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Pulmonary Arterial Hypertension in Women
Memon HA, Park MH. Pulmonary Arterial Hypertension in Women. Methodist DeBakey Cardiovasc J. 2017;13(4):224-237.doi: 10.14797/mdcj-13-4-224
Pulmonary arterial hypertension (PAH) is characterized by pathological hemodynamic elevation in pulmonary artery pressure. Development of international registries over the last decade has raised awareness about the disease, leading to the development of new and improved therapies. Paradigm shifts such as these warrant review of existing literature regarding PAH, especially in females, as the disease continues to affect women more than males. The aim of this review is to provide an update on the classification, pathophysiology, diagnosis, and treatment of PAH while focusing specifically on its impact on women.Keywords
pulmonary artery hypertension , hypertension , women , pregnancy
Pulmonary hypertension (PH) is characterized by an elevation in pulmonary artery (PA) pressure due to various cardiopulmonary diseases. A resting mean pulmonary artery pressure (mPAP) of 14 ± 3 mm Hg is considered normal, whereas PH is defined as mPAP ? 25 mm Hg.1,2 Pulmonary arterial hypertension (PAH) includes a heterogeneous group of disorders characterized by pulmonary vascular remodeling that leads to right heart failure (RHF). It is defined hemodynamically by the presence of precapillary PH with a mPAP ? 25 mm Hg, pulmonary artery wedge pressure (PAWP) < 15 mm Hg, and pulmonary venous resistance (PVR) > 3 Wood units.2 This review discusses the classification, pathophysiology, diagnosis, and treatment of PAH with a special focus on women.
Previously classified as either primary or secondary PH,3 classification of PH has now evolved to allow different types of PH to be grouped together based on similar pathophysiology and responses to treatment (Table 1).4 Modifications have led to the current five-group classification of PH, with PAH designated as Group 1 PH.4 PAH is subcategorized into the following four causes based on the underlying etiology driving the vascular remodeling: idiopathic PAH (IPAH); heritable PAH (HPAH); drug- and toxin-induced PAH; and PAH associated with conditions such as connective tissue disease (CTD), HIV infection, portal hypertension, congenital heart disease (CHD), and schistosomiasis.4
Pulmonary artery hypertension is a rare disease with an annual incidence of 2 to 8 cases per million population.5-7 Population-based incidence gauged from studies have estimated the prevalence of PAH to range from 15 cases per million in France to 52 per million in Scotland.5,6 Current data regarding epidemiology and outcomes has been derived from registries. The prospective U.S. National Institutes of Health (NIH) 1987 registry reported the mean age of patients with IPAH as 36 ± 15 years, with only 9% of the patients > 60 years.8 In contrast, contemporary registries all report a higher mean age of patients with PAH and IPAH. The French registry found the mean age to be 52 ± 15 years, with 25% of patients with any form of PAH > 60 years.6 Similarly, the REVEAL registry (Registry to Evaluate Early and Long-term PAH Disease Management) noted a mean age of 53 ± 14 years for the same patients.9 A higher mean age in contemporary registries does not necessarily reflect a change in biological phenotype of PAH but, more likely, an increasing awareness of PAH as well as widespread availability of echocardiograms to aid in its diagnosis. Heart failure with preserved ejection fraction (HFpEF), which affects older individuals and relies on measurement of PAWP, is often misdiagnosed as PAH and may also contribute to the increased mean age.
Much is still unknown about racial predisposition of PAH as only few registries have explored this aspect. The NIH registry reported the distribution of its patients as 85.4% white, 12.3% African American, and 2.3% Hispanic, and REVEAL found similar patterns of distribution.10 When adjusted for age and sex, the proportion of whites in REVEAL was found to be similar to the U.S. population. However, the same population was found to be overrepresented for African Americans (12.2% vs 10.9%) and underrepresented for Hispanic (8.9% vs 11.5%) and Asian/Pacific Islander (3.3% vs 4.3%) patients.10
Both old and contemporary registries have shown that PAH predominantly affects females. The NIH cohort noted that females were 1.8 times more likely to be affected by PAH relative to their male counterparts.10 Both the REVEAL and the French registry found this ratio to be 3.6:1 and 1.9:1, respectively.10 It is hypothesized that the stronger female predisposition seen in current U.S. registries may be secondary to the increased use of hormonal contraceptives in the 1980s.
The COMPERA (the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension) registry from Europe enrolled patients from 2007 to 2011 and noted a female predominance that decreased with increasing age. While an overall 1.8:1 female-to-male ratio was observed, the ratio was noted to be 2.3:1 in patients aged 18 to 65 years and 1.2:1 when only patients > 65 years were analyzed.11 This difference in age and associated changes in hormonal milieu support the hypothesis of hormonal influence being key in PAH development.
Heritable PAH and IPAH occur twice as frequently in females compared to males. Similarly, PAH associated with CTD is reported to occur in a female-to-male ratio of 3.8:1. In addition, women with systemic sclerosis are eight times more likely than men to suffer from PAH.6,12
Registries have been instrumental in determining survival for their individual cohorts and developing tools such as prognostic equations. As the first to assess mortality and only one to determine natural progression of PAH, the NIH registry reported a 1-year survival of 68% and mean survival of 2.8 years.8 In the 19 years since this report, survival for PAH patients has improved. The French registry found 1-year survival of patients with PAH due to IPAH or with familial or anoreixgen-associated PAH to be 89.3%, while the NIH equation projected it as 71.8%.6 Similarly, the REVEAL registry demonstrated a 1-year survival of prevalent and newly diagnosed PAH patients as 90.4% and 86.3%, respectively.13 Table 2 summarizes survival and incidence of PAH in these registries.
Recent registries have shown that females with PAH have better survival compared to males. Both the REVEAL and the French registries demonstrated that males with PAH were twice as likely to die compared to females, irrespective of disease severity and surrogates such as 6-minute walk distance (6MWD).6,14,15 The REVEAL registry's updated analysis in 2015 demonstrated that survival continued to favor women 5 years after enrollment. This gender-based difference in mortality was noted regardless of PAH being incident (53 ± 4% vs 63 ± 2%) or prevalent (57 ± 2% vs 68 ± 1%).13
PAH is caused by changes in pulmonary vasculature that result in sustained vasoconstriction, pulmonary vascular remodeling, inflammation, and in situ thrombosis within the small pulmonary arteries and arterioles. Histologically, all arterial layers undergo changes in PAH that lead to development of intimal hyperplasia, medial hypertrophy, adventitial proliferation, and in situ thrombosis.16-18 Furthermore, endothelial cells can undergo uncontrolled replication to create plexiform lesions that are pathognomonic for PAH.
Endothelial dysfunction in PAH also affects the relative proportions of vasoconstrictors to vasodilators. Levels of vasoconstrictors such as thromboxane, endothelin, and serotonin tend to be higher compared to vasodilatory substances such as prostacyclin, nitric oxide (NO), and vasoactive intestinal polypeptide, causing increased resistance in the pulmonary vasculature.19,20
Prostacyclin is a potent vasodilator and inhibits platelet aggregation and smooth muscle proliferation. Studies have demonstrated decreased production of prostacyclin in patients with PAH compared to controls.19 Similarly, NO produced by nitric oxide synthetase (NOS) within vessels causes vasodilation and inhibits platelet activation and vascular smooth muscle proliferation. Effects of NO are mediated by cyclic guanosine monophosphate (cGMP) that is inactivated by phosphodiesterase. Patients with PAH have decreased NOS activity and NO bioavailability, thus leading to vasoconstriction.21 Endothelin-1 (ET-1), a smooth muscle mitogen, is the main vasoconstrictor in PAH.22 Plasma levels of ET-1 in PAH patients are usually increased and are shown to be inversely proportional to the degree of pulmonary blood flow and cardiac output.23
Pathological examination of PAs in PAH has shown the presence of inflammatory cell infiltrate and elevation in serum levels of inflammatory cytokines such as interleukin-1 (IL-1), IL-6, and tumor necrosis factor (TNF). Among these, IL-6 has been studied the most. IL-6 knock-out mice were found to be resistant to hypoxia-induced PH, whereas increases in IL-6 expression led to PH.24
PAH occurs in genetically predisposed individuals. It is inherited as an autosomal dominant trait with variable penetrance, such that between 10% and 20% of patients with the concerned mutations develop PAH.25 A major genetic pathway was attributed to the transforming growth factor beta (TGF-b ) family. Serine/threonine receptor kinase encoded by the bone morphogenetic protein receptor type 2 (BMPR2) gene belongs to this family and is involved in the development of PAH in 75% of inherited cases. Mutations in BMPR2 affect signal transduction, leading to cellular proliferation.26 Another TGF-b superfamily receptor implicated in patients with hereditary hemorrhagic telangiectasia and PAH is activin receptor-like kinase 1 (Alk1).26,27
Estrogen affects the cardiopulmonary system through two receptors that have opposing effects: estrogen receptor (ER) a and ERb .28 ERa has pro-proliferative properties that have been associated with decreased expression of BMPR2 in model systems.29 Studies showing reduced expression of BMPR2 in patients with PAH, regardless of their genotype, have also demonstrated that the presence of estrogen predisposes to PAH.30 In contrast, ERb has antifibrotic, anti-inflammatory, antihypertrophic, and vasodilatory properties in both the right ventricle and lungs.28 Thus, while the role of estrogen in the pathogenesis of PAH may be incompletely understood, experimental studies demonstrate that estrogen has an overall protective effect on the cardiovascular system. Concurrently, in light of the opposing action of the two estrogen receptors, the same studies also highlight the significance of creating estrogen receptor-specific PAH therapies.
