Physiopathology arterial hypertension pdf

Another feature of arterial hypertension is a resetting of the baroreflexes and decreased baroreceptor sensitivity. The renin—angiotensin system is involved at least in some forms of hypertension e. Elderly or black patients tend to have low-renin hypertension. Others have high-renin hypertension and these are more likely to develop myocardial infarction and other cardiovascular complications.

In human essential hypertension, and experimental hypertension, volume regulation and the relationship between blood pressure and sodium excretion pressure natriuresis are abnormal. Considerable evidence indicates that resetting of pressure natriuresis plays a key role in causing hypertension.

In patients with essential hypertension, resetting of pressure natriuresis is characterized either by a parallel shift to higher blood pressures and salt-insensitive hypertension, or by a decreased slope of pressure natriuresis and salt-sensitive hypertension. The cardiac consequences of hypertension are left ventricular hypertrophy and coronary artery disease. Left ventricular hypertrophy is caused by pressure overload and is concentric.

There is an increase in muscle mass and wall thickness but not ventricular volume. Left ventricular hypertrophy impairs diastolic function, slowing ventricular relaxation and delaying filling. Left ventricular hypertrophy is an independent risk factor for cardiovascular disease, especially sudden death. The consequences of hypertension are a function of its severity.

There is no threshold for complications to occur as elevation of blood pressure is associated with increased morbidity throughout the whole range of blood pressure Table 1.

Coronary artery disease is associated with, and accelerated by, chronic arterial hypertension, leading to myocardial ischaemia and myocardial infarction.

Indeed, myocardial ischaemia is much more frequent in untreated or poorly controlled hypertensive patients than in normotensive patients.

Two main factors contribute to myocardial ischaemia: a pressure related increase in oxygen demand and a decrease in coronary oxygen supply resulting from associated atheromatous lesions. Hypertension is a significant risk factor for death from coronary artery disease.

Heart failure is a consequence of chronic pressure overload. It may start as diastolic dysfunction and progresses to overt systolic failure with cardiac congestion. Strokes are major complications of hypertension; they result from thrombosis, thrombo-embolism, or intracranial haemorrhage.

Renal disease, initially revealed by micro-albuminaemia may progress slowly and becomes evident in later years. All anti-hypertensive drugs must act by decreasing the cardiac output, the peripheral vascular resistance, or both. Life-style modification is the first step in the treatment of hypertension; it includes moderate sodium restriction, weight reduction in the obese, decreased alcohol intake, and an increase in exercise.

Drug therapy is necessary when the above measures have not been successful or when hypertension is already at a dangerous stage Stage 3 when first recognized. Low-dose diuretic therapy is effective and reduces the risk of stroke, coronary heart disease, congestive heart failure, and total mortality.

Whilst thiazides are most commonly used, loop diuretics are also used successfully and the association with a potassium sparing diuretic reduces the risk of both hypokalaemia and hypomagnesaemia.

Even in small doses diuretics potentiate other antihypertensive drugs. The risk of sudden death is reduced when potassium-sparing diuretics are used. In the long-term, spironolactones reduce morbidity and mortality in patients with heart failure that is a typical complication of long-standing hypertension.

These side-effects have to be taken into consideration in the evaluation of the benefits of treatment. They are effective but their introduction in the presence of heart failure has to be very cautious, starting with very low doses to avoid an initial worsening of heart failure.

Calcium channel blockers can be divided into dihydropyridines e. Both groups decrease peripheral vascular resistance but verapamil and diltiazem have negative inotropic and chronotropic effects. Short-acting dihydropyridines such as nifedipine cause reflex sympathetic activation and tachycardia, while long-acting drugs such as amlodipine and slow-release preparations of nifedipine cause less sympathetic activation.

Short-acting dihydropyridines appear to increase the risk of sudden death. However, the systolic hypertension in Europe SYST-EUR trial which compared nitrendipine with placebo had to be stopped early because of significant benefits of active therapy.

Diltiazem and verapamil are contraindicated in heart failure. Nifedipine is effective in severe hypertension and can be used sublingually; there is need for caution because of the risk of excessive hypotension. ACE inhibitors are increasingly being used as first line therapy. They have relatively few side-effects and contraindications except bilateral renal artery stenoses. Though ACE inhibitors are effective in unilateral renovascular hypertension, there is risk of ischaemic atrophy.

Therefore, angioplasty or surgical renal artery reconstruction are preferable to long-term purely medical therapy.

ACE inhibitors are first choice agents in diabetic hypertensive patients as they slow down the progression of renal dysfunction. In hypertension with heart failure, ACE inhibitors are also first choice drugs. The HOPE trial has shown that ramipril reduced the risk of cardiovascular events even in the absence of hypertension.

