Skin capillary density in infants born to normotensive mothers: a comparison between singleton and twin infants.

OBJECTIVE: Twin infants tend to have LBW and microvascular alterations but do not appear to have an increase in cardiovascular mortality later in life as singleton infants. We hypothesized that twin infants born to normotensive mothers would not have capillary rarefaction at birth. METHODS: We studied 26 dizygotic twin infants and compared them with 115 consecutive singleton infants to normotensive mothers. We used orthogonal polarized spectroscopy to measure basal (i.e., functional) and maximal (i.e., structural) skin capillary density according to a well-standardized protocol. RESULTS: Twin infants have significantly higher BCD (mean difference 4.3 capillaries/mm(2) , 95% CI: 0.4, 8.1, p = 0.03) and have marginally significantly higher MCD (mean difference 3.9 capillaries/mm(2) , 95% CI: -0.6, 8.3, p = 0.086) compared to singleton infants. Birth weight was significantly associated with BCD and MCD (p = 0.003 and 0.006). CONCLUSIONS: Twin infants with low and NBWs tend to have higher functional and structural capillary densities compared to singleton infants. Further longitudinal studies of skin capillary density and of retinal vascular parameters commencing from birth to various stages in early childhood are essential to identify the dynamics and the exact timing, if any, of the remodeling of microcirculation in these individuals.

Oxygen therapy in premature low birth weight infants is associated with capillary loss and increases in blood pressure: a pilot study.

Low birth weight (LBW) and premature birth are known risk factors for future cardiovascular disease and in particular essential hypertension (EH). Capillary rarefaction (CR) is an established hallmark of EH and is known to occur in individuals with a history of LBW. We previously reported that LBW infants do not have CR at birth but rather increased capillary density (CD). We hypothesized that LBW infants undergo a process of accelerated CR in early life, triggered in part by oxygen therapy. We studied 26 LBW infants, of whom 10 infants received oxygen therapy, and compared them to 14 normal birth weight (NBW) infants. We measured CD at 1, 5 and 10 days after birth and again after 40 weeks adjusted gestational age equivalent to birth at full term. We confirmed that LBW infants had higher CD at birth compared to NBW infants and found that significant structural CR occurred at term age in LBW infants who had received oxygen therapy (mean difference -22 capillaries/field, p = 0.007) and in those who did not receive oxygen therapy (mean difference -29 capillaries/field, p < 0.001) compared to baseline at birth. Both LBW groups showed a significant rise in BP at 40 weeks adjusted term age and the rise in systolic (mean difference 24 mm Hg, p < 0.0001) and diastolic BP (mean difference 14 mm Hg, p < 0.001) was more pronounced in the oxygen treated group compared to the nonoxygen group (mean difference 14 mm Hg, p = 0.043 and mean difference = 9 mm Hg p = 0.056 respectively). In conclusion, oxygen therapy in premature LBW infants may induce significant increases in their BP in early life.

Early Life Microcirculatory Plasticity and Blood Pressure Changes in Low Birth Weight Infants Born to Normotensive Mothers: A Cohort Study.

BACKGROUND: Capillary rarefaction (CR) is an established hallmark of essential hypertension (EH). The aim of this study was to examine early changes in capillary density (CD) and blood pressure (BP) in low birth weight (LBW) infants who are at risk of developing EH in later life. METHODS: We studied 77 LBW infants and 284 normal birth weight (NBW) infants, all born to mothers with normotension, in a longitudinal multicenter study. Intravital capillaroscopy was used to measure functional basal capillary density (BCD) and maximal capillary density (MCD) at birth, 3, 6, and 12 months. RESULTS: We found that LBW infants, born preterm and at term, had a significantly higher CD at birth, then underwent significant CR in the 1st 3 months culminating in a CD similar to that seen in NBW infants. NBW infants showed a gradual reduction in CD between birth and 12 months. Non-Caucasian ethnicity and preterm birth were significant predictors of a higher CD at birth. Systolic BP in NBW infants increased significantly from birth to 3 months, and we identified a significant negative correlation between systolic BP and MCD. CONCLUSIONS: This study has identified a process of early "accelerated capillary remodeling" in LBW infants, which corrects their higher CD at birth. This remodeling is unlikely to explain the CR seen in adult individuals with, or at risk of developing EH. Further follow-up studies are required to determine the timing and mechanisms involved in CR, which is likely to occur after the 1st year of life but before early adulthood.

