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    Renal revascularization in resistant hypertension. Prince Marloe,Gupta Aashish,Bob-Manuel Tamunoinemi,Tafur Jose Progress in cardiovascular diseases Renal artery stenosis (RAS) is a common cause of secondary hypertension (HTN) and may lead to resistant (refractory) HTN despite guideline directed medical therapy. Although randomized controlled trials comparing medical therapy to medical therapy and renal artery stenting have shown no benefit with renal artery stenting, according to comparative effectiveness reviews by the Agency for Healthcare Research and Quality, the trials did not enroll patients with the most severe RAS who would be more likely to benefit from renal stenting. Because of limitations of conventional angiography, it is important to assess the hemodynamic severity of moderate (50%-70%) RAS lesions with a hemodynamic measurement. We review techniques to optimize patient selection, to minimize procedural complications, and to facilitate durable patency of renal stenting. We also review the current ACC/AHA Guidelines and SCAI Appropriate Use Criteria as they relate to renal stenting. 10.1016/j.pcad.2019.12.001
    Renal denervation: intractable hypertension and beyond. Ariyanon Wassawon,Mao Huijuan,Adýbelli Zelal,Romano Silvia,Rodighiero Mariapia,Reimers Bernhard,La Vecchia Luigi,Ronco Claudio Cardiorenal medicine BACKGROUND:Hypertension continues to be a major burden of public health concern despite the recent advances and proven benefit of pharmacological therapy. A certain subset of patients has hypertension resistant to maximal medical therapy and appropriate lifestyle measures. A novel catheter-based technique for renal denervation (RDN) as a new therapeutic avenue has great promise for the treatment of refractory hypertension. SUMMARY:This review included the physiology of the renal sympathetic nervous system and the renal nerve anatomy. Furthermore, the RDN procedure, technology systems, and RDN clinical trials as well as findings besides antihypertensive effects were discussed. Findings on safety and efficacy seem to suggest that renal sympathetic denervation could be of therapeutic benefit in refractory hypertensive patients. Despite the fast pace of development in RDN therapies, only initial and very limited clinical data are available. Large gaps in knowledge concerning the long-term effects and consequences of RDN still exist, and solid, randomized data are warranted. 10.1159/000357597
    Systematic review and meta-analysis of the prevalence of resistant hypertension in treated hypertensive populations. Achelrod Dmitrij,Wenzel Ulrich,Frey Simon American journal of hypertension BACKGROUND:Although treatment-resistant hypertension (RH) is a serious burden on population health, there exists uncertainty about its prevalence. Hence, the objectives of this work were to systematically review and critically appraise the literature and to conduct a meta-analysis on the prevalence of RH in treated hypertensive populations. METHODS:PubMed, Cochrane Library, CRD York databases, and study bibliographies were systematically searched for observational and interventional studies that report disease frequency in adult populations. The pooled prevalence was obtained through random-effect modeling. Furthermore, quality assessment, publication bias diagnostics, meta-regression, subgroup analysis by sex, and sensitivity analysis were performed. RESULTS:Out of 318 retrieved studies, 20 observational studies and 4 randomized control trials (RCTs) with a total population of 961,035 were included. The random-effect method for observational studies and RCTs yielded RH prevalence ratios of 13.72% (95% confidence interval (CI) = 11.19%-16.24%) and 16.32% (95% CI = 10.68%-21.95%), respectively. Yet, most studies were incapable of ruling out pseudo-resistance caused by white-coat effect, poor medication adherence, and suboptimal dosing. Differences in RH prevalence by sex were negligible. Meta-regression analysis showed that study-level characteristics had no statistically significant influence on RH prevalence. The inclusion of further studies in the sensitivity analysis concurred with the baseline results (13.19%; 95% CI = 10.89%-15.49%). CONCLUSIONS:Researchers should enhance comparability of future empirical evidence through homogeneous methodologies and comparable baseline populations. This meta-analysis concludes that RH is a frequent phenomenon and further harmonization in terms of RH definition and measurement would be necessary to clearly distinguish true treatment resistance from pseudo-resistance. 10.1093/ajh/hpu151
    Incidence, prevalence, and predictors of treatment-resistant hypertension with intensive blood pressure lowering. Smith Steven M,Gurka Matthew J,Winterstein Almut G,Pepine Carl J,Cooper-DeHoff Rhonda M Journal of clinical hypertension (Greenwich, Conn.) Recent guidelines call for more intensive blood pressure (BP)-lowering and a less-stringent treatment-resistant hypertension (TRH) definition, both of which may increase the occurrence of this high-risk phenotype. We performed a post hoc analysis of 11 784 SPRINT and ACCORD-BP participants without baseline TRH, who were randomized to an intensive (<120 mm Hg) or standard (<140 mm Hg) systolic BP target. Incidence, prevalence, and predictors of TRH were compared using the updated definition (requiring ≥4 drugs to achieve BP < 130/80 mm Hg) during intensive treatment, vs the former definition (requiring ≥4 drugs to achieve BP < 140/90 mm Hg) during standard treatment. Incidence/prevalence of apparent refractory hypertension (RFH; uncontrolled BP despite ≥5 drugs) was similarly compared. Overall, 5702 and 6082 patients were included in the intensive and standard treatment cohorts, respectively. Crude TRH incidence using the updated definition under intensive treatment was 30.3 (95% CI, 29.3-31.4) per 100 patient-years, compared with 9.7 (95% CI, 9.2-10.2) using the prior definition under standard treatment. Point prevalence using the prior TRH definition at 1-year was 7.5% in SPRINT and 14% in ACCORD vs 22% and 36%, respectively, with the updated TRH definition. Significant predictors of incident TRH included number of baseline antihypertensive drugs, having diabetes, baseline systolic BP, and Black race. Incidence of apparent RFH was also significantly greater using the updated vs prior definition (4.5 vs 1.0 per 100 person-years). Implementation of the 2017 hypertension guideline, including lower BP goals for most individuals, is expected to substantially increase treatment burden and incident TRH among the hypertensive population. 10.1111/jch.13550
    A Late Diagnosis of Primary Aldosteronism. Zorzi Francesco,Olivieri Oliviero,Brazzarola Paolo,Pizzolo Francesca High blood pressure & cardiovascular prevention : the official journal of the Italian Society of Hypertension We report the case of a 41-year-old male patient with juvenile onset refractory hypertension while taking four drugs including a diuretic. Fourteen years before he underwent a complete investigation for secondary hypertension (including the aldosterone to renin ratio-ARR) that was negative. Since that, hypertension control gradually worsened, hypertensive organ damage aggravated and hypokalemia developed in spite of ACE inhibitor treatment. At the re-evaluation ARR was elevated, and the further workup for primary aldosteronism demonstrated an unilateral aldosterone producing adenoma that was surgically removed, with subsequent optimal blood pressure control with two anti-hypertensive drugs. In this case, the failure of the first screening prevented a correct diagnosis of primary aldosteronism, with consequent inadequate blood pressure control in following years and end organ damage. The case suggests the need of clinical follow-up and eventual reappraisal of patients showing a condition of refractory hypertension associated with hypokalemia despite a first negative screening test. 10.1007/s40292-017-0191-6
    Proof of concept study: Improvement of echocardiographic parameters after renal sympathetic denervation in CKD refractory hypertensive patients. Kiuchi Márcio Galindo,Mion Decio,Graciano Miguel Luis,de Queiroz Carreira Maria Angela Magalhães,Kiuchi Tetsuaki,Chen Shaojie,Lugon Jocemir Ronaldo International journal of cardiology AIM:Evaluation of the effectiveness of the renal sympathetic denervation (RSD) in reducing lesions of target organs such as the heart and kidneys, in resistant hypertensive CKD patients. METHODS AND RESULTS:Forty-five patients were included and treated with an ablation catheter with open irrigated tip. RSD was performed by a single operator following the standard technique. Patients included with CKD were on stages 2 (n=22), 3 (n=16), and 4 (n=7). Data were obtained at baseline and monthly until the 6th month of follow-up. Twenty-six out of the 45 patients had LVH and nineteen did not present LVH. The LV mass index decreased from 123.70±38.44g/m(2) at baseline to 106.50±31.88g/m(2) at the 6th month after RSD, P<0.0001. The end-diastolic left ventricular internal dimension (LVIDd) reduced from 53.02±6.59mm at baseline to 51.11±5.85mm 6months post procedure, P<0.0001. The left ventricular end-diastolic posterior wall thickness (PWTd) showed a reduction from 10.58±1.39mm at baseline to 9.82±1.15mm at the 6th month of follow-up, P<0.0001. The end-diastolic interventricular septum thickness (IVSTd) also decreased from 10.58±1.39mm at baseline to 9.82±1.15mm 6months post procedure, P<0.0001. The left ventricular ejection fraction (LVEF) improved from 58.90±10.48% at baseline to 62.24±10.50% at the 6th month of follow-up, P<0.0001. When the ∆ between baseline and the 6th month post RSD in LVH patients and non LVH patients were compared to the same parameters no significant difference was found. CONCLUSIONS:The RSD seemed to be feasible, effective, and safe resulting in an improvement of echocardiographic parameters in LVH and non LVH CKD refractory hypertensive patients. 10.1016/j.ijcard.2016.01.088
    Renal sympathetic denervation using an externally irrigated radiofrequency ablation catheter for treatment of resistant hypertension - Acute safety and short term efficacy. Yalagudri Sachin,Raju Narayana,Das Bharati,Daware Ashwin,Maiya Shreesha,Jothiraj Kannan,Ravikishore A G Indian heart journal OBJECTIVES:This study was conducted to assess the acute safety and short term efficacy of renal sympathetic denervation (RSDN) using solid tip radiofrequency ablation (RFA) catheter and saline irrigation through the renal guiding catheter to achieve effective denervation. BACKGROUND:RSDN using a specialized solid-tip RFA catheter has recently been demonstrated to safely reduce systemic blood pressure in patients with refractory hypertension, the limitation being inadequate power delivery in renal arteries. So, we used solid-tip RFA catheter along with saline irrigation for RSDN. METHODS:Nine patients with resistant hypertension underwent CT and conventional renal angiography, followed by bilateral or unilateral RSDN using 5F RFA catheter with saline irrigation through renal guiding catheter. Repeat renal angiography was performed at the end of the procedure. In all patients, pre- and post-procedure serum creatinine was measured. RESULTS:Over 1-month period: 1) the systolic/diastolic blood pressure decreased by -57 ± 20/-25 ± 7.5 mm Hg; 2) all patients experienced a decrease in systolic blood pressure of at least -36 mm Hg (range 36-98 mm Hg); 3) there was no evidence of renal artery injury immediate post-procedure. There was no significant change in serum creatinine level. CONCLUSIONS:This data shows the acute procedural safety and short term efficacy of RSDN using modified externally irrigated solid tip RFA catheter. 10.1016/j.ihj.2015.02.020
    Brain metastasis in colorectal cancer presenting as refractory hypertension. Hassan Syed Moin,Mubarik Ateeq,Muddassir Salman,Haq Furqan Journal of community hospital internal medicine perspectives : Brain metastasis (BM) from colorectal cancer (CRC) is rare with the incidence ranging from 0.6% to 3.2%. There is also an increased incidence of BM with rectal primaries and is consistent with this patient's presentation. Overall, there is scarce literature on the symptoms of patients who present with CRC BMs. : We present a case of brain metastasis in colorectal cancer presenting with hypertensive urgency and severe headache. : This case highlights that neurological deficits are not necessary for BMs in patients with CRC and summarizes and reviews the associated literature regarding BM in CRC. A 57-year-old female with a past medical history of recently diagnosed stage IV moderately differentiated distal rectal adenocarcinoma with liver and lung metastasis was admitted with the primary complaint of hypertensive urgency, severe headache, intractable nausea and vomiting, and diarrhea. Magnetic resonance imaging brain showed a left cerebellar lesion measuring 3.6 × 3.2 × 2.9 cm, ipsilateral transtentorial herniation, and obliteration of the fourth ventricle. The patient was started on steroids and transferred for an urgent neurosurgical intervention to a tertiary care center. : Even though BMs are rare in CRC, clinicians should have a high index of suspicion with complaints like hypertensive urgency, headache, nausea, vomiting, vertigo, and blurring of vision triggering imaging studies to rule out BM. The approach to BM has become increasingly individualized as surgical and radiosurgical therapies have continued to evolve : CRC: Colorectal cancer; BM: Brain metastasis; FOLFOX: Folinic acid, fluorouracil and oxaliplatin; CT: Computed tomography; IV: Intravenous; PO: By mouth; BAER: Brain auditory evoked response hearing testing; SSEP's: Somatosensory evoked potentials; BMFI: Brain metastasis free interval; WBRT: Whole-brain radiation therapy; SRS: Stereotactic radiosurgery. 10.1080/20009666.2018.1490138
    Treatment-Refractory Hypertension and Sleep Apnea. One Step Further. Martínez-García Miguel Ángel,Campos-Rodriguez Francisco,Torres Cortada Gerard Archivos de bronconeumologia 10.1016/j.arbres.2018.08.009
    [Resistant hypertension]. Wojtaszek Ewa,Jaguś Dorota Wiadomosci lekarskie (Warsaw, Poland : 1960) Hypertension is the most common chronic cardiovascular condition, with an increasing prevalence all over the world. Patients with refractory hypertension are the group most at risk for adverse cardiovascular events, but also present a particular diagnostic and therapeutic challenge. The present article reviews the mechanisms of development of resistant hypertension and the possibilities of pharmacological treatment and interventional approaches.