Thus, this ACE inhibitor may exert a protective effect by mechanisms other than the reduction in blood pressure. As angiotensin II stimulates AT 1 -receptors that cause vasoconstriction, angiotensin AT 1 -receptor antagonists are effective antihypertensive drugs.

Losartan, valsartan and candesartan are effective and cause less coughing than ACE inhibitors. Tadalafil was well tolerated in the long-term, with sustained improvements in exercise capacity [ 85 ]. Riociguat directly activates sGC, thus promoting vasodilation.

On sub-analysis, improved exercise capacity was also observed in patients on existing background therapy [ 77 ]. The adverse effects of GC stimulators are similar to PDE-5i, including hypotension and syncope [ 77 ].

Combination therapy with PDE-5i was found to have a non-positive benefit-risk ratio due to increased hypotension and other drug-related side-effects [ 87 ].

Epoprostenol is a synthetic prostacyclin that can only be administered intravenously due to its short half-life 3—5 min and limited stability at room temperature.

Randomised trials have examined the benefit of continuous epoprostenol infusions in patients with iPAH [ 68 , 79 ] and PAH secondary to the scleroderma spectrum of disease [ 67 ], with this regimen producing improved symptomatic control, exercise capacity and haemodynamics [ 67 , 68 , 79 ]. Crucially, one study found improved survival rates among patients with severe iPAH—making epoprostenol the only therapy to-date to demonstrate a reduced mortality rate within a single RCT [ 68 ].

Treprostinil is a prostanoid analogue with similar properties to epoprostenol, but due to its longer half-life, it can be administered through multiple routes. A RCT intended to investigate intravenous IV treprostinil was closed prematurely due to safety considerations [ 88 ].

Observational studies have found short-term IV treprostinil to be tolerable and produce a similar benefit profile to epoprostenol [ 89 , 90 ].

Iloprost is available in IV, oral or aerosol formulations, although the effects of oral iloprost have not yet been studied. Inhaled iloprost, as demonstrated in the AIR Aerosolized Iloprost Randomized study, conferred significant improvements in symptomatic control, haemodynamics, WHO-FC and quality of life, though it was commonly associated with flushing and jaw pain [ 64 ].

Data concerning IV iloprost in PAH is scarce, with an observational study demonstrating limited clinical benefits [ 92 ]. Selexipag is an oral prostacyclin IP receptor agonist which produces vasodilatory and anti-proliferative effects. Selexipag significantly improved 6MWD, but was associated with headache, diarrhoea, nausea and jaw pain [ 75 ].

These findings were similarly demonstrated in a subsequent week study, with both studies showing increased hepatic enzymes as the main adverse event [ 69 , 72 ]. COMPASS-2 is a more recent, month trial involving patients on background sildenafil therapy who were randomised to either bosentan or placebo [ 71 ]. This study did not meet its primary endpoint time to first morbidity or mortality nor its secondary endpoints functional class and PAH hospital-related admissions except for a significant improvement in 6MWD [ 71 ].

Ambrisentan selectively binds to ET A receptors, with minimal binding to vasodilatory endothelial ET B receptors [ 66 ]. Ambrisentan elicited improvements in 6MWD, functional class and TTCW, but produced adverse effects including peripheral oedema, headache and nasal congestion [ 66 ].

Macitentan significantly reduced the composite endpoint morbidity and mortality events, PAH-related hospitalisations, 6MWD and WHO-FC , although the study was insufficiently powered to show significant mortality reduction in sub-analysis [ 80 ].

Combination therapies have been increasingly recognised in the treatment of PAH as they allow the targeting of multiple signalling pathways. Although the meta-analysis demonstrated a reduction in mortality, the analysis was not sufficiently powered to achieve statistical significance [ 93 ].

A recent meta-analysis similarly demonstrated benefits of combination therapy over monotherapy [ 39 ]. Recent long-term trials have revealed that targeted therapies confer significant improvements in clinical outcomes, thereby changing the therapeutic approach to PAH [ 39 , 63 ]. Risk assessment and treatment options should be considered at the time of diagnosis, with the aim of treatment to maintain low risk profiles [ 13 ]. Risk assessment, as discussed earlier, stratifies patients into low, intermediate or high risk of clinical worsening or death, although other prognostic factors should also be considered [ 13 ].

Patients with low or intermediate risk can be initiated on monotherapy, with regular monitoring of treatment response [ 13 ].

Conversely, for high-risk patients, the AMBITION trial highlighted the benefits of immediate combination therapy rather than a graduated, stepwise approach [ 65 ].