Regional left ventricular deformation and geometry analysis provides insights in myocardial remodelling in mild to moderate hypertension.

AIM: In the early stages of hypertension (HTN), when global left ventricular (LV) function is still unaffected, localized geometrical changes suggest changes in regional function. We investigated regional geometry and systolic deformation (using strain/strain rate (S/SR) imaging) in HTN. METHODS AND RESULTS: We studied 74 untreated mild to moderate HTNs and 34 matched normotensives (NTN). All had a standard echo including myocardial velocity data for regional radial and longitudinal deformation. Despite the absence of abnormalities in standard functional indices and LVH, non-uniform changes in regional geometry and deformation were observed. Besides a significant increase in wall thickness (WT) in all HTN segments, there was a gradual increase in WT from apex to base resulting in prominent basal septal hypertrophy. In HTN, regional longitudinal peak systolic SR (SSR) and end-systolic S (ESS) were significantly (P < 0.0001) reduced in the basal septum. In the lateral wall there was an increase in peak SSR and ESS (P < 0.05) basally. The basal septal ESS correlated both with mean arterial pressure and basal septal WT, with lower ESS for higher BP and thicker septum. CONCLUSION: Regionally differing geometrical remodelling occurs early in HTN. Longitudinal ESS and peak SSR are sensitive markers of early changes occurring in HTN.

Renal artery sympathetic denervation: observations from the UK experience.

BACKGROUND: Renal denervation (RDN) may lower blood pressure (BP); however, it is unclear whether medication changes may be confounding results. Furthermore, limited data exist on pattern of ambulatory blood pressure (ABP) response-particularly in those prescribed aldosterone antagonists at the time of RDN. METHODS: We examined all patients treated with RDN for treatment-resistant hypertension in 18 UK centres. RESULTS: Results from 253 patients treated with five technologies are shown. Pre-procedural mean office BP (OBP) was 185/102 mmHg (SD 26/19; n = 253) and mean daytime ABP was 170/98 mmHg (SD 22/16; n = 186). Median number of antihypertensive drugs was 5.0: 96 % ACEi/ARB; 86 % thiazide/loop diuretic and 55 % aldosterone antagonist. OBP, available in 90 % at 11 months follow-up, was 163/93 mmHg (reduction of 22/9 mmHg). ABP, available in 70 % at 8.5 months follow-up, was 158/91 mmHg (fall of 12/7 mmHg). Mean drug changes post RDN were: 0.36 drugs added, 0.91 withdrawn. Dose changes appeared neutral. Quartile analysis by starting ABP showed mean reductions in systolic ABP after RDN of: 0.4; 6.5; 14.5 and 22.1 mmHg, respectively (p < 0.001 for trend). Use of aldosterone antagonist did not predict response (p > 0.2). CONCLUSION: In 253 patients treated with RDN, office BP fell by 22/9 mmHg. Ambulatory BP fell by 12/7 mmHg, though little response was seen in the lowermost quartile of starting blood pressure. Fall in BP was not explained by medication changes and aldosterone antagonist use did not affect response.

Skin capillary density changes in normal pregnancy and pre-eclampsia.

BACKGROUND: Many abnormalities are known to occur in the microcirculation in essential hypertension, including reduction in capillary density or rarefaction. Peripheral vasodilatation and angiogenesis are critical components of the physiological adaptation in normal pregnancy. OBJECTIVE: To investigate the hypothesis that defective angiogenesis, reflected in capillary rarefaction, may be implicated in the clinical syndrome of pre-eclampsia. METHODS: We used intravital capillary video-microscopy to study functional (baseline) and structural (after maximization with venous congestion) skin capillary density in 22 healthy normotensive pregnant women and compared our findings with those in 22 non-pregnant age-matched healthy controls and 11 women whose pregnancies were complicated by pre-eclampsia. RESULTS: We found that both functional and structural capillary density increased during normal pregnancy. Capillary density in pre-eclamptic women was significantly lower both at baseline and after maximization. Skin capillary density appeared to be inversely correlated with blood pressure during pregnancy and in pre-eclampsia. CONCLUSIONS: A low capillary density may account, in part, for the failure of blood pressure to decrease in pre-eclamptic pregnancies, and may reflect the maladaptive cardiovascular response that is part of the pre-eclampsia syndrome.

Microvascular remodelling in preeclampsia: quantifying capillary rarefaction accurately and independently predicts preeclampsia.