Increased afterload in PAH leads to right ventricular (RV) remodeling and can result in RV failure if not treated. Based on the pressure-volume relationship of the heart in chronic PAH, the right ventricle can adapt to elevations in load by increasing contractility to preserve cardiac output, which it does via concentric remodeling. However, persistently elevated PA pressures stretch the RV wall and add sarcomeres to the cardiomyocytes, which in turn leads to increased RV muscle mass and eventual adaptive hypertrophy.31 If ventricular pressures remain uncontrolled, adaptive hypertrophy leads to RV dilation. This results in RV-PA "uncoupling," in which the right ventricle is unable to respond to changes in the afterload.32 Right ventricular dilatation increases wall tension, creating a mismatch between oxygen supply and demand that is thought to be an important mechanism in RV uncoupling. Other major contributors to RV dysfunction include increased chronic activation of the sympathetic pathway, immune activation, cardiomyocyte apoptosis, and oxidative stress.31
The decline in RV function, increase in contraction time, and resulting ventricular asynchrony along with decreased RV stroke volume cause a decrease in left ventricular (LV) preload. Diminished LV filling can also be caused by leftward bowing of the interventricular septum stemming from a prolonged RV contraction time, which in turn triggers a decrease in LV volume during the early phase of diastole. This, together with RV systolic and diastolic dysfunction, causes a decline in cardiac output and subsequent right heart failure in uncontrolled severe PAH. Hence, while RV remodeling may not be implicated in the initial pathogenesis of PAH, it is integral to the subsequent progression of PAH and the patient's prognosis.32
Current guidelines recommend that patients with suspected PAH undergo a comprehensive diagnostic evaluation and early referral to a specialized PH center (Figure 1).33 The initial diagnostic evaluation requires (1) careful screening to determine the presence of risk factors, such as a history of connective tissue disease, liver disease, HIV, and exposure to known drugs and toxins (e.g., methamphetamine use), (2) a detailed family history, and (3) a thorough physical examination to look for signs and symptoms of PH and right heart failure. Additionally, the evaluation should include chest radiographs, electrocardiography, and basic laboratory testing inclusive of connective tissue disease and HIV serologies.
Echocardiography is the most important screening test as it provides essential information regarding cardiac features critical in diagnosing PAH. It can determine tricuspid regurgitation (TR) jet velocity and, using Bernoulli's equation, derive an estimated pulmonary artery systolic pressure (PASP). Most importantly, it helps in RV assessment by measuring the size and function of both the right atrium and ventricle. Even so, echocardiogram has its limitations. Depending on the body habitus and the presence of parenchymal lung disease, TR jet velocity may not be adequate to assess PASP in around 60% of patients who undergo an echocardiogram.34 Furthermore, the RV's complex geometric shape and contractile motion make it difficult to assess right heart function. Nonetheless, enlarged and/or hypertrophied right heart chambers along with a flattened or D-shaped interventricular septum can indicate impaired right heart function.35 In addition, fractional area change of the RV and tricuspid annular plane systolic excursion—the distance that the tricuspid annulus moves toward the RV apex during systole—can assist in determining RV function.36
Right heart catheterization (RHC) is necessary to establish a diagnosis, as the definition of PAH requires that certain hemodynamic parameters be met, including mPAP ³ 25 mm Hg, PAWP ? 15 mm Hg, and PVR > 3 Wood units.4,37 While echocardiography is the key in screening, it lacks the accuracy to diagnose PAH. Accurate measurement of left-sided filling pressure (i.e., PAWP and/or left ventricular diastolic pressure) is critical in correctly diagnosing PAH and distinguishing it from pulmonary venous hypertension (PVH), classified as WHO Group 2 PH. No approved therapies for PVH exist, and PAH-specific treatments in this population can worsen heart failure symptoms. When determining PAWP, close attention must be paid to the timing and wave form characteristics to prevent misdiagnosing PVH as PAH.38 PAWP should be read at the end expiration phase rather than relying on the computer-generated mean pressure, which can be falsely low.38
Right heart catheterization is also needed to assess acute vasoreactivity to determine if the patient should be considered for treatment with high-dose calcium channel blockers. Vasoreactivity is defined as a decrease in mPAP by at least 10 mm Hg to reach an absolute value of 40 mm Hg or less without a decrease in cardiac output.39 Agents used to determine vasoreactivity include inhaled NO, intravenous epoprostenol, or adenosine. Vasoreactivity testing is recommended in IPAH patients only, and development of pulmonary edema during the study should raise suspicion for other diagnoses.39
Since PAH patients most commonly present with dyspnea on exertion, provocative testing could also be performed during RHC.2 Provocative testing involves a fluid challenge with 500 mL of normal saline over 5 to 10 minutes or exercise stress using a supine cycle ergometer, both of which are followed by repeat measurements of PAP, PAWP, and cardiac output.40 This type of testing can reveal hemodynamic abnormalities consistent with PVH, which overlaps with and gets misdiagnosed as PAH.
Patients suspected of having PAH should undergo a ventilation perfusion (V/Q) scan to determine if the cause is chronic thromboembolic pulmonary hypertension (CTEPH). CTEPH is the only form of PH that is potentially curable through pulmonary thromboendarterectomy, a surgical procedure that removes organized thrombi from pulmonary arteries, decreases the obstruction and PVR, and restores RV function. While computed tomography (CT) pulmonary angiography is the imaging modality of choice to rule out acute pulmonary embolism, it lacks sensitivity and specificity to diagnose CTEPH. However, V/Q scan can rule out CTEPH if normal and prompt further testing if abnormal.4,37
Cardiac magnetic resonance imaging (CMR) can be used to evaluate RV structure and function as well as the pulmonary vascular bed and myocardium. With spatial resolution and freedom from acoustic windows, CMR is the gold standard for quantifying RV size and function.41,42 Limitations of CMR include cost, availability, long scan times, and incompatibility with indwelling hardware. Nonetheless, CMR not only plays an integral role in evaluating PAH but can also be used after administration of PAH-specific therapy to track changes in RV size and function, both of which correlate strongly with survival in IPAH patients.43
Pulmonary function tests (PFTs) help to exclude airway or lung parenchymal abnormalities as causes of PH. PFTs in PAH can show mild to moderate reduction of lung volume, which correlates with disease severity.44,45 In PAH, lung diffusion capacity for carbon monoxide (DLCO) may also be low, with a poor outcome noted in those with DLCO < 45%.44,45 PFT findings in PAH overlap with other causes of PH such as interstitial lung disease, making interpretation of PFTs alongside imaging studies such as chest CT important. Due to high prevalence (70-80%) of nocturnal hypoxemia and central sleep apnea in PAH, nocturnal oximetry or polysomnography is also recommended to exclude sleep apnea in these patients.46,47
Therapies specific to PAH exert their effect by augmenting deficient systems (prostacyclin and nitric oxide) or by blocking the endothelin pathway. Since each class and drug has its own unique side effects, treatment requires thoughtful consideration in choosing the initial therapy and close follow-up to assess response and efficacy.
Epoprostenol. Epoprostenol (Flolan) improves functional class, exercise capacity, hemodynamics, and survival in IPAH patients compared to standard treatment, as demonstrated in a landmark randomized trial by Barst and colleagues.48 It is the only therapy shown to demonstrate survival benefit, making it the gold standard for treatment of PAH.48 Intravenous epoprostenol is also effective in treating PAH associated with CTD, HIV, congenital heart disease, and portopulmonary hypertension.49 However, the short half-life (< 6 minutes) requires continued infusion through a tunneled catheter, making intravenous epoprostenol a challenging therapy to implement. Adverse effects of prostanoids are common and include flushing, headaches, jaw and joint pain, and diarrhea.
Treprostinil. Treprostinil (Remodulin) is a prostacyclin analogue that, due to its longer half-life of 4.5 hours and stability at room temperature, can be delivered through a subcutaneous, intravenous, inhaled, and oral route. The subcutaneous form was studied first and demonstrated a modest but statistically significant median increase in 6MWD of 16 meters as well as improved quality of life versus placebo.50 The main side effect of subcutaneous treprostinil is infusion site pain, which improves after proper dose escalation.51 Intravenous treprostinil was approved by the U.S. Food and Drug Administration (FDA) after a study demonstrated improvement in 6MWD and hemodynamics.52 Inhaled treprostinil (Tyvaso) is delivered via a proprietary inhaler 4 to 6 times a day. It was FDA approved after a randomized placebo-controlled study of 235 PAH patients with active symptoms showed an improvement of 6MWD with the addition of inhaled treprostinil to oral bosentan or sildenafil.53
Oral treprostinil (Orenitram) is available as a sustained-release tablet administered twice daily. Results of the phase III FREEDOM-M placebo controlled study, which enrolled 228 treatment-naïve PAH patients, demonstrated significant improvement in median 6MWD.54 However, the FREEDOM-C(2) trial, which enrolled 310 PAH patients receiving background treatment with an endothelin receptor antagonist (ERA) and/or phosphodiesterase type 5 (PDE-5) inhibitors, did not meet the primary end point of significant improvement in 6MWD.55 Enrollment for a clinical trial assessing efficacy of oral treprostinil given three times daily is currently underway.
