An Update on Refractory Hypertension.

PURPOSE OF REVIEW: To update on definition, diagnosis, prevalence, patient characteristics, pathophysiology, and treatment of refractory hypertension (RfHTN). RECENT FINDINGS: Refractory hypertension (RfHTN) is defined as blood pressure (BP) that is uncontrolled despite using ≥ 5 antihypertensive medications of different classes, including a long-acting thiazide diuretic and a mineralocorticoid receptor antagonist (MRA) at maximal or maximally tolerated doses. This new phenotype is different from resistant hypertension (RHTN), defined as BP that is uncontrolled despite using ≥ 3 medications, commonly a long-acting calcium channel blocker (CCB), a blocker of the renin-angiotensin system (angiotensin-converting enzyme [ACE] inhibitor or angiotensin receptor blocker [ARB]), and a diuretic. The RHTN phenotype includes controlled RHTN, BP that is controlled on 4 or more medications. RfHTN is largely attributable to increased sympathetic activity, unlike RHTN, which is mainly due to increased intravascular fluid volume frequently caused by hyperaldosteronism and chronic excessive sodium ingestion. Compared to those with controlled RHTN, patients with RfHTN have a higher prevalence of target organ damage and do not have elevated aldosterone levels. Ongoing clinical trials are assessing the safety and efficacy of using devices to aid with BP control in patients with RfHTN. RfHTN is a separate entity from RHTN and is generally attributable to increased sympathetic activity.

Treatment of Resistant and Refractory Hypertension.

Resistant hypertension (RHTN) is defined as uncontrolled blood pressure despite the use of ≥3 antihypertensive agents of different classes, including a diuretic, usually thiazide-like, a long-acting calcium channel blocker, and a blocker of the renin- angiotensin system, either an ACE (angiotensin-converting enzyme) inhibitor or an ARB (angiotensin receptor blocker), at maximal or maximally tolerated doses. Antihypertensive medication nonadherence and the white coat effect, defined as elevated blood pressure when measured in clinic but controlled when measured outside of clinic, must be excluded to make the diagnosis. RHTN is a high-risk phenotype, leading to increased all-cause mortality and cardiovascular disease outcomes. Healthy lifestyle habits are associated with reduced cardiovascular risk in patients with RHTN. Aldosterone excess is common in patients with RHTN, and addition of spironolactone or amiloride to the standard 3-drug antihypertensive regimen is effective at getting the blood pressure to goal in most of these patients. Refractory hypertension is defined as uncontrolled blood pressure despite use of ≥5 antihypertensive agents of different classes, including a long-acting thiazide-like diuretic and an MR (mineralocorticoid receptor) antagonist, at maximal or maximally tolerated doses. Fluid retention, mediated largely by aldosterone excess, is the predominant mechanism underlying RHTN, while patients with refractory hypertension typically exhibit increased sympathetic nervous system activity.

The Unrecognized Prevalence of Primary Aldosteronism: A Cross-sectional Study.