BACKGROUND: Preeclampsia is a major cause of maternal and neonatal mortality and morbidity. The incidence of preeclampsia seems to be rising because of increased prevalence of predisposing disorders, such as essential hypertension, diabetes, and obesity, and there is increasing evidence to suggest widespread microcirculatory abnormalities before the onset of preeclampsia. We hypothesized that quantifying capillary rarefaction could be helpful in the clinical prediction of preeclampsia. METHODS: We measured skin capillary density according to a well-validated protocol at 5 consecutive predetermined visits in 322 consecutive white women, of whom 16 subjects developed preeclampsia. RESULTS: We found that structural capillary rarefaction at 20-24 weeks of gestation yielded a sensitivity of 0.87 with a specificity of 0.50 at the cutoff of 2 capillaries/field with the area under the curve of the receiver operating characteristic value of 0.70, whereas capillary rarefaction at 27-32 weeks of gestation yielded a sensitivity of 0.75 and a higher specificity of 0.77 at the cutoff of 8 capillaries/field with area under the curve of the receiver operating characteristic value of 0.82. Combining capillary rarefaction with uterine artery Doppler pulsatility index increased the sensitivity and specificity of the prediction. Multivariable analysis shows that the odds of preeclampsia are increased in women with previous history of preeclampsia or chronic hypertension and in those with increased uterine artery Doppler pulsatility index, but the most powerful and independent predictor of preeclampsia was capillary rarefaction at 27-32 weeks. CONCLUSIONS: Quantifying structural rarefaction of skin capillaries in pregnancy is a potentially useful clinical marker for the prediction of preeclampsia.

Capillary remodelling in normal pregnancy: Can it mediate the progressive but reversible rise in blood pressure? Novel insights into cardiovascular adaptation in pregnancy.

OBJECTIVE: To conduct a longitudinal study of skin capillary density changes throughout normal pregnancy and correlate them to changes in blood pressure. DESIGN: Prospective, longitudinal cohort study. SETTING: London teaching hospital. STUDY DESIGN: Two hundred and twenty-five Caucasian, Primigravid women with singleton pregnancy, normotensive throughout pregnancy, and with normal pregnancy outcomes. We used intra-vital video microscopy to measure basal (i.e. functional) and maximal (i.e. structural) skin capillary density (CD) according to a well-validated protocol. The subjects were studied at baseline (11-16weeks gestation) and at four consecutive visits (20-24weeks, 27-32weeks, 34-38weeks, and 5-15weeks postpartum). Blood pressure measurements were taken during the same visits. RESULTS: We found that normal pregnancy was associated with progressive capillary rarefaction, with the overall trend in the fall in both functional and structural CD being statistically significant (p<0.001). The fall in CD was a remarkable mirror image to a progressive rise in systolic and diastolic blood pressures, there being a significant correlation between systolic blood pressure and structural CD. Postpartum measurements of both CD and blood pressure were similar to base line levels. CONCLUSIONS: Progressive capillary rarefaction is a normal accompaniment of human pregnancy that may mediate the progressive rise in systolic and diastolic pressures. Both the CD and blood pressure changes are reversible, returning to baseline in the puerperium.

Structural capillary rarefaction and the onset of preeclampsia.

OBJECTIVE: To estimate if reduced capillary density (ie, capillary rarefaction) precedes the onset of preeclampsia and if it could play a role in its pathogenesis. Capillary rarefaction is a consistent finding in essential hypertension. METHODS: In this longitudinal cohort study, we recruited 322 consecutive white women, of whom 305 women completed the study. We used intravital video microscopy to measure basal (ie, functional) and maximal (ie, structural) skin capillary densities according to a well-validated protocol and measured plasma angiogenic and antiangiogenic factors. Women were studied at five consecutive predetermined visits. RESULTS: Preeclampsia occurred in 16 women (mean onset at 35.6±4.8 weeks of gestation), 272 women had normal pregnancies, eight had hypertension, and nine pregnancies were complicated by intrauterine growth restriction. In women with a normal pregnancy, significant reduction in maximal capillary density occurred at 27-32 weeks but had resolved by the puerperium. In contrast, in women who later developed preeclampsia, structural rarefaction was greater and occurred earlier at 20-24 weeks of gestation and persisted into the puerperium. We also found that the change in soluble Endoglin from 11-16 weeks of gestation to 27-32 weeks of gestation was significantly correlated with the change in structural capillary density. CONCLUSION: Significant structural capillary rarefaction precedes the onset of preeclampsia and could play a role in its pathogenesis. LEVEL OF EVIDENCE: II.

