Cardiac re-synchronization therapy: effects on myocardial perfusion at rest, after vasodilation and oxygen consumption.

AIM: Cardiac resynchronization therapy (CRT) has been shown to improve haemodynamics and clinical symptoms in heart failure patients. The present study evaluated the effects of a 4-month CRT on myocardial blood flow (MBF) at rest, after vasodilation and on myocardial oxygen consumption (MVO(2)). PATIENTS, METHODS: We studied 16 patients with idiopathic dilated cardiomyopathy prior to and during CRT performed as biventricular pacing. Resting MBF and MVO(2) were determined from an (11)C-acetate PET study and vasodilator MBF from a (13)N-ammonia study. RESULTS: MBF at rest (0.55 +/- 0.10 ml/min/g), after vasodilation (1.20 +/- 0.45 ml/min/g), and MVO2 (0.082 +/- 0.014/min) did not change by mid-term CRT at a global level (0.57 +/- 0.11 ml/min/g; 1.32 +/- 0.49 ml/min/g; 0.085 +/- 0.018/min), whereas the rate pressure product (RPP) normalised MVO(2) decreased from 0.104 +/- 0.024 to 0.086 +/- 0.018/min (p = 0.02). At baseline, the regional analysis revealed significantly higher values for all parameters in the lateral wall than for those in the other walls. Under CRT the regional differences between the resting parameters equalized and all parameters showed significant lower coefficients of variation. CONCLUSION: Effects of mid-term CRT on resting MBF, vasodilator MBF and MVO(2) occur at a regional level. The resynchronization is associated with a more homogenous distribution pattern of these parameters among the myocardial walls. Substantial alterations to global MBF at rest, after vasodilation or to MVO(2) are not detectable. Regarding the RPP normalised MVO(2), there is evidence of improved ventricular efficiency through CRT.

Improvement in coronary flow reserve determined by positron emission tomography after 6 months of cholesterol-lowering therapy in patients with early stages of coronary atherosclerosis.

BACKGROUND: Early stages of coronary atherosclerosis are characterized by a mainly functional impairment of coronary vasodilator capacity under the impact of such risk factors as hypercholesterolemia. The goal of this study was to determine whether 6-month cholesterol-lowering therapy improves coronary flow reserve in patients with angina, reduced flow reserve despite minimally diseased coronary vessels or even normal angiogram, and mild to moderately elevated LDL levels on average. METHODS AND RESULTS: We noninvasively investigated 23 consecutive patients (18 men, 5 women; mean age, 56+/-7.6 years) with a mean LDL level of 165+/-34 mg/dL at baseline by PET for myocardial blood flow measurement with [13N]ammonia at rest and under dipyridamole stress (0.56 mg/kg) before and after lipid-lowering therapy with simvastatin for 6 months. Between baseline and the 6-month follow-up, total cholesterol concentration fell from 241+/-44 to 168+/-34 mg/dL, and the LDL level decreased from 165+/-34 to 95+/-26 mg/dL (P<0.001). Overall, coronary flow reserve increased from 2.2+/-0.6 to 2.64+/-0.6 (P<0.01). Maximal coronary flow increased significantly from 182+/-36 to 238+/-58 mL/minx100 g (P<0.001) at follow-up. Minimum coronary resistance declined significantly from 0. 51+/-0.12 to 0.40+/-0.14 mm Hg. mL-1. minx100 g (P<0.001). Concomitantly, a regression of anginal symptoms was observed in most patients. CONCLUSIONS: Our results suggest that cholesterol-lowering therapy with simvastatin may improve overall coronary vasodilator capacity assessed noninvasively by PET in patients with mild to moderate hypercholesterolemia. Consequently, intensive lipid-lowering therapy is considered a vasoprotective treatment for selected patients in very early stages of coronary atherosclerosis with the potential of preventing further disease progression.

Improvement of coronary vasodilatation capacity through single LDL apheresis.