Often, IV epoprostenol is prioritised in high-risk patients given that this agent has been demonstrated to improve 3-month mortality rate of patients with severe PAH [ 13 , 68 ].

Patients refractory to treatment may be considered for lung transplantation or balloon atrial septostomy, the discussion of which exceeds the scope of this review. Since bosentan induces cytochrome P isoenzymes CYP3A4 and CYP2C9, and sildenafil is metabolised by these same isoenzymes, care should you taken to avoid drug-drug interactions.

Furthermore, PAH-targeted medications should be used cautiously in patients taking co-existing antihypertensives to avoid systemic hypotension. The past few decades have seen dramatic changes in the understanding and management of PAH, leading to improved symptomatic control, exercise tolerance and progression free survival [ 38 , 39 , 63 ]. However, there have been variable definitions in study endpoints—particularly TTCW, complicating its interpretation in meta-analyses [ 39 ].

This endpoint includes a collection of outcomes, including symptomatic worsening, lack of improvement, PAH-related hospital admissions, transplantation and mortality [ 94 ]. However, PAH-related hospitalisation, mortality and transplantation often follows clinical deterioration and hence TTCW may underestimate the true mortality and morbidity [ 39 ].

Further research should have a consistent definition in study endpoints and broader analysis of total PAH-related events [ 39 , 94 ].

Nevertheless, clinical worsening and mortality was still prevalent in these studies despite adequate therapy [ 39 , 63 ] indicating the need for identification of novel therapeutic agents. Research is currently underway to investigate the role of oestrogen [ 95 ], tyrosine kinase inhibitors [ 96 ] and BMPRII gene activation [ 97 ], amongst many others in the management of PAH.

Substantial advancements in the understanding and management of PAH have been made in the recent decades. The current understanding of PAH aetiology includes the nitric oxide, prostacyclin-thromboxane and endothelin-1 pathways.

This has led to five classes of drugs which target these the pathways: namely phosphodiesterase-5 inhibitors, soluble guanylate cyclase inhibitors, prostacyclin analogues, prostacyclin receptor agonists and endothelin receptor antagonists. Recent long-term trials have shown evidence of progression-free survival with initial, or early, addition of these drugs, either in isolation or in combination with other drug classes.

In particular, emerging evidence has favoured the use of initial combination therapies in high risk patients. These medications are recommended with general and supportive measures; however, the evidence supporting these practices is heterogeneous and inconclusive.

Ongoing study into alternative pathways involved in PAH pathogenesis represent opportunities for future targets in PAH management.

All authors were involved in the drafting of the manuscript. All authors agreed with the final version of this manuscript. National Center for Biotechnology Information , U. Journal List Diseases v. Published online May Norris S. Lan , 1 Benjamin D. Massam , 1 Sandeep S.

Kulkarni , 1 and Chim C. Find articles by Norris S. Benjamin D. Find articles by Benjamin D. Sandeep S. Find articles by Sandeep S. Chim C. Author information Article notes Copyright and License information Disclaimer. Received Apr 27; Accepted May This article has been cited by other articles in PMC. Abstract Pulmonary arterial hypertension PAH , the first category of pulmonary hypertension, is a chronic and progressive disorder characterised by angioproliferative vasculopathy in the pulmonary arterioles, leading to endothelial and smooth muscle proliferation and dysfunction, inflammation and thrombosis.

Keywords: pulmonary arterial hypertension, nitric oxide, prostacyclin-thromboxane, endothelin-1, phosphodiesterase-5 inhibitor, soluble guanylate cyclase stimulators, prostacyclin analogues, prostacyclin receptor agonists, endothelin receptor antagonists, mortality. Table 1 Classification of pulmonary hypertension [ 1 ]. Open in a separate window. Table 2 Prognostic risk stratification of pulmonary arterial hypertension.

Genetics Heritable PAH hPAH , a subcategory of PAH, exhibits an autosomal dominant pattern of inheritance, with several associated germline gene mutations having been identified [ 15 ]. Pathophysiology PAH may be idiopathic or secondary to various conditions, but regardless of the underlying aetiology, patients exhibit similar pathological changes which include enhanced pulmonary arteriole contractility, endothelial dysfunction, remodelling and proliferation of both endothelial and smooth muscle cells, and in situ thrombi [ 5 ].

Figure 1. Prostacyclin-Thromboxane A 2 Pathway Prostacyclins are produced in endothelial cells from arachidonic acid via cyclooxygenase and prostacyclin synthase.

