Resistant hypertension: what the cardiologist needs to know

Treatment-resistant hypertension (TRH) affects between 3 and 30% of hypertensive patients, and its presence is associated with increased cardiovascular morbidity and mortality. Until recently, the interest on these patients has been limited, because providing care for them is difficult and often frustrating. However, the arrival of new treatment options [i.e. catheter-based renal denervation (RDN) and baroreceptor stimulation] has revitalized the interest in this topic. The very promising results of the initial uncontrolled studies on the blood pressure (BP)-lowering effect of RDN in TRH seemed to suggest that this intervention might represent an easy solution for a complex problem. However, subsequently, data from controlled studies have tempered the enthusiasm of the medical community (and the industry). Conversely, these new studies emphasized some seminal aspects on this topic: (i) the key role of 24 h ambulatory BP and arterial stiffness measurement to identify ‘true' resistant patients; (ii) the high prevalence of secondary hypertension among this population; and (iii) the difficulty to identify those patients who may profit from device-based interventions. Accordingly, for those patients with documented TRH, the guidelines suggest to refer them to a hypertension specialist/centre in order to perform adequate work-up and treatment strategies. The aim of this review is to provide guidance for the cardiologist on how to identify patients with TRH and elucidate the prevailing underlying pathophysiological mechanism(s), to define a strategy for the identification of patients with TRH who may benefit from device-based interventions and discuss results and limitations of these interventions, and finally to briefly summarize the different drug-based treatment strategie

Investigating the Efficacy of Radiofrequency Renal Artery Denervation: From Bench to Bedside

Hypertension is a prevalent condition affecting one third of the adult population worldwide. Medications alone have failed to control the blood pressure (BP) in a large proportion of the hypertensive population. Therefore, renal artery denervation (RAD) was developed for the management of resistant hypertension. However, its efficacy was found to be inconsistent in clinical trials. Delivery of effective ablation that results in sufficient nerve injury is one important criterion for a successful procedure. This thesis focuses on evaluation of various commercially available RAD devices and understanding their unique properties and limitations. Using an in-house built renal artery phantom model, we demonstrated that single electrode Symplicity Flex produced larger lesions, in depth and width compared to multi-electrode EnligHTN when both systems were used under identical experimental conditions, and with optimal vessel wall contact. Clinically, in a small cohort of patients who underwent RAD using either systems, we found no significant difference in office BP reduction between the two systems and both groups had a significant reduction in office BP, which persisted up to 4 years. When the new generation multi-electrode Symplicity Spyral and multi-electrode EnligHTN systems were assessed in the same model, EnligHTN lesions were larger in depth. However, lesion depth of the new generation devices was reduced by 30-40% compared to older generation devices. In a phantom model of branch renal artery, Symplicity Spyral produced lesion that were of similar size and with bigger circumferential coverage compared to main vessel phantom model. No overheating at the electrode-tissue interface occurred during branch ablation. Overall, this thesis broadens our knowledge in the field of RAD with respect to information regarding properties and limitation of different RAD systems and it aids in refining the procedure in order to achieve the best clinical outcome

Cardio-Renal Mechanisms Of Fructose-Induced Salt-Sensitive Hypertension

Dietary consumption of fructose facilitates increased intestinal fluid absorption and renal sodium reabsorption, thereby increasing fluid retention. The net result of this is a sustained increased in extracellular fluid volume that leads to states of hypervolemia and subsequent hypertension. Simultaneously, arterial pressure is being elevated by increased autonomic drive stemming from the sympathetic nervous system and various other endovascular proteins that induce vasoconstriction. Under these conditions, the addition of high dietary sodium promotes hypertension prior to the development of significant metabolic disturbances; the subtlety of which may go unnoticed by patients for prolonged periods. While much is understood regarding the multifactorial pathologies of this model of hypertension, few studies have investigated the chronic effects of this disease and the end-organ damage that may result. The highest consumers of fructose are adolescents and young adults, and despite this demographic factor a disparity in the amount of research investigating the chronic effects of such a diet on developing physiologic systems exists. Using techniques such ultrasonography, telemetry, and metabolic caging systems, we sought to determine the acute and chronic effects of fructose and high salt feeding in both adult and adolescent rats. The results of these studies confirmed conclusions from prior studies in that fructose induces a state of salt-sensitivity. Over time this prolonged period of hypertension eventually leads to diastolic dysfunction and left ventricular hypertrophy. The novel-most finding of this study, however, was the discovery that fructose feeding at a young age induces salt-sensitive states governed by renal mechanisms and that this sensitivity is retained into adulthood even following the restoration of a healthy diet. Taken together, these results indicate the inherent risks associated with moderate fructose consumption and highlight the importance healthy dietary habits in promoting cardiovascular and renal health throughout life