Iloprost. Inhaled iloprost (Ventavis) was the first inhaled therapy approved for PAH after a placebo-controlled randomized trial of 207 patients met a composite end point of improvement in functional class by at least one level and increase in 6MWD by at least 10%.56 Due to its short half-life, inhaled iloprost is administered 6 to 9 times daily with cough being its most commonly reported side effect.
Selexipag. Selexipag is an oral prostacyclin IP receptor agonist that is hydrolyzed by enzymes to an active metabolite with a half-life of about 8 hours.57,58 A phase II study demonstrated that selexipag not only decreased PVR but was also well tolerated at doses less than 800 mg twice daily.59 In the pivotal GRIPHON trial, 1,156 patients were randomized to receive placebo or selexipag in 1:1 design, with 80% of the patients on background treatment with endothelin receptor antagonists and/or PDE-5 inhibitors. This study demonstrated a significant decrease in morbidity irrespective of background therapy.60
Endothelin Receptor Antagonists
Endothelin receptor antagonists are orally active medications that bind to endothelin receptors A and B in the PA smooth muscle.
Bosentan. A dual endothelin receptor blocker, bosentan (Tracleer) was the first oral therapy to be approved for PAH in 2001. BREATHE-1 studied bosentan in a placebo-controlled trial with a primary end point of change in 6MWD and secondary end point of time to clinical worsening, which was defined as time to death, lung transplantation, hospitalization for PH, lack of clinical improvement, need for epoprostenol therapy, or atrial septostomy. After 16 weeks, treatment with bosentan showed a significant increase in 6MWD and delay in time to clinical worsening. Bosentan is metabolized by the P450 enzyme systems, hence its primary side effect is an increase in hepatic transaminases that is dose dependent and reversible.61 Therefore, liver function tests are required before drug initiation and monthly thereafter. Bosentan has also been shown to have teratogenic effects in animals and may decrease efficacy of hormonal contraception in women. Thus, women using bosentan must be counseled to use concurrent barrier methods and not rely on oral contraception alone.
Ambrisentan. Ambrisentan (Letairis) is a relatively selective endothelin receptor antagonist that was studied in the ARIES I and II trials conducted in the United States and Europe/South America, respectively.62 These combined studies enrolled approximately 400 patients in a placebo-controlled trial and showed significant increases in 6MWD, delayed time to clinical worsening, and improvement in functional class.62 Major side effects of ambrisentan are peripheral edema and worsening heart failure symptoms, mostly in elderly patients with features of HFpEF. Unlike bosentan, ambrisentan is not hepatotoxic but is teratogenic.
Macitentan. Macitentan (Opsumit) is the most recent ERA approved for PAH and has enhanced tissue penetration. SERAPHIN, the first long-term, event-driven trial in PAH, was a double-blind placebo controlled study with mortality and morbidity as the primary end point. Compared to placebo, macitentan demonstrated a reduction in events by 30% in the 3-mg group (97.5% CI 4-48%; P = .0108) and 45% in the 10-mg group (97.5% CI 24-61%; P = .0001), irrespective of background therapy.63 Macitentan also reduced the risk of mortality and hospitalization for PAH by 33% and 50% for the 3- and 10-mg groups, respectively.64 A macitentan dose of 10 mg once daily has been approved for WHO Group I PAH to delay disease progression. The incidence of liver transaminase elevation (i.e., greater than 3 times the upper limit of normal) in the SERAPHIN study was 3.4% for macitentan and 4.5% for placebo.63 Liver function testing is recommended prior to initiation and should be repeated during therapy as clinically indicated. The main side effects of macitentan are anemia, nasopharyngitis, and headache.
Phosphodiesterase-5 Inhibitors
Phosphodiesterase-5 (PDE5) inhibitors act on the isoform of PDE5 within the pulmonary vasculature and cause vasodilation by increasing levels of cyclic guanosine monophosphate, which plays an important role in processes that influence vascular tone, endothelial cellular proliferation, and fibrosis.
Sildenafil. SUPER-1, a placebo-controlled trial, studied the effects of sildenafil (Revatio) in 278 patients with PAH. Improvement in 6MWD, functional class, and hemodynamics with no significant difference in incidence of clinical worsening was noted between the treated and placebo groups.65 Sildenafil was well tolerated, with side effects including headache and epistaxis. Visual disturbances reported in patients using sildenafil have raised concerns, especially among those with diabetes and cardiovascular risk factors. Nonetheless, no significant reports of ophthalmologic disturbances have been reported with chronic use in PAH patients.
Tadalafil. Tadalafil (Adcirca) is a selective PDE5 inhibitor approved after the randomized placebo-controlled PHIRST trial demonstrated improvement in 6MWD in a dose-dependent manner, with 40 mg leading to a statistically significant increase in 6MWD and improvement in time to clinical worsening.66 Tadalafil has frequent side effects that include dose-related headache, myalgia, and flushing.
In a retrospective analysis of data from the PHIRST trial, Mathai et al. noted that men on tadalafil therapy were more likely to achieve a minimal important difference in 6MWD.67 In contrast, a pooled analysis of data collected from six randomized placebo-controlled trials demonstrated that treatment with ERA resulted in a 6MWD of 29.7 m greater in women compared to men.68 It is interesting to note this gender-based difference in treatment with ERA and tadalafil, as it demonstrates the heterogeneity of therapeutic responses to various classes of medications in the phenotypically diverse patients with PAH.
Soluble Guanylate Cyclase Stimulators
Riociguat (Adempas) is an oral soluble guanylate cyclase stimulator (sGC) that produces more cyclic guanosine monophosphate by way of a dual mode of action. Riociguat sensitizes sGC to low levels of endogenous NO and, in the absence of NO, directly stimulates sGC via a different binding site.69,70 Riociguat was studied in PATENT-1 in 445 treatment-naïve PAH patients as well as those receiving ERAs or inhaled/subcutaneous prostanoids. The results showed a significant increase in 6MWD and significant decreases in PVR (P = .0001) and clinical worsening (P = .0046).69 Riociguat was also approved for inoperable CTEPH or recurrent PH after pulmonary thromboendarterectomy based on positive results from the CHEST-1 study, thereby becoming the only medical therapy for Group IV PH.70
Calcium Channel Blockers
Calcium channel blockers (CCBs) were the first group of agents to be used in PAH after early studies in the 1990s.71 However, acute vasoreactivity in most patients resulted in clinical decompensation and significant morbidity and mortality.72,73 In a recent analysis of 70 patients with IPAH who demonstrated acute vasoreactivity on CCBs, only 6.8% remained stable for more than 1 year.74 Based on hemodynamic comparison between patients who remained stable on CCBs and those who did not, CCBs can be considered as initial therapy in patients with IPAH but without RHF who demonstrate a favorable acute response, defined as a fall in mPAP of at least 10 mm Hg to 40 mm Hg or less with increased or unchanged cardiac output.33,72-74 Close follow-up to assess clinical response is critical in these patients so that PAH-specific treatment can be initiated if functional class does not improve to I or II on CCBs. Among CCBs, amlodipine is the most commonly used agent, followed by diltiazem or long-acting nifedipine.
