Prognostic Value of Cardiac Magnetic Resonance-Derived Right Ventricular Remodeling Parameters in Pulmonary Hypertension: A Systematic Review and Meta-Analysis.

Background Cardiac right ventricular remodeling plays a substantial role in pathogenesis, progression, and prognosis of pulmonary hypertension. Cardiac magnetic resonance is considered an excellent tool for evaluation of right ventricle. However, value of right ventricular remodeling parameters derived from cardiac magnetic resonance in predicting adverse events is controversial. Methods The Pubmed (MEDLINE), Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure platform (CNKI), China Science and Technology Journal Database (VIP), and Wanfang databases were systematically searched until November 2019. Studies reporting hazard ratios (HRs) for all-cause death and composite end point of pulmonary hypertension were included. Univariate HRs were extracted from the included studies to calculate pooled HRs of each right ventricular remodeling parameter. Results Eight studies with 1120 patients examining all-cause death (female: 44%-92%, age: 40-67 years old, follow-up time: 27-48 months) and 10 studies with 604 patients examining composite end point (female: 60%-83%, age: 29-57 years old, follow-up time: 10-68 months) met the criteria. Right ventricular ejection fraction was the only parameter which could predict both all-cause death (pooled HR=0.95; P=0.014) and composite end point (pooled HR=0.95; P<0.001), although right ventricular end-diastolic volume index (pooled HR=1.01; P<0.001), right ventricular end-systolic volume index (pooled HR=1.01, P=0.045), and right ventricular mass index (pooled HR=1.03, P=0.032) only predicted composite outcome. Similar results were observed when we conducted the meta-analysis among patients with World Health Organization type I of pulmonary hypertension. Conclusions Cardiac magnetic resonance-derived right ventricular remodeling parameters have independent prognostic value for all-cause death and composite end point of patients with pulmonary hypertension. Right ventricular ejection fraction was the strongest prognostic factor among all the right ventricular remodeling parameters. Right ventricular mass index, right ventricular end-diastolic volume index, and right ventricular end-systolic volume index also demonstrated prognostic value.

Prognostic significance of electrocardiographic right ventricular hypertrophy in the general population.

BACKGROUND: Echocardiographically detected right ventricular hypertrophy (RVH) is associated with cardiovascular disease (CVD) and mortality. However, the prognostic significance of electrocardiographic (ECG)RVH criteria as predictors of poor outcomes in the general population is unclear. METHODS: This study included 7857 participants (59.8 ±â€¯13.4 years, 52.6% women) from the Third National Health and Nutrition Examination Survey. Sixteen different ECG-RVH criteria were created from digitally recorded and centrally processed electrocardiograms. All-cause mortality was ascertained using the National Death Index. Cox proportional hazards analysis was used to examine the association between baseline ECG-RVH criteria and all-cause mortality. RESULTS: The prevalence of RVH varied widely among the criteria. The lowest ECG-RVH prevalence was 0.09% (using S > R in I, II, III) while the highest prevalence was 20.7% (using (R I + S III) - (S I + R III) < 15 mm). During a median follow-up of 14 years, 2812 deaths occurred. The mortality rate was highest among participants with ECG-RVH defined as R:S ratio V5 < 0.75. In multivariable adjusted models, 9 out of the 16 ECG-RVH criteria were significantly associated with all-cause mortality. When ECG-RVH was defined as the presence of any ECG-RVH criteria, each additional ECG-RVH criteria was associated with 6% increased risk of all-cause mortality (HR (95% CI):1.06(1.03,1.10)). CONCLUSIONS: There is a wide variation in the prevalence of ECG-RVH when different criteria are applied in the general population. However, the presence of ECG-RVH by most criteria regardless of prevalence was associated with poor prognosis suggesting that appropriate choice of criteria may enhance the utilization of these ECG markers in risk stratification.

Utility of the amplitude of RV1+SV5/6 in assessment of pulmonary hypertension.

