Increased cardiac mRNA expression of matrix metalloproteinase-1 (MMP-1) and its inhibitor (TIMP-1) in DCM patients.

Left ventricular dilation and myocardial remodeling are hallmarks of dilated cardiomyopathy (DCM). It is assumed that left ventricular dilation is caused by the disintegration of the collagenous network by increased collagenolytic activity of matrix metalloproteinases (MMPs) and their adequate tissue inhibitors (TIMPs). In this study the myocardial MMP-1 and TIMP-1 mRNA expressions were investigated by using real-time quantitative PCR analysis from right septal endomyocardial biopsies of patients with dilated cardiomyopathy (n = 46) and control subjects (n = 11). The volume density (Vv%) of collagen was measured morphometrically. Classification was done according to LV diameters [left ventricular enddiastolic diameter (LVEDD, cm) calculated to body surface area (BSA, m(2))] into three DCM groups: group I (LVEDD-BSA > 2.7-3.0 cm/m(2)), group II ( > 3.0-3.6 cm/m(2)), group III ( > 3.6 cm/m(2)), controls (< 2.7 cm/m(2)). Compared with controls, the MMP-1 expression in patients with DCM was significantly increased (119.2 +/- 45.2 vs. 1.3 +/- 0.4; p < 0.001) as was TIMP-1 expression (9.6 +/- 1.2 vs. 1.3 +/- 0.4; p < 0.01). Moreover the MMP-1 and TIMP-1 expression varied according to LV diameter: group I (MMP-1: 8.7 +/- 3.5; p = 0.33; TIMP- 1: 4.5 +/- 1.2; p < 0.01); group II (MMP-1: 211.4 +/- 86.0; p < 0.001; TIMP-1: 12.5 +/- 1.9 ; p < 0.001); group III (MMP-1: 38.8 +/- 22.6; p < 0.01; TIMP-1: 8.1 +/- 1.7; p < 0.001). Compared with controls, the collagen level in DCMPt. was significantly increased: 5.0 +/- 0.6 vol% vs 1.2 +/- 0.2 vol% p < 0.001 and correlates with LV diameter. This study reveals that the overexpression of MMP-1, which is associated with an increased ratio of MMP-1/TIMP-1 in DCM, indicates an activated collagenolytic system while replacement fibrosis is accumulating. The MMP-1 overexpression is mainly found in moderately dilated DCM hearts (group II) indicating the dynamic process of LV dilation and the importance of collagenases in the early phase of LV remodeling.

[Influence of cardiac circulation and medication on the perfusion of the intestine]. / Einfluss der kardialen Zirkulation und einer herzwirksamen Medikation auf die Durchblutung der Bauchorgane.

Perfusion of the abdomen is determined by cardiac function and circulation. Intestinal ischemia can be caused by Non occlusive bowel ischemia (NOD) that is important in internal as well as surgical intensive care medicine. Cardiac medication can influence perfusion of the bowel: 1) digitalis increases muscular tonus and decreases perfusion regulation b) diuretics lead to hypovolemia, hypotonia and malperfusion, c) antihypertensive medication can cause intraoperative hypotension that demands catecholamines, d) catecholamines can reduce perfusion by pathologic vasoconstriction in the splanchnicus area. Preoperative medication should respect 1) preoperatively taken ACE-inhibitors should be given postoperatively, as they have protective influence on the microcirculation of the bowel, 2) beta-blockers stabilize the myogenic tonus of the abdominal vessels, reduce an overshot of the parasympatheticus and diminish the risk of neurogenic abdominal shock, 3) catecholamines should be used with respect to ischemia of the bowel. Therapy of NOD should be focused on the primary vascular and hemodynamic causes and also take care for bacterial translocation and consecutive sepsis.

Elevated serum markers for collagen synthesis in patients with hypertrophic cardiomyopathy and diastolic dysfunction.