Currently, there are two evidence-based, expert-consensus guidelines regarding treatment of PAH. They differ primarily in their recommendations about upfront combination therapy. The 2014 CHEST guidelines for PAH suggest treatment based on the patient's functional class.75 The 2015 AMBITION trial advocates upfront initiation of combination treatment with ambrisentan and tadalafil and has become the basis of current recommendations for PAH patients.76 Since the CHEST guidelines were created prior to the release of AMBITION's results, they discuss the prospect of combination therapy but do not offer any strong recommendations. Rather, they suggest that functional class II or III patients with no evidence of disease progression start on oral monotherapy with an ERA, PDE5, or cGS stimulator with a "stepwise addition" approach. Additionally, functional class III patients who deteriorate despite oral monotherapy, those with rapid disease progression, and any functional class IV patients should be treated with prostacyclin infusion.75
The 2015 ESC/ERS guidelines equally recommend both stepwise initial monotherapy and upfront combination therapy with two or more agents.37 Although both approaches received Class I recommendation, only the combination of ambrisentan and tadalafil received Class I recommendation, with weaker recommendations for other dual combinations given the lack of supporting evidence. As there have been no direct comparisons between ERAs, PDE5 inhibitors, selexipag, and riociguat, all of them received Class I recommendations for use as monotherapy in functional class II and III patients.37
Pregnancy Counseling
Pregnancy is ill-advised and contraindicated in PAH due to high maternal and fetal mortality.37,77 Maternal survival and fetal outcomes are noted to be worse in patients with severe PAH compared to those with mild disease, with RHF being the main cause of poor outcomes.77,78 Pregnancy is associated with physiologic changes that increase pulmonary flow, such as increased circulating volume and cardiac output. Unlike normal pulmonary vasculature, the remodeled vasculature of a patient with PAH cannot accommodate and compensate for the increased pulmonary blood flow.77,79,80 Labor and childbirth cause further volume shifts and resultant hemodynamic changes that add stress to the already compromised right ventricle in PAH patients, resulting in worsening PH and RHF.77,78 Although animal studies suggest that vasodilation from increased estrogen levels during pregnancy can improve RV function, the accompanying estrogen-induced proliferation of PA smooth muscle cells is thought to nullify this potential benefit.81 Hence, the risk for decompensation, RHF, and mortality in pregnant patients with PAH remains high, especially during the third trimester, between 20-24 weeks, and in the postpartum period.77
Given the heightened risk of fetal and maternal mortality in PAH, patients and their families should be counseled regarding contraception and the need to avoid pregnancy as soon as PAH is diagnosed. Further assessment to determine individual risk during pregnancy should be conducted at a PH center experienced in managing pregnant women with PAH.37,77 Several contraception options for patients with PAH are discussed below.
Contraceptive Methods
Hormonal contraception is available in progestin-only or combined estrogen and progestin formulation. Use of contraceptives containing estrogen is relatively contraindicated in patients with PAH due to the increased risk of venous thromboembolism (VTE) associated with their use.77 Given that pulmonary embolism can be fatal in the setting of preexisting RV dysfunction, estrogen-containing contraceptives are avoided in PAH. Progestin-only contraception, however, is a suitable alternative for patients who cannot use permanent methods of contraception. Progestin-only contraception is available in the form of pills, injections, implants, and intrauterine devices (IUDs), although injections are generally avoided in PAH due to the increased risk of VTE.77 While prior data regarding this risk was conflicting, pooled data in a recent meta-analysis demonstrated that injectable progestin was associated with a 2-fold increase in risk of VTE.82 Progestin-only implants and IUDs are thus the preferred hormonal methods of contraception in PAH patients and are considered as safe and efficacious as surgical sterilization.77 Progestin-alone implants available in various formulations prove to be efficacious for varying durations (3-5 years).
An intrauterine device is another effective form of contraception in women with PAH. While both copper and progestin-releasing IUDs are available, the lower rate and amount of uterine bleeding associated with the progestin-releasing IUD makes it preferable to copper. While IUDs are safe for use in patients with PAH, great caution should be exercised during placement as manipulation of the cervix can lead to vasovagal reactions that are difficult to resolve in these patients.77 Several barrier methods including diaphragms and cervical caps can be used in patients with PAH. However, given the high failure rate of these methods, they are not recommended as the only method of contraception in PAH patients.77
Since no temporary form of contraception is 100% effective, some PH centers favor permanent contraception such as tubal ligation or device implantation into the fallopian tube for their patients. These procedures require careful assessment and evaluation regarding the modes of anesthesia and surgical approach and should be done in a center with a multidisciplinary PH team.
Despite counseling, patients with PAH may choose to become pregnant, or those with no prior diagnosis may present with an initial diagnosis of PAH during pregnancy. In either condition, elective termination of pregnancy should be offered regardless of their functional class.77 With the overall high risk in these patients, it is advised that therapeutic abortion be carried out at an experienced PH center. The procedure is safest when carried out in the first trimester but can be performed during the second trimester until fetal viability is achieved.77,83,84
If patients refuse termination, it is imperative that care be transitioned to a team of specialists that include a PH specialist, obstetrician, intensivist, and neonatologist at an experienced PH center.77,83 Close follow-up is advised to monitor the fetus for appropriate growth and the mother for worsening PH, with the mother also receiving regular echocardiograms.77 Concurrent evaluation for lung transplantation, especially in high-risk patients, should be conducted as it may be warranted emergently in the event of decompensation.84 Given the increased risk of hemodynamic complications in the event of premature labor, it is not uncommon for patients to be preemptively hospitalized during the second trimester.78 Additionally, if indicated and required, early delivery after the second trimester should be considered in high-risk patients.77
According to ESC/ERS guidelines, it is essential to treat pregnant PAH patients with PAH-specific medications.37 As ERAs have teratogenic side effects, their use during pregnancy is contraindicated in patients with PAH. Once an appropriate regimen is determined, it is vital to continue monitoring and making adjustments to the dose since certain physiologic changes and complications of pregnancy can affect the absorption and bioavailability of these medications.
A greater understanding of PAH, discovery of robust markers for prognostication, and new PAH-specific therapies have led to improved survival and quality of life in women with PAH. However, therapies for PAH are still riddled with limitations, hence PAH as a disease entity still remains largely incurable. Increased efforts aimed at early recognition and diagnosis of the disease and increasing our understanding of the mechanisms of RV failure are underway—measures that hopefully will lead to longer and better lives for our patients.
- The development of the NIH registry has increased awareness and understanding of pulmonary arterial hypertension (PAH), leading to new and improved PAH-specific therapies and, in turn, improved survival compared to 20 years ago.
- Mortality in PAH remains high, and survival decreases further in women with PAH who choose to become pregnant.
- Pregnancy in PAH is ill-advised, and women with PAH should be counseled to use any of the effective contraception methods available.
- Patients with PAH who choose to pursue pregnancy should be referred to and managed at a pulmonary hypertension center under the care of experts experienced in treating such patients.
Conflict of Interest Disclosure
The authors have completed and submitted the Methodist DeBakey Cardiovascular Journal Conflict of Interest Statement and none were reported.References
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- Hatano S, Strasser T. Primary Pulmonary Hypertension. Report on a WHO meeting. World Health Organization meeting; 1973 Oct 15-17; Geneva, Switzerland.
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- Peacock AJ, Murphy NF, McMurray JJ, Caballero L, Stewart S. An epidemiological study of pulmonary arterial hypertension. Eur Respir J. 2007 Jul; 30(1):104-9.
- Humbert M, Sitbon O, Chaouat A, et al. Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med. 2006 May 1;173(9):1023-30.
- Jansa P, Jarkovsky J, Al-Hiti H, et al. Epidemiology and long term survival of pulmonary arterial hypertension in the Czech Republic: a retrospective analysis of a nationwide registry. BMC Pulm Med. 2014 Mar 15;14:45.
- Rich S, Dantzker DR, Ayres SM, et al. Primary pulmonary hypertension. A national prospective surgery. Ann Intern Med. 1987 Aug;107(2):216-23.
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- Frost AE, Badesch DB, Barst RJ, et al. The changing picture of patients with pulmonary arterial hypertension in the United States: how REVEAL differs from historic and non-US contemporary registries. Chest. 2011 Jan;139(1):128-37.
- Hoeper MM, Huscher D, Ghofrani HA, et al. Elderly patients diagnosed with idiopathic pulmonary arterial hypertension: results from the COMPERA registry. Int J Cardiol. 2013 Sep 30; 168(2):871-80.
- Chung L, Farber HW, Benza R, et al. Unique predictors of mortality in patients with pulmonary arterial hypertension associated with systemic sclerosis in the REVEAL registry. Chest. 2014 Dec;146(6):1494-504.
- Farber HW, Miller DP, Poms AD, et al. Five-year outcomes of patients enrolled in the REVEAL registry. Chest. 2015 Oct;148(4):1043-54.
- Benza RL, Miller DP, Gomberg MM, et al. Predicting survival in pulmonary arterial hypertension: insights from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL). Circulation. 2010 Jul 13;122(2):164-72.
- Humbert M, Sitbon O, Chaouat A, et al. Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation. 2010 Jul 13;122(2):156-63.
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- Voelkel NF, Tuder RM, Weir EK. Pathophysiology of primary pulmonary hypertension. In: Rubin L, Rich S, editors. Primary pulmonary hypertension. New York: Marcel Dekker; 1997. p. 83-129.
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- Glaid A, Yanagisawa M, Langleben D, et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med. 1993 Jun 17;328(24):1732-9.
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- Umar S, Rabinovitch, Eghbali. Estrogen Paradox in Pulmonary Hypertension. Am J Resp Crit Care Med. 2012 Jul 15;186(2):125-31.
- Austin ED, Hamid R, Hemnes AR, et al. BMPR2 expression is suppressed by signaling through the estrogen receptor. Biol Sex Differ. 2012 Feb 20;3(1):6.
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- Boggaard HJ, Abe K, Vonk Noordegraaf A, Voelkel NF. The right ventricle under pressure: cellular and molecular mechanisms of right heart failure in pulmonary circulation. Chest. 2009 Mar;135(3):794-804.
- Aguero J, Ishikawa K, Hadri L, et al. Characterization of right ventricular remodeling and failure in a chronic pulmonary hypertension model. Am J Physiol Heart Circ Physiol. 2014 Oct 15;307(8):H1204-15.
- McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol. 2009 Apr 28;53(17):1573-619.
- Sciomer S, Badagliacca R, Fedele F. Pulmonary hypertension: echocardiographic assessment. Ital Heart J. 2005;6:840-5.
- Bossone E, Duong-Wagner TH, Paciocco G, et al. Echocardiographic features of primary pulmonary hypertension. J Am Soc Echocardiogr. 1999 Aug;12(8):655-62.
- Ling LF, Marwick TH. Echocardiographic assessment of right ventricular function: How to account for tricuspid regurgitation and pulmonary hypertension. JACC Cardiovasc Imaging. 2012 Jul;5(7):747-53.
- GalieÌ N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: the Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Respir J. 2015 Oct;46(4):903-75.
- Ryan JJ, Rich JD, Thiruvoipati T, Swamy R, Kim GH, Rich S. Current practice for determining pulmonary capillary wedge pressure predisposes to serious errors in the classification of patients with pulmonary hypertension. Am Heart J. 2012 Apr;163(4):589-94.
- Tonelli AR, Alnuaimat H, Mubarak K. Pulmonary vasodilator testing and use of calcium channel blockers in pulmonary arterial hypertension. Respir Med. 2010 Apr;104(4):481-96.
- Barnett CF, Alvarez P, Park MH. Pulmonary Arterial Hypertension: Diagnosis and Treatment. Cardiol Clin. 2016 Aug;34(3):375-89.
- Boxt LM, Katz J. Magnetic resonance imaging for quantitation of right ventricular volume in patients with pulmonary hypertension. J Thorac Imaging. 1993;8:92-7.
- Swift AJ, Rajaram S, Condliffe R, et al. Diagnostic accuracy of cardiovascular magnetic resonance imaging of right ventricular morphology and function in the assessment of suspected pulmonary hypertension: results from the ASPIRE registry. J Cardiovasc Magn Reson. 2012 Jun 21;14:40.
- Peacock AJ, Crawley S, McLure L, et al. Changes in right ventricular function measured by cardiac magnetic resonance imaging in patients receiving pulmonary arterial hypertension-targeted therapy: the EURO-MR study. Circ Cardiovasc Imaging. 2014 Jan;7(1):107-14.
- Trip P, Nossent EJ, de Man FS, et al. Severely reduced diffusion capacity in idiopathic pulmonary arterial hypertension: patient characteristics and treatment responses. Eur Respir J. 2013 Dec;42(6):1575-85.
- Sun XG, Hansen JE, Oudiz RJ, Wasserman K. Pulmonary function in primary pulmonary hypertension. J Am Coll Cardiol. 2003 Mar 19;41(6):1028-35.
- Jilwan FN, Escourrou P, Garcia G, Jais X, Humbert M, Roisman G. High occurrence of hypoxemic sleep respiratory disorders in precapillary pulmonary hypertension and mechanisms. Chest. 2013 Jan;143(1):47-55.
- Rafanan AL, Golish JA, Dinner DS, Hague LK, Arroliga AC. Nocturnal hypoxemia is common in primary pulmonary hypertension. Chest. 2001 Sep;120(3):894-9.
- Barst R, Lewis R, Long W, et al. A comparison of continuous intravenous epoprostenol with conventional therapy for primary pulmonary hypertension. N Engl J Med. 1996 Feb 1;334(5):296-301.
- Galiè N, Corris PA, Frost A, et al. Updated treatment algorithm of pulmonary arterial hypertension. J Am Coll Cardiol. 2013 Dec 24;62(25 Suppl):D60-72.
- Simonneau G, Barst RJ, Galiè N, et al. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension. Am J Respir Crit Care Med. 2002;165:800-4.
- Mather M, McDevitt S, Saggar R. Subcutaneous treprostinil in pulmonary arterial hypertension: practical considerations. J Heart Lung Transplant. 2010 Nov;29(11):1210-7.
- Tapson VF, Gomberg-Maitland M, McLaughlin V, et al. Safety and efficacy of IV treprostinil for pulmonary arterial hypertension: a prospective, multicenter, open-label, 12-week trial. Chest. 2006 Mar;129(3):683-8.
- McLaughlin VV, Benza RL, Rubin LJ, et al. Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: a randomized controlled clinical trial. J Am Coll Cardiol. 2010 May 4;55(18):1915-22.
- Jing ZC, Parikh K, Pulido T, et al. Efficacy and safety of oral treprostinil monotherapy for the treatment of pulmonary arterial hypertension: a randomized, controlled trial. Circulation. 2013 Feb 5;127(5):624-33.
- Tapson VF, Jing ZC, Xu KF, et al. Oral treprostinil for the treatment of pulmonary arterial hypertension in patients receiving background endothelin receptor antagonist and phosphodiesterase type 5 inhibitor therapy (the FREEDOM-C2 study): a randomized controlled trial. Chest. 2013 Sep;144(3):952-8.
- Olschewski H, Simonneay G, Galiè N, et al. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med. 2002 Aug 1;347(5):322-9.
- Mubarak KK. A review of prostaglandin analogs in the management of patients with pulmonary arterial hypertension. Respir Med. 2010 Jan;104(1):9-21.
- Kuwano K, Hashino A, Asaki T, et al. 2-[4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy]-N-(methylsulfonyl)acetamide (NS-304), an orally available and long-acting prostacyclin receptor agonist prodrug. J Pharmacol Exp Ther. 2007 Sep;322(3):1181-8.
- Simonneau G, Lang I, Torbicki A, et al. Efficacy, safety, and tolerability of ACT-293987, a novel oral, non-prostanoid, prostaglandin I2 (IP) receptor agonist: results from a phase IIa study in pulmonary arterial hypertension (PAH). Am J Respir Crit Care Med. 2010;181:A2515.
- Sitbon O, Channick R, Chin KM, et al. Selexipag for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med. 2015 Dec 24;373(26):2522-33.
- Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002 Mar 21;346(12):896-903.
- Galiè N, Olschewski H, Oudiz R, et al. Ambrisentan for the treatment of pulmonary arterial hypertension. Results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2. Circulation. 2008 Jun 10;117(23):3010-9.
- Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013 Aug 29;369(9):809-18.
- Channick RN, Delcroix M, Ghofrani HA, et al. Effect of macitentan on hospitalizations: results from SERAPHIN trial. JACC Heart Fail. 2015 Jan;3(1):1-8.
- Galiè N, Ghofrani HA, Torbicki A, et al.; Sildenafil Use in Pulmonary Arterial Hypertension (SUPER) Study Group. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med. 2005 Nov 17;353(20):2148-57.
- Galiè N, Brundage BH, Ghofrani HA, et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation. 2009 Jun 9;119(22):2894-903.
- Mathai SC, Hassoun PM, Puhan MA. Sex differences in response to tadalafil in pulmonary arterial hypertension. Chest. 2015 Jan;147(1):188-97.
- Gabler NB, French B, Strom BL. Race and sex differences in response to endothelin receptor antagonists for pulmonary arterial hypertension. Chest. 2012 Jan;141(1):20-6.
- Ghofrani HA, Galiè N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013 Jul 25;369(4):330-40.
- Ghofrani HA, Hoeper MM, Halank M, et al. Riociguat for chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension: a phase II study. Eur Respir J. 2010 Oct;36(4):792-9.
- Rich S, Kaufmann E, Levy PS. The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Engl J Med. 1992 Jul 9;327(2):76-81.
- Badesch DB, Abman SH, Ahearn GS, et al. Medical therapy for pulmonary arterial hypertension. ACCP evidence-based clinical practice guidelines. Chest. 2004 Jul;126(1 Suppl):35S-62S.
- Barst RJ, Gibbs SR, Hossein A, et al. Updated evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol. 2009 Jun 30;54(1 Suppl):S78-84.
- Sitbon O, Humbert M, Jais X, et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation. 2005 Jun 14;111(23):3105-11.
- Taichman DB, Ornelas J, Chung L, et al. Pharmacologic therapy for pulmonary hypertension in adults: CHETS guideline and expert panel report. Chest. 2014 Aug;146(2):449-75.
- Galiè N, Barbera J, Frost W, et al. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. N Engl J Med. 2015 Aug 27;373:834-44.
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text:
The Taipei based King Shih Architects realised the center for this year's International Floral Expo in Taipei, a horticultural event authorized by AIPH and hosted by Taipei City Government. The complex includes a Gift Shop Pavilion, an Outlook Pavilion and the Expo Hall with its stunning meshed roof that has a span of up to 65 m.
Site Plan
"A diagonal circulation system formulates the Area into exhibition lots of triangles and hexagons. An east-west major path connects a footbridge to the west and a tunnel to the east that lead to other areas. A North-south major path leads visitors to corners in this Park. Several existing landscape elements are kept and become an auxiliary circulation.
Expo Hall is located on southern side, easily accessible from the street for its need of stage installation. Gift Shop Pavilion is located at a critical point of visitors' route on the north. Outlook Pavilion is on an existing terrain to the east that overlooks the Park."
