Ambulatory Blood Pressure and Number of Subclinical Target Organ Injury Markers in Youth: The SHIP AHOY Study.

Background: Hypertension in adolescence is associated with subclinical target organ injury (TOI). We aimed to determine whether different blood pressure (BP) thresholds were associated with increasing number of TOI markers in healthy adolescents. Methods: 244 participants (mean age 15.5±1.8 years, 60.1% male) were studied. Participants were divided based on both systolic clinic and ambulatory BP (ABP), into low- (<75 th percentile), mid- (75 th -90 th percentile) and high-risk (>90 th percentile) groups. TOI assessments included left ventricular mass, systolic and diastolic function, and vascular stiffness. The number of TOI markers for each participant was calculated. A multivariable general linear model was constructed to evaluate the association of different participant characteristics with higher numbers of TOI markers. Results: 47.5% of participants had at least one TOI marker: 31.2% had one, 11.9% two, 3.7% three, and 0.8% four. The number of TOI markers increased according to the BP risk groups: the percentage of participants with more than one TOI in the low-, mid-, and high groups based on clinic BP was 6.7%, 19.1%, and 21.8% (p=0.02), and based on ABP was 9.6%, 15.8%, and 32.2% (p<0.001). In a multivariable regression analysis, both clinic BP percentile and ambulatory SBP index were independently associated with the number of TOI markers. When both clinic and ABP were included in the model, only the ambulatory SBP index was significantly associated with the number of markers. Conclusion: High SBP, especially when assessed by ABPM, was associated with an increasing number of subclinical cardiovascular injury markers in adolescents.

Pediatric Primary Hypertension: An Underrecognized Condition: A Scientific Statement From the American Heart Association.

The overall prevalence of hypertension in childhood is 2% to 5%, and the leading type of childhood hypertension is primary hypertension, especially in adolescence. As in adults, the leading risk factors for children with primary hypertension are excess adiposity and suboptimal lifestyles; however, environmental stress, low birth weight, and genetic factors may also be important. Hypertensive children are highly likely to become hypertensive adults and to have measurable target organ injury, particularly left ventricular hypertrophy and vascular stiffening. Ambulatory and home blood pressure monitoring may facilitate diagnosis. Primordial prevention of hypertension through public health implementation of healthier diet and increased physical activity will reduce the prevalence of primary hypertension, and evidence-based treatment guidelines should be implemented when hypertension is diagnosed. Further research to optimize recognition and diagnosis and clinical trials to better define outcomes of treatment are needed.

The enigma of primary hypertension in childhood.

Beginning in the 1970s, hypertension in children and adolescents has been defined as systolic and/or diastolic blood pressure (BP) that is equal to or greater than the 95th percentile of the normal BP distribution in healthy children. The definition of hypertension in adults is based on longitudinal data that links a BP level with an increased risk for subsequent adverse outcomes related to hypertension including heart failure, kidney failure, stroke, or death. The statistical definition of hypertension continues to be used in childhood because there have been no data that link a BP level in childhood with a heightened risk for adverse outcomes in adulthood. Findings from clinical and epidemiologic research have advanced understanding of high BP in childhood. While hypertension in some children can be secondary to underlying kidney, cardiovascular, or endocrine disorder, it is now known that primary (essential) hypertension can be present in childhood. The prevalence of hypertension in childhood is approximately 2-5% and another 13-18% of children and adolescents have elevated BP and are at heightened risk for developing hypertension. The leading cause of childhood hypertension is primary hypertension, especially in adolescents. For children and adolescents with secondary hypertension, the treatment can focus on managing the underlying cause of hypertension. Less is known about managing primary hypertension in childhood, including diagnosis, evaluation, treatment, and possibilities for prevention. The phenotype of primary hypertension in childhood and recent findings will be discussed.

Association of Blood Pressure-Related Increase in Vascular Stiffness on Other Measures of Target Organ Damage in Youth.

