A novel stop mutation truncating critical regions of the cardiac transcription factor NKX2-5 in a large family with autosomal-dominant inherited congenital heart disease.

We report on a familial screen of five female members in three generations affected by an autosomal-dominant inherited atrioventricular (AV) conduction block associated with atrial septal defects (ASD) and other congenital cardiovascular diseases (CCVD), such as pulmonary artery stenosis (PAS), patent foramen ovale (PFO) and ventricular septal defect (VSD). We tested the cardiac transcription factor NKX2-5 which is known to cause CCVD with variable phenotype and penetrance by direct sequencing of the two NKX2-5 coding exons in the index patient and identified a novel heterozygous c.325G> T mutation in exon 1 of the gene. This mutation co-segregated with the disease in the family and was present in all five affected family members, but not in 100 control chromosomes. The c.325G > T mutation is predicted to introduce a stop codon at amino-acid position 109 (p.E109X). The truncated protein lacks all of the functionally important domains of the cardiac transcription factor. Therefore, it is very likely that this novel mutation causes a complete loss of NKX2-5 function and haploinsufficiency is the pathophysiological mechanism underlying the disease in the family.

[Silent myocardial ischemia in hypertensive patients]. / Stumme Myokardischämie bei Hypertonikern.

Silent myocardial ischemia occurs in hypertensive individuals with a prevalence of approximately 35%. ST-alterations are triggered by a) hypertensive peaks and b) heart rate increase. Like in patients with coronary heart disease most ischemic events occur without angina. They are clinically silent. In daily practice silent myocardial ischemia may be detected by ECG under physical load or with 24 h Holter ECG-monitoring. The latter can detect ischemic events missed by ECG-monitored exercise tolerance. In hypertensive patients the simultaneous, ST-triggered recording of ECG and blood pressure data is more meaningful. Patients with silent ischemia are at higher risk than individuals without. Angor is not as strong a determinant of risk as silent ischemia. Hypertensive patients without coronary artery disease (CAD) who have silent ischemia may even have a worse prognosis than those with known CAD. It is therefore important to substantiate the objective extent of silent ischemia by ST-analysis. If detected it has to be included into therapeutic considerations with the goal to prevent such episodes by antihypertensive treatment.

Elevated serum concentrations of soluble adhesion molecules in coronary artery disease and acute myocardial infarction.

OBJECTIVES: Adhesion molecules are involved in a number of chronic conditions and diseases like rheumatoid arthritis, tumor growth and wound repair. Soluble adhesion molecules (SAM) play an important role in angiogenesis which is a common aspect of the conditions mentioned above and atherosclerosis. The aim of the present study was to assess the prevalence and the impact of elevated soluble adhesive molecule plasma concentrations in patients with atherosclerosis. DESIGN AND SUBJECTS: In this study, we measured the soluble forms of intercellular adhesive molecule (sICAM), endothelial adhesive molecule (sELAM) and vascular adhesive molecule (sVCAM) using a sandwich ELISA technique in plasma of patients with acute myocardial infarction (AMI), coronary heart disease (CHD) and in healthy subjects (HS). RESULTS: Patients suffering from CHD and AMI showed significant higher plasma concentrations of sICAM (p <0. 05 and p <0.005), sELAM (p <0.01 and p <0.001) and sVCAM (p <0.001 and p <0.005) than HS. In patients with fatal outcome of myocardial infarction the plasma concentrations of sICAM, sELAM and sVCAM were significantly elevated compared to surviving patients (p <0.005; p <0.005; p <0.05). In patients undergoing thrombolytic therapy there were no significant differences of plasma adhesive molecule concentrations. The levels of SAM were not related to other risk factors like diabetes, nicotin abuse, hyperlipidemia, hypertension and a familiary history of cardiovascular disease. CONCLUSIONS: Elevated levels of SAMs are found in patients with coronary heart disease. High SAM levels in plasma seem to be a prognostic factor in acute myocardial infarction. This effect is independent from other concomitant risk factors. Our results suggest that SAMs are involved both in acute phase of myocardial infarction and chronic process of atherosclerosis. It seems that similiar to other chronic inflammatory diseases, atherosclerosis seems to be modulated by soluble forms of adhesive molecules.