Expo Hall
"The structure is a web of uniform depth composed of (1) primary arch member with spans that varies from 35 to 65 meters, and (2) secondary net member that spans diagonally. This arrangement makes use of the strength of the cocoon-like shell and reduces 15% unit steel weight compared to truss structure.
These structural members form a pattern of triangles and hexagons, which is further accentuated by two tones of polycarbonate panels along with curtain wall extrusions. Hollow section of the 25mm thick panel provides certain thermal and sound insulation.
The 1200-seating is arranged in concentric layout to provide the shortest as well as most even sightlines. Four colors are chosen for the seating, and arranged in linear pattern to echo the knitting motif.
The Hall is with natural light and ventilation, spot cooling is provided only at stage area. Vehicles may enter from service entry on the back and reach stage area for stage installation.
The space carries a clear orientation in relation to its surrounding while the sheltering sphere carries a sense of floating lightweight like a balloon."
Gift Shop Pavilion
"To provide unobstructed view of the Park, the Pavilion is composed of six flower-shaped units, with three one-story and three two-story units that have no peripheral columns. Each unit is cantilevered, umbrella type of steel structure composed of triangular and hexagonal shapes with only one central column shaft that also provides mechanical services, reminiscent and also functions like the stem of a lotus plant.
An open, weaved bamboo screen is the only definition of boundary. There is a shallow pond in front to provide separation from visitors' path and also reflection of the pavilion. Indigenous fabric pattern is applied on tile arrangements on the wall as well as the pond."
Outlook Pavilion
"It is a folded-plate reinforced concrete structure. Interior ceiling is covered with mosaic tiles of linear patterns. Exterior wall is of architectural concrete finish imprinted with pine grains from formwork panels, like abstract shadow of wood decking cast on the walls."
Design team:
King Shih Architects: Erin C. Shih, Gene K. King, Bruce C. Wang, Yin-Chieh Hsu, Chin-Kuo Chang, Pei-Yu Lai, Ming-Yuan Lee, Ming-Wei Wu, Sufa Pai, Chun-Te Chou, Pao-Tun Cham, Chee-Chiang Lee, Chao-Yuan Huang
Project partners:
Engineers: Supertech (Structural), Handar (MEP), Shunn-Maw (HVAC), CWI (Lighting)
General Contractor: San Sin Construction Company
to the King Shih Architects profile @ Architonic

subset: commoncrawl


text:
Oil ends a losing streak as it closes slightly higher
NEW YORK - It wasn't a convincing move higher, but oil managed to rise Thursday for the first time in six days.
Benchmark oil gained 32 cents to finish at $86.05 a barrel in New York. The price had dropped $6.37 a barrel, or 7 percent, over the previous five trading sessions.
Brent crude added 64 cents to end at $108.49 a barrel in London.
The market may have been biding time ahead of Friday's report on gross domestic product. Analysts are estimating that the U.S economy grew 1.8 percent in the third quarter.
Any reading above that could spark a rise in oil to the $87 to $88 a barrel level, said Jim Ritterbusch of Ritterbusch and Associates.
Cheaper oil and falling gasoline futures have brought relief to U.S. drivers at the gas pump. The nationwide average for a gallon or regular fell another 2 cents overnight to $3.60 a gallon. Gasoline was at $3.74 just a week ago.
In Houston Thursday, the average price was $3.384 a gallon, down from $3.403 Wednesday.
In other futures trading in New York:
1 Natural gas prices fell 1.6 cents to finish at $3.434 per million British thermal units after the government said supplies of the fuel rose last week.
1 Wholesale gasoline rose 7.34 cents, nearly 3 percent, to end at $2.676 a gallon. Gasoline futures had dropped about 12 percent over a two-week period.
1 Heating oil rose 2.3 cents to finish at $3.062 a gallon.


text:
Although personal finance is personal, millions of Americans look to the experts for advice and guidance when it comes to spending, budgeting and saving their money. If you want to get a handle on your finances but aren't sure which personal finance guru is for you, allow me to help. Although the main goal of these personal finance experts is to help you get a handle on your finances, each takes a little different approach to achieving the same goal.
Dave Ramsey
Dave Ramsey's best selling book "The Total Money Makeover" walks you through what he calls the Baby Steps. After completing these initial steps, which include starting a beginner emergency fund and putting 15 percent into your retirement account, you will find yourself with a paid-off mortgage, a healthy retirement fund, savings for your kids' college education and more.
My big takeaway with the Ramsey plan is the guy thinks debt is evil. The only debt that he won't yell at you about is a mortgage and then only if the mortgage payment is no more than 25 percent of your monthly net income on a 15-year fixed note. The conservative mortgage and credit guidelines aren't for everyone, but Ramsey fans love him, to the tune of more than 4 million listeners for his daily radio talk show. His site:
Suze Orman
With her telltale blonde locks and upbeat yet sometimes boisterous attitude, Suze Orman is one of the most popular personal finance gurus out there. Orman is the author of a bevy of personal finance books including "The Money Book for the Young, Fabulous & Broke," "The 9 Steps to Financial Freedom" and "Women & Money." She is also the host of "The Suze Orman Show" on CNBC.
While Orman also encourages viewers to get out of debt — especially in today's economic climate — she doesn't take the hard line approach to debt that Ramsey does. Ramsey loathes the FICO scoring system, but Orman understands that for the vast majority of Americans, having a good FICO score is necessary.
David Bach
David Bach is the new face of Equifax, one of the three main credit bureau reporting systems. Bach recently released his newest book, "Debt Free for Life," which includes an easy-to-follow system to help Americans get out of debt. Like Ramsey and Orman, Bach encourages Americans to get out of debt sooner vs. later.
In addition to his newest book, Bach is also the author of the "Automatic Millionaire," "Start Over," "Finish Rich" and "Go Green, Live Rich." Bach's eco-friendly personal finance book helps demystify the "going green is expensive" myth. Achieving better financial health while keeping the environment in mind doesn't have to be mutually exclusive, and Bach helps you reach both goals.
Clark Howard
Host of "The Clark Howard Show," Howard helps Americans make better financial choices and avoid getting ripped off. Howard is a consumer advocate who offers practical and easy-to-implement financial advice via his daily radio show as well as his HLN weekend television show.
Clark is also the author of several popular books including one specifically for parents — "Clark Smart Parents, Clark Smart Kids: Teaching Kids of Every Age the Value of Money." If you are a parent and struggle with personal finance, start teaching your kids about money and how it works now so they can avoid those same struggles in their future.
There are certainly more experts in the personal finance world than the four listed here, but if you want to make a change in your finances and want some guidance in making this change, one of these books is a good place to start. The good news is, your library should have a copy, so you won't have to shell out any dough to start getting your financial house in order.


text: Friday, July 13, 2012 Move Forward Radio Program: Preparing for the London Games To offer a glimpse into how athletes prepare to compete in the Olympic and Paralympic Games, APTA will host a 1-hour program on Move Forward Radio called "Reaching the Top of Your Game" on July 17, 7 pm-8 pm, ET. Amber Donaldson, PT, DPT, M Physio (Manip), SCS, CSCS, manager of the United States Olympic Committee Sports Medicine Clinic in Colorado Springs, Colorado, will join other APTA members, including Scott Weiss, PT, DPT, ATC, CSCS, physical therapist for the US Sailing Team and owner of Bodhizone for Human Performance and Sports Physical Therapy based in New York City, and Denise Hutchins, PT, International Paralympic Committee Athletics Classifier and vice chair of Wheelchair and Ambulatory Sports, USA. People across the country can listen online and call in to the show to ask questions or submit them in advance via Twitter by tweeting @MoveForwardPT and using the hashtag #MoveForward. Read APTA's press release for more information about the physical therapists who work with these elite athletes. Comments I always love seeing our profession at work. exemplifying everything from start to finish. Here is to all of those gearing up for another year of great Olympic performances. Wow! July is packed full of goodness and great topics for all of us to reach the top. Posted by email@example.com on 7/16/2012 8:52 PM


text:
DMB necesitaba un nuevo diseño de logotipo y lanzó un concurso de diseño en 99designs.
Un ganador ha sido elegido entre 50 diseños de 11 diseñadores freelance.
This event is part of a much larger food and wine festival and will be new this year.
Event Description:
If you've always wanted to experience the glamor of the high-fashion world—adorned with expensive jewels and your own photo shoot, join us for Frosted. Diamonds are a girl's best friend and so are rubies, topaz, opals and plenty of other incredible gemstones. Guests will get to take their photo in a select piece of jewelry from a stunning collection. There will also be dazzling runway fashions; frosted martinis and champagnes; bite size frosted cupcakes; sparkly makeovers and more.
If you have ever seen the movie "How to Lose a Guy in 10 Days", the idea for this event came from that movie.
Trendy women, ages 25-55, are the target audience for this event. "Frosted" is a new event that is part of a larger week long series of events, so the logo needs to stand out among all other logos in emails, newsletters, brochures etc.