Hemodynamic alterations at the Blood-Brain Barrier and optimization of renal denervation treatment to prevent vascular impairment

Les cèl·lules endotelials microvasculars cerebrals de la Barrera Hematoencefàlica exhibeixen un fenotip protector que està altament induït per estímuls bioquímics i biomecànics. Entre aquests, la tensió tallant és una força mecànica provocada per la circulació que intensifica la unió cel·lular i limita el transport a nivell capil·lar. Diferents estudis han provat que els patrons de flux anormals redueixen les propietats funcionals de l’endoteli macrovascular. Les alteracions hemodinàmiques i estructurals, com la hipertensió o la rigidesa arterial, són alguns exemples de condicions vasculars que augmenten la tensió tallant i la pulsatilitat, les quals arriben i afecten aigües avall a la unitat neurovascular. Altres estudis clínics mostren que aquestes alteracions son rellevants en la patogènesi de malalties neurodegeneratives com alguns tipus de demència i esclerosi múltiple. En aquest treball, s’han avaluat els efectes de l’augment de la tensió tallant i la pulsatilitat a nivell cel·lular a la Barrera Hematoencefàlica com a interfase entre el sistema vascular i cerebral. S’ha dissenyat i caracteritzat un model in vitro dinàmic de la Barrera Hematoencefàlica per a permetre el cultiu de cèl·lules endotelials microvasculars i exposar-les a tensió tallant i a factors solubles produïts per cèl·lules veïnes en cocultiu. S’han exposat cèl·lules endotelials microvasculars cerebrals humanes a patrons de flux fisiològics i patològics. El rang fisiològic va augmentar la expressió dels marcadors d’unió estreta Zonula Occludens 1 i Claudina 5. Tant la tensió tallant elevada com la pulsatilitat van disminuir l’expressió d’aquests marcadors al nivell basal i van alterar la morfologia de les unions estretes i la activitat del transportador actiu P-glicoproteïna. A més, es van exposar cèl·lules a tensió tallant seguida per condicions fisiològiques i es va observar una recuperació reversible de l’expressió dels marcadors d’unió estreta. També es va constatar que les condicions hemodinàmiques que alteren el fenotip de barrera van correlacionar amb vies de senyalització relacionades amb les unions estretes. Aquestes troballes suggereixen que, en cas de restauració de les condicions de flux, les propietats funcionals de la Barrera Hematoencefàlica podrien recuperar-se. Evidències recents dels efectes de la denervació renal pel tractament de la hipertensió i dels marcadors de Barrera Hematoencefàlica fan d’aquesta tecnologia un candidat apte per la restauració de la hemodinàmica cerebrovascular. La denervació renal és una tecnologia innovadora pel tractament de la hipertensió resistent que es basa en l’ablació dels nervis simpàtics al voltant de les arteries renals. Tot i que s’ha demostrat la seva seguretat, els resultats d’eficàcia obtinguts en estudis clínics són encara poc concloents. La comprensió de la microanatomia arterial és essencial per predir futurs resultats d’eficàcia. S’ha realitzat un estudi in vivo per avaluar la distribució de nervis i ganglis limfàtics al voltant d’arteries renals i l’efecte de tractaments de denervació senzills i dobles. Es van identificar les regions distals de l’arteria renal com a localitzacions òptimes pel tractament, donat que aquestes van presentar una major densitat de nervis propers a la paret arterial i una menor àrea de ganglis limfàtics. El tractament doble va incrementar l’arc circumferencial afectat en les arteries renals i per tant presenta una probabilitat més elevada per incrementar l’eficàcia. Els patrons de tensió tallant anormals, inherents a malalties vasculars sistèmiques, condueixen al deteriorament de la Barrera Hematoencefàlica. Aquest pot corregir-se mitjançant intervencions hemodinàmiques. La denervació renal és un tractament amb potencial que necessita una major caracterització per poder correlacionar els seus efectes a la pressió sanguínia i a les propietats funcionals de la Barrera Hematoencefàlica.Las células endoteliales microvasculares cerebrales de la Barrera Hematoencefálica exhiben un fenotipo protector que está altamente inducido por estímulos bioquímicos y biomecánicos. Entre ellos, la tensión cortante es una fuerza mecánica provocada por la circulación que intensifica la unión celular y limita el transporte a nivel capilar. Distintos estudios han probado que los patrones de flujo anormales reducen las propiedades funcionales del endotelio macrovascular. Las alteraciones hemodinámicas y estructurales, como la hipertensión o la rigidez arterial, son algunos ejemplos de condiciones vasculares que aumentan la tensión cortante y la pulsatilidad, las cuales alcanzan y afectan aguas abajo en la unidad neurovascular. Otros estudios clínicos muestran que dichas alteraciones son relevantes en la patogénesis de enfermedades neurodegenerativas como algunos tipos de demencia y esclerosis múltiple. En este trabajo, se han evaluado los efectos del aumento de la tensión cortante y la pulsatilidad a nivel celular en la Barrera Hematoencefálica como interfaz entre el sistema vascular y cerebral. Se ha diseñado y caracterizado un modelo in vitro dinámico de la Barrera Hematoencefálica para permitir el cultivo de células endoteliales microvasculares y exponerlas a tensión cortante y a factores solubles producidos por células vecinas en cocultivo. Se han expuesto células endoteliales microvasculares cerebrales humanas a patrones de flujo fisiológicos y patológicos. El rango fisiológico aumentó la expresión de los marcadores de unión estrecha Zonula Occludens 1 y Claudina 5. Tanto la tensión cortante elevada como la