    Renal denervation for resistant hypertension: yes. Boschetti Enrico,Alrashdi Yahya,Schillaci Giuseppe Internal and emergency medicine Sympathetic overactivity may have a role in triggering and maintaining resistant hypertension, and catheter-based renal denervation (RDN) has emerged as a promising treatment in refractory hypertension. Recently, the results of the Symplicity HTN-3, the first randomized, sham-controlled trial, failed to confirm the previously reported BP-lowering effects of RDN, although definitive conclusions cannot be drawn due to a number of study limitations. Consequently, although some centers halted their RDN programs, research continues and both the concept of denervation and treatment strategies are being redefined. A new generation of sham-controlled trials is currently underway with the aim of detecting which patients are expected to achieve the most beneficial effect from RDN. In this article, we examine the current data on RDN and discuss some insights and future opportunities. 10.1007/s11739-016-1429-3
    Current Status of Renal Artery Angioplasty and Stenting for Resistant Hypertension: A Case Series and Review of the Literature. Manolis Antonis S,Manolis Antonis A,Melita Helen Current hypertension reviews BACKGROUND:Renal artery stenosis (RAS) has a high prevalence in older patients, especially in the context of general atherosclerosis. It is frequently associated with resistant hypertension and impaired renal function and their attendant consequences. The issue whether revascularization via percutaneous renal angioplasty and stenting (PRA/S) can benefit these patients remains unsettled. OBJECTIVE:To present a case series of patients with refractory hypertension and RAS undergoing PRA/S and also to provide an extensive review of the literature on the current status of PRA/S for resistant hypertension. METHODS:Data of all consecutive patients undergoing PRA/S by a single operator over 1 year were prospectively collected. These were 9 patients with hypertension refractory to drug therapy who also had other clinical cardiac problems that led to their hospitalization, including flash pulmonary edema and coronary artery disease. They were all receiving ≥3 antihypertensive drugs and renal angiography revealed critical RAS (unilateral in 3 and bilateral in 6). In addition, an extensive literature review of the topic was carried out in PubMed, Scopus and Google Scholar. RESULTS:PRS was successful in all 9 high-risk RAS patients with resistant hypertension (5 men, mean age 71 years) without complications and helped in bringing under control their elevated blood pressure (BP) and in maintaining their renal function over a mean of 21 months. Literature review of this controversial topic indicates that in carefully selected patients, PRA/S may play an important role in controlling BP, alleviating symptoms and perhaps preventing renal failure, albeit without concrete evidence of significantly affecting hard end-points of renal events, major cardiovascular events and death. Randomized controlled studies (RCTs), including a large one (CORAL trial), although heavily criticized, have not provided evidence in favor of revascularization. Although RCTs are rather neutral, a multitude of prospective, observational cohort studies, comparing the outcomes of patients after PRA/S have demonstrated significant improvement in systolic and diastolic BP in about two thirds and improvement and/or stabilization in renal function in 30-40% of patients undergoing PRA/S. Nevertheless, the issue remains unsolved and a subject of future studies for further more definitive settlement. Suggestions have been made to adopt physiological and functional renal lesion assessment that may enhance patient selection, at least for RAS cases of moderate lesion severity. Based on this small case series and on exhaustive literature review, an algorithm for approaching patients with significant RAS is herein proposed. CONCLUSION:In high-risk RAS patients with truly resistant hypertension, flash pulmonary edema, and/or rapid deterioration of renal function, PRA/S, a procedure with currently high technical success, may constitute the only viable option. Importantly, despite the unfavorable results of RCTs, current guidelines have not yet changed and clinicians should continue to abide by them. They recommend PRA/S as a reasonable option for patients with hemodynamically significant (especially ostial) RAS and uncontrolled, resistant or malignant hypertension, recurrent, unexplained congestive heart failure or pulmonary edema or unstable angina. 10.2174/1573402113666170804153026
    Renal denervation for resistant hypertension: no. Taddei Stefano,Dal Canto Elisa,Bruno Rosa Maria Internal and emergency medicine In recent years, catheter-based radiofrequency denervation of the renal arteries (RDN) has emerged as a potential treatment for resistant hypertension. Though initial non-randomized and randomized small studies demonstrate large reductions in office blood pressure, RDN superiority to conventional treatment is not confirmed either by randomized controlled trials or by large international registries. Increasing evidence supports the hypothesis that a rational pharmacological therapeutic scheme is equally or more effective; this approach, together with an intervention aimed at increasing patient's compliance with treatment, might solve most of the cases of refractory hypertension. Thus, based on current evidence, renal denervation should not be routinely used to treat resistant hypertension. Though the possibility that RDN might be useful in other subsets of hypertensive patients exists, it has never been proven. Thus, its use should be limited to extreme situations, when all other possible treatments have failed. 10.1007/s11739-016-1428-4
    Importance of thorough investigation of resistant hypertension before renal denervation: should compliance to treatment be evaluated systematically? Rosa J,Zelinka T,Petrák O,Štrauch B,Šomlóová Z,Indra T,Holaj R,Čurila K,Toušek P,Šenitko M,Widimský P,Widimský J Journal of human hypertension Catheter-based renal denervation (RD) has been introduced recently as a potentially effective invasive treatment of refractory hypertension. The proportion of patients with severe hypertension suitable for RD is not clear. The aim of this study was to identify what percentage of patients has truly resistant essential hypertension and are thus potentially eligible for RD. We investigated 205 consecutive patients referred to a university hypertension center for severe hypertension within 12 months. Ambulatory 24-h blood pressure (BP) monitoring (24 h ABPM), secondary hypertension screening and compliance to treatment testing (by use of plasma drug level measurements) were performed in all patients. Fifty-seven patients (27.8%) did not have truly resistant hypertension (RH) based on clinical BP. Among the remaining 122 patients (59.5%) with RH confirmed by 24 h ABPM, 50 patients (24.4% of the original cohort) had a secondary cause of hypertension and in 27 (13.2%) non-compliance to treatment was confirmed. Thus, only 45 patients (22%) had truly resistant essential hypertension and were considered for RD. Only one-third (n=15, 7.3% of the original cohort) was, however, finally referred for RD (14 were excluded due to contraindications for RD and 16 refused the invasive treatment). In conclusion, thorough examination of severe hypertension including 24 h ABPM, secondary hypertension exclusion and drug compliance testing before considering RD reveals that majority of these patients are not suitable for RD. Specifically, compliance to treatment testing should be mandatory in order to identify eligible candidates for RD. 10.1038/jhh.2014.3
    Diagnosis and treatment of resistant hypertension. Waeber Bernard,Volpe Massimo,Ruilope Luis M,Schmieder Roland E Blood pressure Hypertension resistant to lifestyle interventions and antihypertensive medications is a common problem encountered by physicians in everyday practice. It is most often defined as a blood pressure remaining ≥ 140/90 mmHg despite the regular intake of at least three drugs lowering blood pressure by different mechanisms, one of them being a diuretic. It now appears justified to include, unless contraindicated or not tolerated, a blocker of the renin-angiotensin system and a calcium channel blocker in this drug regimen, not only to gain antihypertensive efficacy, but also to prevent or regress target organ damage and delay the development of cardiorenal complications. A non-negligible fraction of treatment-resistant hypertension have normal "out of office" blood pressures. Ambulatory blood pressure monitoring and/or home blood pressure recording should therefore be routinely performed to identify patients with true resistant hypertension, i.e. patients who are more likely to benefit from treatment intensification. 10.3109/08037051.2013.854946
    A practical approach for measurement of antihypertensive medication adherence in patients with resistant hypertension. Corrêa Nathália Batista,de Faria Ana Paula,Ritter Alessandra M V,Sabbatini Andrea Rodrigues,Almeida Aurélio,Brunelli Veridiana,Calhoun David A,Moreno Heitor,Modolo Rodrigo Journal of the American Society of Hypertension : JASH Confirmation of medication adherence is a challenge in clinical practice and essential for the accurate diagnosis of resistant hypertension. Although it is well established that drug adherence is critical for controlling blood pressure, there are still difficulties applying a simple, inexpensive, and reliable assessment of adherence in the clinical setting. We aimed to test a simple method to assess adherence in resistant hypertensive (RH) patients. A pilot study with normotensives or mild/moderate hypertensive subjects was performed to provide a fluorescence cutoff point for adherence. After that, 21 patients referred to the Resistant Hypertension Clinic had triamterene prescribed and were monitored for a 30-day period. We conducted two unannounced randomly selected home visits for urine collection to test drug intake that day. Office, home and 24-hour ambulatory blood pressure, biochemical data, and the 8-item Morisky Medication Adherence Scale (MMAS-8) were systematically acquired. According to adherence indicated by urine fluorescence, subjects were divided into adherent and nonadherent groups. We found 57% of nonadherence. No differences were found between groups regarding baseline characteristics or prescribed medications; Kappa's test showed concordance between adherence through MMAS-8 items and fluorescence (kappa = 0.61; 95% confidence interval: 0.28-0.94; P = .005). Nonadherent patients had higher office (81 ± 11 vs. 73 ± 6 mm Hg, P = .03), 24-hour ambulatory blood pressure monitoring (75 ± 9 vs. 66 ± 7 mm Hg, P = .01), and home blood pressure measurement (77 ± 9 vs. 67 ± 8 mm Hg, P = .01) diastolic blood pressure than their counterparts. Nonadherence to antihypertensive therapy is high in patients with RH, even when assessed in clinics specialized in this condition. Fluorometry to detect a drug in the urine of RH patients is safe, easy, and reliable method to assess adherence. 10.1016/j.jash.2016.03.194
    Drug Development for Hypertension: Do We Need Another Antihypertensive Agent for Resistant Hypertension? Pimenta Eduardo,Calhoun David A Current hypertension reports 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. 10.1007/s11906-016-0634-9
    [Resistant hypertension: An update]. Renna N F Hipertension y riesgo vascular An estimated 10% to 20% of hypertensive patients could be considered resistant to treatment (RH). These are patients who are not controlled using three drugs, at the maximum tolerated doses, including a diuretic, as well as those with high blood pressure controlled using four or more drugs. The term is used to identify patients that might benefit from special diagnostic and/or therapeutic consideration. The term 'refractory hypertension' has recently been proposed as a novel phenotype of antihypertensive failure. It refers to patients whose blood pressure cannot be controlled with maximum treatment. The first studies of this phenotype indicate that it is rare and affects less than 5% of patients with RH. Adherence to or compliance with medical treatment is key to defining resistant hypertension. Closer attention has been paid to clinical and experimental research since the first scientific statement for the diagnosis, assessment and treatment of RH from the American Heart Association, and in the European guidelines, was published in 2008. This review will set out the concepts relating to prevalence, prognosis and compliance and cover the latest developments on this subject. 10.1016/j.hipert.2017.12.005
    Long-term effects of nocturnal continuous positive airway pressure therapy in patients with resistant hypertension and obstructive sleep apnea. Frenţ Ştefan M,Tudorache Voicu M,Ardelean Carmen,Mihăicuţă Stefan Pneumologia (Bucharest, Romania) Obstructive sleep apnea (OSA) is often linked to high blood pressure and has a particularly high prevalence in patients with resistant hypertension. The effect of continuous positive airway pressure (CPAP) therapy on blood pressure (BP) values has been evaluated in several short-term clinical trials with conflicting results. Our aim was to investigate the role of long-term CPAP treatment in achieving BP control in patients who associate OSA and resistant hypertension. We have included in the study 33 patients with resistant hypertension, diagnosed with OSA in our sleep lab. Data was collected initially and after a mean follow-up period of 4 years. Patients were divided into 2 groups according to the use of CPAP therapy. Patients under CPAP therapy (n = 12) exhibited a higher reduction in both systolic and diastolic pressure and BP control was achieved in 75% of cases, while patients without CPAP treatment (n = 21) remained with refractory hypertension in proportion of 90.5%. A de-escalation of antihypertensive drug regimen by discontinuation of 1 or more drugs was observed in 41.6% (n = 5) of patients from CPAP group and in the other 33.4% (n = 4) the medication remained unchanged, but BP control was reached. Using a direct logistic regression model for examining the impact of different confounders on the probability of diagnosis of resistant hypertension at follow-up, the only statistically significant predictor found was the lack of CPAP usage.
