Reinhard Volkmann

A novel cellular marker of insulin resistance and early atherosclerosis in humans is related to impaired fat cell differentiation and low adiponectin

The epidemic increase in type 2 diabetes can be prevented only if markers of risk can be identified and used for early intervention. We examined the clinical phenotype of individuals characterized by normal or low IRS‐1 protein expression in fat cells as well as the potential molecular mechanisms related to the adipose tissue. Twenty‐five non‐obese individuals with low or normal IRS‐1 expression in subcutaneous abdominal fat cells were extensively characterized and the results compared with 71 carefully matched subjects with or without a known genetic predisposition for type 2 diabetes. In contrast to the commonlyused risk marker, knownheredity for diabetes, low cellular IRS‐1 identified individuals who were markedly insulin resistant, had high proinsulin and insulin levels, and exhibited evidence of early atherosclerosis measured as increased intima media thickness in the carotid artery bulb. Circulating levels of adiponectin were also significantly reduced. Gene analyses of fat cells in a parallel study showed attenuated expression of several genes related to fat cell differentiation (adiponectin, aP2, PPARγ, and lipoprotein lipase) in the group of individuals characterized by a low IRS‐1 expression and insulin resistance. A low IRS‐1 expression in fat cells is a marker of insulin resistance and risk for type 2 diabetes and is associated with evidence of early vascular complications. Impaired adipocyte differentiation, including low gene expression and circulating levels of adiponectin, can provide a link between the cellular marker and the in vivo phenotype.—Jansson, P.‐A., Pellmé, F., Hammarstedt, A., Sandqvist, M., Brekke, H., Caidahl, K., Forsberg, M., Volkmann, R., Carvalho, E., Funahashi, T., Matsuzawa, Y., Wiklund, O., Yang, X., Taskinen, M.‐R., Smith, U. A novel cellular marker of insulin resistance and early atherosclerosis in humans is related to impaired fat cell differentiation and low adiponectin. FASEB J. 17, 1434–1440 (2003)

Renal Function and Upper Urinary Tract Configuration Following Urinary Diversion to a Continent Ileal Reservoir (Kock Pouch): A Prospective 5 To 11-Year Followup after Reservoir Construction

We followed 17 patients who underwent urinary diversion via a continent ileal reservoir (Kock pouch) with yearly examinations for 5 to 11 years postoperatively. The examinations involved control of renal function and configuration of the upper urinary tract. In 5 patients the upper urinary tract had become dilated during followup and in 2 of these renal scarring also had developed. All 5 patients had endured temporary outflow obstruction or reflux (stricture, overdistension of the reservoir or a defective antireflux valve). Of the patients 1 had a marked decrease in renal function before the outflow obstruction was corrected by an operation. Routine blood chemistry study was normal and hyperchloremic acidosis was not noted in any patient. After peroral loading of 6 patients with ammonium chloride significant excretion of titratable acid was found in the urine. Substitution with vitamin B12 was given to 6 patients due to subnormal values in 2 and borderline values in 4.

Obese children show increased intimal wall thickness and decreased pulse wave velocity

Objective:  Childhood obesity confers an increased risk of vascular changes and adult cardiovascular disease. Using a high‐resolution ultrasound technique that enables separation of intimal and medial layers, we examined the intimal thickness (IT) and intimal–medial thickness (IMT) of radial (RA) and dorsal pedal (DPA) arteries and the pulse wave velocity (PWV) in overweight/obese children and adolescents and in healthy subjects.

