyweight, fraction with strongest complement-inhibitory and minimal anticoagulatory properties, n = 11) or phosphate-buffered saline (controls, n = 9) was administered intracoronarily into ischemic myocardium prior to 120 min of reperfusion. RESULTS: sTyr-PAA significantly reduced infarct size (from 61.0 ± 12.0% of the ischemic area at risk to 39.4 ± 17.0%), plasma creatine kinase, local complement deposition and tissue factor upregulation, without affecting systemic coagulation. Protection was associated with significantly reduced myocardial neutrophil extravasation and translated into a significant improvement of ejection fraction and left ventricular enddiastolic pressure. CONCLUSIONS: sTyr-PAA protected significantly against myocardial I/R injury without substantially affecting systemic coagulation. Local intravascular sTyr-PAA administration may prove advantageous in situations where bleeding complications are likely or are to be avoided at all costs.

Persistent diastolic dysfunction late after valve replacement in severe aortic regurgitation.

BACKGROUND: Regression of left ventricular (LV) hypertrophy with normalization of diastolic function has been reported in patients with aortic stenosis late after aortic valve replacement (AVR). The purpose of the present study was to evaluate the effect of AVR on LV function and structure in chronic aortic regurgitation early and late after AVR. METHODS AND RESULTS: Twenty-six patients were included in the present analysis. Eleven patients with severe aortic regurgitation were studied before, early (21 months) and late (89 months) after AVR through the use of LV biplane angiograms, high-fidelity pressure measurements, and LV endomyocardial biopsies. Fifteen healthy subjects were used as controls. LV systolic function was determined from biplane ejection fraction and midwall fractional shortening. LV diastolic function was calculated from the time constant of LV relaxation, peak filling rates, and myocardial stiffness constant. LV structure was assessed from muscle fiber diameter, interstitial fibrosis, and fibrous content. LV muscle mass decreased significantly by 38% early and 55% late after surgery. Ejection fraction was significantly reduced preoperatively and did not change after AVR (P=NS). LV relaxation was significantly prolonged before surgery (89+/-28 ms) but was normalized late after AVR (42+/-14 ms). Early and late peak filling rates were increased preoperatively but normalized postoperatively. Diastolic stiffness constant was increased before surgery (22+/-6 versus 9+/-3 in control subjects; P=0.0003) and remained elevated early and late after AVR (23+/-4; P=0.002). Muscle fiber diameter decreased significantly after AVR but remained increased at late follow-up. Interstitial fibrosis was increased preoperatively and increased even further early but decreased late after AVR. Fibrosis was positively linearly correlated to myocardial stiffness and inversely correlated to LV ejection fraction. CONCLUSIONS: Patients with aortic regurgitation show normalization of macroscopic LV hypertrophy late after AVR, although fiber hypertrophy persists. These changes in LV myocardial structure late after AVR are accompanied by a change in passive elastic properties with persistent diastolic dysfunction.

Dual low response to acetylsalicylic acid and clopidogrel is associated with myonecrosis and stent thrombosis after coronary stent implantation.

BACKGROUND: Impaired response to antiplatelet therapy with acetylsalicylic acid (ASA) and clopidogrel (CLO) has been associated with an increased risk of stent thrombosis and ischemic events after coronary stent implantation. We sought to investigate whether patients with a low response (LR) to ASA or CLO are at increased risk for periprocedural and short-term ischemic events after coronary stent implantation. METHODS: A total of 219 patients pretreated with ASA and CLO underwent percutaneous coronary intervention (PCI) with stent implantation. Whole blood impedance platelet aggregometry was performed with the Multiplate analyzer (Dynabyte, Munich, Germany) to test the response to ASA (ASPI test) and CLO (ADP test) within 12 to 18 hours after PCI. Patients were classified as ASA-LR, CLO-LR, dual LR, and controls. Study end points included myocardial infarction, stent thrombosis, and death assessed during the periprocedural period and at 30 days. RESULTS: Acetylsalicylic acid-LR was present in 34 (16%), CLO-LR in 33 (15%), and dual LR in 19 (9%) patients. Percutaneous coronary intervention-related myocardial infarction was encountered in 19 (9%) patients, with the highest incidence in dual-LR group (26.3%, P = .039). Composite ischemic events at 30 days were significantly more frequent in the dual-LR group than in other groups (36.8% vs 8.8% ASA-LR vs 6.1% CLO-LR vs 6.8% controls, P < .001). In multivariable analysis, dual LR (odds ratio 7.35, 95% CI 2.21-24.42, P < .001) and multivessel PCI (odds ratio 4.56, 95% CI 1.33-15.62, P = .016) were independently associated with ischemic events at 30 days. CONCLUSION: Dual LR to ASA and CLO is associated with an increased risk for short-term ischemic events after coronary stent implantation.

