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1.  Saudi experience in the management of pulmonary arterial hypertension; the outcome of PAH therapy with the exclusion of chronic parenteral prostacyclin 
Annals of Thoracic Medicine  2015;10(3):204-211.
The purpose of this study is to present our center's experience in managing patients with pulmonary arterial hypertension (PAH). The main objective is to describe patients' management profile and treatment outcome.
This study presents the results from a single pulmonary hypertension (PH) specialized center in Saudi Arabia. Both incidence and prevalence cases are included. We have previously reported the clinical and physiological characteristics at the time of diagnosis for this cohort of patients. In this study, we describe the clinical management and the outcome of therapy in the same cohort, who were prospectively followed for a mean of 22 months.
A total of 107 patients were identified as having PAH. At the time of enrollment, 56.1% of patients were in modified New York Heart Association functional class (NYHA FC) III and 16.8% were in IV. Phosphdiesterase-5 inhibitor was the most commonly used target therapy (82.2%) followed by endothelin receptors antagonist (74.4%). Only five patients (4.7%) were candidate to use calcium channel blockers. Seventy-nine patients (73.8 %) received a combination nonparenteral target therapy. Thirty-one patients (28.9%) died during the follow-up period. Modified NYHA FC III and IV patients, portopulmonary hypertension, heritable PAH, and PAH associated with connective tissue diseases had the highest mortality rate (P < 0.001).
Our patients are detected at advanced stage of the disease, and thus the mortality is still unacceptably high. Advanced functional class at presentation and certain disease subgroups are associated with increased mortality.
PMCID: PMC4518352
Mortality; prostacyclin; pulmonary arterial hypertension; Saudi association for pulmonary hypertension; target therapy
2.  Disparities in Health Care Delivery and Hospital Outcomes between Non-Saudis and Saudi Nationals Presenting with Acute Coronary Syndromes in Saudi Arabia 
PLoS ONE  2015;10(4):e0124012.
Saudi Arabia has a non-Saudi workers population. We investigated the differences and similarities of expatriate non-Saudi patients (NS) and Saudi nationals (SN) presenting with acute coronary syndromes (ACS) with respect to therapies and clinical outcomes.
The study evaluated 2031 of the 5055 ACS patients enrolled in the Saudi Project for Assessment of Acute Coronary Syndrome (SPACE) from 2005 to 2007. Propensity score matching and logistic regression analysis were performed to account for major imbalances in age and sex in the two groups.
The mean patient age was 56.2±9.8, and 83.5% of the study cohort were male. SN were more likely to have risk factors of atherosclerosis. ST-elevation MI (STEMI) was the most common ACS presentation in NS, while non-ST ACS was more common in SN. The median symptom-to-door time was significantly greater in NS patients (Median 175 min (197) vs. 130 min (167), p=0.027). The only difference in pharmacological therapies between the two groups was that NS were more likely to receive fibrinolytic therapy. NS were less likely than SN to undergo percutaneous coronary interventions (PCI; 32.6% vs. 42.8%, p=0.0001) or primary PCI (7.8% vs. 22.8%, p<0.001). Hospital mortality, cardiogenic shock, and heart failure were significantly higher in NS compared to SN. After adjusting for baseline variables and therapies, the odds ratios for hospital mortality and cardiogenic shock in NS were 2.9 (95% CI 1.5–6.2, p=0.004) and 2.8 (95% CI 1.5–4.9, p<0.001), respectively.
Our findings indicate disparities in hospital care between NS and SN ACS patients. NS patients had worse hospital outcomes, which may reflect unequal health coverage and access-to-care issues.
PMCID: PMC4399885  PMID: 25881231
3.  Saudi Guidelines on the Diagnosis and Treatment of Pulmonary Hypertension: Pulmonary hypertension due to left heart disease 
Annals of Thoracic Medicine  2014;9(Suppl 1):S47-S55.