pulsatilidad disminuyeron la expresión de dichos marcadores a niveles basales y alteraron la morfología de las uniones estrechas y la actividad del transportador activo P glicoproteína. Además, se expusieron células a tensión cortante alterada seguida por condiciones fisiológicas y se observó una recuperación reversible de la expresión de marcadores de unión estrecha. También se constató que las condiciones hemodinámicas que alteran el fenotipo de barrera correlacionaron con vías de señalización relacionadas con las uniones estrechas. Estos hallazgos sugieren que, en caso de restauración de las condiciones de flujo, las propiedades funcionales de la Barrera Hematoencefálica podrían recuperarse. Evidencias recientes de los efectos de la denervación renal para el tratamiento de la hipertensión y de marcadores de Barrera Hematoencefálica hacen de esta tecnología un candidato apto para la restauración de la hemodinámica cerebrovascular. La denervación renal es una tecnología novedosa para el tratamiento de la hipertensión resistente que se basa en la ablación de los nervios simpáticos alrededor de las arterias renales. Aunque se ha demostrado su seguridad, los resultados de eficacia obtenidos en estudios clínicos son aún poco concluyentes. El entendimiento de la microanatomía arterial es esencial para predecir futuros resultados de eficacia. Se ha realizado un estudio in vivo para evaluar la distribución de nervios y ganglios linfáticos alrededor de arterias renales y el efecto de tratamientos de denervación sencillos y dobles. Se identificaron las regiones distales de la arteria renal como localizaciones óptimas para el tratamiento ya que estas presentaron mayor densidad de nervios cercanos a la pared arterial y la menor área de ganglios linfáticos. El tratamiento doble incrementó el arco circunferencial afectado en las arterias renales y por lo tanto presenta una mayor probabilidad para incrementar la eficacia. Los patrones de tensión cortante anormales, inherentes a enfermedades vasculares sistémicas, conducen al deterioro de la Barrera Hematoencefálica. Éste puede corregirse mediante intervenciones hemodinámicas. La denervación renal es un tratamiento con potencial que necesita una mayor caracterización para poder correlacionar sus efectos en la presión sanguínea y las propiedades funcionales de la Barrera Hematoencefálica.Microvascular endothelial cells at the Blood-Brain Barrier exhibit a protective phenotype, which is highly induced by biochemical and biomechanical stimuli. Amongst them, shear stress, a mechanical force prompted by circulation, enhances junctional tightness and limits transport at capillary-like levels. It has long been proven that abnormal flow patterns reduce functional features of macrovascular endothelium. Hemodynamic and structural alterations such as hypertension or arterial stiffness are examples of vascular conditions that increase shear stress and pulsatility, which reach and affect downstream at the neurovascular unit. Clinical studies have shown that such alterations are relevant in the pathogenesis of neurodegenerative diseases such as types of dementia and multiple sclerosis. In this work, the effects of high shear stress and pulsatile stimuli were evaluated at the cellular level of the Blood-Brain Barrier as the interface between the vascular and cerebral systems. A dynamic in vitro model of the Blood-Brain barrier was designed and characterized in order to allow exposure of microvascular endothelial cells to shear stress and soluble factors produced by neighboring cells in co-culture. Human brain microvascular endothelial cells were exposed to both physiological and pathological flow patterns. Physiologic shear upregulated the expression of tight junction markers Zonula Occludens 1 and Claudin-5. High shear stress and/or pulsatility, decreased their expression to basal levels and altered junctional morphology and P-glycoprotein efflux activity. Furthermore, cells were exposed to altered shear stress patterns followed by restoration of physiological capillary-like conditions. Reversible recovery on the expression of tight junction markers was observed. Flow conditions that disturb barrier phenotype commensurated with junctional signaling pathways. This finding suggests that if flow conditions are restored, the Blood-Brain Barrier functional features may be recovered. Recent evidence of effects of renal denervation in hypertension treatment and Blood-Brain Barrier markers makes this technology a suitable candidate for hemodynamic cerebrovascular restoration. Renal denervation is a novel technology for treatment of resistant hypertension by ablation of sympathetic nerves in renal arteries. While proven safe, efficacy results in clinical trials are still inconclusive. Understanding arterial microanatomy is critical to predict future efficacy outcomes. An in vivo study was performed to evaluate nerve and lymph node distributions around renal arteries and the effect of single and dual denervation treatments. Distal regions of the renal artery were identified as the optimal target locations, as they showed the highest nerve density close to the lumen and the lowest lymph node area. Dual treatment increased circumferential affected arc in renal arteries and have a higher probability to increase efficacy. Abnormal shear stress inherent to systemic vascular disease leads to Blood-Brain Barrier impairment, which could be reverted by hemodynamic interventions. Renal denervation is a potential therapy that needs to be further characterized in order to correlate its effects on blood pressure decrease and functional features of the Blood-Brain Barrier.