Early and late coronary stent thrombosis of sirolimus-eluting and paclitaxel-eluting stents in routine clinical practice: data from a large two-institutional cohort study.

BACKGROUND: Stent thrombosis is a safety concern associated with use of drug-eluting stents. Little is known about occurrence of stent thrombosis more than 1 year after implantation of such stents. METHODS: Between April, 2002, and Dec, 2005, 8146 patients underwent percutaneous coronary intervention with sirolimus-eluting stents (SES; n=3823) or paclitaxel-eluting stents (PES; n=4323) at two academic hospitals. We assessed data from this group to ascertain the incidence, time course, and correlates of stent thrombosis, and the differences between early (0-30 days) and late (>30 days) stent thrombosis and between SES and PES. FINDINGS: Angiographically documented stent thrombosis occurred in 152 patients (incidence density 1.3 per 100 person-years; cumulative incidence at 3 years 2.9%). Early stent thrombosis was noted in 91 (60%) patients, and late stent thrombosis in 61 (40%) patients. Late stent thrombosis occurred steadily at a constant rate of 0.6% per year up to 3 years after stent implantation. Incidence of early stent thrombosis was similar for SES (1.1%) and PES (1.3%), but late stent thrombosis was more frequent with PES (1.8%) than with SES (1.4%; p=0.031). At the time of stent thrombosis, dual antiplatelet therapy was being taken by 87% (early) and 23% (late) of patients (p<0.0001). Independent predictors of overall stent thrombosis were acute coronary syndrome at presentation (hazard ratio 2.28, 95% CI 1.29-4.03) and diabetes (2.03, 1.07-3.83). INTERPRETATION: Late stent thrombosis was encountered steadily with no evidence of diminution up to 3 years of follow-up. Early and late stent thrombosis were observed with SES and with PES. Acute coronary syndrome at presentation and diabetes were independent predictors of stent thrombosis.

Sirolimus-eluting and paclitaxel-eluting stents for coronary revascularization.

BACKGROUND: Sirolimus-eluting stents and paclitaxel-eluting stents, as compared with bare-metal stents, reduce the risk of restenosis. It is unclear whether there are differences in safety and efficacy between the two types of drug-eluting stents. METHODS: We conducted a randomized, controlled, single-blind trial comparing sirolimus-eluting stents with paclitaxel-eluting stents in 1012 patients undergoing percutaneous coronary intervention. The primary end point was a composite of major adverse cardiac events (death from cardiac causes, myocardial infarction, and ischemia-driven revascularization of the target lesion) by nine months. Follow-up angiography was completed in 540 of 1012 patients (53.4 percent). RESULTS: The two groups had similar baseline clinical and angiographic characteristics. The rate of major adverse cardiac events at nine months was 6.2 percent in the sirolimus-stent group and 10.8 percent in the paclitaxel-stent group (hazard ratio, 0.56; 95 percent confidence interval, 0.36 to 0.86; P=0.009). The difference was driven by a lower rate of target-lesion revascularization in the sirolimus-stent group than in the paclitaxel-stent group (4.8 percent vs. 8.3 percent; hazard ratio, 0.56; 95 percent confidence interval, 0.34 to 0.93; P=0.03). Rates of death from cardiac causes were 0.6 percent in the sirolimus-stent group and 1.6 percent in the paclitaxel-stent group (P=0.15); the rates of myocardial infarction were 2.8 percent and 3.5 percent, respectively (P=0.49); and the rates of angiographic restenosis were 6.6 percent and 11.7 percent, respectively (P=0.02). CONCLUSIONS: As compared with paclitaxel-eluting stents, the use of sirolimus-eluting stents results in fewer major adverse cardiac events, primarily by decreasing the rates of clinical and angiographic restenosis.

