The cardiac microvasculature in hypertension, cardiac hypertrophy and diastolic heart failure.

Recent studies revealed an exceedingly high mortality with diastolic heart failure that was previously regarded as relatively benign compared to systolic heart failure. Prominent risk factors for diastolic heart failure are increasing age, hypertension and diabetes. These risk factors are associated with coronary microvascular rarefaction and resultant decreased coronary flow reserve, thereby rendering the myocardium vulnerable to ischemia. We discuss the importance of angiogenic gene programming in preserving the coronary microvasculature, preserving cardiac function and altering disease course. Further, we discuss the possible utility of therapies that activate hypoxia inducible factor-1 in preventing rarefaction of the coronary microvasculature and maintaining cardiac diastolic function.

Calcium-activated potassium channels contribute to human coronary microvascular dysfunction after cardioplegic arrest.

BACKGROUND: Cardioplegic arrest (CP) followed by reperfusion after cardiopulmonary bypass induces coronary microvascular dysfunction. We investigated the role of calcium-activated potassium (K(Ca)) channels in this dysfunction in the human coronary microvasculature. METHODS AND RESULTS: Human atrial tissue was harvested before CP from a nonischemic segment and after CP from an atrial segment exposed to hyperkalemic cold blood CP (mean CP time, 58 minutes) followed by 10-minute reperfusion. In vitro relaxation responses of precontracted arterioles (80 to 180 mum in diameter) in a pressurized no-flow state were examined in the presence of K(Ca) channel activators/blockers and several other vasodilators. We also examined expression and localization of K(Ca) channel gene products in the coronary microvasculature using reverse transcriptase-polymerase chain reaction, immunoblot, and immunofluorescence photomicroscopy. Post-CP reperfusion relaxation responses to the activator of intermediate and small conductance K(Ca) channels (IK(Ca)/SK(Ca)), NS309 (10(-5) M), and to the endothelium-dependent vasodilators, substance P (10(-8) M) and adenosine 5diphosphate (10(-5) M), were significantly reduced compared with pre-CP responses (P<0.05, n=8/group). In contrast, relaxation responses to the activator of large conductance K(Ca) channels (BK(Ca)), NS1619 (10(-5) M), and to the endothelium-independent vasodilator, sodium nitroprusside (10(-4) M), were unchanged pre- and post-CP reperfusion (n=8/group). Endothelial denudation significantly diminished NS309-induced vasodilatation and abolished substance P- or adenosine 5 diphosphate-induced relaxation (P<0.05), but had no effect on relaxation induced by either NS1619 or sodium nitroprusside. The total polypeptide levels of BK(Ca), IK(Ca), and SK(Ca) and the expression of IK(Ca) mRNA were not altered post-CP reperfusion. CONCLUSIONS: Cardioplegic arrest followed by reperfusion after cardiopulmonary bypass causes microvascular dysfunction associated with and likely in part due to impaired function of SK(Ca) and IK(Ca) channels in the coronary microcirculation. These results suggest novel mechanisms of endothelial and smooth muscle microvascular dysfunction after cardiac surgery.

Mecanismo de Lesión Tisular en Criocirugía / Mechanisms of Tissue Injury in Cryosurgery

La criocirugía, modalidad efectiva de tratamiento médico, es una técnica quirúrgica que emplea la congelación a temperaturas criogénicas para destruir tejidos biológicos no deseados. El objetivo de la criocirugía es congelar un determinado volumen tisular (para maximizar la destrucción celular) en una región predefinida y provocar necrosis sin daño significativo del tejido sano periférico. Las bases de la criocirugía son: "una rápida congelación, una lenta y completa descongelación, y repetición de los ciclos de congelación-descongelación". Para explicar el daño en una criolesión se han propuesto muchos mecanismos de injuria inducidos por la congelación. Los mecanismos son: (a) lesión celular directa, (b) lesión vascular, (c) apoptosis y (d) lesión inmunológica. La lesión que resulta de la criocirugía es compleja; por lo tanto, para controlar el resultado de este procedimiento es necesario comprender los mecanismos de daño en criocirugía.