Increasing Peripheral Artery Intima Thickness From Childhood to Seniority

Background—Using new, very high-resolution ultrasound biomicroscopy, we examined the thickness of artificial layers of silicone and intima thickness (IT) of radial and anterior tibial arteries in healthy subjects and in patients with vascular disease. Methods and Results—Silicone layers of varying thicknesses and mesenteric artery specimens obtained from 18 patients undergoing colectomy were measured by both ultrasound biomicroscopy (55 MHz) and morphometry. There was high correlation (r>0.9; P<0.0001) between IT and intima area versus ultrasound biomicroscopy. In 90 healthy subjects (aged between 10 and 90 years), radial and anterior tibial arterial IT and intima-media thickness were measured, as was carotid intima-media thickness in 56 of these subjects. Age was strongly related with both media thickness and IT of both peripheral arteries. Correlations were found between carotid intima-media thickness and both radial and anterior tibial IT/intima-media thickness (r=0.44 to 0.53; P<0.0001). The IT-to-lumen diameter ratio increased with age and was larger at all ages in the anterior tibial artery (0.067±0.034) versus the radial artery (0.036±0.012; P<0.0001). A thicker radial intimal layer was found in patients with peripheral artery disease. Conclusion—This study is the first to our knowledge in humans to show the feasibility of measuring IT of the radial and anterior tibial arteries using very high-resolution ultrasound. IT progresses with age, and the IT-to-lumen diameter ratio is largest in the arteries of the foot. Assessment of IT by ultrasound biomicroscopy may aid in detecting early peripheral vascular abnormalities.

Non-invasive ultrasound assessment of renal artery stenosis by means of the gosling pulsatility index

OBJECTIVE To gauge the effectiveness of a new Doppler test for renal artery stenosis (RAS), based on the pulsatility index of the blood flow velocity spectrum within several interlobar arteries of both kidneys. METHODS Twenty normotensive volunteers and 49 hypertensive patients were investigated with ultrasound. Patients with angiographic signs of RAS underwent bilateral renal vein catheterization for renin measurement. Significant RAS was assumed if lateralization of renal vein renin to the stenotic side was proven. RESULTS The pulsatility index was higher in the hypertensives without RAS than in normal volunteers. Side differences between both kidneys were within methodological variations with the exception of one case, in whom side difference was > 0.12. The pulsatility index was lower in kidneys with significant RAS than in kidneys without RAS. In most patients with significant unilateral RAS the side difference was < 0.12. In the other patients with a low pulsatility index and a side difference < 0.12 RAS was found to be bilateral upon angiography. Doppler signals were absent in all kidneys with renal occlusion. CONCLUSIONS A side difference of > or = 0.12 predicts unilateral RAS, whereas the absence of parenchymal Doppler signals indicate occlusive RAS. A low pulsatility index combined with normal side difference may, in hypertensive patients, indicate bilateral RAS. Renovascular hypertension was correctly diagnosed in 84% of the patients and the presence of RAS in 94%.

Reduced cardiac vagal activity in obese children and adolescents.

Objective:  Obese children present with various cardiovascular risk factors affecting their future health. In adults, cardiac autonomic function is a major risk factor, predicting cardiovascular morbidity and mortality. We hypothesized that obese children and adolescents had a lower cardiac vagal activity than lean subjects. We measured cardiac spontaneous baroreflex sensitivity (BRS), reflecting the dynamic regulation of cardiac vagal function, in large groups of obese and lean young individuals.

Retrograde blood flow in the aortic arch determined by transesophageal Doppler ultrasound.

Background: Aortic arch atheromas may be important sources of cerebral embolism. Aortic plaques are frequently found somewhat distal to the origin of the cerebral arteries, implying that cerebral embolization from such plaques depends on local retrograde blood flow components in this area. Therefore, we investigated the occurrence of blood flow reversal in this part of the aorta. Furthermore, since the presence and magnitude of retrograde flow might be influenced by aortic wall properties, we also studied the relationship between plaque size and distribution, aortic strain and degree of retrograde flow. Methods: We evaluated aortic arch ante- and retrograde blood flow velocities in 56 patients by transesophageal echocardiography using color-Doppler-guided pulsed-Doppler techniques. The velocity-time integrals (VTI) were measured and the diastolic/systolic VTI ratio was calculated. Results: Retrograde diastolic blood flow was noted in all subjects, and diastolic/systolic VTI ratios were higher (p < 0.05) in patients with plaque ≥4 mm (n = 17) compared to those (n = 39) without. Patients exhibiting plaques exclusively in the aortic arch showed the highest VTI ratios (p < 0.01) and tended to have the lowest strain values. Aortic strain was also reduced in patients >50 years of age (p < 0.01). Conclusions: Our findings demonstrate retrograde aortic flow in all subjects and its proportion increases in subjects with atherosclerosis, particularly in the aortic arch. Aortic plaques situated distally to the origin of the cerebral arteries are therefore possible sources of cerebral emboli.