Pulmonary hypertension (PH) due to left heart disease is the most common cause of pulmonary hypertension in the western world. It is classified as WHO PH group II. Different pathophysiologic abnormalities may take place in this condition, including pulmonary venous congestion and vascular remodeling. Despite the high prevalence of WHO group 2 PH, the major focus of research on PH over the past decade has been on WHO group 1 pulmonary arterial hypertension (PAH). Few investigators have focused on WHO group 2 PH; consequently, the pathophysiology of this condition remains poorly understood, and no specific therapy is available. Clinical and translational studies in this area are much needed and have the potential to positively affect large numbers of patients.
In this review, we provide a detailed discussion upon the pathophysiology of the disease, the recent updates in classification, and the diagnostic and therapeutic algorithms.
PMCID: PMC4114276  PMID: 25076997
Pulmonary hypertension; left heart disease; pulmonary artery wedge pressure; left ventricular end diastolic pressure; Saudi association for pulmonary hypertension guidelines
4.  Saudi guidelines on the diagnosis and treatment of pulmonary hypertension: 2014 updates 
Annals of Thoracic Medicine  2014;9(Suppl 1):S1-S15.
The Saudi Association for Pulmonary Hypertension (previously called Saudi Advisory Group for Pulmonary Hypertension) has published the first Saudi Guidelines on Diagnosis and Treatment of Pulmonary Arterial Hypertension back in 2008.[1] That guideline was very detailed and extensive and reviewed most aspects of pulmonary hypertension (PH). One of the disadvantages of such detailed guidelines is the difficulty that some of the readers who just want to get a quick guidance or looking for a specific piece of information might face.
All efforts were made to develop this guideline in an easy-to-read form, making it very handy and helpful to clinicians dealing with PH patients to select the best management strategies for the typical patient suffering from a specific condition. This Guideline was designed to provide recommendations for problems frequently encountered by practicing clinicians involved in management of PH. This publication targets mainly adult and pediatric PH-treating physicians, but can also be used by other physicians interested in PH.
PMCID: PMC4114283  PMID: 25076987
Pulmonary hypertension; pulmonary vascular resistance; modified functional class; target therapy; SAPH guidelines
5.  Repair of congenital heart disease with associated pulmonary hypertension in children: what are the minimal investigative procedures? Consensus statement from the Congenital Heart Disease and Pediatric Task Forces, Pulmonary Vascular Research Institute (PVRI) 
Pulmonary Circulation  2014;4(2):330-341.
Standardization of the diagnostic routine for children with congenital heart disease associated with pulmonary arterial hypertension (PAH-CHD) is crucial, in particular since inappropriate assignment to repair of the cardiac lesions (e.g., surgical repair in patients with elevated pulmonary vascular resistance) may be detrimental and associated with poor outcomes. Thus, members of the Congenital Heart Disease and Pediatric Task Forces of the Pulmonary Vascular Research Institute decided to conduct a survey aimed at collecting expert opinion from different institutions in several countries, covering many aspects of the management of PAH-CHD, from clinical recognition to noninvasive and invasive diagnostic procedures and immediate postoperative support. In privileged communities, the vast majority of children with congenital cardiac shunts are now treated early in life, on the basis of noninvasive diagnostic evaluation, and have an uneventful postoperative course, with no residual PAH. However, a small percentage of patients (older at presentation, with extracardiac syndromes or absence of clinical features of increased pulmonary blood flow, thus suggesting elevated pulmonary vascular resistance) remain at a higher risk of complications and unfavorable outcomes. These patients need a more sophisticated diagnostic approach, including invasive procedures. The authors emphasize that decision making regarding operability is based not only on cardiac catheterization data but also on the complete diagnostic picture, which includes the clinical history, physical examination, and all aspects of noninvasive evaluation.
PMCID: PMC4070778  PMID: 25006452
congenital heart disease; pulmonary hypertension; cardiac catheterization; pediatric cardiac surgery; postoperative care
6.  Association of angiotensin converting enzyme gene insertion/deletion polymorphism and familial hypercholesterolemia in the Saudi population 
The study of the association between genotype and phenotype is of great importance for the prediction of multiple diseases and pathophysiological conditions. The relationship between angiotensin converting enzyme (ACE) Insertion/Deletion (I/D) polymorphism and Familial Hypercholesterolemia (FH) has been not fully investigated in all the ethnicities. In this study we sought to determine the frequency of I/D polymorphism genotypes of ACE gene in Saudi patients with FH.