Cryosurgery, an effective medical treatment modality, is a surgical technique that employs freezing at cryogenic temperatures to destroy undesirable biological tissue. The goal of cryosurgery is to freeze a specified volume of tissue (to maximize cell destruction) within a predefined target region, resulting in necrosis without significant damage to the surrounding healthy tissues. Factors that facilitate this are: rapid freezing, slow and complete thawing, and repetition of the freeze-thaw cycle. To explain the injury within a cryolesion, many freezing induced injury mechanisms have been proposed. These mechanisms are 1) direct cell injury, 2) vascular injury, 3) cellular apoptosis, and 4) immunologic injury. The injury that results from cryosurgery is complex; therefore, to control the outcome of cryosurgery it is necessary to understand the mechanisms of damage in cryosurgery.

Absence of glutathione peroxidase-1 exacerbates cerebral ischemia-reperfusion injury by reducing post-ischemic microvascular perfusion.

Mice deficient in the anti-oxidant enzyme glutathione peroxidase-1 (Gpx1) have a greater susceptibility to cerebral injury following a localized ischemic event. Much of the response to ischemia-reperfusion is caused by aberrant responses within the microvasculature, including inflammation, diminished endothelial barrier function (increased vascular permeability), endothelial activation, and reduced microvascular perfusion. However, the role of Gpx1 in regulating these responses has not been investigated. Wild-type and Gpx1-/- mice underwent focal cerebral ischemia via mid-cerebral artery occlusion followed by measurement of cerebral perfusion via laser Doppler and intravital microscopy. Post-ischemic brains in wild-type mice displayed significant deficit in microvascular perfusion. However, in Gpx1-/- mice, the deficit in cerebral blood flow was significantly greater than that in wild-type mice, and this was associated with significant increase in infarct size and increased vascular permeability. Ischemia-reperfusion also resulted in expression of matrix metalloproteinase-9 (MMP-9) in endothelial cells. The absence of Gpx1 was associated with marked increase in pro-MMP-9 expression as well as potentiated MMP-9 activity. Pre-treatment of Gpx1-/- mice with the anti-oxidant ebselen restored microvascular perfusion, limited the induction and activation of MMP-9, and attenuated the increases in infarct size and vascular permeability. These findings demonstrate that the anti-oxidant function of Gpx1 plays a critical role in protecting the cerebral microvasculature against ischemia-reperfusion injury by preserving microvascular perfusion and inhibiting MMP-9 expression.

Spontaneous electromyographic activity during microvascular decompression in trigeminal neuralgia.

Intraoperative monitoring of spontaneous facial nerve electromyographic activity during surgery for microvascular decompression in trigeminal neuralgia was evaluated. Fifteen patients with trigeminal neuralgia underwent surgery for microvascular decompression. During the entire operation, free-running facial nerve electromyographic signals were recorded. The data were analyzed with respect to waveform patterns known from vestibular schwannoma-surgery. Special regard was given to the occurrence of A-trains that are associated with postoperative paresis in patients operated on vestibular schwannoma. The spectrum of the observed activities matched patterns known from surgery of vestibular schwannoma; even A-trains, a pattern known to be an indicator of postoperative deterioration of facial nerve function (Romstöck et al., J Neurosurg 2000;93:586-593), were seen in 3 of the 15 patients with trigeminal neuralgia. The quantity of A-trains observed was much less than it is known from patients operated on tumors of the cerebellopontine angle. None of the trigeminal neuralgia-patients experienced postoperative deterioration of facial nerve function. The present study shows that A-trains do not only occur during tumor surgery, but also during procedures with indirect manipulation of the facial nerve. They do not necessarily lead to postoperative paresis as long as certain thresholds concerning amount and length of these A-trains are not exceeded.

Measurement of blood flow in the rotator cuff using laser Doppler flowmetry.

The aim of this study was to define the microcirculation of the normal rotator cuff during arthroscopic surgery and investigate whether it is altered in diseased cuff tissue. Blood flow was measured intra-operatively by laser Doppler flowmetry. We investigated six different zones of each rotator cuff during the arthroscopic examination of 56 consecutive patients undergoing investigation for impingement, cuff tears or instability; there were 336 measurements overall. The mean laser Doppler flowmetry flux was significantly higher at the edges of the tear in torn cuffs (43.1, 95% confidence interval (CI) 37.8 to 48.4) compared with normal cuffs (32.8, 95% CI 27.4 to 38.1; p = 0.0089). It was significantly lower across all anatomical locations in cuffs with impingement (25.4, 95% CI 22.4 to 28.5) compared with normal cuffs (p = 0.0196), and significantly lower in cuffs with impingement compared with torn cuffs (p < 0.0001). Laser Doppler flowmetry analysis of the rotator cuff blood supply indicated a significant difference between the vascularity of the normal and the pathological rotator cuff. We were unable to demonstrate a functional hypoperfusion area or so-called 'critical zone' in the normal cuff. The measured flux decreases with advancing impingement, but there is a substantial increase at the edges of rotator cuff tears. This might reflect an attempt at repair.