Beneficial effect of captopril on systemic lupus erythematosus-like disease in MRL lpr/lpr mice

MRL lpr/lpr (MRL/l) mice exhibit a disease similar to systemic lupus erythematosus (SLE) in humans. To investigate the influence of antihypertensive treatment on this disease, four groups of MRL/l mice were treated with the angiotensin-converting enzyme inhibitor captopril (n = 25), with the sympathetic blocker bretylium (n = 15), and with cyclophosphamide (n = 10). Thirty-five mice did not receive any treatment and served as controls. Survival rate, blood pressure, incidence of proteinuria and hematuria, renal pathology, lymphoid hyperplasia and dermatitis were studied. The survival at the age of 36 weeks was significantly improved by captopril as compared to controls (60 vs. 25%, p = 0.035). The cyclophosphamide group showed no mortality at that time and the bretylium group did not differ from the control group. Captopril and bretylium reduced systolic blood pressure significantly while cyclophosphamide was without effect. Captopril and cyclophosphamide diminished significantly the glomerular damage with less proliferative changes and a decreased incidence of proteinuria. The bretylium-treated animals also exhibited an improved renal pathology index but they did not differ from the controls with respect to proteinuria and hematuria. Lymphoid hyperplasia and dermatitis were decreased only by captopril and cyclophosphamide. It is concluded that captopril improves survival in SLE disease of MRL/l mice, counteracting lymphoid hyperplasia, renal disease, dermatitis and decreasing arterial blood pressure.

Renovascular resistance in primary hypertension: experimental variations detected by means of Doppler ultrasound

Objective To gauge the influence of renovascular resistance changes on blood flow velocity pulsatility in kidneys of hypertensive patients by means of the ultrasonic colour and pulsed-wave Doppler method, since we have previously shown in normotensive subjects that the blood flow velocity pulsatility in renal interlobar arteries varies with changes in renovascular resistance. Methods In six male patients with primary hypertension, renal blood flow velocity profiles were investigated by means of duplex ultrasound. Single-kidney renovascular resistance was assessed by measurements of split renal function (γ-camera renography), renal plasma flow (steady-state para-aminohippurate clearance) and cuff blood pressure. The pulsatility index of the blood flow velocity spectrum in the renal interlobar artery and renovascular resistance were measured either at rest, during infusion of angiotensin II, or after angiotensin converting enzyme inhibition. Results A significant correlation existed between pulsatility index and renovascular resistance (r = 0.50, P< 0.002), which did not improve after correction for the blood pressure pulsatility. Changes of pulsatility index were more closely related (r = 0.64, P< 0.001) to the corresponding changes in renovascular resistance. Conclusions With the two-dimensional image-guided colour and pulsed-wave Doppler method it is possible to assess semiquantitatively small intra-individual changes in renovascular resistance in hypertensive patients by means of pulsatility index measurements. Pharmacologically induced alterations in renovascular haemo-dynamics may therefore be evaluated with this technique.

Changes of blood flow velocity indicating mechanical compression of the vertebral arteries during rotation of the head in the normal human measured with transcranial Doppler sonography

The dynamical changes of blood flow velocity of the intracranial vertebral arteries (VAs) and proximal basilar artery (BA) provoked by rotation of the head in normal volunteers were measured using pulsed-wave transcranial Doppler sonography (TCD). In another group both VAs were examined simultaneously with 2-channel TCD. Blood flow velocities diminished compared to the neutral position in all vessels, independently of the side. Total obstruction of the flow was not observed. Our findings reveal a definitive decrease of blood flow velocity at the vertebrobasilar artery system provoked by rotation of the head in normal humans. This physiological phenomenon is suggested to have an impact on the cerebral blood flow in patients with impaired autoregulation of the cerebral vessels, low volume flow reserve in the contralateral VA or insufficient collateral channels because of normal anatomical variation, especially those patients under general anesthesia or comatose.