BACKGROUND: Primary aldosteronism is a nonsuppressible renin-independent aldosterone production that causes hypertension and cardiovascular disease. OBJECTIVE: To characterize the prevalence of nonsuppressible renin-independent aldosterone production, as well as biochemically overt primary aldosteronism, in relation to blood pressure. DESIGN: Cross-sectional study. SETTING: 4 U.S. academic medical centers. PARTICIPANTS: Participants with normotension (n = 289), stage 1 hypertension (n = 115), stage 2 hypertension (n = 203), and resistant hypertension (n = 408). MEASUREMENTS: Participants completed an oral sodium suppression test, regardless of aldosterone or renin levels, as a confirmatory diagnostic for primary aldosteronism and to quantify the magnitude of renin-independent aldosterone production. Urinary aldosterone was measured in participants in high sodium balance with suppressed renin activity. Biochemically overt primary aldosteronism was diagnosed when urinary aldosterone levels were higher than 12 µg/24 h. RESULTS: Every blood pressure category had a continuum of renin-independent aldosterone production, where greater severity of production was associated with higher blood pressure, kaliuresis, and lower serum potassium levels. Mean adjusted levels of urinary aldosterone were 6.5 µg/24 h (95% CI, 5.2 to 7.7 µg/24 h) in normotension, 7.3 µg/24 h (CI, 5.6 to 8.9 µg/24 h) in stage 1 hypertension, 9.5 µg/24 h (CI, 8.2 to 10.8 µg/24 h) in stage 2 hypertension, and 14.6 µg/24 h (CI, 12.9 to 16.2 µg/24 h) in resistant hypertension; corresponding adjusted prevalence estimates for biochemically overt primary aldosteronism were 11.3% (CI, 5.9% to 16.8%), 15.7% (CI, 8.6% to 22.9%), 21.6% (CI, 16.1% to 27.0%), and 22.0% (CI, 17.2% to 26.8%). The aldosterone-renin ratio had poor sensitivity and negative predictive value for detecting biochemically overt primary aldosteronism. LIMITATION: Prevalence estimates rely on arbitrary and conventional thresholds, and the study population may not represent nationwide demographics. CONCLUSION: The prevalence of primary aldosteronism is high and largely unrecognized. Beyond this categorical definition of primary aldosteronism, there is a prevalent continuum of renin-independent aldosterone production that parallels the severity of hypertension. These findings redefine the primary aldosteronism syndrome and implicate it in the pathogenesis of "essential" hypertension. PRIMARY FUNDING SOURCE: National Institutes of Health.

Association Between Sleep Apnea and Blood Pressure Control Among Blacks.

BACKGROUND: Blacks have a high prevalence of hypertension and uncontrolled blood pressure (BP), each of which may be partially explained by untreated sleep apnea. We investigated the association of sleep apnea with uncontrolled BP and resistant hypertension in blacks. METHODS: Between 2012 and 2016, Jackson Heart Sleep Study participants (N=913) underwent an in-home Type 3 sleep apnea study, clinic BP measurements, and anthropometry. Moderate or severe obstructive sleep apnea (OSA) was defined as a respiratory event index ≥15, and nocturnal hypoxemia was quantified as percent sleep time with <90% oxyhemoglobin saturation. Prevalent hypertension was defined as either a systolic BP ≥130 mm Hg or diastolic BP >80mm Hg, use of antihypertensive medication, or self-report of a diagnosis of hypertension. Controlled BP was defined as systolic BP <130 mm Hg and diastolic BP <80 mm Hg; uncontrolled BP as systolic BP ≥130 mm Hg or diastolic BP ≥80 mm Hg with use of 1 to 2 classes of antihypertensive medication; and resistant BP as systolic BP ≥130 mm Hg or diastolic BP ≥80 mm Hg with the use of ≥3 classes of antihypertensive medication (including a diuretic) or use of ≥4 classes of antihypertensive medication regardless of BP level. Multinomial logistic regression models were fit to determine the association between OSA severity and uncontrolled BP or resistant hypertension (versus controlled BP) after multivariable adjustment. RESULTS: The analytic sample with hypertension (N=664) had a mean age of 64.0 (SD,10.6) years, and were predominately female (69.1%), obese (58.6%), and college educated (51.3%). Among the sample, 25.7% had OSA, which was untreated in 94% of participants. Overall, 48% of participants had uncontrolled hypertension and 14% had resistant hypertension. After adjustment for confounders, participants with moderate or severe OSA had a 2.0 times higher odds of resistant hypertension (95% confidence interval [CI], 1.14-3.67). Each standard deviation higher than <90% oxyhemoglobin saturation was associated with an adjusted odds ratio for resistant hypertension of 1.25 (95% CI 1.01-1.55). OSA and <90% oxyhemoglobin saturation were not associated with uncontrolled BP. CONCLUSION: Untreated moderate or severe OSA is associated with increased odds of resistant hypertension. These results suggest that untreated OSA may contribute to inadequate BP control in blacks.