[Orthostatic hypotension]. / Orthostatische Hypotonie.

We report about a 67-year-old woman presenting with progressive orthostatic vertigo, urinary incontinence and clinical signs of Parkinson's disease. The Schellong test revealed deficient sympathetic orthostatic pressure response without an increase of plasma norepinephrine; therefore, a Shy-Drager syndrome was diagnosed. Because of inefficiency of the general measures (compressive pantyhose), the sympathomimetic agonists, and the centrally active alpha-2-antagonists, norepinephrine was administered via a miniature dosing pump. By this therapeutic regimen a marked improvement of orthostatic hypotension was achieved.

Effects of atrial natriuretic peptide on systemic and renal hemodynamics and renal excretory function in patients with chronic renal failure.

We examined the effects of 60 min alpha-hANP infusion (24 ng/min/kg) on glomerular filtration rate (GFR), renal blood flow (RBF), cardiac index (CI) and blood pressure (BP) in 8 patients with chronic renal failure (CRF) with GFR ranging from 18 to 80 ml/min/1.73 m2 and in 8 control (C) subjects with normal renal function. Basal plasma levels of ANP and cGMP were elevated in CRF (ANP: 60.6 +/- 9.1 vs 13.6 +/- 1.9 pmol/l, p less than 0.05; cGMP: 14.3 +/- 2.9 vs 6.6 +/- 1.1 pmol/ml, p less than 0.05). During ANP infusion, peak levels of cGMP were higher in CRF than in C (27.5 +/- 3.2 vs. 17.3 +/- 1.3 pmol/ml, p less than 0.05). During ANP infusion, GFR increased in CRF by 70.7 +/- 4.2% from 34.5 +/- 6.8 to 57.4 +/- 9.9 ml/min/1.73 m2 (p less than 0.001) as compared to 16.2 +/- 1.4% in C (p less than 0.001 vs CRF). RBF increased in CRF by 43.6 +/- 6.4% and in C by 3.1 +/- 1.2% (p less than 0.01). Basal urinary sodium excretion (UNaV) was slightly lower in CRF than in C but rose to the same level in both groups during ANP infusion. In CRF, as opposed to C, UNaV remained elevated above baseline after the end of the infusion. The effect of ANP on fractional sodium excretion (FENa), however, was more pronounced in C.(ABSTRACT TRUNCATED AT 250 WORDS)

Atrial natriuretic peptide in patients with essential hypertension. Hemodynamic, renal, and hormonal responses.

In six patients with essential hypertension (EH) and in six healthy volunteers (C) the effects of a 60-min intravenous (iv) infusion of human atrial natriuretic peptide (alpha-hANP) (24 ng/min/kg) on systemic and renal hemodynamics and renal excretory function were evaluated. Basal plasma ANP concentrations in patients with EH were higher (P less than .05) than in C (30.9 +/- 4.5 v14.0 +/- 1.7 pmol/L). Maximal effects of alpha-hANP infusion occurred after 30 to 60 min. Blood pressure (BP) declined from 154 +/- 5/109 +/- 4 to 139 +/- 7/94 +/- 4 in EH and from 117 +/- 1/72 +/- 2 to 106 +/- 1/65 +/- 3 mm Hg in C (P less than .05). Cardiac output (CO) increased transiently from 6.1 +/- 0.3 to 6.5 +/- 0.4 L/min in EH and from 6.8 +/- 0.3 to 7.2 +/- 0.5 L/min in C, whereas heart rate (HR) remained constant both in patients with EH and in C (69 +/- 3 to 72 +/- 5 and 60 +/- 3 to 63 +/- 3/min). The increases in urine flow and in urinary sodium excretion from 3.6 +/- 0.2 to 16.0 +/- 2.0 mL/min and from 230 +/- 33 to 1004 +/- 137 mumol/min, respectively, in EH were more pronounced than in C (from 3.9 +/- 1.0 to 8.4 +/- 0.8 mL/min and from 211 +/- 37 to 451 +/- 84 mumol/min); (P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Arterial blood pressure. Correlation with erythrocyte count, hematocrit, and hemoglobin concentration.