Prognostic value of early exercise testing after coronary stent implantation.

The clinical value of early exercise stress testing (EST) after coronary stenting to predict long-term clinical outcomes is unknown. Of 1,000 unselected patients who underwent coronary stenting, 446 random patients underwent early EST the day after intervention. Clinical long-term outcomes (41 +/- 20 months) were correlated with normal (n = 314 [70%]) or positive (n = 102 [23%]) EST results. Patients with inconclusive test results (n = 30 [7%]) were excluded from the analysis. Overall mortality was significantly higher in patients with positive EST results (9.3% vs 3.9%, p = 0.04). Major adverse cardiac events and cardiac mortality also tended to be higher in patients with positive stress test results (45.4% vs 35.4%, p = 0.08, and 4.1% vs 1.1%, p = 0.05, respectively). Patients with the combination of positive stress test results and incomplete revascularization appeared to be the group at highest risk for major adverse cardiac events (47.1% vs 33.3% for patients with normal stress test results and complete revascularization, p = NS). Negative stress test results reduced (odds ratio 0.329, 95% confidence interval 0.120 to 0.905, p = 0.031) and a lower ejection fraction increased (odds ratio 0.942, 95% confidence interval 0.897 to 0.989, p = 0.017) the risk for death. In conclusion, an early stress test after coronary stenting provides important prognostic information. Positive stress test results, especially in combination with incomplete revascularization, are associated with higher mortality, a trend toward more repeat revascularization procedures, and higher risk for major adverse cardiac events.

Effect of atorvastatin and pravastatin on platelet inhibition by aspirin and clopidogrel treatment in patients with coronary stent thrombosis.

We sought to determine a potential interaction between statins and antiplatelet therapy with aspirin and clopidogrel. Previous laboratory studies have shown a possible drug-drug interaction of statins metabolized by cytochrome P450 3A4 and clopidogrel (prodrug metabolized by cytochrome P450 3A4), resulting in an impaired inhibitory effect of clopidogrel on platelet aggregation. However, conclusive prospective data assessing this potentially relevant interaction are lacking. In 73 patients, 23 with previous coronary stent thrombosis (ST) (ST group) and 50 without coronary ST (control group), platelet aggregation was measured 3 times in monthly intervals using light transmission aggregometry (adenosine diphosphate [ADP] and arachidonic acid induction). Measurements were carried out with aspirin monotherapy (100 mg/day), dual antiplatelet therapy with aspirin plus clopidogrel (75 mg/day), and additional treatment of 20 mg/day of atorvastatin or 40 mg/day of pravastatin. ADP (5 and 20 micromol)-induced platelet aggregation was significantly decreased with clopidogrel (p <0.001) but remained stable under additional treatment with atorvastatin or pravastatin in the 2 groups. Patients with previous ST showed a higher ADP-induced aggregation level than control subjects. This difference was not influenced by clopidogrel or statin treatment. In conclusion, patients with previous ST show a higher aggregation level than control subjects independent of statin treatment. Atorvastatin and pravastatin do not interfere with the antiaggregatory effect of aspirin and clopidogrel. In conclusion, drug-drug interaction between dual antiplatelet therapy and atorvastatin or pravastatin seems not to be associated with ST.