A concomitant phenomenon of hypercholesterolemia is reduced coronary vasodilatation capacity due to disturbed endothelial function. Endothelial function can be partially or completely normalized by reducing cholesterol levels through drug therapy, but it is still unclear how rapidly this desired effect is achieved. An interval of between weeks and months has been presumed. LDL apheresis (LDL-A) is capable of achieving a high-degree LDL cholesterol reduction within hours. With positron emission tomography (PET), carried out immediately before and after LDL-A, changes in coronary reserve due to this abrupt LDL cholesterol reduction could be measured both quantitatively and non-invasively. In nine patients (six women, three men) with documented coronary artery disease and hypercholesterolemia, PET was carried out immediately before and 18-20 h after LDL-A. A reduction in LDL cholesterol (from 194 +/- 38 to 81 +/- 20 mg/dl), facilitated significant improvement in myocardial blood flow (MBF) (173 +/- 63 versus 226 +/- 79 ml/min per 100 g) after pharmacologic recruitment of coronary flow capacity (dipyridamole stress), coronary flow reserve (CFR) (1.91 +/- 0.68 versus 2.48 +/- 0.68) and minimum coronary resistance (MCR) (0.61 +/- 0.18 versus 0.43 +/- 0.16 mmHg/100 g per min per ml) within 24 h. Plasma viscosity was reduced slightly, by 6.6%. Probably for the first time, a 30% improvement in coronary vasodilatation capacity could be demonstrated quantitatively and non-invasively by PET after a single LDL-A within 24 h.

Coronary dilatory capacity in idiopathic dilated cardiomyopathy: analysis of 16 patients.

Hemodynamic function and overall coronary blood flow (argon technique) were measured in 16 patients with idiopathic dilated cardiomyopathy (IDC) and in 12 patients without detectable heart disease (control subjects) referred for precordial pain. In patients with IDC, coronary blood flow was normal at rest (78 +/- 17 ml/100 g-min versus 78 +/- 9 in control subjects). During maximal inducible coronary vasodilation (dipyridamole, 0.5 mg/kg), coronary blood flow was significantly reduced (142 +/- 38 ml/100 g.min versus 301 +/- 64 in control subjects; p less than 0.001). Consequently, obtainable minimal coronary resistance was increased in IDC (0.54 +/- 0.20 mm Hg/ml/100 g.min versus 0.23 +/- 0.04 in control subjects; p less than 0.001). In patients with IDC, left ventricular (LV) end-diastolic pressure was significantly increased (19 +/- 11 mm Hg versus 6 +/- 3 in control subjects; p less than 0.005), and the LV ejection fraction was diminished (36 +/- 11% versus 72 +/- 3% in control subjects; p less than 0.001). In patients with IDC, LV end-diastolic pressure correlated significantly with the obtained minimal coronary resistance after application of dipyridamole (r = 0.85; p less than 0.001). LV catheter biopsy specimens revealed no alterations in myocardial microvasculature. Thus, coronary dilatory capacity is impaired in patients with IDC, due partially to an increase in extravascular component of coronary resistance.

Results of heart transplantation in patients with preexisting malignancies.

Twenty patients with end-stage heart failure and preexisting malignancies underwent heart transplantation at a single center, with a neoplasm-free interval before the procedure of 0 to 240 months. Twelve patients were long-term survivors (2 to 72 months); there were 2 early and 6 late deaths, thus justifying heart transplantation in patients with preexisting malignancies in individual cases.

The effect of ion composition on cellular membrane potentials during selective coronary arteriography.

An animal experimental study on seven thoracotomized dogs was designed to investigate the effects of intracoronarily injected sodium meglumine diatrizoate on myocardial electrophysiology and to evaluate the contribution of the corresponding changes of electrolyte levels in coronary blood. For this purpose the effects of alterations in the Na+-, K+- and Ca++-concentrations in coronary blood were studied separately by intracoronarily injected model solutions. Membrane potentials were recorded from the left ventricular myocardium by a modified microelectrode technique which is applicable to the beating and blood perfused heart in situ. Following selective coronary arteriography there was a temporary hyperpolarization of resting potentials and a prolongation of action potentials which may be explained by a contrast-induced local deficiency of potassium and calcium ions and by a relative prevalence of sodium ions in coronary blood. In selective coronary arteriography the synchronicity of cardiac excitation is disturbed by the regional prolongation of action potentials, which may induce ventricular arrhythmias.

Predictors of unsuccessful outcome after percutaneous mitral valvulotomy including a new echocardiographic scoring system.