The relationship between arterial blood pressure and red blood cell variables was investigated in 1013 unselected persons with a blood pressure range of 90 to 225 mm Hg systolic and 50 to 145 mm Hg diastolic. Statistically significant correlations were demonstrated between mean (as well as systolic and diastolic) arterial blood pressure and red blood cell count (r = 0.27; P less than .0001), hematocrit (r = 0.28; P less than .0001), and hemoglobin concentration (r = 0.29; P less than .0001). Average arterial blood pressure was higher in men than in women (133 +/- 16/83 +/- 10 v 124 +/- 16/79 +/- 9 mm Hg, P less than .0001) and this was associated with higher values for erythrocyte count, hemoglobin concentration, and hematocrit in men as compared to women. The significant correlation of blood pressure and hematocrit, which represents one important determinant of blood viscosity, points to a role for rheological factors in the long-term control of blood pressure. Moreover, it might be speculated that the sex difference in blood pressure as observed in the present study may be due, at least in part, to stimulated erythropoiesis in men as compared to women.

Atrial natriuretic peptide in patients with diabetes mellitus type I. Effects on systemic and renal hemodynamics and renal excretory function.

In the present study the effects of 1 h intravenous infusion of alpha-human atrial natriuretic peptide (24 ng/min/kg) on systemic and renal hemodynamics and on renal excretory function were studied in six insulin-treated and metabolically well-controlled patients with diabetes mellitus (DM) type I and in six healthy control subjects (C). Basal plasma atrial natriuretic peptide (ANP) concentration was 14.6 +/- 2.0 in DM patients and 14.9 +/- 1.3 pmol/L in C and rose similarly in both groups to 87.1 +/- 22.1 and to 86.9 +/- 11.1 pmol/L, respectively, during alpha-hANP infusion (P less than .05). Maximal effects of alpha-hANP occurred between 30 and 60 min after the start of the infusion. Mean arterial pressure (MAP) (83 +/- 5 v 81 +/- 3 mm Hg), heart rate (HR) (63 +/- 2 v 64 +/- 4/min) and total peripheral resistance (TPR) (11 +/- 1 v 10 +/- 1 mm Hg.min/L) remained unaltered in patients with DM. In contrast, in C MAP and TPR decreased from 83 +/- 3 to 77 +/- 2 mm Hg and from 12 +/- 1 to 10 +/- 1 1 mm Hg.min/L, respectively (P less than .05), whereas HR increased from 53 +/- 2 to 59 +/- 3 beats/min (P less than .05). Cardiac output (CO) rose initially by 11% and by 9% in DM and C, respectively. Urine flow increased from 4.1 +/- 0.9 to 11.3 +/- 1.5 mL/min in DM patients and from 3.9 +/- 1.0 to 8.4 +/- 0.8 mL/min in C (P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Kinin- and non-kinin-mediated interactions of converting enzyme inhibitors with vasoactive hormones.

The antihypertensive effect of inhibitors of the angiotensin I-converting enzyme (ACE = kininase II) results from their vasodilatory and natriuretic effects as well as their effect on baroreceptor function. In addition to the inhibition of systemic and local angiotensin II formation, other local hormonal systems may also be involved in this effect at multiple target sites. Thus, potentiation of the vasodilator and natriuretic kinin system following inhibition of kininase II is thought to contribute to the persistent hypotensive effect of ACE inhibitors despite normalization of circulating ACE activity. Although increased plasma bradykinin levels cannot be detected, we found that the enhanced kinin-dependent local vascular prostacyclin production can be blunted in vitro by aprotinin, a kallikrein inhibitor. ACE inhibition may affect the atrial natriuretic peptide (ANP) system as the renin-angiotensin system and ANP appear to play antagonistic roles at the peripheral and central nervous system levels. Inhibition of kallikrein or of kininase II were both shown to modulate the natriuretic and vasorelaxant effects of ANP. In hypertensive subjects, we found that ACE inhibition with blood pressure normalization reduces basal and stimulated plasma ANP and blunts the renal sodium excretion in response to saline loading. In contrast, we did not observe effects of acute ACE inhibition in healthy sodium-depleted volunteers on plasma vasopressin under basal conditions or in response to passive tilt. Finally, we investigated the interaction of ACE inhibition with substance P, a powerful endogenous diuretic and natriuretic peptide that may have a transmitter function in the baroreceptor reflex arch.(ABSTRACT TRUNCATED AT 250 WORDS)