Substance P-mediated expression of the pro-angiogenic factor CCN1 modulates the course of colitis.

Substance P (SP) regulates important intestinal functions, such as mucosal permeability, motility, chloride secretion, and inflammation via the neurokinin-1 receptor (NK-1R). Previous reports showed that vascularization and expression of angiogenic factors are evident in the colonic mucosa of rats with colitis and patients with inflammatory bowel disease. Here we determined whether SP is associated with angiogenesis. Human NCM460 colonocytes stably transfected with the human NK-1R (NCM460-NK-1R cells) and mice with dextran sodium sulfate-induced colitis were used. We found that expression of the angiogenic factor CCN1 was increased in the colons of patients with Crohn's disease and ulcerative colitis. Mucosal extracts from inflammatory bowel disease patients induced human intestinal microvascular endothelial cell migration that was inhibited by blockade of CCN1 and its receptor integrin alphavbeta3. Both the degree of angiogenesis and CCN1 expression were elevated in the colons of mice with dextran sodium sulfate-induced colitis, which was reduced by treatment with the NK-1R antagonist CJ-12255. SP also increased CCN1 expression in NCM460-NK-1R colonocytes. SP exposure to human intestinal microvascular endothelial cells co-cultured with NCM460-NK-1R cells induced angiogenic activity that was inhibited by CCN1 silencing. In addition, intracolonic overexpression of CCN1 induced angiogenesis in mouse colon. Thus, SP mediates angiogenesis via CCN1 during colitis.

[Changes in microcirculation of the urinary bladder in patients with stage II prostatic adenoma depending on the treatment method].

To determine microcirculation in the wall of the urinary bladder in prostatic adenoma, we used a laser analyzer of capillary circulation LAKK-01. Two groups participated in the trial: 105 males with stage II prostatic adenoma (the study group) and 25 volunteers (the control group). We estimated normal parameters of microcirculation in the wall of the bladder. In stage II prostatic adenoma the above microcirculation decreased to a subcritical perfusion level. Significantly earlier and complete recovery of microcirculation was observed in patients who had taken cardura (Pfizer) in a dose 2 mg/day for 3 months after transurethral resection of prostatic gland. Thus, 2 mg/day cardura (Pfizer) in patients with prostatic adenoma of stage II after TUR of the prostate promotes early and effective recovery of microcirculation.

Management of petrosal veins during microvascular decompression for trigeminal neuralgia.

OBJECTIVE: Venous compression might be the main cause of incomplete decompression and symptom recurrence after microvascular decompression (MVD) in patients with trigeminal neuralgia. Although it can be killed in most cases, cutting the vein sometimes has the potential risk arising from venous congestion. To maneuver the vein safely, we introduced a temporary occlusion test of the vein. METHODS: Among 407 consecutive MVD cases, 48 (11.8%) offending and 157 block veins were encountered. The vein was cut directly in 147 (71.7%). Owing to the potential risk following killing of the vein, 58 (28.3%) patients underwent venous occlusion test with neurophysiologic monitoring during the operation. The temporal occlusion should be ceased immediately as soon as any changes in brainstem auditory evoked potential (BAEP) or trigeminal evoked potential (TEP) wave figuration turn up; otherwise, it would last for 15 minutes. RESULTS: The occlusion test was negative in 53 (91.4%), while positive in five patients (8.6%). According to the results, we cut the vein in test-negative patients, which made the operation easy and offered a satisfactory decompression. Among the five positive cases, the vein was finally saved in two and cut in three cases. Yet, all the three patients developed a severe ipsilateral cerebellar edema and brainstem shift after the vein was sacrificed. Despite those patients were reoperated on immediately for posterior fossa decompression, they remained equilibrium disorder with numbness in ipsilateral face and mind hemiparesis in contralateral extremities post-operatively. The residual two patients had an incomplete pain relief. CONCLUSION: This venous occlusion test could help the surgeon in making a right decision before manipulation of the petrosal veins during MVD.