Women must buy a ticket to attend this event, so the logo needs to get their attention, draw them into reading the event description, and make them want to attend the event.
Logo Needs:
Needs to say Frosted (name of the event)
If a theme is needed: Be diamond/ jeweled themed. The other meanings of frosted (ice, crystals, frost) may also be used- or surprise us a be creative!
Needs to look Elegant and Formal
Use whatever colors you would like
Needs to be young and trendy
Typeface and Icons: we are fine with either typeface or Icons being used in the logo, or both being used together in the logo.
No Clip art please
File types we need are:
Descubre cómo funciona un concurso de diseño u obtén más información sobre nuestros servicios de diseño de logo.


text:
It may have been a slow weekend in MLS by normal standards, but that doesn't mean there isn't some quality finishing to choose from.
Check out the nominees for this week's AT&T Goal of the Week, including Jaime Castrillon's header off corner kick, a pinpoint header from Eddie Johnson, and a nifty run and finish from Nick LaBrocca
Which goal was the best? That's up for you to decide. Cast your ballot before voting ends for your favorite goal of Week 27! The winner is determined by the total number of votes cast online and via text and is announced on Fridays.
Vote online or text goal code to 22442.
Voting runs until 11:59 pm PT on Thursdays. For complete coverage of the AT&T Goal of the Week—including an archive of past winners—click here.


text:
Finally. Training camp. Actual football stuff to talk about, though some might be overly interested in haircuts and veganism.
Once again, I would like to thank the kind readers and commenters here for helping us get through the most difficult blog time during the very long off-season. Yet another benefit of last year's playoffs is it made dead time season shorter, so I thank the team as well.
Focus of My Camp News (Please skip these preliminaries if you just want non-chatty news news)
This is now my 7th (!) season blogging about the team, and it seems like just yesterday. I sort of see team blogging as having phases:
1. In season: Easy blogging. We watch games, we see them, we discuss them. Hopefully it is good stuff, but I find there are more comments after losses. Please note, I am totally okay with you leaving a comment after a win just to say some newspaper-friendly derivative of "bleep yeah."
2. After season but before training camp: Hard blogging. Feels too long (especially when the Astros/Rockets are um, doing unpleasant things). Important time to write about because the team you build during draft, free agency/coaching acquisitions is the team that determines winning/losing. It's the time when people are looking for team news, often have a hard time finding it because stuff that is happening is mostly not on the field. So, I feel like this is the most important time for me to blog, even if it is just to the most diehardian of you.
3. Training camp. Too easy blogging. There are too many things to write about. This is when I'd like to have a radio show. I could sit here infinity time and just write zillions of words, and there is so much information out there. But that would not be kind to the shape of my backside nor to my mental health.
So, given the choices, my preference is to write things that you might not be seeing elsewhere. Because if someone else is writing about it, then I don't have to. And see my role to sort of cut through to what is important and tell you what is the real deal as I see it.
You will see lots and lots of camp hype. About players running around in shorts. I try not to participate in that.
What I spend a lot of time at this time of year is trying to figure out what is hype and hyperbole, and what is coach talk, and what is real. Won't say I always get that right, but if you are a long time reader here and play fantasy football, you weren't completely surprised by the emergence of Arian Foster his rookie year, drafted Arian Foster his breakout first full season, and you didn't draft Dominick Davis his final season.
Day 1 Camp
As always if you have a particular question about something, please ask, and I'm pretty good about answering if an answer exists. And unlike cable news pundits, if I don't think something has an answer based on facts, observations, I'm not going to make something up. Imagine that. (In other words, don't gripe about my updates being not detailed enough. The comments of my posts are usually like reading a second blog post).
Difference Between OTAs/Minicamps and Training Camp: What is worth noting is during OTAs/minicamps it seemed like there was more time spent on drills, technique, teaching in position groups. On day 1, they spent some time with this, but very early in the camp, they jumped into WRs against CBs, 7 on 7, more collaborative things that look more like how football is played instead of separate drill stuff.
I think they've transitioned that way for a while. A few years ago, the Texans were having slow offensive starts during games for no apparent reason–false start year, penalty there, drops, too much punting. The following year, they did more jumping right into football-looking things right away in camp to sort of simulate how games go. Yeah, you warm up, do some drills, but you go from the National Anthem, to full contact football on game day.
Matt Schaub/Andre Johnson: The obvious difference between OTAs and Training Camp was seeing both Schaub and Johnson working with the team. They looked normal. Which shouldn't be news but is news. Andre Johnson did a diving catch in camp. Which is both awesome and AYYYYYY!
Heat Acclimation: First day they cut the outside practice short to go inside the practice bubble in the AC so that the players can have more time to acclimate to the heat.
Personally, I thought the temps felt cooler now than they did during OTAs/Minicamps being held later in the morning. Because today there was a slight breeze. There's plenty of hotter training camp days to come.
Cutting the outside practice short was disappointing to fans who came to the open practice but most of the best stuff happened outside. I'm not sure how long they will do this heat acclimation thing going inside. I wouldn't expect that they do it too long. With this many players, it is a little cramped in the practice bubble, and Kubiak doesn't like his older players practicing on turf. Inside they worked on some special teams and some technique things.
Training Camp Battles: As you may know, the main training camp battles/issues are: 1. Right side of the offensive line; 2. Wide receivers behind Andre Johnson and Kevin Walter; 3. Field goal kicker.
I know that there is a lot of teeth gnashing on these issues, but I'm not very concerned relatively speaking. Very concerned is the year the Texans went into the season with zero experienced guys at cornerback and starting a rookie corner. The 2012 training camp battles are more just intriguing. It is possible that these battles mean upgrades at the positions. And the only way you know that for sure is taking the training wheels off, which is what they did with their off-season decisions.
Notably, Kubiak mentioned today that the field goal kickers will get more work early in camp in front of the team because it is a real competition. So far from minicamp, Shayne Graham appeared to have the lead after putting on a long field goal kicking show in front of the team and media.
Really, my major concern with camp is injuries. Get these guys learned up with no season ending/harming injuries in camp, preseason games. Yes, teams of all fans have that concern, but the Texans don't have some of the more positional issues that some other teams have or what they've had in the past.
I think that from top to bottom, the Texans have one of the strongest coaching staffs in the league. Which gives you much more trust in player changes than the never-had-a-good-defense pre-Wade Phillips days. It's taken time to get the guys they want as position coaches and assistants. But I have confidence that the offensive line staff will get the right side of the line together and functional because they've done it before.
As for the wide receivers, the 3-5 WRs aren't going to have a ton of targets because there are too many targets for this offense. They need health of their starters and serviceable, learning upside for the 3-5 guys.
So as I've said before, the best camp news is no real news. No injuries.
You are a NFL, Texans fan? Get on Twitter.
The most real time news from writers, players, fans comes from Twitter. It's like mini blog posts. If you are not on Twitter already as a NFL fan, you should. Trust me. I was skeptical about this at first but not any more.
You can follow me on Twitter @StephStradley, and I will be Tweeting during camp when there is open to the public practices, and after camp for private practices. If tech scares you, I have a brief tutorial about Twitter and who to follow at the bottom of my old post from the Baltimore game.
If you want a list of Texans blogs/websites to check out, I have a list of them on the right margin of my non-Texans, random-writing Steph blog.
Anyway, thanks again for reading and commenting and getting us through the dead time. You ready for some football?


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Kobe Bryant's ruptured Achilles' tendon, which will keep him out of the Los Angeles Lakers' lineup for six to nine months, has added more intrigue to impending free agency for teammate Dwight Howard.
It has been clear since Howard began playing for the Lakers this season that he and Bryant aren't best of friends or teammates.
But a post All-Star break detente, the improvement of the team and its playoff chances, plus the fact the Lakers can offer Howard more money than any other team in free agency, have led some NBA general managers to believe that the 6-11 center would remain in Los Angeles next season in quest of his first championship
The Rockets, Dallas and Atlanta were expected to be among the most aggressive in pursuing him.
With Bryant's injury, they could be back in the game.
Soon after the injury Friday night, Bryant began a "woe is me" Facebook rant that continued with a "Whoa, what am I saying?" before ending with a "woe to anyone who thinks I won't be better than ever." I'm paraphrasing, but you get the point.
His surgeon, Dr. Neal ElAttrache, performed a similar surgery on New England quarterback Tom Brady after the opening game of the 2008 season. Brady missed the remainder of the season but was working out three months after the procedure.
ElAttrache told the Los Angeles Times he believes Bryant could also recuperate faster than others because of his will.
But no one knows that for sure.
Howard, who has averaged 17.1 points and 12.4 rebounds, responded in the first game without Bryant on Sunday night with 26 points and 17 rebounds in a victory in Los Angeles over San Antonio. He has said the right things about taking on more of a leadership role, even visiting Bryant in the hospital.
If Bryant doesn't return in top form, or even if he does but it's not until a few months into next season, does Howard want to take the risk that he's with a team that again will not contend for the championship? The Lakers haven't done that well this season, even with Bryant having an outstanding year
Or would Howard looking forward to taking over Bryant's role as the alpha player.