This is a case–control study carried out purely in Saudi population. Genomic DNA was isolated from 128 subjects who have participated in this study. ACE gene I/D polymorphism was analyzed by polymerase chain reaction in 64 FH cases and 64 healthy controls. There was no statistically significant difference between the groups with respect to genotype distribution. Furthermore, we did not find any significant difference in the frequency of ACE I/D polymorphism in FH subjects when stratified by gender (p = 0.43).
Our data suggest that ACE gene I/D polymorphism examined in this study has no role in predicting the occurrence and diagnosis of FH.
PMCID: PMC4220775  PMID: 24289455
Familial hypercholesterolemia; Angiotensin converting enzyme; Polymorphism
7.  Author's reply 
Annals of Thoracic Medicine  2013;8(2):127-128.
PMCID: PMC3667444  PMID: 23741279
8.  Novel approach for the management of sub-massive pulmonary embolism 
Annals of Thoracic Medicine  2012;7(3):157-161.
Right ventricular (RV) dysfunction has been identified as a poor prognostic indicator in sub-massive pulmonary embolism (SPE). We hypothesized that using selective vasodilator agent is beneficial in improving RV function in patients with this condition.
We used inhaled prostacyclin analogue (Iloprost, Ventavis®) in five patients with SPE. Helical computerized tomography angiogram was confirmatory for pulmonary embolism and echocardiography was used to evaluate the RV status. All patients received inhaled Iloprost, 2.5 to 5 μg every 4 hours for 3 weeks.
Patients were prospectively followed for 3 months. They were assessed at baseline before starting Iloprost treatment and at 3 days, 3 weeks, and 3 months after treatment. All patients showed significant improvement in their functional class, Borg dyspnea score, NT pro-BNP level, and echocardiographic parameters.
In SPE, directing therapy toward decreasing pulmonary vascular resistance improves the associated pulmonary hemodynamic compromise and improves RV function.
PMCID: PMC3425049  PMID: 22924075
Iloprost; pulmonary hypertension; pulmonary vascular resistance; right ventricular function; sub-massive pulmonary embolism
9.  Asymptomatic metastatic osteosarcoma to the right ventricle: Case report and review of the literature 
Metastatic cardiac tumors are far more common than primary tumors, and benign primary cardiac tumors are common than malignant tumors. We report a 22-year-old Saudi woman with right femur osteosarcoma who was found to have a large right ventricular mass by transthoracic and transesophageal echocardiography. Diagnosis was highly suggestive by cardiac magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) scan. We performed a review of the literature for metastatic osteosarcoma of the right ventricle.
PMCID: PMC3809481  PMID: 24174844
RV, right ventricle; TTE, transthoracic echocardiography; TEE, and transesophageal echocardiography; MRI, magnetic resonance imaging; FDG, fluorodeoxyglucose; PET, positron emission tomography; CT, computed tomography; Cardiac tumors; Intracardiac metastasis; Cardiac osteosarcoma
10.  Age and its relationship to acute coronary syndromes in the Saudi Project for Assessment of Coronary Events (SPACE) registry: The SPACE age study☆☆☆ 
To characterize risk profile of acute coronary syndrome (ACS) patients in different age groups and compare management provided to in-hospital outcome.
Prospective multi-hospital registry.
Seventeen secondary and tertiary care hospitals in Saudi Arabia.
Five thousand and fifty-five patients with ACS. They were divided into four groups: ⩽40 years, 41–55 years, 56–70 years and ⩾70 years. Main outcome measures: prevalence, utilization and mortality.