Microcirculatory dysfunction in endotoxemic bowel anastomosis: the pathogenetic contribution of microcirculatory dysfunction to endotoxemia-induced healing impairment.

BACKGROUND: An established intra-abdominal infection as in perforated diverticulitis is considered to contribute to anastomotic healing impairment. Since microvascular dysfunction in sepsis is known to be due to organ failure, the influence of inflammation on the anastomotic microcirculation needs further investigation. MATERIAL AND METHODS: Sixty BALB/c mice (n = 10 per group and day 2, 4, and 7) were randomized to two groups: Control and Sepsis (lipopolysaccharide administration 2 mg/kg bodyweight 18 h before colon surgery). All animals underwent colonic anastomosis. Immediately after its completion intravital fluorescence microscopy of the anastomosis was performed, and both macroscopic and histological parameters were assessed on days 2, 4, and 7 postoperatively. Additionally, immunohistology was performed for CD31 (platelet endothelial cell adhesion molecule-1), single-strand DNA, and inducible nitric oxide synthase. RESULTS: As compared to Control the functional capillary network of the perianastomotic region was decreased in Sepsis (P < 0.001) as well as the hemoglobin O(2) saturation in the antimesenteric region of the anastomosis (P < 0.05). Bursting pressure was significantly decreased in Sepsis compared to Control at days 2, 4, and 7. On day 7 there were significant differences between the two groups in the anastomotic region: neutrophil infiltration in Sepsis was higher (P < 0.001); vascular density and differentiation in Sepsis was lower (P < 0.01, P < 0.05, respectively); and apoptosis was higher in Sepsis (P < 0.05). CONCLUSION: The inflammatory state increases microvascular dysfunction at the anastomosis resulting in healing impairment.

Windkesselness of coronary arteries hampers assessment of human coronary wave speed by single-point technique.

A novel single-point technique to calculate local arterial wave speed (SPc) has recently been presented and applied in healthy human coronary arteries at baseline flow. We investigated its applicability for conditions commonly encountered in the catheterization laboratory. Intracoronary pressure (P(d)) and Doppler velocity (U) were recorded in 29 patients at rest and during adenosine-induced hyperemia in a distal segment of a normal reference vessel and downstream of a single stenosis before and after revascularization. Conduit vessel tone was minimized with nitroglycerin. Microvascular resistance (MR) and SPc were calculated from P(d) and U. In the reference vessel, SPc decreased from 21.5 m/s (SD 8.0) to 10.5 m/s (SD 4.1) after microvascular dilation (P < 0.0001). SPc was substantially higher in the presence of a proximal stenosis and decreased from 34.4 m/s (SD 18.2) at rest to 27.5 m/s (SD 13.4) during hyperemia (P < 0.0001), with a concomitant reduction in P(d) by 20 mmHg and MR by 55.4%. The stent placement further reduced hyperemic MR by 26% and increased P(d) by 26 mmHg but paradoxically decreased SPc to 13.1 m/s (SD 7.7) (P < 0.0001). Changes in SPc correlated strongly with changes in MR (P < 0.001) but were inversely related to changes in P(d) (P < 0.01). In conclusion, the single-point method yielded erroneous predictions of changes in coronary wave speed induced by a proximal stenosis and distal vasodilation and is therefore not appropriate for estimating local wave speed in coronary vessels. Our findings are well described by a lumped reservoir model reflecting the "windkesselness" of the coronary arteries.

Disruption of Ang-1/Tie-2 signaling contributes to the impaired myocardial vascular maturation and angiogenesis in type II diabetic mice.