    Detection, evaluation, and treatment of severe and resistant hypertension: proceedings from an American Society of Hypertension Interactive forum held in Bethesda, MD, U.S.A., October 10th 2013. White William B,Turner J Rick,Sica Domenic A,Bisognano John D,Calhoun David A,Townsend Raymond R,Aronow Herbert D,Bhatt Deepak L,Bakris George L Journal of the American Society of Hypertension : JASH The epidemiology, evaluation, and management of severe and resistant hypertension in the United States (US) are evolving. The American Society of Hypertension held a multi-disciplinary forum in October 2013 to review the available evidence related to the management of resistant hypertension with both drug and device therapies. There is strong evidence that resistant hypertension is an important clinical problem in the US and many other regions of the world. Complex drug therapy is effective in most of the patients with severe and resistant hypertension, but there are certain individuals who may be refractory to multiple-drug regimens or have adverse effects that make adherence to the regimen difficult. When secondary forms of hypertension and pseudo-resistance, such as medication nonadherence, or white-coat hypertension based on marked differences between clinic and 24-hour ambulatory blood pressure monitoring, have been excluded, the impact of device therapy is under evaluation through clinical trials in the US and from clinical practice registries in Europe and Australia. Clinical trial data have been obtained primarily in patients whose resistant hypertension is defined as systolic clinic blood pressures of ≥160 mm Hg (or ≥ 150 mm Hg in type 2 diabetes) despite pharmacologic treatment with at least three antihypertensive drugs (one of which is a thiazide or loop diuretic). Baroreceptor stimulation therapy has shown modest benefit in a moderately sized sham-controlled study in drug-resistant hypertension. Patients selected for renal denervation have typically been restricted to those with preserved kidney function (estimated glomerular filtration rate ≥ 45 mL/min/1.73 m2). The first sham-controlled safety and efficacy trial for renal denervation (SYMPLICITY HTN-3) did not show benefit in this population when used in addition to an average of five antihypertensive medications. Analyses of controlled clinical trial data from future trials with novel designs will be of critical importance to determine the effectiveness of device therapy for patients with severe and resistant hypertension and will allow for proper determination of patient selection and whether it will be acceptable for clinical practice. At present, the focus on the management of severe and resistant hypertension will be through careful evaluation for pseudo-resistance and secondary forms of hypertension, appropriate use of combination pharmacologic therapy, and greater utility of specialists in hypertension. 10.1016/j.jash.2014.06.005
    Radiosurgical Ablation of the Renal Nerve in a Porcine Model: A Minimally Invasive Therapeutic Approach to Treat Refractory Hypertension. Bhatt Nikhilesh,Long Sarah A,Gardner Edward A,Tay Jonathan,Ladich Elena,Chamberlain David,Fogarty Thomas J,Maguire Patrick J Cureus BACKGROUND:Hypertension is strongly associated with cardiovascular diseases such as heart failure, stroke, kidney disease, and has been correlated with an increased risk for heart attack. Current treatment regimens for hypertension are highly inadequate, with reports indicating that only 50.1% of the clinical population with the disease has their blood pressure under control. OBJECTIVE:To study the feasibility of using minimally invasive radiosurgery to ablate the renal nerves as a novel treatment for refractory hypertension, and to assess the safety and efficacy of such an approach. METHODS:A Hanford porcine (miniswine) model (N = 6) was used to investigate the feasibility of using the CyberHeart radiosurgical platform (CyberHeart Inc., Mountain View, CA, USA) to create safe renal nerve ablations. Norepinephrine (NE) levels were measured pre and post treatment. Additionally, renal nerve and arterial histology were studied to examine effect. RESULTS:Plasma norepinephrine levels showed a decrease over the six-month time point. Urea, nitrogen, and creatinine levels showed no changes post procedure. Histology documented no significant arterial injury in targeted areas. Renal nerves documented histologic change consistent with nerve ablation. CONCLUSION:CyberHeart radiosurgery of the renal nerve is feasible and resulted in norepinephrine reduction and renal nerve injury consistent with radiosurgical targeted ablation. 10.7759/cureus.1055
    New therapies for arterial hypertension. Pagliaro Beniamino,Santolamazza Caterina,Rubattu Speranza,Volpe Massimo Panminerva medica Arterial hypertension is the most common chronic disease in developed countries and it is the leading risk factor for stroke, ischemic heart disease, congestive heart failure, chronic renal failure and peripheral artery disease. Its prevalence appears to be about 30-45% of the general population. Recent European guidelines estimate that up to 15-20% of the hypertensive patients are not controlled on a dual antihypertensive combination and they require three or more different antihypertensive drug classes to achieve adequate blood pressure control. The guidelines confirmed that diuretics, beta-blockers, calcium-channel blockers, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are suitable for the initiation and maintenance of antihypertensive treatment, either as monotherapy or in combination therapy. Very few antihypertensive agents have reached the market over the last few years, but no new therapeutic class has really emerged. The long-term adherence to cardiovascular drugs is still low in both primary and secondary prevention of cardiovascular diseases. In particular, the issue of compliance is persistently high in hypertension, despite the fixed-dose combination therapy. As a consequence, a cohort of high-risk hypertensive population, represented by patients affected by refractory and resistant hypertension, can be identified. Therefore, the need of controlling BP in high-risk patients may be addressed, in part, by the development of new drugs, devices and procedures that are designed to treat hypertension and comorbidities. In this review we will comprehensively discuss the current literature on recent therapeutic advances in hypertension, including both medical therapy and interventional procedures.
    Bilateral renal artery stenosis as a cause of refractory intradialytic hypertension in a patient with end stage renal disease. Wolfmueller Zachary,Goyal Kunal,Prasad Bhanu BMC nephrology BACKGROUND:We report a 61-year-old female with end-stage renal disease (ESRD) secondary to polycystic kidney disease (PKD) complicated by intradialytic hypertension (IDH). Increased sympathetic drive leading to increased stroke volume and/or vasoconstriction with an inappropriate increase in peripheral vascular resistance (PVR) has been postulated to be the cause of IDH. CASE PRESENTATION:Attempts to control her blood pressure by reducing her goal weight; increasing dialysis times/ frequency and decreasing her sodium concentrate in the dialysis fluid were unsuccessful. Acting upon literature evidence suggesting renovascular disease as a cause of IDH, we referred her to an interventional radiologist for evaluation of the renal arteries. Selective angiogram of both renal arteries revealed right sided atherosclerotic renal artery stenosis (RAS) treated with insertion of a balloon mounted 6 mm stent and left sided fibromuscular dysplasia (FMD) treated with 5 mm balloon angioplasty. CONCLUSIONS:This case highlights the need for interrogating the renal arteries radiologically for a potential cause in difficult to control IDH and comments on the association between PKD and FMD that has not yet been reported. 10.1186/s12882-018-1191-z
    Effects of renal sympathetic denervation on cardiac sympathetic activity and function in patients with therapy resistant hypertension. van Brussel Peter M,Eeftinck Schattenkerk Daan W,Dobrowolski Linn C,de Winter Robbert J,Reekers Jim A,Verberne Hein J,Vogt Liffert,van den Born Bert-Jan H International journal of cardiology BACKGROUND:Renal sympathetic denervation (RSD) is currently being investigated in multiple studies of sympathetically driven cardiovascular diseases such as heart failure and arrhythmias. Our aim was to assess systemic and cardiac sympatholytic effects of RSD by the measurement of cardiac sympathetic activity and cardiovascular parameters. METHODS:A total of 21 consecutive patients with refractory hypertension (daytime ambulatory blood pressure (BP)≥150/100 mmHg despite the use of 3 or more antihypertensive drugs), no evidence for secondary hypertension and normal renovascular anatomy were included. RSD was performed with the Medtronic Symplicity renal denervation catheter with an average of 4.2 (range 3-6) ablations per renal artery. To assess cardiac sympathetic activity, 123I-mIBG cardiac scintigraphy was performed before and 6 weeks after. In addition, the effect of RSD on peripheral BP and cardiac hemodynamics were assessed non-invasively. RESULTS:123I-mIBG uptake before and after RSD was 1.7±0.4% vs. 1.7±0.5% at 15 min. and 1.4±0.4% vs. 1.5±0.5% after 4 h. As a consequence, washout rate was similar before (33.7±11.7%) and after RSD (30.1±12.6%, p=0.27). In line with earlier RSD studies, a significant drop in systolic office BP (-12.2 mmHg, p=0.04) was detected, whereas the decrease in ambulatory BP was not significant. No changes were seen in heart rate, stroke volume or left ventricular contractility, both in supine position and after standing. CONCLUSION:In concert with previous reports, RSD leads to a significant drop in office BP. However, a reduction in sympathetic activity could not be demonstrated on a cardiac level. 10.1016/j.ijcard.2015.09.025
    Resistant or refractory hypertension: are they different? Modolo Rodrigo,de Faria Ana Paula,Almeida Aurélio,Moreno Heitor Current hypertension reports Resistant hypertension (RHTN) consists in a condition where blood pressure (BP) levels remain uncontrolled despite the use of at least three drugs or if the control happens with four or more drugs. Throughout the last 50 years, it has been increasingly studied, and its phenotypes have been identified. The term refractory hypertension has been used concurrently with RHTN all those years, but in the last decade, it has been applied to the most afflicted part of RHTN--defined as the uncontrolled RHTN or as the uncontrolled RHTN who needs five or more drugs. Differences between those two phenotypes are being recently identified, especially classifying refractory subjects as having more: (1) cardiovascular risk, (2) target organ damage, (3) African-descending race, (4) coronary heart disease and myocardial ischemia, (5) aldosterone excess, (6) deregulation of adipokines, and (7) possible sympathetic hyperactivation. We review the most important studies in both resistant and refractory hypertension to gather the up-to-date data regarding the characteristics of these two high-risk groups of patients. 10.1007/s11906-014-0485-1
    A Complicated Case of Resistant Hypertension. Chiarito Mauro,Scotti Andrea,A Pivato Carlo,Cottone Giuseppe,Ballarotto Carlo,Godino Cosmo,Margonato Alberto Acta medica Iranica A 47-year-old woman presented with a history of resistant arterial hypertension, associated with disabling headache. She was subjected to an enormous number of tests in order to identify an underlying cause of secondary hypertension, such as pheochromocytoma or Cushing syndrome, but all the most common causes of secondary hypertension were investigated and gradually excluded. Factitious use of amphetamine or cocaine was excluded, and therapy compliance was verified by witnessed ingestion of drug therapy, in order to rule out Munchausen syndrome. The patient underwent a first transcatheter renal denervation (RDN) with poor effect on blood pressure (BP) at long term follow up. Because of extremely poor control of BP values, a second RDN was performed two years later, again with inadequate long term efficacy. Despite an uncontrollable pre-procedural BP, RDN had an excessive BP lowering effect in this patient, but only for few months. In conclusion, a definitive diagnosis was not performed in our patient, despite an extremely deepened examination of the most common cause of refractory hypertension.