BACKGROUND: Hypertension-related increased arterial stiffness predicts development of target organ damage (TOD) and cardiovascular disease. We hypothesized that blood pressure (BP)-related increased arterial stiffness is present in youth with elevated BP and is associated with TOD. METHODS: Participants were stratified by systolic BP into low- (systolic BP <75th percentile, n=155), mid- (systolic BP ≥80th and <90th percentile, n=88), and high-risk BP categories (≥90th percentile, n=139), based on age-, sex- and height-specific pediatric BP cut points. Clinic BP, 24-hour ambulatory BP monitoring, anthropometrics, and laboratory data were obtained. Arterial stiffness measures included carotid-femoral pulse wave velocity and aortic stiffness. Left ventricular mass index, left ventricular systolic and diastolic function, and urine albumin/creatinine were collected. ANOVA with Bonferroni correction was used to evaluate differences in cardiovascular risk factors, pulse wave velocity, and cardiac function across groups. General linear models were used to examine factors associated with arterial stiffness and to determine whether arterial stiffness is associated with TOD after accounting for BP. RESULTS: Pulse wave velocity increased across groups. Aortic distensibility, distensibility coefficient, and compliance were greater in low than in the mid or high group. Significant determinants of arterial stiffness were sex, age, adiposity, BP, and LDL (low-density lipoprotein) cholesterol. Pulse wave velocity and aortic compliance were significantly associated with TOD (systolic and diastolic cardiac function and urine albumin/creatinine ratio) after controlling for BP. CONCLUSIONS: Higher arterial stiffness is associated with elevated BP and TOD in youth emphasizing the need for primary prevention of cardiovascular disease.

Cardiovascular Risk Factors and Target Organ Damage in Adolescents: The SHIP AHOY Study.

BACKGROUND: Development of cardiovascular disease in adults has been directly linked to an adverse metabolic phenotype. While there is evidence that development of these risk factors in childhood persists into adulthood and the development of cardiovascular disease, less is known about whether these risk factors are associated with target organ damage during adolescence. METHODS: We collected data from 379 adolescents (mean age 15.5, 60% male) with blood pressure between the 75th and 95th percentile to determine if there is a metabolic phenotype that predicts cardiovascular changes (left ventricular mass, systolic and diastolic function, pulse wave velocity, and renal function). We determined the number of risk factors for cardiovascular disease (hypertension, dyslipidemia, obesity, and insulin resistance) present in each participant. Generalized linear models were constructed to determine if the number of cardiovascular risk factors (CVRFs) were associated with measures of target organ damage. RESULTS: The number of CVRFs present were associated with statistically significant differences in increased left ventricular mass index, increased pulse wave velocity, decreased peak longitudinal strain, urine albumin to creatine ratio and echocardiographic parameters of diastolic dysfunction. Generalized linear models showed that dyslipidemia and insulin resistance were independently associated with markers of diastolic dysfunction (P ≤ .05) while increased blood pressure was associated with all makers of target organ damage (P ≤ .03). CONCLUSIONS: These data suggest the of the number of CVRFs present is independently associated with early changes in markers of target organ damage during adolescence.

Approach to Hypertension in Adolescents and Young Adults.

PURPOSE OF REVIEW: The prevalence of hypertension in adolescents and young adults has increased in part due to the obesity epidemic. The clinical impact and future cardiovascular risk of this underestimated public health problem is an evolving field. RECENT FINDINGS: The development of hypertension is predicted by tracking of elevated blood pressure from childhood to adulthood. Young hypertensive individuals have lower awareness, slower diagnosis rates, and poorer blood pressure control than older patients. Increased awareness, appropriate screening, early identification, and individualized treatment approaches for elevated blood pressure could prevent development of hypertension in adulthood and cardiovascular events in later life. The optimal blood pressure management for young adults with a low 10-year risk of atherosclerotic cardiovascular disease of < 10% remains challenging due to lack of randomized controlled trials. Evidence-based recommendations are needed to implement appropriate measures for time of treatment initiation, preferred antihypertensive drug class to be used and optimal target blood pressure level from childhood through young adulthood.

Pediatric and Adult Ambulatory Blood Pressure Thresholds and Blood Pressure Load as Predictors of Left Ventricular Hypertrophy in Adolescents.

[Figure: see text].

Management of Stage 1 Hypertension in Adults With a Low 10-Year Risk for Cardiovascular Disease: Filling a Guidance Gap: A Scientific Statement From the American Heart Association.