OBJECTIVE: Microvascular insufficiency represents a major cause of end-organ failure among diabetics. The current studies were undertaken to determine whether dysregulation of the angiopoietins/Tie-2 system would result in an impairment of smooth muscle cell (SMC) recruitment and vascular maturation, which contributes to impaired angiogenesis in diabetes. METHODS AND RESULTS: Tie-2 expression was significantly attenuated, whereas angiopoietin-2 (Ang-2) was increased in db/db mice subjected to myocardial ischemia. Our morphological analysis showed that the number of SMC coverage area per neovessel was significantly reduced in db/db mice. This was accompanied by a significant reduction of myocardial capillary density and arteriole formation. Interestingly, Angiopoietin-1(Ang-1)-induced SMC recruitment and vessel outgrowth were severely impaired in db/db mice. Our in vitro studies further demonstrated that exposure of mouse heart endothelial cells to high glucose resulted in a significant upregulation of Ang-2 and a downregulation of Tie-2 expression. These alterations led to a significant impairment of Ang-1-induced Akt and eNOS phosphorylation, along with a remarkable impairment of Ang-1-induced endothelial cell migration and endothelial cell spheroid sprouting. Ang-1 gene transfer restored Tie-2 expression and rescued these abnormalities in diabetes. CONCLUSIONS: Our findings underscore the important role of Ang-1-Tie-2 signaling in the diabetes-induced impairment of vascular maturation and angiogenesis.

Kupffer cell blockade improves the endotoxin-induced microcirculatory inflammatory response in obstructive jaundice.

Cholestasis predisposes to hypersensitivity to LPS, leading to potential septic complications. We set out to characterize the involvement of Kupffer cell (KC) activation in the hepatic microcirculatory and structural consequences of obstructive jaundice in the presence and absence of acute endotoxemia. The hepatic microcirculatory consequences of 3-day extrahepatic bile duct ligation (BDL) were assessed in rats. The contributions of changes in hepatic perfusion, leukocyte influx, and proinflammatory cytokine release to the development of hepatic structural damage were also determined. Furthermore, the corresponding consequences of BDL in combination with acute (2-h) endotoxemia (1 mg kg(-1) LPS, i.v.) were compared with those observed after LPS alone. In a second series, the same protocols were applied in identical groups of rats where the KC function was inhibited with 24-h gadolinium chloride pretreatment (10 mg kg(-1), i.v.). Bile duct ligation induced minor inflammatory reactions but caused a marked reduction in hepatic sinusoidal perfusion and severe histological damage. LPS treatment, however, elicited an approximately 5-fold increase in leukocyte adherence in the central venules and pronounced IL-6 and TNF-alpha release, but without significant structural damage. The combination of BDL with LPS enhanced the perfusion failure, leukocyte sticking/deposition, and proinflammatory cytokine release; most of these changes can be effectively ameliorated by gadolinium chloride. In conclusion, when obstructive jaundice is followed by a second hit of LPS, perfusion failure, liver inflammation, and structural damage are enhanced, the KCs playing a decisive role in this scenario. Therapeutic strategies aimed at KC blockade can potentially reduce the risk of inflammatory complications in cholestasis.

The influence of selenium substitution on microcirculation and glutathione metabolism after warm liver ischemia/reperfusion in a rat model.

Ischemia/reperfusion (I/R) injury is a variable yet unavoidable complication in liver surgery and transplantation. Selenium-dependent glutathione-peroxidases (GPx) and selenoproteins function as antioxidant defense systems. One target in preventing I/R injury is enhancing the capacity of endogenous redox defense. It was the aim of this study to analyze the effects of selenium substitution on liver microcirculation, hepatocellular injury and glutathione status in a model of partial warm liver ischemia in the rat. Sodium selenite was administered in three different dosages i.v.: 0.125 microg/g, 0.25 microg/g and 0.375 microg/g body weight and compared to an untreated control group (each n=10). Intravital microscopy was performed after 70 min of partial warm liver ischemia and 90 min of reperfusion. Liver tissue and plasma samples were taken at the end of the experiment for laboratory analysis. Microcirculation improved significantly in all therapy groups in contrast to control animals. ALT levels decreased significantly whereas malondialdehyde levels remained unchanged. In liver tissue, selenium supplementation caused an increase in the amount of total and reduced glutathione without changes in oxidized glutathione. This effect is likely mediated by selenite itself and selenoprotein P rather than by modulating GPx activity. We were able to show that selenite substitution has an immediate protective effect on I/R injury after warm hepatic ischemia by acting as a radical scavenger and preserving the antioxidative capacity of the liver.