Prediction of improved therapeutics for fabry disease patients generated by mutagenesis of the α-galactosidase A active site, dimer interface, and glycosylation region.

Fabry disease is an X-linked lysosomal storage disorder caused by the deficiency of the enzyme, α-galactosidase A that induces the accumulation of the substrate globotriaosylceramide. Currently approved enzyme replacement therapy using recombinant human α-galactosidase A improves patient symptoms but a majority of patients experience adverse events due to the multiple infusions required for full therapeutic efficacy. Our approach is to use medicinal chemistry and phylogenic comparisons to introduce mutations into the human enzyme to increase catalytic activity and/or stability to generate an improved therapeutic enzyme that may require fewer infusions. We designed mutations at three regions of the human α-galactosidase A: the active site, the dimer interface, and a site for glycosylation. The M208E mutation, adjacent to the Y207 active site residue, increased enzyme activity 3.01-fold. This mutation introduced a charged Glu residue that is adjacent to the Y207 active site residue and close to a site of N-glycosylation. The W277C mutation, designed to promote dimer stability, introduced a strong thiol-aromatic interaction (Cys-Phe) at the dimer interface and increased activity 2.31-fold. The W277C and M208E mutations modify the structure of the enzyme into forms with enhanced thermal stability 3.7- and 3.9-fold, respectively and positive cooperativity resulting in increased Hill coefficient from 1.0 to 4.60 and 3.47, respectively. Enhanced thermal stability and positive cooperativity predict improved in vivo activity and superior therapeutic properties. Our results demonstrate the value of in vitro mutagenesis for α-galactosidase A and support future perspectives to validate these results in Fabry disease patients.

[Lancet Commission on Hypertension Group position statement on the global improvement of accuracy standards for devices that measure blood pressurePosicionamento do Grupo da Lancet Commission on Hypertension sobre a melhoria global dos padrões de acurácia para aparelhos que medem a pressão arterial]. / Declaración de posición del Grupo de la Comisión Lancet de Hipertensión con respecto a la mejora mundial de las normas de exactitud para los dispositivos de medición de la presión arterial.

The Lancet Commission on Hypertension identified that a key action to address the worldwide burden of high blood pressure (BP) was to improve the quality of BP measurements by using BP devices that have been validated for accuracy. Currently, there are over 3 000 commercially available BP devices, but many do not have published data on accuracy testing according to established scientific standards. This problem is enabled through weak or absent regulations that allow clearance of devices for commercial use without formal validation. In addition, new BP technologies have emerged (e.g. cuffless sensors) for which there is no scientific consensus regarding BP measurement accuracy standards. Altogether, these issues contribute to the widespread availability of clinic and home BP devices with limited or uncertain accuracy, leading to inappropriate hypertension diagnosis, management and drug treatment on a global scale. The most significant problems relating to the accuracy of BP devices can be resolved by the regulatory requirement for mandatory independent validation of BP devices according to the universally-accepted International Organization for Standardization Standard. This is a primary recommendation for which there is an urgent international need. Other key recommendations are development of validation standards specifically for new BP technologies and online lists of accurate devices that are accessible to consumers and health professionals. Recommendations are aligned with WHO policies on medical devices and universal healthcare. Adherence to recommendations would increase the global availability of accurate BP devices and result in better diagnosis and treatment of hypertension, thus decreasing the worldwide burden from high BP.