Endothelin-1 Pathway Endothelin-1 ET-1 is a peptide that acts as a potent vasoconstrictor [ 34 ]. Management of PAH Treatment of PAH has progressed significantly over the past few decades in both its complexity and efficacy [ 38 , 39 ]. Figure 2. General and Supportive Therapies Supportive care remains the mainstay of PAH management despite insufficient and heterogeneous data supporting these practices [ 13 ]. Calcium Channel Blockers Calcium channel blockers CCB inhibit the inflow of calcium into smooth muscle cells, thereby causing vasodilation.

Targeted Therapies Specific therapies which address the underlying pathophysiology of PAH include phosphodiesterase-5 inhibitors PDE-5i , guanylate cyclase GC stimulators, prostacyclin analogues, prostacyclin receptor agonists, and endothelin receptor antagonists ERA. Table 3 Summary of randomised clinical trials of drugs approved for treatment of pulmonary arterial hypertension. Phosphodiesterase-5 Inhibitors Sildenafil is a selective PDE-5i which is predominantly prescribed orally but can be administered intravenously for long-term patients who are unable to tolerate oral formulations.

Prostacyclin Analogues Epoprostenol is a synthetic prostacyclin that can only be administered intravenously due to its short half-life 3—5 min and limited stability at room temperature.

Prostacyclin Receptor Agonists Selexipag is an oral prostacyclin IP receptor agonist which produces vasodilatory and anti-proliferative effects. Combination Therapies Combination therapies have been increasingly recognised in the treatment of PAH as they allow the targeting of multiple signalling pathways.

Future Research The past few decades have seen dramatic changes in the understanding and management of PAH, leading to improved symptomatic control, exercise tolerance and progression free survival [ 38 , 39 , 63 ]. Conclusions Substantial advancements in the understanding and management of PAH have been made in the recent decades.

Author Contributions All authors were involved in the drafting of the manuscript. Conflicts of Interest The authors declare no conflict of interest. References 1. Hoeper M. Definitions and diagnosis of pulmonary hypertension. Moreira E. Prevalence of pulmonary hypertension in the general population: The rotterdam study.

Strange G. Pulmonary hypertension: Prevalence and mortality in the armadale echocardiography cohort. Badesch D. Pulmonary arterial hypertension: Baseline characteristics from the reveal registry. Tuder R. Find this resource:. Hypertension ;e13— Global burden of hypertension and systolic blood pressure of at least to mm Hg, — JAMA ;— Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for countries and territories, a systematic analysis for the Global Burden of Disease Study Differences in prevalence, awareness, treatment and control of hypertension between developing and developed countries.

J Hypertens ;— A meta-analysis of the mechanism of blood pressure change with aging. J Am Coll Cardiol ;— Hypertension prevalence and blood pressure levels in 6 European countries, Canada, and the United States. JAMA ;—9. Hemodynamic patterns of age-related changes in blood pressure. The Framingham Heart Study. Circulation ;— Menopause and hypertension: an age-old debate.

Hypertension ;—9. Taddei S. Blood pressure through aging and menopause. Climacteric ;12 Suppl — European Cardiovascular Disease Statistics Brussels: European Heart Network; Hypertension ;—17 Find this resource:. Int J Cardiol ; —8. Outpatient hypertension treatment, treatment intensification, and control in Western Europe and the United States. Arch Intern Med ;—7. Hypertension types defined by clinic and ambulatory blood pressure in 14 patients referred to hypertension clinics worldwide.

Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies.

Blood pressure and incidence of twelve cardiovascular diseases: lifetime risks, healthy life-years lost, and age-specific associations in 1. Blood pressure, systolic and diastolic, and cardiovascular risks. US population data. Arch Intern Med ;— Global Burden of hypertension and systolic blood pressure of at least to mm Hg, — Target organ damage and masked hypertension in the general population: the Finn-Home study.

Detection of carotid atherosclerosis in individuals with masked hypertension and white-coat hypertension by self-measured blood pressure at home: the Ohasama study. J Hypertens ;—7. Setting thresholds to varying blood pressure monitoring intervals differentially affects risk estimates associated with white-coat and masked hypertension in the population. Hypertension ;— Prognostic significance of masked and white-coat hypertension in the general population: the Finn-Home Study.

Prognosis of white-coat and masked hypertension: International Database of HOme blood pressure in relation to Cardiovascular Outcome. Prevalence of masked hypertension and its association with subclinical cardiovascular disease in African Americans: results from the Jackson Heart Study. J Am Heart Assoc ;5:e White-coat and masked hypertension as risk factors for progression to sustained hypertension: the Finn-Home study.