    [The first experience with the use of catheter denervation of renal arteries in patients with refractory hypertension]. Kucherov V V,Fursov A N,Chernetsov V A,Potekhin N P,Chernov S A,Sokolianskiĭ N V,Makeeva T G,Zakharova E G Klinicheskaia meditsina The prevalence of refractory arterial hypertension in Russia is estimated at 15%. We report the first experience with surgical treatment of this pathology. The method is based on the reduction of activity of the sympathetic nervous system by selective breaking of connections between of neurons with the help of interventional intravascular radiowave ablation. Renal endovascular sympathetic denervation allows to more effectively control AP and optimize antihypertensive therapy but does not ensure recovery from AH.
    [What are the pharmacological options for treating resistant hypertension?] Martell-Claros N,Abad-Cardiel M Hipertension y riesgo vascular When treating a patient with resistant hypertension therapy should be optimize in order to prescribe three antihypertensive drugs at full doses, being powerful drugs, having 24-hour coverage, and showing synergistic effects. Diuretic therapy is of special relevance. The fourth drug should be an aldosterone antagonists. In the case of intolerance, or when control is not achieved, drugs from other type of antihypertensive drugs should be, sometimes allowing adequate blood pressure control. 10.1016/S1889-1837(18)30060-6
    Effect of continuous positive airway pressure in patients with true refractory hypertension and sleep apnea: a post-hoc intention-to-treat analysis of the HIPARCO randomized clinical trial. Navarro-Soriano Cristina,Martínez-García Miguel-Angel,Torres Gerard,Barbé Ferrán,Caballero-Eraso Candela,Lloberes Patricia,Diaz Cambriles Trinidad,Somoza María,Masa Juan F,González Mónica,Mañas Eva,de la Peña Mónica,García-Río Francisco,Montserrat Josep M,Muriel Alfonso,Oscullo Grace,Feced Olmos Laura,García-Ortega Alberto,Calhoun David,Campos-Rodriguez Francisco, Journal of hypertension RATIONALE:Continuous positive airway pressure (CPAP) can significantly reduce blood pressure (BP) levels in patients with resistant hypertension and sleep apnea (OSA); however, the effect on patients with refractory hypertension (RfH) is not known. This study seeks to evaluate the effect of CPAP treatment on BP levels in patients with OSA and RfH, compared with those with OSA and resistant hypertension. METHODS:Post-hoc analysis of the HIPARCO randomized clinical trial on the effect of CPAP treatment on BP levels in patients with resistant hypertension. Those patients with uncontrolled 24-h ambulatory BP monitoring readings (>130 and/or >80 mmHg) in SBP or DBP were considered to have resistant hypertension (if they were taking three or four antihypertensive drugs) or RfH (if they were taking at least five drugs). OSA patients were randomized to receive CPAP or usual care for 3 months. They underwent a second 24-h ambulatory BP monitoring study to establish the effect of CPAP treatment on BP levels in both groups. RESULTS:A total of 98 patients were randomized to CPAP (19 RfH/79 resistant hypertension) and 96 to usual care (21 RfH/75 resistant hypertension). BP readings dropped more marked in patients with RfH than resistant hypertension, in both 24-h SBP (-9 vs. -1.6 mmHg, P = 0.021) and 24-h DBP (-7.3 vs. -2.3 mmHg, P = 0.074), especially at night (-11.3 vs. -3.8, P = 0.121 and -8.8 vs. -2.2, P = 0.054) respectively. Adjusted difference between groups was statistically significant in 24-h SBP levels (-7.4 mmHg, P = 0.021). CONCLUSION:CPAP lowers BP levels in both resistant hypertension and RfH patients although the degree of this reduction is higher in those with RfH especially during the night. 10.1097/HJH.0000000000002053
    Precision Medicine in Patients With Resistant Hypertension and Obstructive Sleep Apnea: Blood Pressure Response to Continuous Positive Airway Pressure Treatment. Sánchez-de-la-Torre Manuel,Khalyfa Abdelnaby,Sánchez-de-la-Torre Alicia,Martinez-Alonso Montserrat,Martinez-García Miguel Ángel,Barceló Antonia,Lloberes Patricia,Campos-Rodriguez Francisco,Capote Francisco,Diaz-de-Atauri Maria José,Somoza Maria,González Mónica,Masa Juan-Fernando,Gozal David,Barbé Ferran, Journal of the American College of Cardiology BACKGROUND:In patients with resistant hypertension (RH) and obstructive sleep apnea (OSA), the blood pressure response to continuous positive airway pressure (CPAP) treatment is highly variable and could be associated with differential micro-ribonucleic acid (miRNA) profiles. Currently, no available methods exist to identify patients who will respond favorably to CPAP treatment. OBJECTIVES:The aim of this study was to identify plasma miRNA profiles that predict blood pressure responses to CPAP treatment. METHODS:Cardiovascular system-focused circulating miRNA expression was evaluated in plasma samples using an 84-miRNA array among patients with RH and OSA at baseline and after 3 months of adherent CPAP use. Pathway analysis and miRNA target gene enrichment were performed in silico. Plasma levels of peptides and hormones related to cardiovascular function were also measured. RESULTS:The OSA responder group exhibited blood pressure decreases exceeding the observed median (>4.5 mm Hg) after CPAP, which were not present in the nonresponder group (≤4.5 mm Hg) (p < 0.01). Three miRNAs provided a discriminatory predictive model for such a favorable blood pressure response to CPAP (area under the curve: 0.92; p = 0.01). Additionally, CPAP treatment significantly altered a total of 47 plasma miRNAs and decreased aldosterone-to-renin ratios in the responder group (p = 0.016) but not in the nonresponder group. CONCLUSIONS:A singular pre-CPAP treatment cluster of 3 plasma miRNAs predicts blood pressure responses to CPAP treatment in patients with RH and OSA. CPAP treatment is accompanied by changes in cardiovascular system-related miRNAs that may potentially influence the risk for cardiovascular disease among patients with OSA and RH. (Effect of Continuous Positive Airway Pressure [CPAP] Treatment in the Control of Refractory Hypertension; NCT00616265). 10.1016/j.jacc.2015.06.1315
    [Programs for Continuing Medical Education: A session; 4. Diagnosis and novel therapies of refractory hypertension]. Ichihara Atsuhiro Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine
    [Refractory Hypertension and Intermittent Claudication Caused by Distal Elephant Trunk Stenosis 10 Years After Total Arch Replacement for Stanford Type A Aortic Dissection;Report of a Case]. Nakawatase Satoshi,Shibukawa Takanori,Iwaguro Tetsuya,Asae Yoshinori,Miyamoto Yoshiyuki,Miyamoto Masaoki,Okumoto Yasushi,Kimura Keizo,Otani Akinobu,Shirakawa Takashi,Sakagoshi Nobuo Kyobu geka. The Japanese journal of thoracic surgery A 49-year-old man was admitted to our hospital because of intermittent claudication and refractory hypertension 10 years after surgery to Stanford type A acute aortic dissection. He underwent total arch replacement with an elephant trunk of 22 mm in diameter. Transesophageal echocardiography revealed that distal end of the elephant trunk was stenosed. Systolic blood pressure gradient over this portion reached to more than 100 mmHg. Folding of elephant trunk and thrombus formation were considered to be the cause. Thoracic endovascular aortic repair relieved stenosis and intermittent claudication, and enabled better blood pressure control.
    Stenosis of the iliac artery after kidney transplantation as a cause of refractory hypertension and intermittent claudication. Sobrino Díaz Lucía,Mosquera Rey Vicente,Rodríguez García Minerva,Alonso Pérez Manuel,Ridao Cano Natalia,Díaz Corte Carmen,Zanabili Al-Sibbai Ahmad Amer Nefrologia : publicacion oficial de la Sociedad Espanola Nefrologia 10.1016/j.nefro.2017.05.006
    Renal Intra-Arterial Heparin Flushing for Blood Pressure Control in Refractory Hypertension: A New Method to Salvage the Unsalvageable Renal Artery Stenosis. Putra Bayushi Eka,Jonny ,Soewandi Alfonsus Hilarius Indian journal of nephrology Refractory hypertension is a type of hypertension that requires special attention. Secondary causes of hypertension should be considered when uncontrolled blood pressure is present, especially in younger patients (<30 years). In this case, the presence of bilateral renal artery stenosis resulted in refractory hypertension and end-stage renal disease requiring renal replacement therapy in the form of hemodialysis. The main challenges will be discussed in this case is to deliver the most beneficial therapy considering the very limited option for revascularization therapy because of the late presentation of patient's condition. Intra-arterial heparin flushing was chosen for this patient to consider the advantages over the risks arising from the actions taken. 10.4103/ijn.IJN_194_18
    Beyond Resistant Hypertension. Martínez-García Miguel-Angel,Navarro-Soriano Cristina,Torres Gerard,Barbé Ferrán,Caballero-Eraso Candela,Lloberes Patricia,Diaz-Cambriles Teresa,Somoza María,Masa Juan F,González Mónica,Mañas Eva,de la Peña Mónica,García-Río Francisco,Montserrat Josep María,Muriel Alfonso,Selma-Ferrer Maria Jose,García Ortega Alberto,Campos-Rodriguez Francisco, Hypertension (Dallas, Tex. : 1979) Obstructive sleep apnea (OSA) is an independent cause of resistant hypertension (RH) but its association with refractory hypertension (RfH), a recently described form of severe hypertension, has not yet been investigated. This study seeks to analyze the association between the presence and severity of OSA/OSA syndrome with RfH and to compare it with a group of patients with OSA/OSA syndrome and RH. We conducted a multicenter, cross-sectional study of consecutive patients diagnosed with RH by means of 24-hour ambulatory blood pressure monitoring. Those patients with blood pressure levels ≥130/80 mm Hg, despite taking at least 5 antihypertensive drugs, were considered to have true RfH. All patients underwent a sleep study and completed a detailed clinical history related to OSA, current medication, and cardiovascular diseases. Overall, 229 patients were included (mean age, 58.3 years; 63% male), of whom 42 (18.3%) satisfied the criteria for RfH. Compared with those with RH, patients with RfH had a higher cardiovascular risk profile, higher blood pressure measurements, and a 2-fold greater risk of having both severe OSA (odds ratio, 2.1, with a prevalence of apnea-hypopnea index ≥15, 95.2% and apnea-hypopnea index ≥30, 64.3%) and OSA syndrome (apnea-hypopnea index ≥5+Epworth Sleepiness Scale >10; odds ratio, 1.9; 52.4% versus 37.3%; P=0.023), as well as higher OSA severity (apnea-hypopnea index, 41.8 versus 33.8 events/h; P=0.026). Patients with RfH had an even greater prevalence and severity of OSA and OSA syndrome than RH patients, highlighting the need to identify these patients to refer them to sleep units on a preferential basis. 10.1161/HYPERTENSIONAHA.118.11170
    Familial aortic coarctation: a rare cause of refractory hypertension in the elderly: a case report. Lara-Rojas Carmen M,Bernal-Lopez M Rosa,Lopez-Carmona M Dolores,Gomez-Huelgas Ricardo Medicine We report the first case of late presentation of familial aortic coarctation, a rare cause of hypertension. Diagnosis of familial aortic coarctation in the elderly is exceptional, given that in the absence of endovascular or surgical repair patients do not usually survive beyond 50 years of age. Our case concerns a 72-year-old woman with hypertension of long evolution, control of which improved markedly after endovascular repair of the coarctation. Her son had undergone surgery for repair of aortic coarctation at the age of 23 years. 10.1097/MD.0000000000000467
    [Renal denervation in refractory hypertension: joint statement of the German hypertension league DHL eV and the German societies of cardiology, angiology, nephrology and radiology]. Vonend Oliver,Böhm Michael,Eckert Siegfried,Hausberg Martin,Rittger Harald,Rump Lars-Christian,Schmieder Roland,Schulte Karl-Ludwig,Schunkert Heribert,Uder Michael,Veelken Roland,Vorwerk Dierk,Weil Joachim,Wenzel Ulrich,Mahfoud Felix Deutsche medizinische Wochenschrift (1946) Arterial hypertension is a major risk factor for cardiovascular mortality and remains insufficiently controlled in Germany. The sham controlled Symplicity HTN-3 trial did meet its primary safety endpoint but failed to meet its primary efficacy endpoint. Renal denervation can not replace established, well-proven therapies. It can only be used in selected truly resistant hypertensive patients as an additive approach and should be performed by specialized centers only. Randomized controlled trials are needed to further evaluate renal denervation. 10.1055/s-0041-100835
    The Effects of Sertraline in Controlling Refractory Hypertension in Women with Premenstrual Syndrome. Ranjbar Fatemeh,Akbarzadeh Fariborz,Asadlou Mahboub Iranian journal of psychiatry The aim of this study was to evaluate the effect of Premenstrual Syndrome (PMS) treatment with selective serotonin reuptake inhibitor (SSRI) on treatment response of refractory hypertension of the patients. This was a triple-blind randomized clinical trial conducted on female patients suffering from refractory hypertension and PMS at the same time. We obtained informed consent from 40 patients who had inclusion criteria and selected 20 patients for the intervention (sertraline 50 mg daily) and 20 for the control groups. The study period was five weeks. The mean of systolic and diastolic blood pressure before and after intervention was measured separately for each individual in each group and the mean of blood pressure of the members of the two groups were compared with each other. The mean age of the participants was 43.60 ± 4.57. In this study, systolic and diastolic blood pressure of both groups reduced after intervention. The mean of systolic blood pressure was reduced by 40.86 mmHg in the intervention group and this reduction was 16 mm Hg in control group after intervention (P<0.001). Comparing this reduction between the two groups, we found that reduction rate in systolic blood pressure of the two groups did not have a significant statistical difference before and after the intervention (P = 0.11). Mean of diastolic blood pressure also showed reduction of 9.17 mm Hg and that of control group showed 6.7-mmHg reduction. Reduction rate of diastolic blood pressure in the intervention group had a statistically significant difference with that of the control group (P<0.017).‎‎ : Administration of sertraline is more effective in controlling diastolic blood pressure in women suffering from refractory hypertension and comorbid PMS.