Treatment-Resistant Hypertension: An Update in Device Therapy

Resistant hypertension (RH) is a clinical condition in which the hypertensive patient has become resistant to drug therapy and is often associated with increased cardiovascular morbidity and mortality. Several signaling pathways have been studied and related to the development and progression of RH: modulation of sympathetic activity by leptin and aldosterone, primary aldosteronism, arterial stiffness, endothelial dysfunction, and variations in the renin-angiotensin-aldosterone system (RAAS)

Resistant hypertension: what the cardiologist needs to know.

Treatment-resistant hypertension (TRH) affects between 3 and 30% of hypertensive patients, and its presence is associated with increased cardiovascular morbidity and mortality. Until recently, the interest on these patients has been limited, because providing care for them is difficult and often frustrating. However, the arrival of new treatment options [i.e. catheter-based renal denervation (RDN) and baroreceptor stimulation] has revitalized the interest in this topic. The very promising results of the initial uncontrolled studies on the blood pressure (BP)-lowering effect of RDN in TRH seemed to suggest that this intervention might represent an easy solution for a complex problem. However, subsequently, data from controlled studies have tempered the enthusiasm of the medical community (and the industry). Conversely, these new studies emphasized some seminal aspects on this topic: (i) the key role of 24 h ambulatory BP and arterial stiffness measurement to identify 'true' resistant patients; (ii) the high prevalence of secondary hypertension among this population; and (iii) the difficulty to identify those patients who may profit from device-based interventions. Accordingly, for those patients with documented TRH, the guidelines suggest to refer them to a hypertension specialist/centre in order to perform adequate work-up and treatment strategies. The aim of this review is to provide guidance for the cardiologist on how to identify patients with TRH and elucidate the prevailing underlying pathophysiological mechanism(s), to define a strategy for the identification of patients with TRH who may benefit from device-based interventions and discuss results and limitations of these interventions, and finally to briefly summarize the different drug-based treatment strategies