A Comissão Lancet sobre Hipertensão Arterial identificou que uma iniciativa central para enfrentar a carga mundial da hipertensão arterial seria a melhoria na qualidade da mensuração da pressão arterial pelo uso aparelhos de pressão arterial validados quanto à acurácia. Atualmente, existem mais de 3 000 aparelhos de pressão arterial disponíveis comercialmente; entretanto, muitos não têm dados publicados sobre testes de acurácia realizados de acordo com padrões científicos estabelecidos. Este problema resulta de regulamentação fraca ou inexistente, o que permite a aprovação para uso comercial de dispositivos sem validação formal. Além disso, surgiram novas tecnologias de mensuração da pressão arterial (por exemplo, sensores sem algemas) sem consenso científico quanto aos padrões de acurácia. No conjunto, essas questões contribuem para a oferta generalizada de dispositivos de pressão arterial clínica e domiciliar com acurácia limitada ou incerta, levando a diagnóstico, gerenciamento e tratamento inadequados da hipertensão em escala global. Os problemas mais significativos relacionados com a acurácia dos dispositivos de pressão arterial podem ser resolvidos por regulamentação que imponha a obrigatoriedade de validação independente dos aparelhos de pressão arterial, de acordo com a norma universalmente aceita pela Organização Internacional de Normalização. Esta é uma recomendação fundamental para a qual existe uma necessidade internacional urgente. Outras recomendações essenciais incluem o desenvolvimento de padrões de validação especificamente para novas tecnologias de mensuração da pressão arterial e listas on-line de aparelhos com acurácia adequada que sejam acessíveis aos consumidores e profissionais de saúde. As recomendações estão alinhadas com as políticas da Organização Mundial da Saúde (OMS) sobre dispositivos médicos e atenção universal à saúde. A adesão às recomendações aumentaria a oferta global de dispositivos de pressão arterial com acurácia adequada e resultaria em melhor diagnóstico e tratamento da hipertensão arterial, diminuindo assim a carga mundial dessa doença.

Resistant Hypertension Management: Comparison of the 2017 American and 2018 European High Blood Pressure Guidelines.

PURPOSE OF REVIEW: To compare European and American guidelines for the diagnosis, evaluation, and management of resistant hypertension. RECENT FINDINGS: Resistant hypertension is defined as high blood pressure that remains above goal with the use of 3 or more antihypertensive agents, commonly a renin-angiotensin blocker (either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker), a long-acting calcium channel blocker, and thiazide or thiazide-like diuretic. Resistant hypertension is common, with a recent analysis indicating that it affects approximately 17-19% of adult Americans with hypertension. Pseudocauses of apparent resistant hypertension, including inaccurate blood pressure measurement, white coat effect, undertreatment, and poor medication adherence, must be excluded in order to confirm true resistant hypertension. Evaluation of resistant hypertension requires identifying and treating secondary causes of hypertension, including obstructive sleep apnea, primary aldosteronism, and renal artery stenosis. Treatment of resistant hypertension includes a combined use of lifestyle modification and prescription of effective multiple-drug combinations. Preferential use of a long-acting thiazide-like diuretic, either chlorthalidone or indapamide, and a mineralocorticoid receptor blocker, most commonly spironolactone, is recommended if needed to achieve blood pressure control. Aside for small exceptions, European and American guidelines agree in terms of recommendations for diagnosing, evaluating, and treating resistant hypertension.

Role of Mineralocorticoid Receptors in Obstructive Sleep Apnea and Metabolic Syndrome.

PURPOSE OF REVIEW: This review will summarize recent developments in the research on the mineralocorticoid receptor and its impact on obstructive sleep apnea and metabolic syndrome. RECENT FINDINGS: Aldosterone excess plays an important role in the association between resistant hypertension and obstructive sleep apnea. The prevalence of obesity is increasing rapidly worldwide and is especially common among patients with obstructive sleep apnea, resistant hypertension, and metabolic syndrome, suggesting probable mechanistic links between these three conditions. Mineralocorticoid receptor expression is increased in obese individuals, which may contribute to the common association between obesity and hyperaldosteronism. Mineralocorticoid receptor blockers reduce the severity of obstructive sleep apnea among resistant hypertension patients. A large body of literature demonstrates a strong association between obesity, hyperaldosteronism, resistant hypertension, and sleep apnea, including specific benefit of treatment with mineralocorticoid receptor blockers for these separate disorders.

National patterns in intensity and frequency of outpatient care for apparent treatment-resistant hypertension.