OBJECTIVES: The hypothesis of impaired collagenolysis in patients with hypertrophic cardiomyopathy (HCM) was tested by measuring serum markers of type-I collagen metabolism. These markers were correlated with echocardiographic parameters of diastolic function. BACKGROUND: HCM is a common disease in the adult population with a wide range of clinical manifestations. Left ventricular hypertrophy and increased intramyocardial collagen content are known to cause diastolic dysfunction in patients with HCM. METHODS: In 26 patients with HCM and 38 control subjects (aged: 57+/-3 and 54+/-2 years, p=n.s.) serum levels of collagenolytic matrixmetalloproteinase-1 (MMP-1) and its inhibitor TIMP-1, the markers for collagen type-I synthesis (PICP) and degradation (ICTP) were determined by ELISA and RIA. Diastolic function were determined by Doppler echocardiography. RESULTS: Free TIMP-1 was elevated in HCM compared to controls (216,78+/-9,89 vs 183.77+/-7.57 ng/ml ; p=0.006) as well as PICP (165.92+/-10.26 vs 114.57+/-6.38 mug/l; p<0.001). Free MMP-1 was significantly lower in HCM (1.13+/-0.20 vs 2.33+/-0.34; p=0.01). ICTP did not differ. The MMP-1/TIMP-1 ratio was significantly lower in HCM (0.006+/-0.001 vs 0.012+/-0.001, p=0.003). PICP correlated positively with diastolic E/A ratio (r=0.389; p=0.05) and septal thickness (r=0.484; p=0.01). CONCLUSIONS: Serum marker of collagen synthesis (PICP) is increased in patients with HCM. Increased marker for inhibition of collagenolysis (TIMP-1) and a disturbed balance of collagen synthesis and degradation (ratio) with a predominance of inhibition of collagenolysis indicates collagen accumulation (fibrosis), which explains passive diastolic dysfunction in patients with HCM.

[Reduced distensibility of the hypertensive heart under stress as an early sign of diastolic dysfunction]. / Gestörte Dehnbarkeit des Hochdruckherzens unter Belastung als früher Marker einer diastolischen Dysfunktion.

BACKGROUND: Hypertensive patients often present with exertional dyspnoea. However it is questioned whether it results from a systolic, early- or late diastolic impairment of left ventricular function. PATIENTS AND METHODS: Our study included 21 hypertensive patients (7 female; 14 male, median age 56 years) and 12 controls (4 female; 8 male, median age 52 years). All patients had normal epicardial coronary arteries. Parameters of systolic and diastolic heart function at rest and during exercise were analyzed using a combined hemodynamic and radionuclid-angiographic approach. RESULTS: One principal finding was that the investigated hypertensive patients had a normal ejection fraction during exercise (72 % +/- 11 vs 71 % +/- 10 in the control group). However these patients showed an exercise induced increase of pulmonary capillary wedge pressure (17.4 +/- 8 vs 11.5 +/- 5; p = 0.005), a fixed end diastolic volume (82 +/- 21 vs 104 +/- 23 ml/m (2), p = 0.01) and a reduced stroke volume index (58 +/- 1.2 vs 73 +/- 1.4 ml/m (2); p = 0.007). Radionuclid angiography revealed an increased exercise peak filling rate (6.1+/-1.6 vs 4.8+/-1.8 EDV/s; p = 0.04) in hypertensive patients. We assume that exercise capacity (cardiac index = 8.1 +/- 1.8 vs 8.4 +/- 2.2 l/min x m (2); ns) in hypertensive patients without excessive LV hypertrophy is predominantly preserved by an enhanced contractile state and its favorable effects on early diastolic filling. CONCLUSION: An increased left ventricular stiffness during exercise is an early manifestation of hypertensive heart disease.

Disseminated microvascular pulmonary tumor cell embolism: a rare cause of fulminant pulmonary hypertension.

BACKGROUND: Disseminated pulmonary tumor embolization is a rare cause of pulmonary hypertension and is often diagnosed only after the patient has died. CASE REPORT: We report on a 41-year-old male who was admitted because of severe dyspnea and tachycardia. Contrast enhanced spiral computed tomography did neither establish pulmonary thromboembolism nor pulmonary metastasis. Right heart catheterization revealed severe pulmonary hypertension (pulmonary vascular resistance (PVR) 678 dyn x sec x cm(-5)). PVR did not respond to therapy with intravenous nitrate or inhaled iloprost in this critically ill patient. 2 days after admission, the patient died because of refractory right heart failure. Autopsy revealed microscopic pulmonary tumor embolism due to a metastasizing adenocarcinoma of the pancreas. CONCLUSION: Disseminated tumor cell embolism should be considered as a rare differential diagnosis in patients with refractory pulmonary hypertension.