Randomized comparison of a titanium-nitride-oxide-coated stent with a stainless steel stent for coronary revascularization: the TiNOX trial.

BACKGROUND: Stent coating with titanium-nitride-oxide has been shown to reduce neointimal hyperplasia in the porcine restenosis model. We designed a prospective, randomized, clinical study to investigate the safety and efficacy of titanium-nitride-oxide-coated stents compared with stainless steel stents. METHODS AND RESULTS: Ninety-two patients with de novo lesions were randomly assigned to treatment with titanium-nitride-oxide-coated stents (n=45) or stainless steel stents of otherwise identical design (n=47; control). Baseline characteristics were similar in both groups. At 30 days, no stent thromboses or other adverse events had occurred in either group. Quantitative coronary angiography at 6 months revealed lower late loss (0.55+/-0.63 versus 0.90+/-0.76 mm, P=0.03) and percent diameter stenosis (26+/-17% versus 36+/-24%, P=0.04) in lesions treated with titanium-nitride oxide-coated than in control stents. Binary restenosis was reduced from 33% in the control group to 15% in the titanium-nitride oxide-coated stent group (P=0.07). Intravascular ultrasound studies at 6 months showed smaller neointimal volume in titanium-nitride-oxide-coated stents than in control stents (18+/-21 versus 48+/-28 mm3, P<0.0001). Major adverse cardiac events at 6 months were less frequent in titanium-nitride-oxide-coated stents than in control stent-treated patients (7% versus 27%, P=0.02), largely driven by a reduced need for target-lesion revascularization (7% versus 23%, P=0.07). CONCLUSIONS: Revascularization with titanium-nitride-oxide-coated stents is safe and effective in patients with de novo native coronary artery lesions. Titanium-nitride-oxide-coated stents reduce restenosis and major adverse cardiac events compared with stainless steel stents of otherwise identical design.

Stent thrombosis is associated with an impaired response to antiplatelet therapy.

OBJECTIVES: We sought to evaluate the response to antiplatelet therapy in patients with stent thrombosis (ST). BACKGROUND: Stent thrombosis is associated with considerable morbidity and mortality. An impaired response to antiplatelet therapy might be related to an increased risk for ST. METHODS: Eighty-two patients were included in the present study: 23 patients with previous ST, 50 matched controls (coronary stenting without ST), and 9 healthy volunteers. Platelet aggregation (PA) was studied (optical aggregometry) under monotherapy with acetylsalicylic acid (ASA) 100 mg daily for one month, followed by dual therapy with ASA 100 mg and clopidogrel 75 mg daily (loading dose 300 mg) for another month. RESULTS: Maximal (5 and 20 micromol) adenosine diphosphate-induced PA was significantly higher in patients with ST compared with controls (5 micromol, p < 0.005; 20 micromol, p < 0.05) and volunteers (5 micromol, p < 0.005; 20 micromol, p < 0.05). Resistance to ASA (>20% aggregation with 0.5 mg/ml arachidonic acid) was more prevalent in patients with ST (48%) compared with control patients (32%, p = ns) and volunteers (0%, p = 0.01). Clopidogrel significantly reduced PA in all three groups, but intergroup differences persisted. Clopidogrel resistance (<10% relative change) was similar in patients with ST, control patients, and volunteers (4%, 6%, and 11%, respectively, all p = NS). However, combined ASA and clopidogrel resistance was more prevalent in patients with ST (52%) compared with controls (38%, p = NS) and volunteers (11%, p < 0.05). CONCLUSIONS: Patients with previous ST show an impaired response to antiplatelet therapy with ASA compared with controls and volunteers. Additional treatment with clopidogrel is not able to overcome these differences in PA. Acetylsalicylic acid but not clopidogrel resistance appears to be associated with ST.

Sirolimus-eluting stents associated with paradoxic coronary vasoconstriction.