BACKGROUND: Apparent treatment-resistant hypertension (aTRH) is associated with an increased risk of adverse cardiovascular outcomes. We studied the frequency and intensity of care for aTRH among participants aged 65 years and older in the US-based REGARDS study linked with Medicare claims. METHODS: Blood pressure (BP) was measured twice and averaged. aTRH was defined by the use of ≥3 classes of antihypertensive medication and uncontrolled BP (UaTRH, systolic/diastolic BP ≥140/90 mmHg), or ≥4 classes with controlled BP (CaTRH). Participants were categorized as not having aTRH (no aTRH), CaTRH or UaTRH. RESULTS: Among 4650 participants with hypertension, 468 (10.1%) had UaTRH, 247 (5.3%) had CaTRH, and 3935 (84.6%) had hypertension but did not have aTRH. For hypertension-related visits, those with UaTRH saw primary care physicians and cardiologists more frequently than those without aTRH (mean primary care visits per year: 2.77 vs 2.27, P<.001; cardiologists: 0.50 vs 0.35, P=.014). Among those with UaTRH, CaTRH, and no aTRH, respectively 73.5%, 68.0%, and 67.5% had >1 hypertension-related visit per year. Among those with UaTRH, males vs females (prevalence ratio=0.78; 95% CI 0.69-0.89), whites vs blacks (0.88; 95% CI 0.78-0.99), and current smokers vs non-smokers (0.66; 95% CI 0.48-0.89) were less likely to receive >1 hypertension-related visit per year. Diagnostic intensity, measured by testing for end organ damage and secondary hypertension, was similar between groups. CONCLUSIONS: Many people with UaTRH are not seen more than once per year for hypertension and may benefit from increased care.

Refractory versus resistant hypertension.

PURPOSE OF REVIEW: Refractory hypertension is a recently proposed phenotype of antihypertensive treatment failure. As such it represents an extreme subtype of resistant or difficult-to-treat hypertension. Resistant hypertension is relatively common with an estimated prevalence of 10-20% of treated hypertensive patients. It is typically defined as having an uncontrolled blood pressure on three or more antihypertensive medications, including a diuretic. Refractory hypertension is rare with a prevalence of approximately 5% of patients with uncontrolled resistant hypertension. It is defined as an uncontrolled blood pressure with the use of five or more antihypertensive medications, including a long-acting thiazide diuretic, such as chlorthalidone, and a mineralocorticoid receptor antagonist such as spironolactone. RECENT FINDINGS: Persistent excess fluid retention is thought to commonly underlie development of resistant hypertension, recent studies suggest that refractory may be more likely attributable to heightened sympathetic output as opposed to inappropriate fluid retention. SUMMARY: Treatment recommendations for resistant hypertension are generally based on intensification of diuretic therapy, especially with combined use of chlorthalidone and spironolactone. Although fuller elucidation is needed, such an approach may not be appropriate for refractory hypertension, which instead, may require effective sympathetic inhibition, either with medications or device-based approaches.

Drug Development for Hypertension: Do We Need Another Antihypertensive Agent for Resistant Hypertension?

The prevalence of resistant hypertension is seemingly much lower than had been reported in early studies. Recent analyses suggest that <5 % of treated hypertensive patients remain uncontrolled if fully adherent to an optimized antihypertensive treatment. However, these patients do have increased cardiovascular risk and need effective therapeutic approaches. Drug development is a high-risk, complex, lengthy, and very expensive process. In this article, we discuss the factors that should be considered in the process of developing a new agent for treatment of resistant hypertension.

Comparisons of sleep apnoea rate and outcomes among patients with resistant and non-resistant hypertension.