High blood pressure (BP) is the leading cause of worldwide cardiovascular disease morbidity and mortality. Patients and clinicians dealing with hypertension have benefited from the evidence of event-based randomized controlled clinical trials. One result from those trials has been the development of evidence-based guidelines. The commitment to using evidence from these event-based randomized trials has been a cornerstone in the development of guideline treatment recommendations. However, in some situations, evidence from event-based trials is not available to guideline writers or clinicians for assistance in treatment decision making. Such is the case for the management of many patients with stage 1 hypertension. The purpose of this scientific statement is to provide information complementary to the 2017 Hypertension Clinical Practice Guidelines for the patient with untreated stage 1 hypertension (systolic BP/diastolic BP, 130-139/80-89 mm Hg) with a 10-year risk for atherosclerotic cardiovascular disease <10% who fails to meet the systolic BP/diastolic goal (<130/80 mm Hg) after 6 months of guideline-recommended lifestyle therapy. This statement provides evidence from sources other than event-based randomized controlled clinical trials and offers therapy options for consideration by clinicians.

Macrophage and adipocyte interaction as a source of inflammation in kidney disease.

In obesity, adipose tissue derived inflammation is associated with unfavorable metabolic consequences. Uremic inflammation is prevalent and contributes to detrimental outcomes. However, the contribution of adipose tissue inflammation in uremia has not been characterized. We studied the contribution of adipose tissue to uremic inflammation in-vitro, in-vivo and in human samples. Exposure to uremic serum resulted in activation of inflammatory pathways including NFκB and HIF1, upregulation of inflammatory cytokines/chemokines and catabolism with lipolysis, and lactate production. Also, co-culture of adipocytes with macrophages primed by uremic serum resulted in higher inflammatory cytokine expression than adipocytes exposed only to uremic serum. Adipose tissue of end stage renal disease subjects revealed increased macrophage infiltration compared to controls after BMI stratification. Similarly, mice with kidney disease recapitulated the inflammatory state observed in uremic patients and additionally demonstrated increased peripheral monocytes and inflammatory polarization of adipose tissue macrophages (ATMS). In contrast, adipose tissue in uremic IL-6 knock out mice showed reduced ATMS density compared to uremic wild-type controls. Differences in ATMS density highlight the necessary role of IL-6 in macrophage infiltration in uremia. Uremia promotes changes in adipocytes and macrophages enhancing production of inflammatory cytokines. We demonstrate an interaction between uremic activated macrophages and adipose tissue that augments inflammation in uremia.

Life-Course Implications of Pediatric Risk Factors for Cardiovascular Disease.

The concept that origins of cardiovascular disease (CVD) begin in childhood is supported by substantial evidence. Prospective studies beginning in childhood report associations of childhood obesity, abnormal blood pressure (BP), dyslipidemia, diabetes, and tobacco use with intermediate CVD markers, including left ventricular hypertrophy and vascular stiffness in young adulthood. Trajectory analyses from longitudinal studies describe discrete BP pathways from childhood to young adult status of hypertension and prehypertension. Among individuals with familial hypercholesterolemia, abnormal low-density lipoprotein cholesterol levels are present in childhood. Some children are at risk for future CVD owing to hereditary factors, psychosocial stress, race, low birth weight, or other nonmodifiable exposures. Behavioural factors, including suboptimal diet, sedentary activity, and tobacco use, in childhood augment risk and can be modified to reduce risk. Pharmacologic treatments are reserved for those at high levels of the BP and cholesterol distributions and for those with diabetes and additional risk factors.

Subclinical Systolic and Diastolic Dysfunction Is Evident in Youth With Elevated Blood Pressure.

Hypertension is associated with cardiovascular events in adults. Subclinical changes to left ventricular strain and diastolic function have been found before development of decreased left ventricular ejection fraction and cardiovascular events. Our objective was to study effects of blood pressure (BP) on ventricular function in youth across the BP spectrum. Vital signs and labs were obtained in 346 participants aged 11 to 19 years who had BP categorized as low-risk (N=144; systolic BP <75th percentile), mid-risk (N=83; systolic BP ≥80th and <90th percentile), and high-risk (N=119; systolic BP ≥90th percentile). Echocardiography was performed to assess left ventricular strain and diastolic function. Differences between groups were analyzed by ANOVA. General linear models were constructed to determine independent predictors of systolic and diastolic function. Mid-risk and high-risk participants had greater adiposity and more adverse metabolic labs (lower HDL [high-density lipoprotein], higher glucose, and higher insulin) than the low-risk group. Mid-risk and high-risk participants had significantly lower left ventricular ejection fraction and peak global longitudinal strain than the low-risk group (both P≤0.05). The E/e' ratio was higher in the high-risk group versus the low-risk and mid-risk groups, and the e'/a' ratio was lower in the high-risk versus the low-risk group (both P≤0.05). BP and adiposity were statistically significant determinants of left ventricular systolic and diastolic function. Subclinical changes in left ventricular systolic and diastolic function can be detected even at BP levels below the hypertensive range as currently defined.