OBJECTIVES: The purpose of the present study was to assess coronary vasomotor response to exercise after sirolimus-eluting stent (SES) implantation. BACKGROUND: Sirolimus-eluting stents have been shown to markedly reduce the incidence of angiographic and clinical restenosis. However, long-term effects of sirolimus on endothelial function are unknown. METHODS: Coronary vasomotion was evaluated with biplane quantitative coronary angiography at rest and during supine bicycle exercise in 25 patients with coronary artery disease. Eleven patients were treated with a bare-metal stent (BMS) (control group) and 14 patients underwent SES implantation (sirolimus group) for de novo coronary artery lesions. Both groups were studied 6 +/- 1 month after the intervention. Minimal luminal diameter; stent diameter; and proximal, distal, and reference vessel diameter were determined. RESULTS: The reference vessel showed exercise-induced vasodilation (+13 +/- 4%) in both groups. Vasomotion within the stented vessel segments was abolished. In controls, the adjacent segments proximal and distal to the stent showed exercise-induced vasodilation (+15 +/- 3% and +17 +/- 4%, respectively). In contrast, there was exercise-induced vasoconstriction of the proximal and distal vessel segments adjacent to SESs (-12 +/- 4% and -15 +/- 6%, respectively; p < 0.001 vs. corresponding segments of controls). Sublingual nitroglycerin was associated with maximal vasodilation of the proximal and distal vessel segments in both groups. CONCLUSIONS: Implantation of a BMS does not affect physiologic response to exercise proximal and distal to the stent. However, SESs are associated with exercise-induced paradoxic coronary vasoconstriction of the adjacent vessel segments, although vasodilatory response to nitroglycerin is maintained. These observations suggest (drug-induced) endothelial dysfunction as the underlying mechanism.

Exercise-induced coronary artery vasodilation is not impaired by stent placement.

BACKGROUND: Stenting has proved beneficial for treating threatened closure and reducing restenosis after balloon angioplasty. However, the implantation of a coronary metallic prosthesis has been related to impaired vasomotion distal to the stent as assessed by acetylcholine infusion. Thus, the purpose of the present study was to determine the vasomotion of stented coronary arteries and to assess its influence on the vasomotion of adjacent vessel segments during bicycle exercise. METHODS AND RESULTS: Biplane quantitative coronary angiography was performed at rest and during bicycle exercise in 26 patients with coronary artery disease. Twelve patients had single vessel disease with stable angina pectoris (controls; group 1). Fourteen patients underwent coronary stenting for therapeutic reasons and were studied 10+/-3 months after the intervention (group 2). Minimal luminal area, stent area, and proximal and distal vessel areas were determined. In controls (group 1), vasoconstriction of the stenotic artery (- 29+/-4%; P<0.001) was observed during exercise, whereas the normal segment showed vasodilation (15+/-4%; P<0.05). In group 2, vasomotion of the stented segment was eliminated (0+/-1%), whereas the proximal and distal segments showed exercise-induced vasodilation (8+/-2% and 11+/-3%, respectively; P<0.005), which was not different from control segments (10+/-2%). Sublingual nitroglycerin was associated with maximal vasodilation of the proximal and distal vessel segments (30+/-8% and 38+/-13%, respectively; P<0.005). CONCLUSIONS: In contrast to the vasoconstriction of vessels in control patients, normal vasodilation of proximal and distal segments occurred during the physiological stress of exercise in patients with coronary stent placement. As expected, vasomotion was abolished in the stented region.

Deleterious effect of coronary brachytherapy on vasomotor response to exercise.