BACKGROUND AND OBJECTIVE: We directly compared sleep apnoea (SA) rates and risk of cardiovascular and mortality outcomes among SA patients with resistant hypertension (RH) and non-RH within a large diverse hypertension population. METHODS: A retrospective cohort study between 1 January 2006 and 31 December 2010 among hypertensive adults (age ≥ 18 years) was performed within an integrated health system. Rates of SA in RH and non-RH were determined. Multivariable logistic regression analyses were used to calculate OR for SA. Cox proportional hazard modelling was used to estimate hazard ratios (HRs) for cardiovascular and mortality outcomes between SA in RH versus SA in non-RH adjusting for age, gender, race, BMI, chronic kidney disease and other comorbidities. RESULTS: SA was identified in 33 682 (7.2%) from 470 386 hypertensive individuals. SA in RH accounted for 5806 (9.6%) compared to SA in non-RH 27 876 individuals (6.8%). Multivariable OR (95% CI) for SA was 1.16 (1.12, 1.19), 3.57 (3.47, 3.66) and 2.20 (2.15, 2.25) for RH versus non-RH, BMI ≥ 30, and males, respectively. Compared to SA in non-RH individuals, SA in RH had a multivariable adjusted HR (95% CI) of 1.24 (1.13, 1.36), 1.43 (1.28, 1.61), 0.98 (0.85, 1.12) and 1.04 (0.95, 1.14) for ischaemic heart event (IHE), congestive heart failure (CHF), stroke and mortality, respectively. CONCLUSION: We observed a modest increase in likelihood for SA among RH compared to non-RH patients. Risks for IHE and CHF were higher for SA in RH compared to SA in non-RH patients; however, there were no differences in risk for stroke and mortality.

BP Targets in Hypertension: What Should We Do Now That SPRINT Is Out?

Systolic blood pressure (SBP) is an important predictor of cardiovascular disease (CVD) outcomes. Lowering SBP has been shown to reduce CVD morbidity and mortality, but the optimal SBP target continues to be a topic of intense debate. The Systolic Blood Pressure Intervention Trial (SPRINT) reported a significantly lower risk for CVD outcomes and all-cause mortality by targeting SBP <120 mmHg compared with <140 mmHg in a population of hypertensive persons at high CV risk. In this review, we discuss the strengths, limitations, and generalizability of SPRINT findings to other hypertensive populations that were excluded from the trial, including those with diabetes or prior stroke, <50 years old, and at lower CVD risk. We will focus on the implications of SPRINT findings for appropriate BP targets in high-risk groups of hypertensive persons, including the elderly and those with chronic kidney disease (CKD). We will also address the cost-effectiveness of intensive BP treatment as implemented in SPRINT and the implications of SPRINT for health care policy and future BP guidelines.

Comparative risk of renal, cardiovascular, and mortality outcomes in controlled, uncontrolled resistant, and nonresistant hypertension.

We sought to compare the risk of end-stage renal disease (ESRD), ischemic heart event (IHE), congestive heart failure (CHF), cerebrovascular accident (CVA), and all-cause mortality among 470,386 individuals with resistant and nonresistant hypertension (non-RH). Resistant hypertension (60,327 individuals) was subcategorized into two groups: 23,104 patients with cRH (controlled on four or more medicines) and 37,223 patients with uRH (uncontrolled on three or more medicines) in a 5-year retrospective cohort study. Cox proportional hazard modeling was used to estimate hazard ratios adjusting for age, gender, race, body mass index, chronic kidney disease (CKD), and comorbidities. Resistant hypertension (cRH and uRH), compared with non-RH, had multivariable adjusted hazard ratios (95% confidence intervals) of 1.32 (1.27-1.37), 1.24 (1.20-1.28), 1.46 (1.40-1.52), 1.14 (1.10-1.19), and 1.06 (1.03-1.08) for ESRD, IHE, CHF, CVA, and mortality, respectively. Comparison of uRH with cRH had hazard ratios of 1.25 (1.18-1.33), 1.04 (0.99-1.10), 0.94 (0.89-1.01), 1.23 (1.14-1.31), and 1.01 (0.97-1.05) for ESRD, IHE, CHF, CVA, and mortality, respectively. Men and Hispanics had a greater risk for ESRD within all three cohorts. Individuals with resistant hypertension had a greater risk for ESRD, IHE, CHF, CVA, and mortality. The risk of ESRD and CVA were 25% and 23% greater, respectively, in uRH compared with cRH, supporting the linkage between blood pressure and both outcomes.