Renal denervation restores autonomic imbalance and prevents atrial fibrillation in patients with hypertensive heart disease : a pilot study

Thesis (PhD)--Stellenbosch University, 2020.ENGLISH ABSTRACT: Background: Atrial fibrillation (AF) is associated with increased cardiovascular morbidity and mortality, but it is uncertain if catheter-based renal denervation (RD) can reduce AF in patients with hypertensive heart disease (HHD). Methods: Patients who were ≥ 55 years old, in sinus rhythm, taking ≥ 3 anti-hypertensive drugs including a diuretic, with echocardiogram-confirmed HHD and suspected coronary artery disease, were randomised to undergo RD or sham procedure. Patients with renal impairment, significant valvular heart disease and untreated thyroid disease were excluded. The primary endpoint, the first episode of subclinical AF (SAF) lasting ≥ 6 minutes, was detected using an implantable loop recorder which was scanned every six months. Six-month follow-up (6MFU) office systolic blood pressure (SBP), cardiovascular mortality and restoration of autonomic imbalance were secondary endpoints. Results: Eighty patients were randomised: 42 underwent RD and 38 a sham procedure. After an average follow-up of three years, fewer RD patients experienced SAF: 6 of 42 patients (14.3%) vs 15 of 38 (39.5%) sham patients (odds ratio (OR), 0.26; 95% CI, 0.1 to 0.71, p = 0.01). Fast AF (ventricular rate ≥ 100 bpm) occurred in 10 sham patients (26.3%) vs 1 RD patient (2.4%): OR, 14.64; 95% CI, 1.77 to 120.91; p = 0.002). The incidence of cardiovascular death was higher in the sham than RD group (6 of 38 (15.8%) vs 1 of 42 (2.4%): OR, 7.69; 95% CI, 0.88 to 67.12; p = 0.049). Non-ST elevation myocardial infarction (NSTEMI) incidence was lower in the RD than sham group (2.3% vs 18.4%: OR, 0.108; 95% CI, 0.01–0.92; p = 0.02). The 6MFU between-group SBP difference was not significant (−3.8 mmHg; p = 0.49). Resting and one-minute recovery heart rate did not differ between groups at 6MFU. Conclusion: In patients with HHD, RD reduces subclinical and fast AF, NSTEMI and cardiovascular death independent of lowering blood pressure. RD was not associated with improvement of surrogate markers of autonomic imbalance.Doctora

Treatment-resistant hypertension: A focus on prevalence of nonadherence, associated factors and renal sympathetic denervation

Hypertension is a leading cause of cardiovascular and cerebrovascular morbidity and mortality worldwide. Treatment-resistant hypertension represents a cohort of patients with treated hypertension with at least 3 antihypertensives. In this thesis the important role of adherence testing, and prevalence of non-adherence is described to establish a diagnosis of true treatment-resistant hypertension. A review of renal sympathetic denervation has identified the development and shortcomings of this technique and research studies to date which has been further adapted for use by using carbon dioxide angiography in a pilot study of patients with chronic kidney disease to eliminate the risk of contrast-induced nephropathy associated with the commonly used iodinated contrast agents. A study was designed and conducted to describe the phenotypical and biochemical characteristics of patients with true treatment-resistant hypertension and to assess fluid and tissue body composition, arterial stiffness, endothelial dysfunction, inflammation and presence of obstructive sleep apnoea in these patients. The results have shown that patients with true treatment-resistant hypertension have a metabolic-syndrome-like phenotype with a high risk of future cardiovascular events, evidence of hyperaldosteronism, higher endothelial dysfunction and inflammation but similar levels of arterial stiffness when compared to non-treatment-resistant hypertension patients