BACKGROUND: Intracoronary radiotherapy (brachytherapy) has been proposed as treatment option for in-stent restenosis. Long-term results of brachytherapy with regard to vascular integrity and vasomotor responsiveness are unknown. The purpose of the present study was to determine the vasomotor response after brachytherapy and to assess its influence on vasomotion during exercise. METHODS AND RESULTS: Biplane quantitative coronary angiography was performed at rest and during bicycle exercise in 27 patients with coronary artery disease. Fourteen patients underwent coronary stenting and were studied 10+/-3 months after intervention (control group). Thirteen patients were treated with brachytherapy (Guidant Galileo System) for in-stent restenosis with a mean dosis of 20 Gy at 1 mm into the vessel wall and were studied 9+/-1 months after radiation (brachytherapy group). Minimal luminal area, stent area, and proximal, distal, and a reference vessel area were determined. The reference vessel showed exercise-induced vasodilation (26+/-4%, P<0.001) in both groups. Vasomotion within the stented vessel segments was abolished. In control subjects, the proximal and distal segments showed exercise-induced vasodilation (17+/-2% and 22+/-7%, respectively; P<0.005). In contrast, there was exercise-induced vasoconstriction in the proximal and distal vessel segments of the brachytherapy group (-14+/-3% and -16+/-4%, respectively; P<0.01). Sublingual nitroglycerin was associated with maximal vasodilation of the proximal and distal vessel segments in both groups. CONCLUSIONS: Normal vessel segments elicit flow-mediated vasodilation during exercise. Stent implantation does not affect physiological response to exercise proximal and distal to the stent. Brachytherapy eliminates exercise-induced vasodilation, although dilatory response to nitroglycerin is maintained, suggesting endothelial dysfunction as the underlying mechanism.

New treatment strategies for hypertrophic obstructive cardiomyopathy: alcohol ablation of the septum: the new gold standard?

Hypertrophic cardiomyopathy is a primary myocardial disorder with an autosomal pattern of inheritance characterized by inappropriate myocardial hypertrophy. Annual mortality has been reported to be 1% to 2% and sudden death represents the most common cause. Treatment strategies are 1) medical therapy in patients with mild to moderate symptoms, 2) reduction of septal hypertrophy by surgical myectomy or alcohol ablation, and 3) implantation of an automatic cardioverter-defibrillator in the presence of non-sustained ventricular tachyarrhythmias. A debate has been started on whether surgical myectomy or alcohol ablation of the septum is the appropriate treatment for hypertrophic obstructive cardiomyopathy. Surgical (transaortic) myectomy has been the gold standard in the past 20 to 30 years for treatment of symptomatic patients with significant hemodynamic outflow tract obstruction. However, modern interventional technologies allow reduction of the myocardial septum by injection of alcohol into the first or second septal branch under guidance of two-dimensional (2D)-contrast echocardiography. This percutaneous technique not only has a lower morbidity than surgical myectomy but can be guided precisely by 2D echocardiography. One potential complication is transient (<30%) or permanent (<10%) atrioventricular block III; however, this complication is relatively rare. A randomized trial comparing the two treatment modalities is lacking, and the chance is small that such a trial will be performed because alcohol ablation can be done with high success and low complication rates, leaving only complex interventions (with valvular reconstructions and so on) for surgical myectomy.

Early exercise after coronary stenting is safe.

OBJECTIVES: In this study, we sought to assess safety of symptom-limited exercise stress tests the day after coronary stenting. BACKGROUND: Isolated cases of coronary stent thrombosis have been linked to early exercise stress testing, thereby questioning the safety of unrestricted physical activity after the coronary procedure. METHODS: At a single center, 1,000 patients were randomized to a symptom-limited stress test the day after coronary stenting or no stress test. The antiplatelet regimen consisted of acetylsalicylic acid and postprocedural ticlopidine or clopidogrel. The primary end point of the study was the incidence of clinical stent thrombosis at 14 days. The secondary end point was the occurrence of access site complications. RESULTS: Clinical stent thrombosis occurred in five patients (1%) undergoing stress test and in five patients (1%) randomized to no stress test (p = 1.0). Access site complications were detected in 4% and 5.2% of cases, respectively (p = 0.37). CONCLUSIONS: Symptom-limited exercise stress testing the day after coronary stenting does not increase the risk of clinical stent thrombosis or access site complications. Further investigations on safety of early vigorous exercise after coronary stenting in a non-supervised setting are warranted.