The former seems to more suit Howard's personality. It seems from his past that he would prefer to be recognized as a superstar, in his case, Superman, without having to carry a team. In that case, Houston would be the best fit for him because he be a dominant player on a team that also has James Harden and Jeremy Lin. They could run the offense, through him when they're not literally running, and he could become the defensive stopper.
Some have argued that the Rockets don't need Howard because of the improved play of Omer Asik. There is some merit to that. Asik indeed has been better than anyone expected, but he will never be the offensive threat in the low post that Howard has been throughout his career.
The addition of Howard would turn the Rockets into one of the Western Conference favorites, especially with San Antonio aging, and back into a championship contender within two seasons.


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Mazda Tribute Expert Review
The 2010 Mazda Tribute is largely a carryover from last year's model, adding a few minor features to the SUV's aging package. Styling-wise, the re-bodied Ford Escape is nothing spectacular. Mazda says the Tribute offers "more traditional sport-utility vehicle styling" than the rest of its lineup -- meaning it is plain, large, and simple.
It can be had in four trim levels (i Sport, i Touring, i Grand Touring, and s Grand Touring) with two engine options (2.5-liter I-4, 3.0-liter V-6) and in either front- or four-wheel drive. There's also a very limited (300 units) Tribute Hybrid-Electric Vehicle (HEV) for those living in California that uses a version of the hybrid drivetrain found in the Escape.
Compared to other Mazdas, the Tribute is one of the brand's most capable soft-roaders given its smallish dimensions and available Active Torque Control Coupling (ATCC) four-wheel drive system.
Bodystyles: SUVEngines: 2.5L I-4, 3.0L V-6, 2.5L I-4 w/electric motorTransmissions: 6-speed automatic, 5-speed manual, continuously variable transmission (CVT)Models: i Sport, i Touring, i Grand Touring, s Grand Touring, HEV
For 2010 the Mazda Tribute gets ambient temperature gauges, garage door openers, and two new colors (Steel Blue, Ingot Silver). Grand Touring and HEV models receive an electrochromatic rearview mirror with backup camera display. The HEV also gets a one-touch open and close moonroof.
The 2010 Mazda Tribute isn't striking, just to the point. Many of its traits, such as a high belt line and a tall roof, are typical fare for an SUV. The unpainted underbody plastic is an eyesore, but also relatively functional should the little ute ever s
The Tribute features 16-inch alloys, air conditioning, and cloth seats are standard equipment on all models, as are power locks and windows. With the 60/40 folding rear seats completely down, there is 67.2 cubic-feet of cargo space.
The Tribute's 2.5-liter mill provides enough spunk for jaunts around town, but for that extra grunt when towing or on uncertain terrain, go for the 4x4 with a 3.0-liter. Both are relatively fuel efficient and are flex fuel capable.
Driver and passenger front and side airbags are standard, along with side air curtains, traction control and Dynamic Stability Control.
Tribute i 4x2 with manual: 22 mpg city/28 mpg highwayTribute i 4x2 with automatic: 20 mpg city/28 mpg highwayTribute i 4x4 with automatic: 19 mpg city/28 mpg highwayTribute s 4x2 with automatic: 18 mpg city/26 mpg highwayTribute s 4x4 with automatic:
- Great highway mileage
- Cargo capacity
- Old styling
A Plain Jane that only shines in HEV form
- Ford Escape
- Honda Pilot
- Nissan Rogue


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Surprised by conservative criticism of redesigned application's use of 'parent' in place of 'mother' and 'father,' Clinton intervenes with compromise.
A weekend dust-up pitting gay rights advocates against cultural conservatives prompted the State Department on Monday to recast a newly redesigned passport application form.
On Dec. 22, 2010, State's Bureau of Consular Affairs published what it assumed to be a routine announcement of a new forgery-resistant version of its Consular Report of Birth Abroad form, which verifies that a child born to American parents overseas is a U.S. citizen.
But an unobtrusive final paragraph of the announcement mentioned that the wording of applications -- for both the birth abroad form and the DS 11 form used by anyone applying for a U.S. passport -- would henceforth use the word "parent" instead of "mother" or "father."
"These improvements are being made to provide a gender-neutral description of a child's parents and in recognition of different types of families," the announcement said.
Gay rights groups applauded the change as a step away from discrimination against same-sex parents with U.S. citizenship who bear children abroad.
But the conservative Family Research Council blasted the move as a violation of the 1996 Defense of Marriage Act and called on Congress to overturn the change.
After news reports on the move appeared on Jan. 8, Secretary of State Hillary Clinton intervened and altered the final wording to read "mother or parent 1" and "father or parent 2."
An official in the Bureau of Consular Affairs told Government Executive: "Secretary Clinton was aware of the importance of the change but not aware of the nitty-gritty details. Once she was made aware, she decided to revise the wording."
During Saturday's daily briefing, State officials said Clinton's thinking was related to a desire to avoid a fight with newly empowered Republican House members who might be considering cuts in spending on the department's foreign operations.
Paul Guequierre, deputy press secretary for the Human Rights Campaign, a Washington lesbian and gay rights advocacy group, said on Monday: "We applaud Secretary Clinton's modification of new State Department rules. . . . This change is an important step forward in recognizing that there is a range of family structures in our country, including families headed by same-sex couples."
Peter Sprigg, a senior fellow for policy studies at the Family Research Council, said: "We are certainly happy that the State Department recognizes the existence of motherhood and fatherhood. But they continue to try and promote a redefinition of marriage and the family, which is still a concern for us."
NEXT STORY: Postal Service will cut more of its workforce


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Man found shot dead in car
Second homicide in neighborhood this week
JACKSONVILLE, Fla. – Police are trying to figure out who shot a man found dead in a car in Springfield Sunday late afternoon.
Jacksonville Sheriff's officers said just before 6 p.m., a man in his mid 30's was found dead in a car crashed into a fence at the corner of 4th and Walnut Streets. They said they don't know if the man was targeted or the victim of a random shooting.
A homicide detective said the victim is a black man and was found in the driver's seat. They said they weren't sure if the car was in motion, but it was in the reverse position.
Officers were called to the scene after someone reported hearing gunshots.
"We are early in the investigation. We really aren't sure what the motivation is but we are working towards that," Lonnie Mills with the Jacksonville Sheriff's Office said. "There may have been another vehicle but like I said we haven't been given that information. None of the citizens that have called have given us that suspect information at all."
Kevin Gilmore recently moved to the neighborhood from North Carolina sand said this is the second homicide in the area in a week.
"It makes me feel very unsettling. I have five children," Gilmore said. "It's pretty bad. And we thought this was a very good area."
He said if he had not gone out to a park with his children to feed the ducks, they would have been in their front yard playing, just yards from the crime scene.
"You know the violence has got to stop around here," he said. "I think a heavier police presence and get all the riff raff out of here, if this community wants to revive itself."
Gilmore said he is giving the neighborhood a chance and said the crime could have happened anywhere. He said it's a beautiful, historic neighborhood and calls the incident "unfortunate."
"I talked to a neighbor and I heard that right by our house, two doors down, but it's all on the same lot, that someone was in the car and shot with an AK-47. I know what type of gun that is, automatic rifle that can go through walls, trees. Like I said, we have 5 kids and all the houses by us are vacant."
Anyone with information on the incident is asked to call Crime Stoppers at 866-845-TIPS.
Copyright 2012 by News4Jax.com. All rights reserved. This material may not be published, broadcast, rewritten or redistributed.


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Venues: Hartsdown Leisure Centre, Hartsdown Road, Margate CT9 5QX
Time: 18.00-20.00
Cost: £8 per candidate.
Judge 1:
Contemporary Issues:
Contemporary Issues is a Mandatory CPD required by the British Swimming Officials Licensing requirements (M5) and aimed at Swimming Technical Officials who are already licensed (renewal due within next four years) or wish to become a licensed British Swimming Official. The workshop covers: the ASA Code of Ethics; Safeguarding and Protecting Children and Vulnerable Adults; Embracing Diversity; Health and Safety; Officials Training and the World of Swimming.
NB: Judge 2 candidates are welcome to attend session 2 of the judge 1 course if they would like to.
To book a place, contact use this form or email Malcolm Keysell direct. If you book and then are unable to make a session, please use this form to let the organisers know you will not be attending.


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Would you like to schedule a FREE roof inspection?
Roofer in Spring Hill 34609 Hernando County Florida
When roofing or re-roofing job is needed on your roofing system, and bet you can't do the job by yourself, it is time that you call roofing contractors. Roofing contractors' jobs consists of, setting up roof, checking the degree of damage, suggest possible treatments, or the very least provides you roofing job estimation. They can tell you which portion of your roof is badly harmed and which one that requires instant action. They can guidance you what materials and roofing products to utilize.
Roofing professional is a requirement due to the fact that you wanted your roofing or reroofing task be done perfectly well, since if even you have the most expensive materials and tools, everything will spoil if installation is refrained from doing by a specialist. Getting the services of a roofer is a sensible choice to make, lest you see you loan going down the drain.
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