Capillary remodeling in infants born to hypertensive pregnancy: pilot study.

BACKGROUND: Capillary rarefaction is pathognomonic of essential hypertension. We have previously shown significant capillary rarefaction in normotensive adult offspring of hypertensive parents, suggesting a familial predisposition in which capillary rarefaction represents a primary vascular abnormality that antedates the onset of sustained elevation of blood pressure (BP). We have recently reported that low-birth weight (LBW) infants, born at term or preterm, to normotensive mothers do not have capillary rarefaction at birth. We hypothesized that infants born to mothers with hypertensive disorders of pregnancy (HDP) would have significant capillary rarefaction at birth when compared to infants of normotensive mothers. METHODS: We studied 22 infants born to hypertensive mothers and compared them to 40 normal birth weight infants born at term to normotensive mothers. We used orthogonal polarized spectroscopy to measure basal (i.e., functional) and maximal (i.e., structural) skin capillary densities according to a well-validated protocol. RESULTS: We found that term infants born to hypertensive mothers had significantly lower maximal capillary density (MCD) (mean difference of -5.0 capillaries/mm(2); P < 0.05). However, preterm infants with LBW born to hypertensive mothers tended to have higher basal and maximal skin capillary densities compared with term infants. CONCLUSIONS: While the results in term infants are consistent with our belief that capillary rarefaction in essential hypertension is likely to be a primary vascular abnormality, the results in preterm infants may suggest that the intrauterine environment may exert some influences on the remodeling of the microcirculation which may delay the onset of capillary rarefaction in these infants.

Mid-trimester blood pressure drop in normal pregnancy: myth or reality?

BACKGROUND: Current dogma states that there is a mid-trimester fall in blood pressure (BP) in uncomplicated pregnancy. In the early stages of a longitudinal study of microcirculatory changes in pregnancy, we noted an absence of this mid-trimester fall. METHOD: We prospectively studied this phenomenon in all our subsequent recruits. From a total of 326 women, 255 primigravid white women normotensive at booking and after delivery were studied. Serial BP measurements were taken under controlled conditions through to 38 weeks gestation. BP measurements by midwives were extracted from the case notes of 51 women within this cohort and analysed to validate the results. SBP progressively increased from the first trimester through to 38 weeks gestation. RESULTS: The increase from baseline at 13 weeks was significant when compared with measurements at 22 weeks [mean difference: 2.8 mmHg; 95% (confidence interval) CI 1.9-3.7], 28 weeks (mean difference: 5.0 mmHg; 95% CI 3.5-6.5) and 36 weeks (mean difference: 7.7 mmHg; 95% CI 6.2-9.1). DBP showed a nonsignificant dip at 22 weeks (mean difference: -0.12 mmHg; 95% CI -0.92 to 0.68), a nonsignificant increase at 28 weeks (mean difference: 2.0 mmHg; 95% CI 0.80-3.2) and a significant increase at 36 weeks (mean difference: 6.0; 95% CI 4.6-7.3). In the validation cohort, the SBP (P=0.0001) and DBP showed an increasing trend (P=0.0001). CONCLUSION: BP measured under controlled conditions showed a progressive rise in pregnancy, with no significant mid-trimester drop. The findings were replicated in the routine antenatal clinic measurements.

Low birth weight infants do not have capillary rarefaction at birth: implications for early life influence on microcirculation.

Low birth weight predicts adult essential hypertension and is linked to increased cardiovascular mortality in adult life. A reduction in capillary density (ie, rarefaction) is a hallmark of essential hypertension, and evidence suggests that rarefaction precedes the onset of the rise in blood pressure, because it is found in normotensive individuals at high risk of developing hypertension, suggesting that rarefaction is likely to be a primary structural abnormality. We hypothesized that low birth weight infants would have significant capillary rarefaction at birth. We studied 44 low birth weight infants born to normotensive mothers (33 were born preterm, birth weight: 1823±446 g; and 11 were born at term, birth weight: 2339±177 g) and compared them with 71 infants born at term with normal weight (birth weight: 3333±519 g). We used orthogonal polarized spectroscopy to measure basal (ie, functional) and maximal (ie, structural) skin capillary densities. Low birth weight infants, whether born preterm or at term, had significantly higher functional capillary density (mean difference of 10.5 capillaries per millimeter squared; 95% CI: 6.6-14.4 capillaries per millimeter squared; P<0.0001) and higher structural capillary density (mean difference of 11.1 capillaries per millimeter squared; 95% CI: 7.6-14.5 capillaries per millimeter squared; P<0.0001) when compared with normal weight term infants. We conclude that low birth weight infants born to normotensive mothers do not have capillary rarefaction at birth. These results contradict what might have been predicted from the concept of the intrauterine origins of adult disease and suggest that microcirculatory abnormalities observed in individuals of low birth weight occur in postnatal life rather than during their intrauterine existence.