Results: Ninety-four percent of patients <40 years compared to 68% of patients >70 years were men. Diabetes was present in 70% of patients aged 56–70 years. Smoking was present in 66% of those <40 years compared to 7% of patients >70 years. Fifty-three percent of the patients >70 years and 25% of those <40 years had history of ischemic heart disease. Sixty percent of patients <40 years presented with ST elevation myocardial infarction (STEMI) while non-ST elevation myocardial infarction was the presentation in 49% of patients >70 years. Thirty-four percent of patients >70 years compared to 10% of patients <40 years presented >12 h from symptom onset with STEMI. Fifty-four percent of patients >70 compared to 64–71% of those <70 years had coronary angiography. Twenty-four percent of patients >70 compared to 34–40% of those <70 years had percutaneous coronary intervention. Reperfusion shortfall for STEMI was 16–18% in patients >56 years compared to 11% in patients <40 years. Mortality was 7% in patients >70 years compared to 1.6–3% in patients <70 years. For all comparisons (p < 0.001).
Young and old ACS patients have unique risk factors and present differently. Older patients have higher in-hospital mortality as they are treated less aggressively. There is an urgent need for a national prevention program as well as a systematic improvement in the care for patients with ACS including a system of care for STEMI patients. For older patients there is a need to identify medical as well as social factors that influence the therapeutic management plans.
PMCID: PMC3727458  PMID: 23960662
Age; Mortality; In-hospital outcome; Acute coronary syndrome
11.  Baseline characteristics, management practices, and in-hospital outcomes of patients with acute coronary syndromes: Results of the Saudi project for assessment of coronary events (SPACE) registry 
The Saudi Project for Assessment of Coronary Events (SPACE) registry is the first in Saudi Arabia to study the clinical features, management, and in-hospital outcomes of acute coronary syndrome (ACS) patients.
We conducted a prospective registry study in 17 hospitals in Saudi Arabia between December 2005 and December 2007. ACS patients included those with ST-elevation myocardial infarction (STEMI), non-ST elevation myocardial infarction and unstable angina; both were reported collectively as NSTEACS (non-ST elevation acute coronary syndrome).
5055 patients were enrolled with mean age ± SD of 58 ± 12.9 years; 77.4% men, 82.4% Saudi nationals; 41.5% had STEMI, and 5.1% arrived at the hospital by ambulance. History of diabetes mellitus was present in 58.1%, hypertension in 55.3%, hyperlipidemia in 41.1%, and 32.8% were current smokers; all these were more common in NSTEACS patients, except for smoking (all P < 0.0001). In-hospital medications were: aspirin (97.7%), clopidogrel (83.7%), beta-blockers (81.6%), angiotensin converting enzyme inhibitors/angiotensin receptor blockers (75.1%), and statins (93.3%). Median time from symptom onset to hospital arrival for STEMI patients was 150 min (IQR: 223), 17.5% had primary percutaneous coronary intervention (PCI), 69.1% had thrombolytic therapy, and 14.8% received it at less than 30 min of hospital arrival. In-hospital outcomes included recurrent myocardial infarction (1.5%), recurrent ischemia (12.6%), cardiogenic shock (4.3%), stroke (0.9%), major bleeding (1.3%). In-hospital mortality was 3.0%.
ACS patients in Saudi Arabia present at a younger age, have much higher prevalence of diabetes mellitus, less access to ambulance use, delayed treatment by thrombolytic therapy, and less primary PCI compared with patients in the developed countries. This is the first national ACS registry in our country and it demonstrated knowledge-care gaps that require further improvements.
PMCID: PMC3727434  PMID: 23960654
Acute coronary syndromes; Acute myocardial infarction; Unstable angina; Registry; Saudi Arabia; Middle East
12.  Glycogen Synthase Kinase 3beta Contributes to Proliferation of Arterial Smooth Muscle Cells in Pulmonary Hypertension 
PLoS ONE  2011;6(4):e18883.