Successful thrombolysis of st. Jude medical aortic prosthesis with tissue-type plasminogen activator in a pregnant woman: a case report.

Mechanical valve thrombosis is a life-threatening event. Pregnancy is associated with a hypercoagulable state that further emphasizes the importance of adequate anticoagulation. This is associated with a therapeutic dilemma. Continued anticoagulation with warfarin throughout the first trimester can result in fetopathic effects, while replacement of warfarin by heparin between 6 and 12 weeks of gestation does not completely prevent the risk of valve thrombosis. There are a small number of reported cases of pregnant women with prosthetic heart valve thrombosis under low molecular weight heparin and consecutive lytic therapy. The authors report a 33-year-old pregnant woman with a St. Jude Medical aortic prosthesis, anticoagulated with a therapeutic dosage of low molecular weight heparin from 6 weeks of gestation, who developed prosthetic heart valve thrombosis at 17 weeks of gestation. A thrombolysis with recombinant tissue-type plasminogen activator (50 mg for 2 hours) was performed. Under thrombolysis, ST-segment elevation in leads II, III, aVF, V5, and V6 developed electrocardiographically with a maximal creatine kinase (CK) of 349 U/L (CK-MB isoenzyme of 48 U/L). Echocardiography revealed normal function of the St. Jude Medical aortic prosthesis 2 hours after thrombolysis and normal wall motions. Short-course thrombolytic therapy appears to be an effective alternative to surgical intervention for the treatment of thrombotic dysfunction of valve prostheses in pregnancy.

Myocardial collagen type I and impaired left ventricular function under exercise in hypertrophic cardiomyopathy.

BACKGROUND: Transaortic subvalvular myectomy (TSM) reduces left ventricular outflow tract gradient and improves symptoms and working capacity in patients with hypertrophic obstructive cardiomyopathy (HOCM). Nevertheless, TSM does not completely restore normal ventricular function, and some patients complain of symptoms despite optimal surgical results. Abnormal myocardial collagen structure in hypertrophic cardiomyopathy might be an indicator of impaired cardiac function. METHODS: Nine patients with HOCM were investigated. Myocytic diameter, collagen volume fraction and light absorbance of immunohistochemically stained collagen subtype I and its product (Coll I(prod)) were measured quantitatively in myectomy specimens. Patients underwent symptom-limited bicycle exercise testing with equilibrium radionuclide angiocardiography to determine ejection fraction (EF). Right heart catheterization was performed simultaneously in order to measure pulmonary capillary wedge pressure (PCWP) as a parameter of global ventricular diastolic filling and cardiac index (CI) as a parameter of functional capacity. RESULTS: Postoperatively, CI increased from 3.1 +/- 0.4 to 5.7 +/- 1.3 l/min/m(2) under exercise. EF was normal at rest (64 +/- 9 %) but did not increase significantly under exercise (66 +/- 14 %). Coll I(prod) (13.62 +/- 7.35 Vv%(prod)) correlated inversely with EF under exercise (r = -0.64; p = 0.05). PCWP increased under exercise from 8 +/- 2 mmHg at rest to 22 +/- 9 mmHg (p = 0.01). Coll I(prod) correlated with PCWP under exercise (r = 0.90; p = 0.001). CONCLUSIONS: Increased collagen subtype I is a predictor of diastolic as well as systolic dysfunction under exercise in patients with HCM after successful TSM.

[ Update 2001. Myocarditis--cardiomyopathy]. / Update 2001. Myokarditis--Kardiomyopathie.

Myocarditis is a common cardiological disease. New molecular biological and immunohistological methods have confirmed the persistence of viral infection and chronic myocardial inflammation in a considerable number of patients. A causal link between viral myocarditis and the development of dilated cardiomyopathy has been recognized. This has prognostic implications and helps for the decision of a specific immunosuppressive, immunomodulatory and antiviral therapy.

Preconditioning during percutaneous transluminal coronary angioplasty by endogenous and exogenous adenosine.