Primordial Prevention of High Blood Pressure in Childhood: An Opportunity Not to be Missed.

Hypertension is a condition with increased risk for subsequent adverse events, and treatment of hypertension is prescribed for primary prevention of adverse events. Primordial prevention is a concept that precedes primary prevention and focuses on risk factor prevention. Primordial prevention of hypertension consists of strategies to maintain blood pressure in a normal range and prevent development of elevated blood pressure or hypertension. Childhood is a period in which primordial prevention could be effective and if sustained throughout childhood could contribute to a healthier young adulthood. Targets for primordial prevention in childhood include preventing and reducing childhood obesity, achieving an optimal diet that includes avoiding excessive salt consumption, and removing barriers to physical activity and healthy sleep throughout childhood. Primordial prevention also includes the prenatal period wherein some maternal conditions and exposures are associated with higher blood pressure in child offspring.

Maternal and gestational influences on childhood blood pressure.

Exposures that contribute to a sub-optimal intrauterine environment can have an effect on the developing fetus. Impaired fetal growth that results in low birth weight is an established risk factor for cardio-metabolic disorders later in life. Recent epidemiologic and prospective cohort studies that include the maternal and gestational period have identified maternal and gestational conditions that confer increased risk for subsequent cardio-metabolic disorders in the absence of low birth weight. Maternal pre-conception health status, including chronic obesity and type 2 diabetes, increase risk for childhood obesity and obesity-related higher blood pressure (BP) in child offspring. Maternal gestational exposures, including gestational diabetes, gestational hypertension, and preeclampsia, are associated with higher BP in offspring. Other maternal exposures such as cigarette smoke and air pollution also increase risk for higher BP in child offspring. Recent, but limited, data indicate that assisted reproductive technologies can be associated with hypertension in childhood, despite otherwise normal gestation and healthy newborn. Gestational exposures associated with higher BP in childhood can be related to familial lifestyle factors, genetics, or epigenetic modification of fetal deoxyribonucleic acid (DNA). These factors, or combination of factors, as well as other adverse intrauterine conditions, could induce fetal programing leading to health consequences in later life. Current and developing research will provide additional insights on gestational exposures and fetal adjustments that increase risk for higher BP levels in childhood.

Association of Blood Pressure Level With Left Ventricular Mass in Adolescents.

Hypertension is associated with left ventricular hypertrophy (LVH), a risk factor for cardiovascular events. Since cardiovascular events in youth are rare, hypertension has historically been defined by the 95th percentile of the normal blood pressure (BP) distribution in healthy children. The optimal BP percentile associated with LVH in youth is unknown. We aimed to determine the association of systolic BP (SBP) percentile, independent of obesity, on left ventricular mass index (LVMI), and to estimate which SBP percentile best predicts LVH in youth. We evaluated SBP, anthropometrics, and echocardiogram in 303 adolescents (mean age 15.6 years, 63% white, 55% male) classified by SBP as low-risk (L=141, <80th percentile), mid-risk (M=71, 80-<90th percentile), or high-risk (H=91, ≥90th percentile) using the mean of 6 measurements at 2 visits according to the 2017 guidelines. Logistic regression was used to determine the sensitivity and specificity of various SBP percentiles associated with LVH. Results: BP groups did not differ by age or demographics but differed slightly by body mass index. Mean BP, LVMI, and prevalence of LVH increased across groups (BP: L=111/75, M=125/82, and H=133/92 mm Hg; LVMI: L=31.2, M=34.2, and H=34.9 g/m2.7; LVH: L=13%, M=21%, H=27%, all P<0.03). SBP percentile remained a significant determinant of LVMI after adjusting for covariates. The 90th percentile for SBP resulted in the best balance between sensitivity and specificity for predicting LVH (LVMI≥38.6 g/m2.7). Abnormalities in cardiac structure in youth can be found at BP levels below those used to define hypertension.