    [Baroreceptor activation therapy for therapy-resistant hypertension: indications and patient selection : Recommendations of the BAT consensus group 2017]. Koziolek M,Beige J,Wallbach M,Zenker D,Henning G,Halbach M,Mader N,Mahfoud F,Schlieper G,Schwenger V,Hausberg M,Börgel J,Lodde M,van der Giet M,Müller-Ehmsen J,Passauer J,Parmentier S,Lüders S,Krämer B K,Büttner S,Limbourg F,Jordan J,Vonend O,Predel H-G,Reuter H Der Internist Baroreceptor activation therapy (BAT) has been available for several years for treatment of therapy-refractory hypertension (trHTN). This procedure is currently being carried out in a limited number of centers in Germany, also with the aim of offering a high level of expertise through sufficient experience; however, a growing number of patients who are treated with BAT experience problems that treating physicians are confronted with in routine medical practice. In order to address these problems, a consensus conference was held with experts in the field of trHTN in November 2016, which summarizes the current evidence and experience as well as the problem areas in handling BAT patients. 10.1007/s00108-017-0308-y
    Resistant/Refractory Hypertension and Sleep Apnoea: Current Knowledge and Future Challenges. Oscullo Grace,Torres Gerard,Campos-Rodriguez Francisco,Posadas Tomás,Reina-González Angela,Sapiña-Beltrán Esther,Barbé Ferrán,Martinez-Garcia Miguel Angel Journal of clinical medicine Hypertension is one of the most frequent cardiovascular risk factors. The population of hypertensive patients includes some phenotypes whose blood pressure levels are particularly difficult to control, thus putting them at greater cardiovascular risk. This is especially true of so-called resistant hypertension (RH) and refractory hypertension (RfH). Recent findings suggest that the former may be due to an alteration in the renin-angiotensin-aldosterone axis, while the latter seems to be more closely related to sympathetic hyper-activation. Both these pathophysiological mechanisms are also activated in patients with obstructive sleep apnoea (OSA). It is not surprising, therefore, that the prevalence of OSA in RH and RfH patients is very high (as reflected in several studies) and that treatment with continuous positive airway pressure (CPAP) manages to reduce blood pressure levels in a clinically significant way in both these groups of hypertensive patients. It is therefore necessary to incorporate into the multidimensional treatment of patients with RH and RfH (changes in lifestyle, control of obesity and drug treatment) a study of the possible existence of OSA, as this is a potentially treatable disease. There are many questions that remain to be answered, especially regarding the ideal combination of treatment in patients with RH/RfH and OSA (drugs, renal denervation, CPAP treatment) and patients' varying response to CPAP treatment. 10.3390/jcm8111872
    Single-side renal sympathetic denervation to treat malignant refractory hypertension in a solitary kidney patient. Ribichini Flavio,Ferrara Angela,Pighi Michele,Pesarini Gabriele,Gambaro Alessia,Valvo Enrico,Lupo Antonio,Vassanelli Corrado Journal of nephrology Renal sympathetic denervation (RSD) is emerging as a new therapeutic option for patients with severe hypertension refractory to medical therapy. Patients affected by renovascular or anatomical abnormalities have hitherto been systematically excluded from clinical trials with RSD because of concern about safety and the unknown efficacy of the procedure in this subgroup of patients. We describe the management of a case of RSD in a single-kidney patient with refractory hypertension; the patient had had a previous surgical right nephrectomy for renal cell carcinoma that subsequently required no other oncologic treatment. After multidisciplinary assessment, the patient underwent RSD. The procedure was performed through a 6F femoral access using the Symplicity™ RSD system (Medtronic, Mountain View, CA, USA). Radiofrequency was applied to the renal artery wall in 6 different points under general sedation with midazolam to control back pain caused by the procedure, that was performed without periprocedural complications. The patient was discharged 2 days later after a control of the vascular access site and routine biochemical examinations. The following 9-month follow up showed a significant reduction in blood pressure and stable renal function, without signs of renal damage. Our report confirms the feasibility of RSD in this delicate context, without evident negative effects on kidney function and with a significant reduction in blood pressure. Future studies are needed to fully clarify the value of RSD in single-kidney patients. 10.1007/s40620-014-0059-y
    Renal Artery Denervation in Patient After Heart and Kidney Transplantation With Refractory Hypertension. Protasiewicz M,Banasik M,Kurcz J,Podgórski M,Zembala M,Zakliczyński M,Mysiak A,Boratyńska M,Klinger M Transplantation proceedings We describe the case of a 54-year-old patient after renal and heart transplantation in whom uncontrolled hypertension was diagnosed. Despite combined antihypertensive therapy, no significant therapeutic effect was achieved. Clinical assessment of ambulatory blood pressure monitoring (ABPM) revealed the ineffectiveness of a bisoprolol, nitrendypin, klonidyn, ramipryl, furosemide, and doxasosine combination used at high doses. High blood pressure levels with their effect on a hypertrophic transplanted heart (left ventricular mass 254 g) and poor renal graft function (39 mL/kg/min) posed an extremely high risk of future cardiovascular complications, and were the reason to perform a native renal arteries denervation. The procedure was carried out through the right femoral artery with the use of a 6F guiding catheter. During a 1-year observation, significant decreases in ABPM systolic and diastolic blood pressures were observed after the procedure (168/88 mm Hg vs 154/77 mm Hg, respectively). Moreover a significant regression of left ventricular mass (215 g/m(2)) and stable renal graft function were noted. The presented case shows that native renal arteries denervation may be successful and safe in kidney and heart transplant recipients. Moreover, during the 1-year follow-up, the reduction in blood pressure was followed by a reduction in transplanted heart hypertrophy, both leading to regression of cardiovascular risk for the patient. 10.1016/j.transproceed.2016.01.043
    The Potential Role of Obstructive Sleep Apnoea in Refractory Hypertension. Oscullo Grace,Sapiña-Beltrán E,Torres Gerard,Zaldivar Enrique,Barbé Ferran,Martinez-Garcia Miguel Angel Current hypertension reports PURPOSE OF REVIEW:This review seeks to present an overview of the recently found association between refractory hypertension (RfH) and obstructive sleep apnoea (OSA). RECENT FINDINGS:RfH was recently defined as an extreme phenotype of resistant hypertension characterized by the lack of blood pressure control despite using ≥ 5 antihypertensive drugs at optimal doses. Current data support that the pathophysiological pathway of both types of hypertension is different. The main mechanism involved in resistant hypertension is fluid retention whereas in the case of RfH is the sympathetic over-activity. OSA is now recognized as a cause of hypertension (especially in the case of difficult-to-treat hypertension). It seems that the biological mechanism linking OSA and arterial hypertension is the sympathetic over-activity related to the respiratory events (apnoeas and hypopnoeas) during the night. So, it is not surprising that, although the literature is scarce, some studies have found a very high prevalence of OSA and an excess of sympathetic activity in patients with RfH. Finally, a very recent study demonstrated that continuous positive airway pressure (CPAP) treatment, which controls sympathetic activation in OSA patients, achieves very significant reductions in blood pressure levels in RfH patients, even greater than in those with resistant (non-refractory) hypertension. The prevalence of OSA in patients with RfH is very high. CPAP treatment achieves a clinically significant reduction in blood pressure levels in those patients with RfH (especially in night readings). Patients with RfH must be sent to a sleep unit for a study. 10.1007/s11906-019-0963-6
    Renal sympathetic denervation for the treatment of refractory hypertension. Leong Kui Toh Gerard,Walton Antony,Krum Henry Annual review of medicine Resistant hypertension poses significant health concerns. There are strong demands for new and safe therapies to control resistant hypertension while addressing its common causes, specifically poor compliance to lifelong polypharmacy, lifestyle modifications, and physician inertia. The sympathetic nervous system plays a significant pathophysiological role in hypertension. Surgical sympathectomy for blood pressure reduction is an old but extremely efficacious therapeutic concept, now abandoned with the dawn of a safer contemporary pharmacology era. Recently, clinical studies have revealed promising results for safe and sustained blood pressure reduction with percutaneous renal sympathetic denervation. This is a novel, minimally invasive, device-based therapy, specifically targeting and ablating the renal artery nerves with radiofrequency waves without permanent implantation. There are also reported additional benefits in related comorbidities, such as impaired glucose metabolism, renal impairment, left ventricular hypertrophy, heart failure, and others. This review focuses on how selective renal sympathetic denervation works, its present and potential therapeutic indications, and its future directions. 10.1146/annurev-med-051812-145353
    Antihypertensive Medication Adherence and Confirmation of True Refractory Hypertension. Siddiqui Mohammed,Judd Eric K,Dudenbostel Tanja,Gupta Pankaj,Tomaszewski Maciej,Patel Prashanth,Oparil Suzanne,Calhoun David A Hypertension (Dallas, Tex. : 1979) Refractory hypertension (RfHTN) is a phenotype of antihypertensive treatment failure defined as uncontrolled BP despite the use of effective doses of ≥5 antihypertensive medications including a long-acting thiazide-like diuretic (chlorthalidone) and a mineralocorticoid receptor antagonist. The degree of medication nonadherence is unknown among patients with RfHTN. In this prospective evaluation, 54 patients with apparent RfHTN were recruited from the University of Alabama at Birmingham Hypertension Clinic after having uncontrolled BP at 3 or more clinic visits. All patients' BP was evaluated by automated office BP and 24-hour ambulatory BP monitoring (n=49). Antihypertensive medication adherence was determined by measuring 24-hour urine specimens for antihypertensive medications and their metabolites by high-performance liquid chromatography-tandem mass spectrometry (n=45). Of the 45 patients who completed 24-hour ambulatory BP monitoring, 40 (88.9%) had confirmed RfHTN based on an elevated automated office BP (≥130/80 mm Hg), mean 24-hour ABP (≥125/75 mm Hg), and mean awake (day-time) ABP (≥130/80 mm Hg). Out of the 40 fully evaluated patients with RfHTN, 16 (40.0%) were fully adherent with all prescribed medications. Eighteen (45.0%) patients were partially adherent and 6 (15.0%) had none of the prescribed agents detected in their urine. Of 18 patients who were partially adherent, 5 (12.5%) were adherent with at least 5 medications, including chlorthalidone and the mineralocorticoid receptor antagonist, consistent with true RfHTN. Of patients identified as having apparent RfHTN, 52.5% were adherent with at least 5 antihypertensive medications, including chlorthalidone and a mineralocorticoid receptor antagonist, confirming true RfTHN. These findings validate RfHTN as a rare, but true phenotype of antihypertensive treatment failure. 10.1161/HYPERTENSIONAHA.119.14137