Xanthurenic acid translocates proapoptotic Bcl-2 family proteins into mitochondria and impairs mitochondrial function.

BACKGROUND: Xanthurenic acid is an endogenous molecule produced by tryptophan degradation, produced in the cytoplasm and mitochondria. Its accumulation can be observed in aging-related diseases, e.g. senile cataract and infectious disease. We previously reported that xanthurenic acid provokes apoptosis, and now present a study of the response of mitochondria to xanthurenic acid. RESULTS: Xanthurenic acid at 10 or 20 microM in culture media of human aortic smooth muscle cells induces translocation of the proteins Bax, Bak, Bclxs, and Bad into mitochondria. In 20 microM xanthurenic acid, Bax is also translocated to the nucleus. In isolated mitochondria xanthurenic acid leads to Bax and Bclxs oligomerization, accumulation of Ca2+, and increased oxygen consumption. CONCLUSION: Xanthurenic acid interacts directly with Bcl-2 family proteins, inducing mitochondrial pathways of apoptosis and impairing mitochondrial functions.

Regional myocardial ischemia in hypertrophic cardiomyopathy: impact of myectomy.

OBJECTIVE: Chest pain is a common finding in patients with hypertrophic cardiomyopathy and can be observed in 40% to 50% of all patients. However, the pathogenesis of these ischemia-like symptoms is still unclear. METHODS: Twenty-two patients with hypertrophic cardiomyopathy and 15 controls underwent positron emission tomography for evaluation of regional myocardial perfusion and coronary flow reserve (hyperemic/baseline myocardial blood flow). Myocardial perfusion (mL/min/g) was measured using [(13)N]ammonia at rest and during hyperemia with dipyridamole (0.56 mg/kg intravenously). Regional coronary flow reserve was assessed in 3 planes (apical, midventricular, basal) in 4 regions (septal, anterior, lateral, inferior). Patients were divided into 2 groups: group 1 consisted of 11 patients treated with surgical myectomy (age 56 +/- 10 years) and group 2 consisted of 11 patients treated medically (age 53 +/- 13 years). RESULTS: Mean global coronary flow reserve was 3.87 +/- 0.92 in controls but 2.31 +/- 0.40 in operated (P <.001 vs controls) and 1.76 +/- 0.58 in medically treated patients (P <.001 vs controls, P <.05 vs operated). Similarly, septal coronary flow reserve was 4.19 +/- 1.22 in controls but significantly reduced in operated patients (2.26 +/- 0.48, P <.001 vs controls) and in medically treated patients (1.76 +/- 0.58; P <.001 vs controls). However, septal flow reserve was significantly higher in operated patients than in patients with medically treated hypertrophic cardiomyopathy (+37%, P <.05), mainly due to a reduced resting myocardial perfusion. CONCLUSIONS: Global and regional myocardial perfusion is reduced in patients with hypertrophic cardiomyopathy. However, myectomy may have a beneficial effect on septal perfusion and flow reserve. Thus, ischemia seems to play an important role in the symptomatology and pathophysiology of hypertrophic cardiomyopathy.

Betablockers in heart failure: Carvedilol Safety Assessment (CASA 2-trial).

BACKGROUND: Betablockers are a cornerstone in the treatment of patients with chronic heart failure (CHF). The purpose of the present study was to assess safety and tolerability of carvedilol in CHF-patients. METHODS: 66 general practitioners, who were supervised by a local cardiologist, enrolled 151 CHF-patients. All patients were on standard therapy with ACE-inhibitors and diuretics. Carvedilol treatment was started with 3.125 mg twice daily and slowly uptitrated in 2-week intervals to 2x25 mg per day. Mean follow-up was 12 weeks. RESULTS: 145 of the 151 patients (96%) finished the study according to protocol, six patients were lost to follow-up (4%). 59 patients (41%) experienced minor and nine (6%) serious adverse events. 68 were under maximal therapy with 50 mg daily, 33 received 25 mg, and 15 12.5 mg. Overall tolerability was good and NYHA-class fell significantly from 2.2 to 1.8 (P<0.001). Mean heart rate decreased from 78 to 69 bpm (P<0.001), mean systolic blood pressure from 137 to 132 mmHg (P<0.001) and mean diastolic blood pressure from 80 to 76 mmHg (P<0.001). Quality of life significantly improved under carvedilol with a reduction in the Minnesota living with heart failure score from 1.28 to 0.88 (P<0.001). CONCLUSIONS: Carvedilol is well tolerated in CHF-patients treated by general practitioners. Serious adverse events and hospitalisations are rare. Thus, carvedilol is a safe drug in the treatment of CHF-patients and can be easily initiated and managed by the general practitioner.