Effect of modest salt reduction on skin capillary rarefaction in white, black, and Asian individuals with mild hypertension.

Microvascular rarefaction occurs in hypertension. We carried out a 12-week randomized double-blind crossover trial to determine the effect of a modest reduction in salt intake on capillary rarefaction in 71 whites, 69 blacks, and 29 Asians with untreated mildly raised blood pressure. Both basal and maximal (during venous congestion) skin capillary density were measured by capillaroscopy at the dorsum and the side of the fingers. In addition, we used orthogonal polarization spectral imaging to measure skin capillary density at the dorsum of the fingers and the hand web. With a reduction in salt intake from 9.7 to 6.5 g/day, there was an increase in capillary density (capillaries per millimeter squared) from 101+/-21 to 106+/-23 (basal) and 108+/-22 to 115+/-22 (maximal) at the dorsum, and 101+/-25 to 107+/-26 (basal) and 110+/-26 to 116+/-26 (maximal) at the side of the fingers (P<0.001 for all). Orthogonal polarization spectral imaging also showed a significant increase in capillary density both at the dorsum of the fingers and the web. Subgroup analysis showed that most of the changes were significant in all of the ethnic groups. Furthermore, there was a significant relationship between the change in 24-hour urinary sodium and the change in capillary density at the side of the fingers. These results demonstrate that a modest reduction in salt intake, as currently recommended, improves both functional and structural capillary rarefactions that occur in hypertension, and a larger reduction in salt intake would have a greater effect. The increase in capillary density may possibly carry additional beneficial effects on target organs.

How to detect early left atrial remodelling and dysfunction in mild-to-moderate hypertension.

BACKGROUND AND OBJECTIVES: Early changes in left atrial function in hypertension are difficult to assess quantitatively. Measuring atrial reversal flow into the pulmonary veins and regional left atrial deformation parameters assessed by Tissue Doppler-derived strain/rate (S/SR) imaging could provide quantitative assessment of left atrial deformation. We aimed to quantify changes in left atrial volume and deformation and pulmonary flow reversal (PVREVERS) in hypertension to detect subclinical left atrial dysfunction. DESIGN, SETTING AND PATIENTS: In 74 hypertensive and 34 age-matched normotensive patients (mean age 49 +/- 1.4 vs. 44.2 +/- 2.1 years) echo studies were performed, including measurements of LAV during reservoir, conduit and pump phases and standard indices reflecting left ventricular filling. S/SR was measured in the lateral left atrial wall. Total deformation (STOTAL) and the contribution to early (SE-index) and late (SA-index) filling were calculated. RESULTS: Hypertensive patients had significantly impaired diastolic function and increased left atrial volume during all phases. Only LAVCONDUIT significantly correlated with both ventricular hypertrophy and parameters of diastolic function. Velocity time integral of PVREVERS correlated with blood pressure and LAVCONDUIT. In hypertensive patients STOTAL was significantly higher (54.9 +/- 2.6 vs. 45.5 +/- 2.7%, P < 0.03) and SE-index was lower (P < 0.0001). This was compensated for by an increased SA-index (P < 0.0001) and SR during atrial contraction (-4.9 +/- 0.2 vs. -2.9 +/- 0.3 1/s, P < 0.0001). SA-index correlated significantly with blood pressure (R = 0.4; P < 0.0001) and PVREVERS (R = 0.3; P < 0.001). CONCLUSION: Changes in left atrial function due to hypertensive diastolic impairment are best reflected by LAVCONDUIT expansion. Hypertensive atrial dilatation is related to increase in PVREVERS. Left atrial S/SR offers a clinically valuable approach to detecting subclinical atrial dysfunction.