BACKGROUND AND AIMS OF THE STUDY: Percutaneous mitral valvulotomy has been shown to be an accept able alternative to surgery as treatment for selected patients with severe mitral stenosis. Uncertainty still exists regarding predictors of unsuccessful outcome. MATERIALS AND METHODS: 308 patients with severe mitral stenosis underwent Inoue single balloon valvulotomy over a 48-month period and were followed up for a mean of 14.5 +/- 16.8 months (range one to 64 months). Two hundred and sixty-seven (Group I) improved clinically and remained stable throughout the follow up, while subsequent surgery was required in 41 (Group II) after 38.2 +/- 143.5 days (range one to 1,212). Clinical and echocardiographic parameters of the two groups were compared to find significant predictors of an unsuccessful outcome. RESULTS: Significant differences between the groups were observed for NYHA class (2.7 +/- 0.6 vs. 2.9 +/- 0.6, p < 0.05), mitral valve area (1.0 +/- 0.3 vs. 0.9 +/- 0.2 cm2, p < 0.01), left atrial end-systolic dimension by echo (51.3 +/- 8.0 vs. 55.4 +/- 10.2 mm, p < 0.01) and an echocardiographic scoring system including grading for eccentricity of the mitral orifice and distribution of commissural calcification (7.5 +/- 2.0 for Group I and 8.7 +/- 2.0 for Group II, p < 0.001). CONCLUSIONS: Mitral valves that are more likely to have an unsuccessful outcome can be identified by hemodynamic, clinical and echocardiographic criteria, including grading for eccentricity of the mitral orifice and distribution of commissural calcification.

DPTI/STTI--an index of the myocardial oxygen supply/demand ratio?

The DPTI/STTI (diastolic pressure-time index/tension-time index) ratio is applied as an indicator of myocardial ischemia particularly in cardiovascular and anesthesiologic care units. The validity of the DPTI/STTI ratio was examined in intact dogs with large variations of oxygen supply and demand. The correlation of DPTI/STTI to the directly measured oxygen supply/demand ratio was poor even under maximal coronary vasodilation. Many data points were far below the critical DPTI/STTI values (reported previously) without occurrence of myocardial ischemia, failure, or edema. Therefore caution is necessary if the DPTI/STTI ratio is to applied to humans.

Validity of myocardial oxygen consumption parameters.

The purpose of this study was to examine any reported indices for estimating myocardial oxygen consumption (MVO2) under uniform experimental conditions at maximal variation of hemodynamics and MVO2. One hundred sixty-two steady states were analyzed in 10 closed-chest dog experiments. Myocardial blood flow was directly measured by a different pressure catheter in the coronary sinus. The indirect values of MVO2 calculated from 24 indices were compared with directly measured MVO2. Throughout a wide range of hemodynamic states, the best correlate with MVO2 was found to be the additive parameter Et (r = 0.96). Any indices that do not incorporate potentially important changes of MVO2 related to both myocardial contractility and ventricular dimensions show unsatisfactory correlations with MVO2 at extreme changes of hemodynamics. Tension-time index (TTI) correlates poorly with MVO2 (r = 0.63). This result is due to the neglect of contractility. Pressure-heart rate product (P X HR) correlates with MVO2 with r = 0.86. Better results for TTI and P X HR, as reported in previous works, are reproducible by dividing our data into two groups of different inotropic states. At normal and moderate inotropic stimulation the correlation for TTI rises to r = 0.96, and for P X HR to r = 0.91. This augmentation is to be referred to the close relationship (r = 0.92) of peak ventricular pressure to maximum rate of pressure rise in this group. The additive parameter E1 is the best, both at moderate (r = 0.97) and at maximal inotropic stimulation (r = 0.87), and is to be preferred for indirect estimation of MVO2. Results are discussed with regard to the clinical application of MVO2 indices.

Comparison of myocardial oxygen consumption indices in man.

Hemodynamic indices of myocardial oxygen consumption (MVO2) were examined in 13 patients with coronary heart disease. The specific aim of this study was to investigate whether clinical results agree with experimental findings in animals. During hemodynamic and respiratory steady-state conditions at rest, the MVO2 (7.6-14.2 ml/min/100 g) was measured directly by myocardial blood flow (argon method) and arterio-coronary venous oxygen content difference. MVO2 was compared with five indirect indices of MVO2. A complex additive parameter consisting of five components of MVO2 had the highest correlation with MVO2 (r = 0.97), as was also demonstrated in a recent experimental study at maximum changes in hemodynamics and MVO2. More easily measurable predictors of MVO2 such as tension-time index (r = 0.923), product of mean systolic aortic pressure and square root of heart rate (r = 0.928), pressure rate product (r = 0.915), and triple product (r = 0.941) were less closely correlated with MVO2. The lower correlations of the readily obtainable indices of MVO2 are probably related to their failure to incorporate factors such as contractility and ventricular dimensions, which are known to exert an important influence on MVO2. The excellent correlation of the hemodynamic additive parameter with MVO2 supports the theoretical concept and the implications of the experimental study. The accurate prediction of MVO2 is based on adequate measurement of MVO2 for the velocity of tension development and maintenance of tension during systolic ejection period, both of which are integrated in the additive index.

Decrease in cardiotoxicity of contrast media in coronary angiography by addition of calcium ions: a combined experimental and clinical study.