Cardiac rotation and relaxation in patients with chronic heart failure.

BACKGROUND: The normal left ventricle shows a systolic wringing motion with clockwise rotation at the base and counterclockwise rotation at the apex. PURPOSE: The aim of the present study was (1) to assess left ventricular (LV) contraction and relaxation in patients with chronic heart failure (CHF), and (2) to evaluate the effect of medical therapy on LV contraction-relaxation behavior. METHODS: Magnetic resonance was used to examine LV motion by labeling specific LV regions in three planes (myocardial tagging). Twenty-three subjects were included, nine healthy controls and 14 CHF patients. Cardiac motion was determined from the deformation of a rectangular grid in a basal and apical plane. CHF patients were put on triple therapy with ACE-inhibitors, beta-blockers and spironolactone. Follow-up examination (n=9) was performed after 6 months. RESULTS: In controls, systolic rotation was -9.5+/-2 degrees at the base and +3.3+/-1 degrees at the apex. In CHF patients, rotation was reduced both at the base (-3.4+/-2 degrees , P<0.01) and the apex (+0.9+/-3 degrees , P<0.05). Similarly, regional ejection fraction (REF) was reduced in CHF patients both at the base and the apex. Medical therapy was associated with an improvement in REF, but systolic rotation improved only at the base (-4.6+/-2 degrees , P<0.05). CONCLUSIONS: Systolic wringing motion with clockwise rotation at the base and counterclockwise rotation at the apex is maintained in CHF although reduced. Heart failure treatment is associated with an improvement in REF, whereas rotation improved only at the base, but not at the apex. Thus, there is an uncoupling between regional shortening and rotation in CHF patients.

Are there sex differences in regional systolic function and wall stress in hypertrophic obstructive cardiomyopathy? A three-dimensional echocardiography study.

OBJECTIVES: Sex-related differences in left ventricular (LV) systolic function have been previously reported in patients with aortic stenosis and hypertensive heart disease. The goal of this study was to determine systolic function of the LV in male and female patients with hypertrophic obstructive cardiomyopathy and to relate it to wall thickness and wall stress, respectively. BACKGROUND: Wall thickening, a parameter of regional systolic function, is determined by wall thickness and wall stress. A comprehensive analysis of regional LV function was performed from multiplane transesophageal echocardiography with 3-dimensional reconstruction of the LV. METHODS: In 21 patients (11 men and 10 women) 4 parallel (2 basal and 2 apical) equidistant short-axis cross sections from base to apex were obtained from the reconstructed LV. In each short axis, 24 wall-thickness measurements were carried out in 15-degree intervals at end-diastole (ED) and end-systole. Thus, a total of 192 measurements were obtained in each patient. Wall thickening, a parameter of regional systolic function, was calculated as the difference of ED and end-systolic wall thickness, and fractional thickening as thickening divided by ED thickness. RESULTS: Fractional thickening and wall stress were inversely related to ED wall thickness in both men and women. Women showed better LV systolic function when compared with men (P <.001). However, when corrected for wall stress, which was lower in women, there was no sex difference in systolic function. CONCLUSIONS: There are regional differences in LV systolic function in men and women that depend on regional wall thickness and wall stress.