Electrocardiogram (ECG) has been widely used for assessment of right ventricular (RV) hypertrophy (RVH) in patients with pulmonary hypertension (PH). However, it still remains unclear which ECG criteria of RVH are useful to predict for the severity of PH. The aim of our study was to examine the utility of ECG findings of RVH in assessment of PH. A total of 53 patients (42 women, mean age; 57.6 ± 16.4 years) with pre-capillary PH, who were diagnosed by right heart catheterization, underwent blood sampling, ECG, and cardiac magnetic resonance within a week before the right heart catheterization. We assessed the traditional ECG criteria of RVH in PH patients, and compared to age- and gender-matched control subjects without PH confirmed by 2-dimensional echocardiography (n = 42, mean age 55.3 ± 15.9 years). We also analyzed the clinical variables associated with ECG findings in patients with PH. Mean pulmonary arterial pressure (mPAP), cardiac index, and pulmonary vascular resistance (PVR) in PH patients were 35.3 ± 11.9 mmHg, 2.82 (2.09-3.45) L/min/m2, and 576 ± 376 dyne·sec·cm-5, respectively. The prevalence of right axis deviation (43.4%), R:S ratio V1 > 1 (32.1%), and RV1+SV5/6 > 10.5 mm (69.8%) in PH patients was greater than those in control subjects (p < 0.001). In univariate analysis, mPAP, PVR, RV wall thickness, RV mass index, RV volume, and RV ejection fraction (EF) (inversely) were significantly correlated with the amplitude of RV1+SV5/6. Multiple regression analysis revealed that mPAP and RVEF (inversely) were independently associated with the amplitude of RV1+SV5/6 (R2 = 0.282). Also, we performed the survival analysis among pre-capillary PH patients. During a mean follow-up of 3.7 years, patients with ≥ 16.4 mm of RV1+SV5/6 had worse prognosis than those with < 16.4 mm (Log rank p = 0.015). In conclusion, the amplitude of SV1+RV5/6 could be the most useful factor reflected for RV remodeling, hemodynamics and survival in patients with pre-capillary PH.

Preoperative Predictors of Death and Sustained Ventricular Tachycardia After Pulmonary Valve Replacement in Patients With Repaired Tetralogy of Fallot Enrolled in the INDICATOR Cohort.

BACKGROUND: Risk factors for adverse clinical outcomes have been identified in patients with repaired tetralogy of Fallot before pulmonary valve replacement (PVR). However, pre-PVR predictors for post-PVR sustained ventricular tachycardia and death have not been identified. METHODS: Patients with repaired tetralogy of Fallot enrolled in the INDICATOR cohort (International Multicenter TOF Registry), a 4-center international cohort study, who had a comprehensive preoperative evaluation and subsequently underwent PVR were included. Preprocedural clinical, ECG, cardiovascular magnetic resonance, and postoperative outcome data were analyzed. Cox proportional hazards multivariable regression analysis was used to evaluate factors associated with time from pre-PVR cardiovascular magnetic resonance until the primary outcome: death, aborted sudden cardiac death, or sustained ventricular tachycardia. RESULTS: Of the 452 eligible patients (median age at PVR, 25.8 years), 36 (8%) reached the primary outcome (27 deaths, 2 resuscitated death, and 7 sustained ventricular tachycardia) at a median time after PVR of 6.5 years. Cox proportional hazards regression identified pre-PVR right ventricular ejection fraction <40% (hazard ratio, 2.39; 95% CI, 1.18-4.85; P=0.02), right ventricular mass-to-volume ratio ≥0.45 g/mL (hazard ratio, 4.08; 95% CI, 1.57-10.6; P=0.004), and age at PVR ≥28 years (hazard ratio, 3.10; 95% CI, 1.42-6.78; P=0.005) as outcome predictors. In a subgroup analysis of 230 patients with Doppler data, predicted right ventricular systolic pressure ≥40 mm Hg was associated with the primary outcome (hazard ratio, 3.42; 95% CI, 1.09-10.7; P=0.04). Preoperative predictors of a composite secondary outcome, postoperative arrhythmias and heart failure, included older age at PVR, pre-PVR atrial tachyarrhythmias, and a higher left ventricular end-systolic volume index. CONCLUSIONS: In this observational investigation of patients with repaired tetralogy of Fallot, an older age at PVR and pre-PVR right ventricular hypertrophy and dysfunction were predictive of a shorter time to postoperative death and sustained ventricular tachycardia. These findings may inform the timing of PVR if confirmed by prospective clinical trials.