    Effects of spironolactone on dialysis patients with refractory hypertension: a randomized controlled study. Ni Xiaoying,Zhang Jisheng,Zhang Ping,Wu Fuquan,Xia Min,Ying Guanghui,Chen Jianghua Journal of clinical hypertension (Greenwich, Conn.) The purpose of this study was to evaluate the effects of spironolactone on dialysis patients with refractory hypertension and possible adverse effects. This was a 12-week prospective, randomized, double-blind trial of 82 patients randomly assigned to 12-week treatment with 25 mg/d spironolactone or placebo as add-on therapy. Visits were scheduled at the start of treatment and after 12 weeks. Measurements of 24-hour ambulatory blood pressure (BP) monitoring and morning BP were performed. After 12 weeks, spironolactone significantly improved refractory hypertension. Average placebo-corrected morning BP was reduced by 16.7/7.6 mm Hg. Mean 24-hour ambulatory BP was reduced by 10.9/5.8 mm Hg. In contrast, serum aldosterone levels in the spironolactone group slightly increased and serum potassium levels insignificantly increased. This study has demonstrated that spironolactone (50 mg) safely and effectively reduces BP in patients with refractory hypertension undergoing dialysis. 10.1111/jch.12374
    A Young Female With Refractory Hypertension. Nassiri Nima,Maas Marissa,Fichtenbaum Eric J,Aron Monish Urology A 29-year-old female was referred to the urology clinic because of an incidentally found left renal mass discovered during workup for secondary erythrocytosis. Since 12 years of age, she has had headaches and poorly controlled hypertension refractory to trimodal antihypertensive therapy. Laboratory workup revealed markedly elevated aldosterone and renin levels. Computed tomography demonstrated a 3 cm left renal mass. The patient was admitted for intravenous blood pressure control. After partial nephrectomy, aldosterone and renin levels normalized. The patient was weaned off of blood pressure medications. Pathology was consistent with a juxtaglomerular cell tumor secreting renin (ie, reninoma). 10.1016/j.urology.2019.09.033
    Refractory versus resistant hypertension: Novel distinctive phenotypes. Dudenbostel Tanja,Siddiqui Mohammed,Gharpure Nitin,Calhoun David A Journal of nature and science Resistant hypertension (RHTN) is relatively common with an estimated prevalence of 10-20% of treated hypertensive patients. It is defined as blood pressure (BP) >140/90 mmHg treated with ≥3 antihypertensive medications, including a diuretic, if tolerated. Refractory hypertension is a novel phenotype of severe antihypertensive treatment failure. The proposed definition for refractory hypertension, i.e. BP >140/90 mmHg with use of ≥5 different antihypertensive medications, including a diuretic a mineralocorticoid receptor antagonist (MRA) has been applied inconsistently. In comparison to RHTN, refractory hypertension seems to be less prevalent than RHTN. This review focuses on current knowledge about this novel phenotype compared with RHTN including definition, prevalence, mechanisms, characteristics and comorbidities, including cardiovascular risk. In patients with RHTN excess fluid retention is thought to be a common mechanism for the development of RHTN. Recently, evidence has emerged suggesting that refractory hypertension may be more of neurogenic etiology due to increased sympathetic activity as opposed to excess fluid retention. Treatment recommendations for RHTN are generally based on use and intensification of diuretic therapy, especially with the combination of a long-acting thiazide-like diuretic and an MRA. Based on findings from available studies, such an approach does not seem to be a successful strategy to control BP in patients with refractory hypertension and effective sympathetic inhibition in such patients, either with medications and/or device based approaches may be needed.
    Prevalence of refractory hypertension in the United States from 1999 to 2014. Buhnerkempe Michael G,Botchway Albert,Prakash Vivek,Al-Akchar Mohammad,Nolasco Morales Carlos E,Calhoun David A,Flack John M Journal of hypertension OBJECTIVES:Refractory hypertension has been defined as uncontrolled blood pressure (at or above 140/90 mmHg) when on five or more classes of antihypertensive medication, inclusive of a diuretic. Because unbiased estimates of the prevalence of refractory hypertension in the United States are lacking, we aim to provide such estimates using data from the National Health and Nutrition Examination Surveys (NHANES). METHODS:Refractory hypertension was assessed across multiple NHANES cycles using the aforementioned definition. Eight cycles of NHANES surveys (1999-2014) representing 41 552 patients are the subject of this study. Prevalence of refractory hypertension across these surveys was estimated in the drug-treated hypertensive population after adjusting for the complex survey design and standardizing for age. RESULTS:Across all surveys, refractory hypertension prevalence was 0.6% [95% confidence interval (CI) (0.5, 0.7)] amongst drug-treated hypertensive adults; 6.2% [95% CI (5.1, 7.6)] of individuals with treatment-resistant hypertension actually had refractory hypertension. Although the prevalence of refractory hypertension ranged from 0.3% [95% CI (0.1, 1.0)] to 0.9% [95% CI (0.6, 1.2)] over the eight cycles considered, there was no significant trend in prevalence over time. Refractory hypertension prevalence amongst those prescribed five or more drugs was 34.5% [95% CI (27.9, 41.9)]. Refractory hypertension was associated with advancing age, lower household income, black race, and also chronic kidney disease, albuminuria, diabetes, prior stroke, and coronary heart disease. CONCLUSIONS:We provided the first nationally representative estimate of refractory hypertension prevalence in US adults. 10.1097/HJH.0000000000002103
    Prevalence and Clinical Characteristics of Refractory Hypertension. Armario Pedro,Calhoun David A,Oliveras Anna,Blanch Pedro,Vinyoles Ernest,Banegas Jose R,Gorostidi Manuel,Segura Julián,Ruilope Luis M,Dudenbostel Tanja,de la Sierra Alejandro Journal of the American Heart Association BACKGROUND:We aimed to estimate the prevalence of refractory hypertension (RfH) and to determine the clinical differences between these patients and resistant hypertensives (RH). Secondly, we assessed the prevalence of white-coat RfH and clinical differences between true- and white-coat RfH patients. METHODS AND RESULTS:The present analysis was conducted on the Spanish Ambulatory Blood Pressure Monitoring Registry database containing 70 997 treated hypertensive patients. RH and RfH were defined by the presence of elevated office blood pressure (≥140 and/or 90 mm Hg) in patients treated with at least 3 (RH) and 5 (RfH) antihypertensive drugs. White-coat RfH was defined by RfH with normal (<130/80 mm Hg) 24-hour blood pressure. A total of 11.972 (16.9%) patients fulfilled the standard criteria of RH, and 955 (1.4%) were considered as having RfH. Compared with RH patients, those with RfH were younger, more frequently male, and after adjusting for age and sex, had increased prevalence of target organ damage, and previous cardiovascular disease. The prevalence of white coat RfH was lower than white-coat RH (26.7% versus 37.1%, <0.001). White-coat RfH, in comparison with those with true RfH, showed a lower prevalence of both left ventricular hypertrophy (22% versus 29.7%; =0.018) and microalbuminuria (28.3% versus 42.9%; =0.047). CONCLUSIONS:The prevalence of RfH was low and these patients had a greater cardiovascular risk profile compared with RH. One out of 4 patients with RfH have normal 24-hour blood pressure and less target organ damage, thus indicating the important role of ambulatory blood pressure monitoring in guiding antihypertensive therapy in difficult-to-treat patients. 10.1161/JAHA.117.007365
    [Physician knowledge and attitudes on the clinical evaluation and treatment of resistant hypertension: The RESIST study]. Coca A Hipertension y riesgo vascular BACKGROUND:Resistant hypertension (RH) is associated with a high risk of cardiovascular and renal complications. The purpose of this study was to assess the knowledge and attitudes of Primary Care physicians, general medicine doctors, and clinical cardiologists on the management of this condition. MATERIAL AND METHODS:A multicentre, descriptive, observational study based on an ad hoc questionnaire distributed to Primary Care physicians (n=1017) and general medicine physicians/clinical cardiologists (n=457). RESULTS:To establish the diagnosis of resistant hypertension, 69.1% of physicians confirm that systolic/diastolic blood pressure is above 140/90 mmHg, despite treatment. Furthermore, 64.9% only consider this diagnosis if the patient is treated with at least 3 medications, and 50.3% also requires that one of them is a thiazide diuretic (56.7% among specialists, P=.0004). To establish a definite diagnosis of true RH, 89.6% perform 24-h ambulatory blood pressure monitoring (93.3% of specialists, P=.0017), looking specifically for «white-coat» effect in 70.2% of cases. In addition, 79.3% verify that adherence to treatment is adequate. Between 87 and 95% of physicians indicate examinations to exclude causes of secondary hypertension. Up to 54.3% of physicians (71.3% specialists, P<.0001) consider adding a fourth drug and insisting on lifestyle interventions as a priority therapeutic measure. CONCLUSION:These data show that physician knowledge regarding the management of patients with RH is good. Interestingly, this knowledge is somewhat higher among specialists than among Primary Care physicians. 10.1016/j.hipert.2016.07.001
    Hirschsprung's Disease-Related Giant Sigmoid Volvulus Complicated by Refractory Hypertension in an Elderly Man. Wu Shaohan,Sun Xiaofang,Yu Yawei,Shen Yiyu The American journal of case reports BACKGROUND Sigmoid volvulus (SV) is a life-threatening condition occasionally seen in adults. Adult Hirschsprung's disease (HD)-related SV is rarely complicated by difficult-to-control hypertension. In this report we present the case of an elderly man with a rare constellation of HD, SV, and refractory hypertension. CASE REPORT An 82-year-old man had long-term constipation, moderate abdominal pain, and progressive abdominal distension. A CT scan revealed the typical "coffee bean sign". Blood pressure was abnormal high. Subsequently, the patient's condition deteriorated. Therefore, he underwent a Hartmann's procedure. A giant and redundant sigmoid colon (length more than 60 cm, maximal diameter about 15 cm) was demonstrated to be the cause of SV during the process of surgery. Moreover, abdominal compartment syndrome caused by SV resulted in his high and refractory blood pressure (BP). Postoperative pathological results revealed HD in his sigmoid colon. CONCLUSIONS SV is rarely combined with conditions like refractory hypertension or HD among the elderly. Clinical features of SV typically present with long-term constipation, severe abdominal pain, and progressive abdominal distension. The "coffee bean sign" could be observed in imaging examinations. It is important to note that the management of SV is to relieve the obstruction and prevent recurrence, no matter which therapy is used in elderly patients with Hirschsprung's disease. 10.12659/ajcr.908389
    Resistant and refractory hypertension: two sides of the same disease? Muxfeldt Elizabeth Silaid,Chedier Bernardo,Rodrigues Cibele Isaac Saad Jornal brasileiro de nefrologia : 'orgao oficial de Sociedades Brasileira e Latino-Americana de Nefrologia Refractory hypertension (RfH) is an extreme phenotype of resistant hypertension (RH), being considered an uncontrolled blood pressure besides the use of 5 or more antihypertensive medications, including a long-acting thiazide diuretic and a mineralocorticoid antagonist. RH is common, with 10-20% of the general hypertensives, and its associated with renin angiotensin aldosterone system hyperactivity and excess fluid retention. RfH comprises 5-8% of the RH and seems to be influenced by increased sympathetic activity. RH patients are older and more obese than general hypertensives. It is strongly associated with diabetes, obstructive sleep apnea, and hyperaldosteronism status. RfH is more frequent in women, younger patients and Afro-americans compared to RFs. Both are associated with increased albuminuria, left ventricular hypertrophy, chronic kidney diseases, stroke, and cardiovascular diseases. The magnitude of the white-coat effect seems to be higher among RH patients. Intensification of diuretic therapy is indicated in RH, while in RfH, therapy failure imposes new treatment alternatives such as the use of sympatholytic therapies. In conclusion, both RH and RfH constitute challenges in clinical practice and should be addressed as distinct clinical entities by trained professionals who are capable to identify comorbidities and provide specific, diversified, and individualized treatment. 10.1590/2175-8239-JBN-2018-0108