BACKGROUND: The purpose of this study was to assess whether pharmacologic preconditioning by exogenous or endogenous adenosine prevents the deterioration of hemodynamic function and left ventricular performance during percutaneous transluminal coronary angioplasty (PTCA). Ischemic preconditioning renders the heart more resistant to subsequent ischemia. Adenosine plays a key role in its pathogenesis. Coronary angioplasty is a suitable model for the induction of myocardial ischemia. METHODS AND RESULTS: We investigated 30 patients receiving PTCA of the left anterior descending coronary. Patients were randomly allocated to either dipyridamole, leading to the liberation of endogenous adenosine (0.5 mg/kg body weight, intracoronary), exogenous adenosine (20 mg intracoronary), or an equal amount of saline. Chest pain, tolerated inflation time, and ST-segment shift were registered. Left ventricular hemodynamics, isovolumetric phase indexes, indexes of volume, ejection fraction, and indexes of diastolic dysfunction were analyzed. Patients receiving endogenous or exogenous adenosine tolerated longer balloon inflation times (dipyridamole, 208 +/- 23 seconds; adenosine, 188 +/- 41 seconds; control, 153 +/- 36 seconds; P <.05). Deterioration of left ventricular ejection fraction was less severe after adenosine (72% +/- 5% before PTCA vs 64% +/- 6% during angioplasty; P =.11) and could be prevented by intracoronary dipyridamole (69% +/- 12% before PTCA vs 68% +/- 11% after PTCA; P <. 01) compared with the control group (71% +/- 7% before PTCA vs 60% +/- 7% during angioplasty). CONCLUSIONS: Intracoronary application of exogenous adenosine and liberation of endogenous adenosine increase the tolerance to ischemia and prevent deterioration of left ventricular function during ischemia. These findings can be attributed to ischemic preconditioning. However, endogenous adenosine exceeds the protective effects of exogenous adenosine.

Repair of coronary arterioles after treatment with perindopril in hypertensive heart disease.

In hypertensive heart disease, no data are available on the repair of coronary resistance vessels in patients after long-term ACE inhibitor treatment. Fourteen patients with essential hypertension were studied with coronary flow reserve and with transvenous endomyocardial biopsy before and after 12 months of antihypertensive treatment with perindopril (4 to 8 mg/d, mean 5.9+/-2.3 mg/d). Left ventricular muscle mass index decreased by 11% (from 145+/-41 to 128+/-36 g/m(2), P=0.04). Maximal coronary blood flow was increased by 54% (from 170+/-46 to 263+/-142 mL. min(-1). 100 g(-1), P=0.001), and minimal coronary vascular resistance was diminished by 33% (from 0.67+/-0.21 to 0.45+/-0.19 mm Hg. min. 100 g. mL(-1), P=0.001); consequently, coronary reserve increased by 67% from 2.1+/-0.6 to 3. 5+/-1.9 (P=0.001). Structural analysis revealed regression of periarteriolar collagen area by 54% (from 558+/-270 to 260+/-173 microm(2), P=0.04) and of total interstitial collagen volume density by 22% (from 5.5+/-3.8 Vv% to 4.3+/-3.2 Vv%, P=0.04), whereas arteriolar wall area was slightly but not significantly reduced. Long-term therapy with the ACE inhibitor perindopril induces structural repair of coronary arterioles that is mainly characterized by the regression of periarteriolar fibrosis and associated with a marked improvement in coronary reserve. These findings indicate the beneficial reparative effects of ACE inhibition on coronary microcirculation in hypertensive heart disease.

Intracoronary dipyridamole reduces the incidence of abrupt vessel closure following PTCA: a prospective randomised trial.