Hepatic microcirculation in fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD), the most common cause of steatosis, is associated with visceral obesity and insulin resistance. With more severe risk factors (obesity, type 2 diabetes [T2D], metabolic syndrome), steatosis may be complicated by hepatocellular injury and liver inflammation (steatohepatitis or NASH). NASH can lead to perisinusoidal fibrosis and cirrhosis. Fat-laden hepatocytes are swollen, and in steatohepatitis, further swelling occurs due to hydropic change (ballooning) of hepatocytes to cause sinusoidal distortion, as visualized by in vivo microscopy, reducing intrasinusoidal volume and microvascular blood flow. Involvement of other cell types (sinusoidal endothelial cells, Kupffer cells, stellate cells) and recruitment of inflammatory cells and platelets lead to dysregulation of microvascular blood flow. In animal models, the net effect of such changes is a marked reduction of sinusoidal space (approximately 50% of control), and a decrease in the number of normally perfused sinusoids. Such microvascular damage could accentuate further liver injury and disease progression in NASH. The fatty liver is also exquisitely sensitive to ischemia-reperfusion injury, at least partly due to the propensity of unsaturated fatty acids to undergo lipid peroxidation in the face of reactive oxygen species (ROS). This has important clinical consequences, particularly limiting the use of fatty donor livers for transplantation. In this review, we discuss available data about the effects of steatosis and steatohepatitis on the hepatic microvascular structure and sinusoidal blood flow, highlighting areas for future investigation.

Smoking mentholated cigarettes impairs coronary microvascular function as severely as does smoking regular cigarettes.

OBJECTIVE: Smoking mentholated cigarettes inhibits the metabolism of nicotine and increases systemic exposure to cigarette smoke toxins. However, the possible effects of smoking mentholated cigarettes on coronary microvascular functions are unknown. We sought to investigate whether smoking mentholated cigarettes impairs coronary flow reserve (CFR) more so than smoking regular cigarettes. METHODS: Twenty otherwise healthy smokers of regular cigarettes (6 women, 14 men; mean age, 25.6 +/- 6.4 years) and 22 non-smoking control subjects were included in the study. To compare the acute effects of mentholated (0.9 mg nicotine, 11 mg tar, 12 mg carbon monoxide) and regular (0.9 mg nicotine, 12 mg tar, 12 mg carbon monoxide) cigarettes on CFR, all subjects underwent an echocardiographic examination that included CFR measurements at baseline. Twenty to 30 minutes after subjects had smoked 2 regular cigarettes and 2 mentholated cigarettes, CFR was again measured in subjects in the smoking group. RESULTS: In response to smoking 2 regular and 2 mentholated cigarettes, CFR values declined from 2.56 +/- 0.60 to 2.06 +/- 0.38 (P < 0.004) and from 2.56 +/- 0.60 to 2.14 +/- 0.30 (P < 0.005), respectively. Smoking mentholated and regular cigarettes impaired CFR to the same degree (P = 0.547). CONCLUSIONS: When compared with smoking regular cigarettes, smoking mentholated cigarettes has similar acute detrimental effects on coronary microvascular functions.

Incremental value of pulse wave velocity in the determination of coronary microcirculatory dysfunction in never-treated patients with essential hypertension.

BACKGROUND: Coronary microcirculation is disturbed in essential hypertension. We investigated whether arterial stiffness determines coronary flow reserve (CFR) in hypertensive patients. METHODS: We examined 100 never-treated hypertensives and 20 healthy controls. We measured (i) carotid-to-femoral pulse wave velocity (PWV); (ii) Systolic (V (s)) and diastolic (V (d)) coronary flow velocity, time integral (V (TI)-V (d)) of diastolic velocity and CFR after adenosine by transthoracic echocardiography; (iii) ratio of E wave from mitral inflow to Em of mitral annulus, as an index of left ventricular (LV) diastolic pressures using tissue Doppler; (iv) carotid intima-media thickness (IMT), as an index of vascular damage; and (v) 24-h blood pressure parameters using ambulatory blood pressure monitoring. RESULTS: Patients had abnormal PWV, IMT, E/Em, resting V (d)/V (s), and CFR than controls (P < 0.05). In hypertensives, PWV was related to abnormal IMT and E/Em which in turn were related to reduced CFR (P < 0.05). PWV and E/Em were independent determinants of CFR and V (d)/V (s) (P < 0.05) in hypertensives. When added to a model including age, sex, smoking, LV mass (LVM), heart rate, 24-h systolic blood pressure (SBP), and E/Em, PWV had an incremental value in the determination of CFR (r (2) change from 0.25 to 0.46, P < 0.01). PWV >10.7 m/s predicted a CFR <2 with 79 and 75% and a CFR <2.6 with 83 and 82% sensitivity and specificity, respectively, using adjusted-receiver operating characteristic curve (ROC) analysis. CONCLUSIONS: Elevated LV diastolic compressive forces on coronary microcirculation and the presence of generalized vascular damage may explain the association between PWV and CFR. PWV has an incremental value in the determination of impaired coronary microcirculation in hypertensive patients.