    Reliable and easy-to-use LC-MS/MS-method for simultaneous determination of the antihypertensives metoprolol, amlodipine, canrenone and hydrochlorothiazide in patients with therapy-refractory arterial hypertension. Johannsen Jan-Ole,Reuter Hannes,Hoffmann Fabian,Blaich Cornelia,Wiesen Martin H J,Streichert Thomas,Müller Carsten Journal of pharmaceutical and biomedical analysis BACKGROUND:Therapy-refractory arterial hypertension is defined as a blood pressure (BP) in a subset of patients who fail to achieve BP control despite a three-drug regimen (including a diuretic). Various factors have impact on loss of therapy response. Drug-drug-interactions (DDIs) may cause altered pharmacokinetics (PK) of antihypertensive drugs. Upregulation of activity and expression of cytochrome P450 (CYP) enzymes can result in decreased plasma drug levels. Besides these PK considerations a significant problem could be nonadherence to drug therapy. In this regard Therapeutic Drug Monitoring (TDM) is a useful tool for detecting nonadherence. Therefore a LC-MS/MS-method for determination of Metoprolol (MET), Amlodipine (AML), Canrenone (CAN) and Hydrochlorothiazide (HCT) was developed. METHODS:An UHPLC-MS/MS method was developed and validated for simultaneous determination of MET, AML, CAN and HCT in plasma matrix. Extraction of serum samples consisted of simple protein precipitation using acetonitrile. Stable isotope labeled analogues for each antihypertensive were obtained for internal standardization and quantitative analysis ([H]-MET, ([C]-AML, [H]-CAN, [C]-HCT). Calibrators and quality controls were prepared in plasma matrix of normal individuals. Sample preparation: protein precipitation with acetonitrile and addition of internal standard-mix. RESULTS:All analytes were eluted within a runtime of 2.5 min. Linearity experiments were demonstrated in plasma over following concentration ranges: MET: 5-750 μg/l, AML: 1-50 μg/l, CAN: 10-500 μg/l, HCT: 5-500 μg/l (R > 0.993). Chromatographic separation was achieved using a C18 column (50 × 2.1 mm, 1.9 μm particle size) and an isocratic elution. LC-MS/MS analyses were performed on a triple quadrupole mass spectrometer using positive and negative electrospray ionization in selected reaction monitoring (SRM) mode. Ion transitions monitored for quantitation were m/z 268.2 → 74.1 for MET, m/z 409.1 → 238.0 for AML, m/z 341.2 → 91.0 for CAN and m/z 296.0 → 205.1 for HCT. For all analytes, inter- and intra-day precision (CV, %) varied between 1.7 and 14.0 and inter- and intra-day accuracy values ranged from -2.5 to 7.1%. The lower limits of detection and quantification were: 0.08 and 0.23; 0.05 and 0.15; 2.82 and 8.54; and 0.02 and 0.05 μg/l for MET, AML, CAN and HCT, respectively. Results of stability experiments were within the required range of +/- 15%. CONCLUSIONS:Although the level of recommendation of TDM of antihypertensive drugs in patients with refractory hypertension is not yet established, the present LC-MS/MS-method can serve as an effective tool for detection of PK-alterations/nonadherence and may help to monitor antihypertensive pharmacotherapy. 10.1016/j.jpba.2018.11.002
    Severe and refractory hypertension in a young woman. Cuadra René H,White William B Journal of the American Society of Hypertension : JASH Refractory hypertension in a young person is an uncommon clinical problem, but one that may be referred to hypertension specialists. Factitious hypertension is fortunately quite rare but should be considered when evaluating patients who are refractory to numerous classes of antihypertensive therapies and have failed to achieve control despite input from multiple providers. A 19-year-old woman was referred to us after failing to achieve blood pressure control by a primary physician and two subspecialists in nephrology and hypertension; she also had numerous emergency department visits for symptomatic and severe hypertension. Exhaustive diagnostic testing for secondary causes and witnessed medication dosing in an outpatient setting was unrevealing. Subsequent inpatient admission demonstrated normalization of BPs with small doses of intravenous antihypertensive agents. During the hospitalization, she was observed "pocketing" her oral medications in the buccal folds and then discarding them in a trash container. Confrontation by psychiatrists and the hypertension specialists led to the admission that she had learned to start and stop beta-blockers and clonidine to induce severe, rebound hypertension. Factitious and induced hypertension is a rare cause of resistant or refractory hypertension. Nevertheless, hypertension specialists should suspect the diagnosis when there is a history of visits to multiple institutions and physicians, negative secondary workup, absence of overt target organ damage, history of psychiatric illness, and employment in the medical field. 10.1016/j.jash.2016.03.193
    [Treatment options for resistant hypertension: from pseudoresistant to refractory hypertension]. Versmissen Jorie,Hendriks Kelly,van den Meiracker Anton H,Kappers Mariëtte H W Nederlands tijdschrift voor geneeskunde Resistant hypertension is defined as blood pressure above the target level despite treatment with 3 classes of antihypertensive drugs, including a diuretic. A large number of patients meeting the definition of TRH actually have 'pseudoresistant hypertension': there is either a secondary cause of the hypertension, non-adherence, high dietary salt intake, or use of interfering co-medication or recreational drugs. Treating pseudoresistant hypertension is just as challenging as 'true' resistant hypertension since causes of resistance cannot always be eliminated and elimination of causes will not necessarily lead to blood pressure normalization. It is estimated that only 10% of patients with TRH have 'true' resistant hypertension. A very small proportion of these patients is defined as having 'refractory hypertension' because their blood pressure still remains uncontrolled despite extending their medication to five or more agents, including an aldosterone receptor blocker. At present, non-pharmacological, invasive interventions should be considered only in patients with refractory hypertension.
    Pathophysiology and Potential Non-Pharmacologic Treatments of Obesity or Kidney Disease Associated Refractory Hypertension. Le Jemtel Thierry H,Richardson William,Samson Rohan,Jaiswal Abhishek,Oparil Suzanne Current hypertension reports PURPOSE OF REVIEW:The review assesses the role of non-pharmacologic therapy for obesity and chronic kidney disease (CKD) associated refractory hypertension (rf HTN). RECENT FINDINGS:Hypertensive patients with markedly heightened sympathetic nervous system (SNS) activity are prone to develop refractory hypertension (rfHTN). Patients with obesity and chronic kidney disease (CKD)-associated HTN have particularly heightened SNS activity and are at high risk of rfHTN. The role of bariatric surgery is increasingly recognized in treatment of obesity. Current evidence advocates for a greater role of bariatric surgery in the management of obesity-associated HTN. In contrast, renal denervation does not appear have a role in the management of obesity or CKD-associated HTN. The role of baroreflex activation as adjunctive anti-hypertensive therapy remains to be defined. 10.1007/s11906-017-0713-6
    Refractory Hypertension: A Novel Phenotype of Antihypertensive Treatment Failure. Dudenbostel Tanja,Siddiqui Mohammed,Oparil Suzanne,Calhoun David A Hypertension (Dallas, Tex. : 1979) 10.1161/HYPERTENSIONAHA.116.06587
    Refractory and Resistant Hypertension: Antihypertensive Treatment Failure versus Treatment Resistance. Calhoun David A Korean circulation journal Resistant hypertension has for many decades been defined as difficult-to-treat hypertension in order to identify patients who may benefit from special diagnostic and/or therapeutic considerations. Recently, the term "refractory hypertension" has been proposed as a novel phenotype of antihypertensive failure, that is, patients whose blood pressure cannot be controlled with maximal treatment. Early studies of this phenotype indicate that it is uncommon, affecting less than 5% of patients with resistant hypertension. Risk factors for refractory hypertension include obesity, diabetes, chronic kidney disease, and especially, being of African origin. Patients with refractory are at high cardiovascular risk based on increased rates of known heart disease, prior stroke, and prior episodes of congestive heart failure. Mechanisms of refractory hypertension need exploration, but early studies suggest a possible role of heightened sympathetic tone as evidenced by increased office and ambulatory heart rates and higher urinary excretion of norepinephrine compared to patients with controlled resistant hypertension. Important negative findings argue against refractory hypertension being fluid dependent as is typical of resistant hypertension, including aldosterone levels, dietary sodium intake, and brain natriuretic peptide levels being similar or even less than patients with resistant hypertension and the failure to control blood pressure with use of intensive diuretic therapy, including both a long-acting thiazide diuretic and a mineralocorticoid receptor antagonist. Further studies, especially longitudinal assessments, are needed to better characterize this extreme phenotype in terms of risk factors and outcomes and hopefully to identify effective treatment strategies. 10.4070/kcj.2016.46.5.593
    Refractory versus resistant hypertension. Siddiqui Mohammed,Calhoun David A Current opinion in nephrology and 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. 10.1097/MNH.0000000000000286
    Treatment of Resistant and Refractory Hypertension. Acelajado Maria Czarina,Hughes Zachary H,Oparil Suzanne,Calhoun David A Circulation research 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. 10.1161/CIRCRESAHA.118.312156
    [Therapy-resistant and therapy-refractory arterial hypertension]. Wallbach M,Koziolek M J Der Internist Therapy-resistant and therapy-refractory arterial hypertension differ in prevalence, pathogenesis, prognosis and therapy. In both cases, a structured approach is required, with the exclusion of pseudoresistance and, subsequently, secondary hypertension. Resistant hypertension has been reported to be more responsive to intensified diuretic therapy, whereas refractory hypertension is presumed to require sympathoinhibitory therapy. Once the general measures and the drug-based step-up therapy have been exhausted, interventional procedures are available. 10.1007/s00108-018-0430-5
    Refractory Hypertension Is not Attributable to Intravascular Fluid Retention as Determined by Intracardiac Volumes. Velasco Alejandro,Siddiqui Mohammed,Kreps Eric,Kolakalapudi Pavani,Dudenbostel Tanja,Arora Garima,Judd Eric K,Prabhu Sumanth D,Lloyd Steven G,Oparil Suzanne,Calhoun David A Hypertension (Dallas, Tex. : 1979) Refractory hypertension (RfHTN) is an extreme phenotype of antihypertensive treatment failure defined as lack of blood pressure control with ≥5 medications, including a long-acting thiazide and a mineralocorticoid receptor antagonist. RfHTN is a subgroup of resistant hypertension (RHTN), which is defined as blood pressure >135/85 mm Hg with ≥3 antihypertensive medications, including a diuretic. RHTN is generally attributed to persistent intravascular fluid retention. It is unknown whether alternative mechanisms are operative in RfHTN. Our objective was to determine whether RfHTN is characterized by persistent fluid retention, indexed by greater intracardiac volumes determined by cardiac magnetic resonance when compared with controlled RHTN patients. Consecutive patients evaluated in our institution with RfHTN and controlled RHTN were prospectively enrolled. Exclusion criteria included advanced chronic kidney disease and masked or white coat hypertension. All enrolled patients underwent biochemical testing and cardiac magnetic resonance. The RfHTN group (n=24) was younger (mean age, 51.7±8.9 versus 60.6±11.5 years; =0.003) and had a greater proportion of women (75.0% versus 43%; =0.02) compared with the controlled RHTN group (n=30). RfHTN patients had a greater left ventricular mass index (88.3±35.0 versus 54.6±12.5 g/m; <0.001), posterior wall thickness (10.1±3.1 versus 7.7±1.5 mm; =0.001), and septal wall thickness (14.5±3.8 versus 10.0±2.2 mm; <0.001). There was no difference in B-type natriuretic peptide levels and left atrial or ventricular volumes. Diastolic dysfunction was noted in RfHTN. Our findings demonstrate greater left ventricular hypertrophy without chamber enlargement in RfHTN, suggesting that antihypertensive treatment failure is not attributable to intravascular volume retention. 10.1161/HYPERTENSIONAHA.118.10965