Hyperaldosteronism as a common cause of resistant hypertension.

Resistant hypertension affects an estimated 10-15 million American adults and is increasing in prevalence. The etiology of resistant hypertension is almost always multifactorial, including obesity, older age, high dietary salt, chronic kidney disease, and aldosterone excess. Classical primary aldosteronism and lesser degrees of aldosterone excess, possibly originating from visceral adipocytes, contribute broadly to antihypertensive treatment resistance. Treatment of resistant hypertension is predicated on appropriate lifestyle changes and use of effective combinations of antihypertensive agents from different classes. Blockade of aldosterone with spironolactone has been shown to be particularly effective for treatment of resistant hypertension. The antihypertensive benefit of spironolactone is not limited to patients with demonstrable hyperaldosteronism but instead can be effective in resistant hypertensive patients regardless of aldosterone levels. Chlorthalidone is a potent, long-acting thiazide-like diuretic and should be used preferentially to treat resistant hypertension as it is superior to normally used doses of hydrochlorothiazide.

Scaling silicon photonic switch fabrics for data center interconnection networks.

With the rapidly increasing aggregate bandwidth requirements of data centers there is a growing interest in the insertion of optically interconnected networks with high-radix transparent optical switch fabrics. Silicon photonics is a particularly promising and applicable technology due to its small footprint, CMOS compatibility, high bandwidth density, and the potential for nanosecond scale dynamic connectivity. In this paper we analyze the feasibility of building silicon photonic microring based switch fabrics for data center scale optical interconnection networks. We evaluate the scalability of a microring based switch fabric for WDM signals. Critical parameters including crosstalk, insertion loss and switching speed are analyzed, and their sensitivity with respect to device parameters is examined. We show that optimization of physical layer parameters can reduce crosstalk and increase switch fabric scalability. Our analysis indicates that with current state-of-the-art devices, a high radix 128 × 128 silicon photonic single chip switch fabric with tolerable power penalty is feasible. The applicability of silicon photonic microrings for data center switching is further supported via review of microring operations and control demonstrations. The challenges and opportunities for this technology platform are discussed.

Incident ESRD and treatment-resistant hypertension: the reasons for geographic and racial differences in stroke (REGARDS) study.

BACKGROUND: Studies suggest that treatment-resistant hypertension is common and increasing in prevalence among US adults. Although hypertension is a risk factor for end-stage renal disease (ESRD), few data are available for the association between treatment-resistant hypertension and ESRD risk. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: We analyzed data from 9,974 REGARDS (Reasons for Geographic and Racial Differences in Stroke) Study participants treated for hypertension without ESRD at baseline. PREDICTOR: Treatment-resistant hypertension was defined as uncontrolled blood pressure (BP) with concurrent use of 3 antihypertensive medication classes including a diuretic or use of 4 or more antihypertensive medication classes including a diuretic regardless of BP. OUTCOME: Incident ESRD was identified by linkage of REGARDS Study participants with the US Renal Data System. MEASUREMENTS: During a baseline in-home study visit, BP was measured twice and classes of antihypertensive medication being taken were determined by pill bottle inspection. RESULTS: During a median follow-up of 6.4 years, there were 152 incident cases of ESRD (110 ESRD cases among 2,147 with treatment-resistant hypertension and 42 ESRD cases among 7,827 without treatment-resistant hypertension). The incidence of ESRD per 1,000 person-years for hypertensive participants with and without treatment-resistant hypertension was 8.86 (95% CI, 7.35-10.68) and 0.88 (95% CI, 0.65-1.19), respectively. After multivariable adjustment, the HR for ESRD comparing hypertensive participants with versus without treatment-resistant hypertension was 6.32 (95% CI, 4.30-9.30). Of participants who developed incident ESRD during follow-up, 72% had treatment-resistant hypertension at baseline. LIMITATIONS: BP, estimated glomerular filtration rate, and albuminuria assessed at a single time. CONCLUSIONS: Individuals with treatment-resistant hypertension are at increased risk for ESRD. Appropriate clinical management strategies are needed to treat treatment-resistant hypertension in order to preserve kidney function in this high-risk group.