OBJECTIVES: To investigate the effect of intracoronary dipyridamole on the incidence of abrupt vessel closure, myocardial infarction, necessity for bypass grafting, and death following percutaneous transluminal coronary angioplasty (PTCA). PATIENTS: Patients were randomly allocated to receive either conventional pretreatment (heparin 15 000 IU and aspirin 500 mg intravenously) or additional intracoronary dipyridamole (0.5 mg/kg bodyweight). Dipyridamole was administered in 550 PTCA procedures (455 interventions in men, mean (SD) age 59.2 (8.4) years; 74 acute coronary syndromes), while conventional pretreatment was administered in 544 interventions (444 interventions in men 58.3 (7.9) years old; 81 acute coronary syndromes). In 53 interventions bail out stenting was performed for threatened abrupt vessel closure. RESULTS: Intracoronary dipyridamole significantly reduced the incidence of abrupt vessel closure (odds ratio 0.42. 95% confidence interval (CI) 0.22 to 0.79). While abrupt vessel closure occurred in 6.1% of interventions following conventional pretreatment, dipyridamole reduced the incidence to 2.5%. Restricting the analysis to balloon angioplasty, this reduction was observed in patients with stable angina (odds ratio 0.49, 95% CI 0.23 to 0.96) as well as in those with acute coronary syndromes (odds ratio 0.29, 95% CI 0.09 to 0.87). Reduction of secondary end points in the dipyridamole treated patients failed to reach significance in the PTCA group. CONCLUSIONS: Intracoronary dipyridamole before PTCA reduces the incidence of abrupt vessel closure following PTCA for stable angina and acute coronary syndromes.

Coronary reserve and arteriolosclerosis in hypertensive heart disease.

Hypertensive heart disease leads to left ventricular hypertrophy, structural and functional alterations of the myocardium, and to wall thickening and sclerosis of intramural coronary arteries and arterioles, called arteriolosclerosis, that increase myocardial stiffness and cause diastolic dysfunction right from the beginning. Especially, increased content of collagen in the periarteriolar region contributes to impaired coronary reserve that predisposes to myocardial ischemia even in the absence of coronary artery disease and may be an important factor for diastolic and finally systolic dysfunction. Antihypertensive therapy should additionally aim at inducing repair of myocardial and vascular structure.

Management of symptomatic hypertrophic obstructive cardiomyopathy--long-term results after surgical therapy.

BACKGROUND: The natural history of Hypertrophic Obstructive Cardiomyopathy (HOCM), is well known from earlier investigations. The yearly death rate of medically or non-treated patients with HOCM is between 1.7% and 4%. After conservative management with beta-blockers and/or calcium antagonist, early improvement is followed in many patients by a symptomatic and clinical impairment, which today may lead to surgical or interventional treatment. METHODS: From 1963 to 12/1998 a total of 519 patients were operated by transaortic subvalvular myectomy (TSM). The mean age was 49 +/- 11 years (range 3 months - 82 years) in 292 males and 227 females. RESULTS: The early risk was related to the clinical class (NYHA) and the need for additional cardiac procedures during the same intervention. Total early mortality was 4.4% (n=23), in isolated myectomy 3.6% (n= 11). During the last 10 years it could be reduced to 1.9%. The first complete (100%) reinvestigation of 346 patients up to 26 years after surgery (1963-1991) demonstrated a disease-related mortality rate of 5.2% (n=20). The analysis of late deaths showed that disease-related lethal complications (sudden death, life-threatening arrhythmias, valve endocarditis, secondary LV dilatation) were relatively rare, the age-related death rate nearly followed the natural course because of other causes. The cumulative survival rate after 10 years was 88%, after 20-26 years 72%. The yearly disease-related death rate could be reduced to 0.6%. The long-lasting, symptomatic clinical improvement (NYHA I-II), and also the physical and mental capacity with enlargement of the acitivity radius and improvement of quality of life were remarkable. The positive effects of surgical enlargement of the LVOT could be confirmed in the meantime by hemodynamic, rhythmological, echocardiographic investigations as well as endurance tests. CONCLUSION: We have examined the outcome of a large series of patients treated surgically for HOCM since 1963. The majority of patients were in NYHA class III and came to surgery after long-term medical, but finally insufficient, management. The perioperative risk could be reduced considerably during recent years, despite the advanced cardiomyopathy status. The long-term postoperative observation of the patients demonstrated an unexpectedly continuing good outcome. Therefore these results may serve as a standard for assessing the results after the less invasive alcohol-induced transcoronary ablation of septal hypertrophy.

[Hypertrophic cardiomyopathy (HCM). Surgical versus drug therapy]. / Hypertrophische Kardiomyopathie (HCM). Chirurgische versus medikamentöse Therapie.