Risk stratification by self-measured home blood pressure across categories of conventional blood pressure: a participant-level meta-analysis. PLoS Med ;e Determinants of masked hypertension in the general population: the Finn-Home study. J Hypertens ;—8. Prognostic superiority of daytime ambulatory over conventional blood pressure in four populations: a meta-analysis of 7, individuals.

Blood pressure and cardiovascular disease in the Asia Pacific region. Eur Heart J ;— Kannel WB. Risk stratification in hypertension: new insights from the Framingham Study. Cardiovascular mortality in overweight subjects: the key role of associated risk factors.

Prehypertension — prevalence, health risks, and management strategies. Nat Rev Cardiol ;— Adding a life-course perspective to cardiovascular-risk communication.

Nat Rev Cardiol ;—5. Prevalence and progression of subclinical atherosclerosis in younger adults with low short-term but high lifetime estimated risk for cardiovascular disease: the coronary artery risk development in young adults study and multi-ethnic study of atherosclerosis. Circulation ;—9. Jackson R. Cardiovascular risk prediction: are we there yet? Heart ;—3.

Lifetime risks of cardiovascular disease. N Engl J Med ;—9. Hypertension: physiology and pathophysiology. Compr Physiol ;— Guyton AC. Blood pressure control — special role of the kidneys and body fluids.

Science ;—6. Roles of the kidneys and fluid volumes in arterial pressure regulation and hypertension. Chin J Physiol ;— High-salt diet and hypertension: focus on the renin-angiotensin system.

Kidney Blood Press Res ;— Kawarazaki W, Fujita T. The role of aldosterone in obesity-related hypertension. Am J Hypertens ;— Transition from atherosclerosis to aortic aneurysm in humans coincides with an increased expression of RAS components. Atherosclerosis ;— Navar LG. The intrarenal renin-angiotensin system in hypertension. Kidney Int ;— Intratubular renin-angiotensin system in hypertension. Angiotensin II type 2 receptor blockade partially negates antihypertrophic effects of type 1 receptor blockade on pressure-overload rat cardiac hypertrophy.

Hypertens Res ;— Fu Y, Vallon V. Mineralocorticoid-induced sodium appetite and renal salt retention: evidence for common signaling and effector mechanisms. Nephron Physiol ; :8— Renal tubular transport and the genetic basis of hypertensive disease. Clin Exp Nephrol ;—9. Aldosterone resistance: structural and functional considerations and new perspectives.

Mol Cell Endocrinol ;— Ayuzawa N, Fujita T. Activation of mineralocorticoid receptor in salt-sensitive hypertension. Curr Hypertens Rep ; Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension PATHWAY-2 : a randomised, double-blind, crossover trial.

Aldosterone paradox: differential regulation of ion transport in distal nephron. Physiology Bethesda ;— High-NaCl diet impairs dynamic renal blood flow autoregulation in rats with adenine-induced chronic renal failure.

Subtle acquired renal injury as a mechanism of salt-sensitive hypertension. N Engl J Med ;— The plasma renin test reveals the contribution of body sodium-volume content V and renin-angiotensin R vasoconstriction to long-term blood pressure. Salt sensitivity in response to renal injury requires renal angiotensin-converting enzyme. Regression of glomerular and tubulointerstitial injuries by dietary salt reduction with combination therapy of angiotensin II receptor blocker and calcium channel blocker in Dahl salt-sensitive rats.

PLoS One ;9:e Hypertension and kidneys: unraveling complex molecular mechanisms underlying hypertensive renal damage. J Hum Hypertens ;—9. Immune mechanisms in arterial hypertension. J Am Soc Nephrol ;— Phenotyping the microcirculation. Hypertension ;—7. Federal Government. Read our disclaimer for details. Recruitment status was: Recruiting First Posted : November 9, Last Update Posted : November 9, Study Description.

The current aims to combine analysis of different inflammatory biomarkers and BMPR2 mutations, which are currently analyzed in each patient diagnosed with idiopathic or familial PAH, to establish an earlier diagnosis and consequently better orientate the therapeutic strategy in PAH.

Show detailed description. Hide detailed description. Detailed Description:. Human pulmonary arterial cell isolation Another aim is to investigate whether a relationship between impaired BMPR2 signaling and inflammation could result in dysfunction of pulmonary arterial cells in PAH. To achieve our objective, the investigators propose to investigate: i.

Pulmonary tissue collection Lung parenchyma will be collected from i PAH patients at the time of lung transplantation, ii eventually unused donor lungs and iii tissue surrounding lung tumour resection from patients without COPD. FDA Resources. Outcome Measures. Eligibility Criteria.