Pulmonary arterial hypertension (PAH) is a rare progressive pulmonary vascular disorder associated with vascular remodeling and right heart failure. Vascular remodeling involves numerous signaling cascades governing pulmonary arterial smooth muscle cell (PASMC) proliferation, migration and differentiation. Glycogen synthase kinase 3beta (GSK3ß) is a serine/threonine kinase and can act as a downstream regulatory switch for numerous signaling pathways. Hence, we hypothesized that GSK3ß plays a crucial role in pulmonary vascular remodeling.
All experiments were done with lung tissue or isolated PASMCs in a well-established monocrotaline (MCT)-induced PAH rat model. The mRNA expression of Wnt ligands (Wnt1, Wnt3a, Wnt5a), upstream Wnt signaling regulator genes (Frizzled Receptors 1, 2 and secreted Frizzled related protein sFRP-1) and canonical Wnt intracellular effectors (GSK3ß, Axin1) were assessed by real-time polymerase chain reaction and protein levels of GSK3ß, phospho-GSK3ß (ser 9) by western blotting and localization by immunohistochemistry. The role of GSK3ß in PASMCs proliferation was assessed by overexpression of wild-type GSK3ß (WT) and constitutively active GSK3ß S9A by [3H]-thymidine incorporation assay.
Increased levels of total and phosphorylated GSK3ß (inhibitory phosphorylation) were observed in lungs and PASMCs isolated from MCT-induced PAH rats compared to controls. Further, stimulation of MCT-PASMCs with growth factors induced GSK3ß inactivation. Most importantly, treatment with the PDGFR inhibitor, Imatinib, attenuated PDGF-BB and FCS induced GSK3ß phosphorylation. Increased expression of GSK3ß observed in lungs and PASMC isolated from MCT-induced PAH rats was confirmed to be clinically relevant as the same observation was identified in human iPAH lung explants. Overexpression of GSK3ß significantly increased MCT-PASMCs proliferation by regulating ERK phosphorylation. Constitutive activation of GSK3ß (GSK3ß S9A, 9th serine replaced to alanine) inhibited MCT-PASMCs proliferation by decreasing ERK phosphorylation.
This study supports a central role for GSK3ß in vascular remodeling processes and suggests a novel therapeutic opportunity for the treatment of PAH.
PMCID: PMC3078925  PMID: 21533110
13.  Secondary Pulmonary Arterial Hypertension Treated with Endothelin Receptor Blockade 
Texas Heart Institute Journal  2005;32(3):405-410.
Secondary pulmonary arterial hypertension (SPAH) is an adverse outcome of a variety of systemic disorders. These include collagen vascular diseases, chronic thromboembolism, human immunodeficiency virus, portopulmonary hypertension, and other diseases. Progression of SPAH may persist despite stabilization of the causative disease, thereby contributing to the poor quality of life and unfavorable survival in these patients. Treatment of the underlying cause and oxygen supplementation may alleviate symptoms, but no specific therapy to treat SPAH currently exists. Endothelin receptor blockade with bosentan has been shown to be beneficial in the treatment of primary pulmonary hypertension, but efficacy of this therapy in SPAH has not been established.
We describe a case series of 6 patients with disparate causes of SPAH, who benefited from endothelin receptor blockade therapy. The causes of SPAH included collagen vascular disease (scleroderma) (1); systemic lupus erythematosus (2); chronic thromboembolic disease (2); and granulomatous vasculitis from sarcoidosis (1). Therapy with bosentan led to improvements in symptoms, New York Heart Association functional class, and walking distance in all patients. Distance walked in 6 minutes increased from a mean of 151.67 ± 69.30 m at baseline to 314.83 ± 89.09 m after an average of 14 months of bosentan treatment. Pulmonary arterial pressure decreased in most but not all 6 patients on follow-up echocardiography. This case series suggests a role for endothelin receptor blockade therapy in SPAH and should generate further interest in pharmacologic management of SPAH. A prospective controlled clinical trial of bosentan in SPAH is urgently needed.
PMCID: PMC1336721  PMID: 16392231
Bosentan; calcium channel blockers/administration & dosage; endothelin-1/antagonists and inhibitors; epoprostenol/therapeutic use; hypertension, pulmonary/drug therapy; liver/drug effects

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