Hypertrophic cardiomyopathy (HCM) is a disease with different etiological, morphological, functional, clinical and therapeutic aspects. Recent investigations indicate that HCM is considerably widespread in the population (1:500). The causes seem to generate from familial or sporadic abnormalities (mutations). Depending on the clinical aspect, the complaints, and on the basis of morphologic and hemodynamic investigational results, we mainly have to consider two types of medical and surgical management. 1. Hypertrophic nonobstructive cardiomyopathy (HNCM) Patients may have no hemodynamic or morphologic deviations, but may be identified by familial moleculargenetic investigations. Others may have different types of rhythm disturbances which may indicate a higher risk of sudden death. Depending on the degree of hypertrophy, the clinical impairment indicates medical therapy with beta-blockers, Ca antagonists, and antiarrhythmic drugs. In the case of clinical deterioration and manifestation of myocardial insufficiency diuretics, digitalis, ACE inhibitors, and catecholamines are indicated. Further impairment may lead to heart transplantation or as a bridging procedure to implantation of a left ventricular or biventricular assist device until a suitable donor heart is available. 2. Hypertrophic obstructive cardiomyopathy (HOCM) Symptomatic patients may have different localizations of the left ventricular outflow tract obstruction (LVOTO) in the subaortic area (typical form) and in midventricular position of the LV (atypical form). The first therapeutic step is always medical therapy with beta-blockers, Ca antagonists, and antiarrhythmic drugs. Further deterioration toward clinical class III (NYHA) despite long-term medication until recently was generally accepted as indication for transaortic subvalvular myectomy (TSM). Today mostly two other techniques are preferred--if possible Double chamber pacing (DCP) (atrial triggered ventricular pacing), Transcoronary ablation of septal hypertrophy (TASH) (by selective injection of alcohol, 95%, into the first septal branch). Especially in younger patients, after syncope, life-threatening tachyarrhythmias, and after resuscitation, the implantation of a cardioverter defibrillator may be necessary. Comparative prospectively randomized studies between different therapeutic regimens for HOCM are not available. Retrospective analyses of patients after TSM show a considerable clinical improvement. The risk of sudden death is relatively low, but not excluded. Patients after TSM demonstrate advantages concerning the survival rate despite the more deteriorated condition against those after medical therapy only. According to the new interventional techniques, long-term results are not yet available, of course. However, the long-term results after TSM may serve as a comparative standard which have at least to be reached by DCP and/or TASH.

Endogenous plasma endothelin concentrations and coronary circulation in patients with mild dilated cardiomyopathy.

OBJECTIVE: To determine whether increased plasma concentrations of endothelin-1 (ET-1) and big endothelin (BET) play a role in the regulation of coronary circulation in patients with idiopathic dilated cardiomyopathy (IDCM). SETTING: Tertiary referral centre for cardiac diseases. PATIENTS: Fourteen patients (eight male/six female; mean (SD) age 59 (9) years) with IDCM (ejection fraction 36 (9)%) and five normotensive subjects (two male/three female; age 52 (7) years) serving as controls were studied. METHODS: Functional status was classified according to New York Heart Association (NYHA) class. Endogenous ET-1 and BET plasma concentrations from the aorta and the coronary sinus were determined by radioimmunoassay. Coronary blood flow, using the inert chromatographic argon method, myocardial oxygen consumption, and coronary sinus oxygen content under basal conditions were determined. RESULTS: In the aorta, mean (SD) concentrations of ET-1 (IDCM 0.76 (0.25) v controls 0.31 (0.06) fmol/ml; p = 0.002) and BET (IDCM 3.58 (1.06) v controls 2.11 (0.58) fmol/ml; p = 0.014) were increased in patients with IDCM. Aortic ET-1 concentrations correlated positively with NYHA class (r = 0. 731; p < 0.001), myocardial oxygen consumption (r = 0.749; p < 0. 001), and coronary blood flow (r = 0.645; p = 0.003), but inversely with coronary sinus oxygen content (r = -0.633; p = 0.004), which was significantly decreased in IDCM patients (IDCM 4.68 (1.05) v controls 6.70 (1.06) vol%; p = 0.003). CONCLUSIONS: The coronary circulation in patients with IDCM is exposed to an increased endothelin load. ET-1 concentrations correlate with functional deterioration. A decrease of the coronary sinus content of oxygen suggests a mismatch between coronary blood flow and metabolic demand. Thus, ET-1 might be a marker of a disequilibrium between myocardial oxygen demand and coronary blood flow in IDCM.