The cardiotoxicity of commonly used contrast media such as sodium methylglucamine diatrizoate is related to nonphysiologic concentrations of ions and high osmolality. Following injection there is an excessive decrease in ambient calcium which disturbs the extracellular Na+/Ca2+ ratio and results in myocardial depression. In animal studies (anesthetized, intact mongrel dogs) this cardiodepressive effect could be fully compensated by adding 22.5 mEq/1 of ionic calcium to the contrast medium. In 16 patients studied for coronary artery disease (CAD) 72 injections of sodium methylglucamine diatrizoate, mainly in the left coronary artery, were thoroughly investigated. There was marked depression of left ventricular pressure (-22%) and (dP/dt)max (-27%), and marked heart rate slowing (-29%). Added calcium in the concentration cited reduced significantly (p < 0.001) the myocardial depression to -15% and -13%, respectively, but did not completely compensate it. The heart rate slowing was not altered significantly. It was concluded that the addition of calcium may be helpful when studying high-risk patients and using high injection volumes.

Pathomorphological characteristics of resected mitral valves after unsuccessful valvuloplasty.

OBJECTIVE: Percutaneous mitral valvuloplasty has been shown to be an acceptable alternative to surgery as treatment for selected patients with severe mitral stenosis. We examined hemodynamic, echocardiographic, and pathomorphologic findings in a series of 308 patients undergoing balloon valvuloplasty, 41 of whom underwent subsequent surgery, in search of possible predictors of an unsuccessful outcome. INTERVENTION AND RESULTS: Patients with severe mitral stenosis underwent Inoue single ballon valvuloplasty over a 48-month period and had follow-up for a mean of 14.5+/-16.8 months (range 1 to 64 months). Of the 308 patients, 267 (Group I) were clinically improved and stable throughout follow-up, while subsequent surgery was required in 41 (Group II) after 38.2+/-143.5 days (range 1 to 1212). Significant differences between the groups were observed for NYHA class (2.7+/-0.6 vs 2.9+/-0.6, p<0.05), mitral valve area (1.0+/-0.3 vs 0.9+/-0.2 cm2, p<0.01) and left atrial endsystolic dimension by echo (51.3+/-8.0 vs 55.4+/-10.2 mm, p<0.01). Two of the 41 Group II patients underwent surgery for left to right shunting, 1 for tamponade and 2 were lost to follow-up. The excised mitral valves of the remaining 36 patients all showed calcification and/or fibrosis: 9 homogenous, 5 non-homogenous; 19 were classified as having a funnel-shaped deformity, and 3 did not fit into a discrete category. Among the funnel-shaped valves, 13 had a tear versus 6 where dilation was primarily accomplished by stretching. Only one of 9 valves with homogenous calcification was torn, whereas a tear was noted in 3 of the 5 with non-homogenous calcification. CONCLUSION: Funnel-shaped valves and those with non-homogenous distribution of calcification and/or fibrosis appear to be least suitable for balloon valvuloplasty.

[Clinical significance of the cardiovascular risk factor fibrinogen in secondary prevention]. / Klinische Bedeutung des kardiovaskulären Risikofaktors Fibrinogen in der Sekundärprävention.

Seven prospective, epidemiological studies indicate plasma fibrinogen levels (over 300-350 mg/dl) as an important, independent cardiovascular risk factor for subsequent myocardial infarction and stroke. Furthermore, several clinical studies revealed an association between fibrinogen and both the angiographic and clinical degree of coronary heart disease. In addition, a significant relation of fibrinogen with the number of occluded coronary vessels was found. The following pathophysiologic mechanism are of particular importance: Fibrinogen is a main determinant of plasma viscosity and red cell aggregation. Both phenomena deteriorate blood fluidity especially in the microcirculation. Fibrinogen plays a central role in platelet aggregation and performs an essential substrate in the coagulation cascade. Thus, high fibrinogen levels may favor a hypercoagulable state resulting in final thrombotic events of cardiovascular disease. Fibrinogen is also involved in atherogenesis by stimulating proliferation and migration of smooth muscle cells. Several determinants of fibrinogen levels are known. Smoking is the strongest one in healthy persons. This clinically important effect is dose related. Consequently, cessation of smoking is a major step to lower fibrinogen and subsequently the individual cardiovascular risk. Reduction of overweight and maintenance of regular physical activity are further nonpharmacologic means. Fibrates decrease fibrinogen about 10-30% on an average. Finally, intermittent low-dose Urokinase for end-stages of coronary artery disease and LDL-apheresis (HELP) represent additional approaches to reduce fibrinogen.