Left ventricular torsion shear angle volume analysis in patients with hypertension: a global approach for LV diastolic function.

BACKGROUND: Torsion shear angle φ is an important measure of left ventricular (LV) systolic and diastolic functions. Here we provide a novel index utilizing LV normalized torsion shear angle φ ^ volume V ^ loop to assess LV diastolic functional properties. We defined the area within φ ^ V ^ loop as torsion hysteresis area, and hypothesized that it may be an important global parameter of diastolic function. We evaluated the φ ^ changes to increased V ^ during early diastole - d φ ^ / d V ^ as a potential measure of LV suction. METHODS: Sixty resistant hypertension patients (HTN), forty control volunteers were studied using cardiovascular magnetic resonance with tissue tagging. Volumetric and torsional parameters were evaluated. RESULTS: HTN demonstrated concentric remodeling with preserved ejection fraction. HTN had significantly decreased normalized early filling rate, early diastolic mitral annulus velocity and E/A (1.33 ± 1.13 vs. 2.19 ± 1.07, P < 0.0001) vs. control. Torsion hysteresis area was greater (0.11 ± 0.07 vs. 0.079 ± 0.045, P < 0.001) and peak - d φ ^ / d V ^ at early diastole was higher (10.46 ± 8.51 vs. 6.29 ± 3.85, P = 0.002) than control. Torsion hysteresis area was significantly correlated with E/A (r = -0.23, P = 0.025). Thirteen HTN patients had both E/A ratio < 1.12 (Control mean E/A-1SD) and torsion hysteresis area > 0.12 (Control mean torsion hysteresis area + 1SD). CONCLUSIONS: Torsion hysteresis area and peak early diastolic - d φ ^ / d V ^ were significantly increased in hypertensive concentric remodeling. The φ ^ V ^ loop takes into account the active and passive recoil processes of LV diastolic and systolic phases, therefore provides a new global description of LV diastolic function.

Tadalafil-induced improvement in left ventricular diastolic function in resistant hypertension.

PURPOSE: Left ventricular hypertrophy and diastolic dysfunction (LVDD) remain highly frequent markers of cardiac damage and risk of progression to symptomatic heart failure, especially in resistant hypertension (RHTN). We have previously demonstrated that administration of sildenafil in hypertensive rats improves LVDD, restoring phosphodiesterase type 5 (PDE-5) inhibition in cardiac myocytes. METHODS: We hypothesized that the long-acting PDE-5 inhibitor tadalafil may be clinically useful in improving LVDD in RHTN independently of blood pressure (BP) reduction. A single blinded, placebo-controlled, crossover study enrolled 19 patients with both RHTN and LVDD. Firstly, subjects received tadalafil (20 mg) for 14 days and after a 2-week washout period, they received placebo orally for 14 days. Patients were evaluated by office BP and ambulatory BP monitoring (ABPM), endothelial function (FMD), echocardiography, plasma brain natriuretic peptide (BNP-32), cyclic guanosine monophosphate (cGMP) and nitrite levels. RESULTS: No significant differences were detected in BP measurements. Remarkably, at least four echocardiographic parameters related with diastolic function improved accompanied by decrease in BNP-32 in tadalafil use. Although increasing cGMP, tadalafil did not change endothelial function or nitrites. There were no changes in those parameters after placebo. CONCLUSION: The current findings suggest that tadalafil improves LV relaxation through direct effects PDE-5-mediated in the cardiomyocytes with potential benefit as an adjunct to treat symptomatic subjects with LVDD such as RHTN patients.