Evidence of endothelial dysfunction of epicardial coronary arteries in patients with immunohistochemically proven myocarditis.

BACKGROUND: Recent reports indicate that myocarditis can be associated with acute myocardial ischemia and even myocardial infarction in patients with normal arteriograms. We therefore tested the hypothesis that patients with biopsy-proven myocarditis have endothelial dysfunction despite angiographically smooth epicardial coronary arteries. METHODS AND RESULTS: Graded concentrations of the endothelium-dependent vasodilator acetylcholine (10(-6) to 10(-4) mol/L) and for comparison, the non-endothelium-dependent vasodilator nitroglycerin (0.3 mg intracoronary), were infused into the left coronary arteries of 18 patients (mean age 47+/-9 years, 8 women and 10 men) with biopsy-proven myocarditis but without angiographically demonstrable coronary artery disease. Vascular responses were analyzed by quantitative coronary angiography. Three patients had an intact vasodilator response to acetylcholine concentrations of up to 10(-4) mol/L in all segments of the left coronary artery, with a mean dilatation of +9.9%+/-2%. In contrast, paradoxical constriction by acetylcholine occurred in 9 patients, who showed a mean change in coronary artery diameter of - 11%+/-3%. Six patients had no significant change in any segments in response to acetylcholine (-2.5%+/-4%). There was a significant inverse correlation between the number of T-lymphocytes in the myocardium and the response of the epicardial coronary arteries to acetylcholine (Pearson correlation coefficient -0.49, P=.03). CONCLUSIONS: It can be assumed that the process of myocarditis is associated with impairment of endothelium-dependent vasodilation in response to acetylcholine in most patients. Vasoconstriction in the presence of acetylcholine in myocarditis is likely to reflect an abnormality of endothelial function. Endothelial dysfunction of coronary arteries may explain the occurrence of myocardial ischemia in patients with myocarditis.

Assessing the coronary circulation in hypertension.

Systemic arterial hypertension is one of the major risk factors for coronary artery disease, coronary microangiopathy, and left ventricular hypertrophy, all of which can potentially lead to cardiac failure and sudden cardiac death. Coronary flow reserve is defined as the maximal increase in coronary flow above its resting, autoregulated level for a given perfusion pressure. In arterial hypertension functional and structural alterations are observed at the level of epicardial vessels as well as in resistive vessels requiring sophisticated approaches to assess coronary flow reserve and thus myocardial perfusion. Electrocardiographic tests and echocardiography can be regarded as monitoring and screening methods. Myocardial scintography is useful to semiquantitatively estimate hypertension-associated perfusion abnormalities, whereas positron emission tomography provides the only quantitative approach of a non-invasive technique for myocardial blood flow measurement. Invasive methods for the assessment of coronary blood flow need cardiac catheterization procedures, such as techniques requiring catheterization of the coronary sinus, angiographic methods, and guidewire based methods. Thermodilution and venous oxymetry in the coronary sinus systematically underestimate coronary flow reserve and are thus considered as only semiquantitative approaches. In contrast, the gas chromatographic argon method allows a quantitative measurement of coronary blood flow at baseline and during maximum vasodilation; thus it is possible to distinguish between an altered autoregulated and maximal flow as the major cause of a reduced coronary flow reserve and to evaluate long-term therapeutic interventions in hypertensive hearts. Videodensitometric and angiographic methods should be restricted only to patients with coronary microangiopathy or with coronary single-vessel disease. Guidewire-based Doppler techniques are suitable to semiquantitatively assess coronary flow reserve with a considerable spatial and time resolution. Myocardial biopsies may gain insight into hypertension-associated structural alterations in small arterioles. Long-term treatment of hypertensive heart disease aims to normalize blood pressure, to reduce left ventricular hypertrophy and to achieve cardioreparation including reversal of the abnormal structure and function of coronary circulation. Based on the different methods for assessment of coronary circulation the therapeutic value of different classes of antihypertensive therapeutics will be evaluated in this overview.