[Fatigue, exertional dyspnea, unsteady gait]. / Müdigkeit, Belastungsdyspnoe, Gangunsicherheit.

Exertional dyspnea and fatigue dominated the clinical picture of pernicious anemia in a 78 year old man. A disturbed gait indicated concomitant neurologic disorders. A reduced Vitamin B12 level, an abnormal Schillingtest, atrophy of gastric mucosa as well as maturation disturbance of erythrocytes and neutrophils were present as typical signs of the disease. Administration of Cyanocobalamine led to correction of blood values within three weeks.

[The heart ventricle wall in digital subtraction angiocardiography]. / Die Herzkammerwand in der digitalen Subtraktionsangiokardiographie.

Digital subtraction angiography, using a time interval difference mode in relation to a suitable mask, provides a means of showing the myocardium in every phase of the cardiac cycle. The endo- and peri-cardial contours and the thickness of the myocardium in both ventricles can be demonstrated accurately. Artifacts are usually due to displacements of the heart or to tachycardia.

[Exertional dyspnea, chest pain, dizziness]. / Belastungsdyspnoe, Brustschmerz, Schwindel.

A 66 year old patient with chest pain and exertional dyspnea is described. Auscultation and physical examination showed signs of aortic stenosis combined with aortic insufficiency. Electrocardiography revealed left ventricular hypertrophy with associated ST-segment and T-wave abnormalities. Color blood flow imaging confirmed severe combined aortic stenosis and regurgitation, the hemodynamic evaluation demonstrated the indication for aortic valve replacement.

Endobronchial versus intravenous application of the vasopressin derivative glypressin during diagnostic bronchoscopy.

Glypressin is a vasopressin derivative which is used in the present study to stop pulmonary bleeding. The effects of endobronchially versus intravenously applied glypressin were examined during diagnostic fibreoptic bronchoscopy in 27 patients. Transcutaneously measured blood gases and haemodynamics were analysed after 1 mg glypressin was given. The glypressin plasma level was 251 fold higher after the intravenous than after the endobronchial administration. After endobronchial application no significant changes were observed for blood pressure, heart rate or blood gases. Following the intravenous glypressin application there was a significant increase in diastolic blood pressure. The bronchial mucosa pallor appeared earlier after topical than after systemic glypressin application. The haemostyptic effect was similar for both routes of application.

Assessment of beta-blocking activity of low-dose bupranolol.

In the present study an investigation was made on the pharmacodynamic effect of the beta-blocking agent bupranolol in the low-dose range. Bupranolol is usually given in doses of 100 mg twice daily in the treatment of hypertension, however the dose range between 20 and 100 mg was studied using graded isoproterenol injections in healthy volunteers. A significant beta-1-blocking activity was observed for the 20 mg dose already. This effect was reduced after a treatment of 10 days. The effect increased with the higher doses, there might be a linear correlation between the logarithm of the dose and the reduction of the tachycardia after the isoproterenol injections in the low-dose range. It was concluded that using the safe and sensitive isoproterenol injection method, the clinical effect of very low doses of bupranolol may be demonstrated. The low dose might be useful to reduce the reflex tachycardia seen in the treatment of hypertension with vasodilating drugs.

[Exertional dyspnea, fatigue, palpitations]. / Belastungsdyspnoe, Abgeschlagenheit, Palpitationen.

This 52-year old female patient suffered from exertional dyspnea, fatigue and palpitations progressive for some months. She had rheumatic fever in childhood. Physical examination and echocardiography revealed severe pure mitral regurgitation, invasive studies showed dilatation of the left atrium and ventricle, a regurgitant volume of 70% of the stroke volume and mitral valve replacement was performed.