Right Heart End-Systolic Remodeling Index Strongly Predicts Outcomes in Pulmonary Arterial Hypertension: Comparison With Validated Models.

BACKGROUND: Right ventricular (RV) end-systolic dimensions provide information on both size and function. We investigated whether an internally scaled index of end-systolic dimension is incremental to well-validated prognostic scores in pulmonary arterial hypertension. METHODS AND RESULTS: From 2005 to 2014, 228 patients with pulmonary arterial hypertension were prospectively enrolled. RV end-systolic remodeling index (RVESRI) was defined by lateral length divided by septal height. The incremental values of RV free wall longitudinal strain and RVESRI to risk scores were determined. Mean age was 49±14 years, 78% were female, 33% had connective tissue disease, 52% were in New York Heart Association class ≥III, and mean pulmonary vascular resistance was 11.2±6.4 WU. RVESRI and right atrial area were strongly connected to the other right heart metrics. Three zones of adaptation (adapted, maladapted, and severely maladapted) were identified based on the RVESRI to RV systolic pressure relationship. During a mean follow-up of 3.9±2.4 years, the primary end point of death, transplant, or admission for heart failure was reached in 88 patients. RVESRI was incremental to risk prediction scores in pulmonary arterial hypertension, including the Registry to Evaluate Early and Long-Term PAH Disease Management score, the Pulmonary Hypertension Connection equation, and the Mayo Clinic model. Using multivariable analysis, New York Heart Association class III/IV, RVESRI, and log NT-proBNP (N-Terminal Pro-B-Type Natriuretic Peptide) were retained (χ2, 62.2; P<0.0001). Changes in RVESRI at 1 year (n=203) were predictive of outcome; patients initiated on prostanoid therapy showed the greatest improvement in RVESRI. Among right heart metrics, RVESRI demonstrated the best test-retest characteristics. CONCLUSIONS: RVESRI is a simple reproducible prognostic marker in patients with pulmonary arterial hypertension.

Right ventricle dilation as a prognostic factor in refractory acute respiratory distress syndrome requiring veno-venous extracorporeal membrane oxygenation.

BACKGROUND: The aim of this study was to assess the incidence and prognostic role of echocardiographic abnormalities in consecutive patients with refractory acute respiratory distress syndrome (ARDS) before veno-venous extracorporeal membrane oxygenation (VV-ECMO). METHODS: In this study 74 consecutive patients with refractory ARDS underwent echocardiography (transthoracic, transesophageal or both, according to the best acoustic window). Baseline characteristics were collected for all patients and the simplified acute physiology score was calculated. At echocardiography the following parameters were considered: left ventricle (LV) ejection fraction, right ventricle (RV) size and function (by means of tricuspid annular plane excursion [TAPSE]) and systolic pulmonary arterial pressure. RESULTS: At echocardiography, 25 patients showed normal findings (33.8%), 32 patients exhibited isolated pulmonary hypertension (43.2%) and the remaining 17 patients showed RV dilation and pulmonary hypertension (23%). A reduced LVEF (<50%) was observed in 14 patients (18.9%), while RV dysfunction (as indicated by TAPSE<16 mm) was documented in 21 patients (28.4%). The in-Intensive Care Unit [ICU] mortality rate was 41.8%. At stepwise regression analysis the following variables were independent predictor for in-ICU mortality (when adjusted for TAPSE<16 mm): RV end diastolic area/LV end diastolic area (OR 0.21, 95%CI 0.062-0.709, P=0.012), Body Mass Index (BMI) (OR 0.87, 95%CI 0.802-0.958, P=0.004) CONCLUSIONS: In consecutive patients with refractory ARDS, echocardiographic alterations were common, mainly represented by systolic pulmonary hypertension associated or not with RV dilatation. Moreover, RV dilatation and BMI were independent predictors of in-ICU mortality. On clinical grounds, our findings strongly suggest that echocardiography helps to risk stratifying patients with refractory ARDS requiring VV-ECMO.