Hepatic involvement and portal hypertension predict mortality in chronic granulomatous disease.

BACKGROUND & AIMS: Chronic granulomatous disease (CGD) is a rare genetic disorder, predisposing affected individuals to recurrent infectious complications and shortened survival. Liver involvement in CGD includes vascular abnormalities, which may lead to noncirrhotic portal hypertension. METHODS: To evaluate the impact of noncirrhotic portal hypertension on survival in CGD, all records from 194 patients followed up at the National Institutes of Health with CGD were reviewed. Cox proportional hazards regression was used to determine factors associated with mortality. RESULTS: Twenty-four patients died, all from infectious complications. By Cox regression, factors associated with mortality were as follows: (1) decreases in platelet count (>9000/microL/y; hazard ratio, 4.7; P = .007), (2) alkaline phosphatase level increases (>0.25/y; hazard ratio, 4.5; P = .01) and (3) history of liver abscess (hazard ratio, 3.1; P = .03). By regression analysis, decreasing platelet count was associated with increasing portal vein diameter, splenomegaly, increased serum immunoglobulin G level, and increasing number of alanine aminotransferase increases; greater number of alkaline phosphatase level increases and abscess were both associated with increasing age and number of infections. Prospective evaluation revealed increased hepatic-venous pressure gradients in 2 patients with progressive thrombocytopenia, suggestive of portal hypertension. CONCLUSIONS: These data suggest mortality in patients with CGD is associated with the development of noncirrhotic portal hypertension, likely owing to injury to the microvasculature of the liver from repeated systemic and hepatic infections. The slope of decline in platelet count may be a useful measure of progression of portal hypertension over time. Furthermore, the data illustrate the potential independent effect of portal hypertension on clinical outcome outside the setting of cirrhosis.

Skin blood flow in necrobiosis lipoidica diabeticorum.

BACKGROUND: Necrobiosis lipoidica diabeticorum (NLD) is a granulomatous skin reaction found in < 1% of diabetic patients. Our purpose was to determine if NLD represented areas of cutaneous ischemia. METHODS: Using laser Doppler flowmetry, we measured cutaneous blood flow in nine diabetic patients at NLD lesions and at contiguous uninvolved sites. Flow values were also determined at several reference sites noncontiguous with the NLD lesions and compared to age- and sex-matched controls: 24 diabetic subjects without skin abnormalities, 18 diabetic patients with dermopathy, and 40 nondiabetic subjects. RESULTS: NLD lesions exhibited significantly higher blood flow (4.8 +/- 0.7 ml/min/100 g) than areas of unaffected skin close to the lesions (1.2 +/- 0.1 ml/min/100 g) (P < 0.01 for both comparisons). There were no significant differences in flow between normal skin sites in NLD patients and normal sites in diabetic patients without skin lesions. CONCLUSIONS: Our findings refute the hypothesis that NLD is a manifestation of microvascular ischemic disease of the skin. The increased blood flow seen in NLD lesions suggests an ongoing inflammatory process.

Myocardial ischemia in the absence of epicardial coronary artery disease in Friedreich's ataxia.

We present the first in vivo detection of microvascular abnormality in a patient with Friedreich's ataxia (FA) without epicardial coronary artery disease using cardiac magnetic resonance (CMR). The patient had exertional chest pain and dyspnea prompting referral for cardiac evaluation. These symptoms were reproduced during intravenous adenosine infusion, and simultaneous first-pass perfusion imaging showed a significant subendocardial defect; both symptoms and perfusion deficit were absent at rest. Epicardial coronaries were free of disease by invasive angiography; together, these findings support the notion of impaired myocardial perfusion reserve in FA.