[Functionally significant changes in the shape of the right ventricle in digital subtraction angiocardiography]. / Funktionell bedeutsame Formveränderungen des rechten Ventrikels in der digitalen Subtraktionsangiokardiographie.

Experiences in i.v. digital subtraction angiocardiography (DSAC) including so-called parametric imaging for morphological delineation of the right ventricle are illustrated. 32 patients with different anatomical and haemodynamic disturbances of the right ventricle were subjected to these examinations. Special emphasis is placed on pulmonary stenosis, particularly on its infundibular manifestations. For visualisation of muscular or fibrous bulging or other changes of the outflow tract of the right ventricle, analysis of the amplitudes is very suitable to produce cumulative pictures of ventricular wall motion during a cardiac cycle. Obstructive wall alterations within the infundibular part become visible even if they occur only during certain phases of the myocardial action, usually in late systole than otherwise.

[Hemodynamic studies on the action kinetics of phenoxybenzamine in healthy persons and hypertensive patients]. / Hämodynamische Untersuchungen zur Wirkungskinetik von Phenoxybenzamin bei gesunden Personen und Patienten mit Hypertonie.

The hemodynamic profile of the pre- and postsynaptic alpha-receptor blocker phenoxybenzamine (POB) was investigated by a non-invasive technique in healthy subjects and in patients with essential hypertension. At a dose of 0.03 mg POB/kg body weight no hemodynamic changes were detected. POB at a dose of 0.07 mg/kg resulted in an initial transient rise in systemic vascular resistance and mean arterial pressure and a fall in heart rate without changes in stroke volume or cardiac index. 6 h after administration of 0.13 mg POB/kg a transient fall in peripheral vascular resistance and mean arterial pressure with an increase in heart rate and cardiac index was observed. A rise of orthostatic index, however, occurred within 1 h after administration of POB and reached its maximum after 4 h. 8 h after POB no hemodynamic changes were detectable. In patients with essential hypertension a similar fall in systemic vascular resistance and mean arterial pressure was observed after 0.13 mg POB/kg body weight. No change in heart rate occurred and the hemodynamic effects were significant already 3 h after administration of POB and persisted up to 8 h after POB administration. In contrast to healthy subjects, patients with essential hypertension showed no significant changes in the orthostatic index after POB. These hemodynamic findings point to a previously unexpected rapidly reversible functional alpha-receptor blockade by POB.

Baroreflex setting and sensitivity in normal subjects: effects of pharmacologic inhibition of the angiotensin I converting enzyme.

Arterial blood pressure, heart rate and the response of these hemodynamic parameters to exogenous norepinephrine were investigated in healthy volunteers (daily sodium intake of 150 mmol) during a control period and after a single oral dose of 5 mg of the angiotensin I converting enzyme (ACE) inhibitor ramipril (HOE 498). Norepinephrine was infused at doses of 0.1, 0.2 and 0.3 micrograms kg-1 min-1, each for 10 minutes, during control and 3 hours after ramipril administration. Exogenous norepinephrine induced a dose-dependent increase in mean arterial blood pressure from 76.4 +/- 0.9 mm Hg during control to 85.6 +/- 1.5, 92.2 +/- 1.8 and 98.4 +/- 2.4 mm Hg, respectively. Ramipril significantly affected the baroreceptor set point with a decrease in mean blood pressure (72.1 +/- 1.7 vs 76.4 +/- 0.9 mm Hg, p less than 0.01) in the presence of unchanged heart rate (71.7 +/- 0.9 vs 73.6 +/- 1.5 min-1). Baroreceptor sensitivity, estimated by the slope of the delta blood pressure versus delta heart rate relation, was not affected by ACE inhibition. Also, the pressor effect of exogenous norepinephrine was unchanged by converting enzyme inhibition. The present results show that ACE inhibition with ramipril in sodium-replete healthy volunteers induces a decrease in blood pressure that is not accompanied by changes in heart rate, pressor sensitivity to exogenous norepinephrine or baroreceptor sensitivity.