High Arrhythmic Burden but Low Mortality during Long-term Follow-up in Arrhythmogenic Right Ventricular Cardiomyopathy.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with a high incidence of ventricular tachyarrhythmia and sudden death. The mainstay of management is the implantable cardioverter defibrillator (ICD). A small number of patient cohorts have generated a large number of reports. METHODS: Prospective registry data supplemented with clinical and ICD records of 30 patients with ARVC fulfilling the 2010 modified Task Force Criteria. This cohort has not been reported on previously. RESULTS: Median age at diagnosis: 46yrs (range 21-68); 20 (80%) male; six (19%) Maori. Duration of follow-up: 7.4yrs (range 1.7-23). Implantable cardioverter defibrillator implantation in 26; three (12%) for resuscitated sudden cardiac death; 17 (65%) for symptomatic ventricular tachyarrhythmia; three (12%) for syncope; and three (12%) for family history of sudden death attributable to ARVC. Two patients died during follow-up, one had an ICD, though died of a carcinoma. Thirteen (50%) experienced appropriate ICD therapy with median time to therapy 12 months, and four (15%) experienced inappropriate shock therapy. Male gender was an independent predictor of appropriate ICD therapy (HR 1.6, 95% CI 1.5-2.7, P=0.01). CONCLUSIONS: The long-term prognosis of patients with ARVC is favourable although high proportions receive appropriate ICD therapy. Male gender is an independent predictor of appropriate ICD therapy.

Cardiac function in renovascular hypertensive patients with and without renal dysfunction.

BACKGROUND: Hypertension impairs left ventricular (LV) diastolic and systolic function, which might be aggravated by inflammation or neurohumoral activation. We hypothesized that LV diastolic dysfunction is more common in patients with renovascular hypertension (RVHT) compared with essential hypertension (EHT). METHODS: Hypertensive patients who underwent both renal imaging to exclude RVHT and cardiac echocardiography within a 3-year period were identified retrospectively. Patients with significant renovascular disease were included in the RVHT group (n = 75); those without significant renovascular disease were included in the EHT group (n = 69). Cardiac function and structure were compared. RESULTS: Baseline renal function was preserved (serum creatinine ≤ 2mg/dl) in EHT patients and impaired (serum creatinine > 2mg/dl) in only 9 RVHT patients. RVHT patients had higher systolic blood pressure, E/e' ratio, and greater prevalence of concentric hypertrophy but lower estimated glomerular-filtration-rate (eGFR) compared with EHT patients. Increased prevalence of LV diastolic dysfunction remained statistically significant in patients with RVHT after multivariable adjustment for age, sex, blood pressure, eGFR, diabetes, smoking, and statin use, with a relative risk (95% CI) for abnormal E/e' of 1.70 (95% confidence interval = 1.05-2.90; P = 0.03) compared with EHT. RVHT patients with severe renal dysfunction showed greater impairments in cardiac systolic and diastolic function compared with those in EHT patients or preserved renal function RVHT patients. CONCLUSIONS: Among hypertensive patients undergoing echocardiography, cardiac structure and diastolic function are impaired in RVHT patients compared with EHT patients and remain different after adjustment for multiple significant covariables. When associated with significant renal dysfunction, RVHT aggravates LV hypertrophy and both systolic and diastolic dysfunction. Hence, identification of RVHT and renal dysfunction warrants development of targeted management strategies.

Early and late outcomes of total repair of tetralogy of Fallot: risk factors for late right ventricular dilatation.