    Rescue baroreflex activation therapy after Stanford B aortic dissection due to therapy-refractory hypertension. Weipert Kay F,Most Astrid,Dörr Oliver,Helmig Inga,Elzien Meshal,Krombach Gabriele,Hamm Christian W,Erkapic Damir,Schmitt Joern Journal of the American Society of Hypertension : JASH Clinical trials have demonstrated significant and durable reduction in arterial pressure from baroreflex activation therapy (BAT) in patients with resistant arterial hypertension. There is a lack of data, however, concerning the use of BAT in a rescue approach during therapy-refractory hypertensive crisis resulting in life-threatening end-organ damage. Here, we describe the first case in which BAT was applied as a rescue procedure in an intensive care setting after ineffective maximum medical treatment. A 34-year-old male patient presented with Stanford B aortic dissection and hypertensive crisis. The dissection membrane extended from the left subclavian artery down to the right common iliac artery, resulting in a total arterial occlusion of the right leg. After emergency thoracic endovascular aortic repair and femorofemoral crossover bypass, the patient developed a compartment syndrome of the right lower limb, ultimately leading to amputation of the right leg above the knee. Even under deep sedation recurrent hypertensive crises of up to 220 mm Hg occurred that could not be controlled by eight antihypertensive drugs of different classes. Screening for secondary hypertension was negative. Eventually, rescue implantation of right-sided BAT was performed as a bailout procedure, followed by immediate activation of the device. After a hospital stay of a total of 8 weeks, the patient was discharged 2 weeks after BAT initiation with satisfactory blood pressure levels. After 1-year follow-up, the patient has not had a hypertensive crisis since the onset of BAT and is currently on fourfold oral antihypertensive therapy. The previously described bailout procedures for the treatment of life-threatening hypertensive conditions that are refractory to drug treatment have mainly comprised the interventional denervation of renal arteries. The utilization of BAT is new in this emergency context and showed a significant, immediate, and sustained reduction of blood pressure levels after activation. To our knowledge, we report the first case of an immediate activation of a barostim while the device is usually not activated before 2 to 4 weeks after implantation to allow time for the surgical site to heal. During the follow-up period, the healing process was not impaired, and a significant, immediate, and sustained reduction of blood pressure levels after activation could be observed. This treatment option offers maximum adherence to antihypertensive therapy to avoid future cardiovascular end-organ damage and possibly reduce antihypertensive medication and undesirable side effects. 10.1016/j.jash.2016.03.195
    Prevalence, clinical characteristics and echocardiography parameters of non-resistant, resistant and refractory hypertension in Chinese. Cao Gaozhen,Chen Cong,Lin Qingshan,Chen Yan,Zhen Zhe,Zou Yuan,Liu Juhua,Wu Min,Wang Run,Liu Mingya,Zhao Chunting,Lu Shukun,Ng Ming-Yen,Tse Hung-Fat,Yiu Kai-Hang Postgraduate medicine OBJECTIVES:Refractory and resistant hypertension is defined as hypertension that is uncontrolled despite the use of multiple antihypertensives. The aim of the present study is to evaluate the prevalence, both in young and elderly, and the pattern of left ventricular hypertrophy (LVH) in South-Eastern Chinese patients with refractory, resistant and non-resistant hypertension. METHODS:A total of 1455 patients (age 60.3 ± 13.9, male 55.7%) with essential hypertension were recruited. Refractory hypertension was defined as uncontrolled blood pressure (systolic/diastolic, ≥140/90 mm Hg) on ≥5 antihypertensive drug classes. Resistant hypertension was defined as uncontrolled blood pressure (systolic/diastolic, ≥140/90 mm Hg) on 3 or <140/90 mm Hg on ≥4 antihypertensive classes. RESULTS:Among the total population, 1273 (87.4%) patients were considered non-resistant hypertension; 170 (11.7%) with resistant hypertension and 12 (0.8%) with refractory hypertension. The prevalence of the three groups of hypertension were similar between patients age <60 or ≥60. Patients with refractory hypertension had the most dilated LV dimension, greatest left ventricular mass index and highest prevalence of diastolic dysfunction than patients with resistant and non-resistant hypertension. In particular, all patients with refractory hypertension had either concentric or eccentric LVH. CONCLUSIONS:In South-Eastern Chinese patients, the prevalence of refractory and resistant hypertension was 0.8% and 11.7%, respectively. Furthermore, no difference was observed in the hypertensive patterns between patients age <60 and ≥60. Importantly, patients with refractory hypertension had the worst LV remodeling with all suffering from either concentric or eccentric hypertrophy. 10.1080/00325481.2017.1272398
    Resistant and Refractory Hypertension: Antihypertensive Treatment Resistance vs Treatment Failure. Siddiqui Mohammed,Dudenbostel Tanja,Calhoun David A The Canadian journal of cardiology Resistant or difficult to treat hypertension is defined as high blood pressure that remains uncontrolled with 3 or more different antihypertensive medications, including a diuretic. Recent definitions also include controlled blood pressure with use of 4 or more medications as also being resistant to treatment. Recently, refractory hypertension, an extreme phenotype of antihypertensive treatment failure has been defined as hypertension uncontrolled with use of 5 or more antihypertensive agents, including a long-acting thiazide diuretic and a mineralocorticoid receptor antagonist. Patients with resistant vs refractory hypertension share similar characteristics and comorbidities, including obesity, African American race, female sex, diabetes, coronary heart disease, chronic kidney disease, and obstructive sleep apnea. Patients with refractory vs resistant hypertension tend to be younger and are more likely to have been diagnosed with congestive heart failure. Refractory hypertension might also differ from resistant hypertension in terms of underlying cause. Preliminary evidence suggests that refractory hypertension is more likely to be neurogenic in etiology (ie, heightened sympathetic tone), vs a volume-dependent hypertension that is more characteristic of resistant hypertension in general. 10.1016/j.cjca.2015.06.033
    The effects of baroreflex activation therapy on blood pressure and sympathetic function in patients with refractory hypertension: the rationale and design of the Nordic BAT study. Gordin Daniel,Fadl Elmula Fadl Elmula M,Andersson Bert,Gottsäter Anders,Elf Johan,Kahan Thomas,Christensen Kent Lodberg,Vikatmaa Pirkka,Vikatmaa Leena,Bastholm Olesen Thomas,Groop Per-Henrik,Olsen Michael Hecht,Tikkanen Ilkka, Blood pressure OBJECTIVE:To explore the effects of baroreflex activation therapy (BAT) on hypertension in patients with treatment resistant or refractory hypertension. METHODS:This investigator-initiated randomized, double-blind, 1:1 parallel-design clinical trial will include 100 patients with refractory hypertension from 6 tertiary referral hypertension centers in the Nordic countries. A Barostim Neo System will be implanted and after 1 month patients will be randomized to either BAT for 16 months or continuous pharmacotherapy (BAT off) for 8 months followed by BAT for 8 months. A second randomization will take place after 16 months to BAT or BAT off for 3 months. Eligible patients have a daytime systolic ambulatory blood pressure (ABPM) of  ≥145 mm Hg, and/or a daytime diastolic ABPM of  ≥95 mm Hg after witnessed drug intake (including  ≥3 antihypertensive drugs, preferably including a diuretic). RESULTS:The primary end point is the reduction in 24-hour systolic ABPM by BAT at 8 months, as compared to pharmacotherapy. Secondary and tertiary endpoints are effects of BAT on home and office blood pressures, measures of indices of cardiac and vascular structure and function during follow-up, and safety. CONCLUSIONS:This academic initiative will increase the understanding of mechanisms and role of BAT in the refractory hypertension. 10.1080/08037051.2017.1332477
    Refractory Hypertension: Evidence of Heightened Sympathetic Activity as a Cause of Antihypertensive Treatment Failure. Dudenbostel Tanja,Acelajado Maria C,Pisoni Roberto,Li Peng,Oparil Suzanne,Calhoun David A Hypertension (Dallas, Tex. : 1979) Refractory hypertension is an extreme phenotype of treatment failure defined as uncontrolled blood pressure in spite of ≥5 classes of antihypertensive agents, including chlorthalidone and a mineralocorticoid receptor antagonist. A prospective evaluation of possible mechanisms of refractory hypertension has not been done. The goal of this study was to test for evidence of heightened sympathetic tone as indicated by 24-hour urinary normetanephrine levels, clinic and ambulatory heart rate (HR), HR variability, arterial stiffness as indexed by pulse wave velocity, and systemic vascular resistance compared with patients with controlled resistant hypertension. Forty-four consecutive patients, 15 with refractory and 29 with controlled resistant hypertension, were evaluated prospectively. Refractory hypertensive patients were younger (48±13.3 versus 56.5±14.1 years; P=0.038) and more likely women (80.0 versus 51.9%; P=0.047) compared with patients with controlled resistant hypertension. They also had higher urinary normetanephrine levels (464.4±250.2 versus 309.8±147.6 µg per 24 hours; P=0.03), higher clinic HR (77.8±7.7 versus 68.8±7.6 bpm; P=0.001) and 24-hour ambulatory HR (77.8±7.7 versus 68.8±7.6; P=0.0018), higher pulse wave velocity (11.8±2.2 versus 9.4±1.5 m/s; P=0.009), reduced HR variability (4.48 versus 6.11; P=0.03), and higher systemic vascular resistance (3795±1753 versus 2382±349 dyne·s·cm(5)·m(2); P=0.008). These findings are consistent with heightened sympathetic tone being a major contributor to antihypertensive treatment failure and highlight the need for effective sympatholytic therapies in patients with refractory hypertension. 10.1161/HYPERTENSIONAHA.115.05449
    White-Coat Effect Is Uncommon in Patients With Refractory Hypertension. Siddiqui Mohammed,Judd Eric K,Oparil Suzanne,Calhoun David A Hypertension (Dallas, Tex. : 1979) Refractory hypertension is a recently described phenotype of antihypertensive treatment failure defined as uncontrolled blood pressure (BP) despite the use of ≥5 different antihypertensive agents, including chlorthalidone and spironolactone. Recent studies indicate that refractory hypertension is uncommon, with a prevalence of ≈5% to 10% of patients referred to a hypertension specialty clinic for uncontrolled hypertension. The prevalence of white-coat effect, that is, uncontrolled automated office BP ≥135/85 mm Hg and controlled out-of-office BP <135/85 mm Hg, by awake ambulatory BP monitor in hypertensive patients overall is ≈30% to 40%. The prevalence of white-coat effect among patients with refractory hypertension has not been previously reported. In this prospective evaluation, consecutive patients referred to the University of Alabama at Birmingham Hypertension Clinic for uncontrolled hypertension were enrolled. Refractory hypertension was defined as uncontrolled automated office BP ≥135/85 mm Hg with the use of ≥5 antihypertensive agents, including chlorthalidone and spironolactone. Automated office BP measurements were based on 6 serial readings, done automatically with the use of a BpTRU device unobserved in the clinic. Out-of-office BP measurements were done by 24-hour ambulatory BP monitor. Thirty-four patients were diagnosed with refractory hypertension, of whom 31 had adequate ambulatory BP monitor readings. White-coat effect was present in only 2 patients, or 6.5% of the 31 patients with refractory hypertension, suggesting that white-coat effect is largely absent in patients with refractory hypertension. These findings suggest that white-coat effect is not a common cause of apparent lack of BP control in patients failing maximal antihypertensive treatment. 10.1161/HYPERTENSIONAHA.117.09464