[Histamine effects on the heart with special reference to cardiac side effects of H2 receptor antagonists]. / Histaminwirkungen am Herzen unter besonderer Berücksichtigung kardialer Nebenwirkungen von H2-Rezeptor-Antagonisten.

The existence of cardiac h1- and h2-receptors is evidenced by pharmacologic studies. Despite of the relatively high content of cardiac histamine it is not clarified whether histamine actually plays a physiologic role - apart from pharmacologic effects - in the regulation of myocardial function and coronary blood flow. Under pathophysiologic conditions (during anaphylaxis, surgical procedures, accidents, stress etc.), however, when a local or systemic histamine release occurs both hemodynamic and arrhythmogenic effects are evident. Numerous studies in animal models conclusively demonstrated a role of cardiac histamine as a major mediator of serious arrhythmias. Consequently, a combination of h1- and h2-receptor antagonists (f.e. Dimetinden/Cimetidin) was recommended as a prophylactic treatment against severe anaphylaxis including life-threatening arrhythmias for cardiac patients at risk. There is pharmacologic evidence of both a positive inotropic and chronotropic effect in the human heart via h2-receptor and stimulation of adenylate cyclase. Histamine-induced coronary effects such as vasoconstriction via h1-receptor and coronary dilatation via h2-receptor are not yet sufficiently validated. Studies on the human heart in vitro using coronary strips from explanted hearts and in vivo investigations on the intact coronary system yielded conflicting results. H2-receptor blocking agents cimetidine, ranitidine and famotidine have qualitatively a different pharmocodynamic spectrum of side effects due to differences in chemical structure. Data on cardiac arrhythmias are mostly associated to cimetidine. Symptomatic bradycardia were reported for both ranitidine and cimetidine. A possible negative inotropic effect of famotidine, although presently not validated, requires further studies. Causative and adverse side effects of cimetidine on the cardiovascular system, however, are to be expected extremely seldom due to easily reversible competetive h2-receptor binding. For prophylaxis rapid intravenous injections of h2-blockers, particularly in elder patients with cardiac diseases, should be avoided. Compared to cimetidine, a tendency of explainable difference seems to become apparent for ranitidine and famotidine due to higher receptor affinity.

[Changes in life style as a causal therapeutic approach in coronary heart disease]. / Lebensstiländerung als kausaler Therapieansatz der koronaren Herzkrankheit.

Life style measures (weight reduction and control, reduction of total fat calories to < 30% of total calories, modification of fat intake to increased monounsaturated vegetable fat, increased intake of dietary fibers, increased physical activity, controlled stress relaxation) are the basis of longterm therapy of coronary heart disease. For transformation to daily life both patient and doctor need motivation, information, patience, and realistic aims. For realization the 10 rules of medical information should be followed. The patient must be informed that the "new lifestyle" is not punishing but means a new quality of life. With respect to the most important metabolic syndrome with hyperinsulinemia due to insulin resistance, weight reduction is the most important measure for preventing complications of atherosclerosis. The patient should use a diary for weight control and blood pressure self-measurement. Secondary prevention of CHD has been shown useful and effective; however, most patients need additionally drug therapy to avoid or retard progression of the coronary heart disease. The targets for cholesterol and blood pressure control are low; the responsibility of the patient remains high. Besides weight reduction, stopping smoking, lowering lipids, controlling hypertension, and aspirin are the most important.

[Villous rectal adenomas and secretory diarrhea]. / Villöse Rektumadenome und sekretorische Diarrhoe.

Hypersecretion following villous adenomatosis of the rectum is demonstrated by two single case studies. Both patients exhibited a secretory diarrhea with a 2.000-2.500 and 1.000 ml daily stool volume respectively, resulting in severe and life-threatening (first patient) loss of water and electrolytes. With increasing stool volume, rising concentrations of Na and Cl were observed in the stool and approached plasma levels. Consecutively the potassium concentration decreased to values between 15 and 23.4 mmol/l in the first severe case and to 28 and 31 mmol/l in the patient with the lowest stool volume. Elevated PG-E2 concentrations in the fluid moiety of the stool (up to 13.3 ng/ml and 0.98 ng/ml respectively) as well as the response to treatment with Indomethacin support the idea of a PG-E2 induced pathological loss of water and electrolytes. While 100 mg Indomethacin/day led to cessation of symptoms in the less severe case, even 400 mg Indomethacin/day were not able to reduce the massive rectal water loss in the first most severe patient to less than 1,000 ml/day. Surgical removal of villous adenoma showing hypersecretory activity is the only promising therapy. In case of inoperability, denial of surgical intervention or just for palliative treatment prior to surgery we recommend the inhibition of PG-synthesis with Indomethacin.