OBJECTIVES: This study was undertaken to assess the early and long-term results of total repair of tetralogy of Fallot (TOF) and to identify the risk factors associated with late right ventricular (RV) dilatation. METHODS: The medical records of 326 patients (male:female = 192:134) who underwent total repair of TOF at Pusan National and Dong-A University Hospitals between July 1991 and May 2011 were retrospectively reviewed. Median age and weight at the time of operation were 13.0 months and 8.7 kg, respectively. Right ventricular end-diastolic dimensions and left ventricular end-diastolic dimensions were obtained during follow-up echocardiography to identify the risk factors associated with late RV dilatation. RESULTS: There were one operative death (0.3%) and 8 late deaths (2.5%). Of late deaths, two were related to operation-related cardiac problems. Overall survival rates at 5, 10, and 15 years were 97.0%, 95.4%, and 95.4%, and the corresponding freedom from cardiac death were 98.8%, 98.8%, and 98.8%, respectively. Freedom from re-operation and re-intervention were 84.4%, 74.2% and 74.2%. Six patients underwent pulmonary valve replacement during the follow-up period. Transannular patch (P = 0.036) and postoperative ventilator support period (P < 0.001) were found to be significant risk factors of late RV dilatation in multivariate analysis. CONCLUSIONS: Total correction of TOF can be performed with a very low mortality rate. However, the postoperative re-operation or re-intervention rates remain relatively high. Late RV dilatation after total repair of TOF was found to be associated with transannular patch enlargement and a longer postoperative ventilator support period.

Causes of sudden death in patients with obstructive sleep apnea.

There are few autopsy studies of patients dying suddenly with obstructive sleep apnea (OSA). Twenty-five forensic autopsies of unexpected sudden death in individuals with OSA were reviewed. The causes of death were as follows: cardiomyopathy (n = 11); sudden unexpected death without morphologic findings (SUDNA, n = 6); and other cardiovascular diseases not related to OSA (n = 8). The cardiomyopathy group comprised five hearts with concentric left ventricular hypertrophy without dilatation and six with left ventricular diameter >4 cm (dilated cardiomyopathy). Four of six hearts in the SUDNA group showed right ventricular dilatation compared with seven of 11 showed cardiomyopathy and one of eight miscellaneous. The degree of obesity was greatest in the dilated cardiomyopathy group (10 of 11 obese) followed by the SUDNA group (four of six obese). The cardiac findings in patients dying suddenly and unexpectedly with OSA include nonspecific cardiomyopathy, other cardiac conditions, and hearts without a morphologic cause of death, which show frequent right ventricular dilatation as the only finding.

Endothelial-like progenitor cells engineered to produce prostacyclin rescue monocrotaline-induced pulmonary arterial hypertension and provide right ventricle benefits.

BACKGROUND: Intravenous prostacyclin is approved for treating pulmonary arterial hypertension (PAH), but it has a short half-life and must be delivered systemically via an indwelling intravenous catheter. We hypothesize that localized jugular vein delivery of prostacyclin-producing cells may provide sustained therapeutic effects without the limitations of systemic delivery. METHODS AND RESULTS: We generated a vector expressing a human cyclooxygenase isoform 1 and prostacyclin synthase fusion protein that produces prostacyclin from arachidonic acid. Endothelial-like progenitor cells (ELPCs) were transfected with the cyclooxygenase isoform 1-prostacyclin synthase plasmid and labeled with lentivirus expressing nuclear-localized red fluorescent protein (nuRFP). The engineered ELPCs (expressing cyclooxygenase isoform 1-prostacyclin synthase and nuRFP) were tested in rats with monocrotaline (MCT)-induced PAH. In PAH prevention studies, treatment with engineered ELPCs or control ELPCs (expressing nuRFP alone) attenuated MCT-induced right ventricular systolic pressure increase, right ventricular hypertrophy, and pulmonary vessel wall thickening. Engineered ELPCs were more effective than control ELPCs in all variables evaluated. In PAH reversal studies, engineered ELPCs or control ELPCs increased the survival rate of rats with established PAH and decreased right ventricular hypertrophy. Engineered ELPCs provided a survival benefit 2 weeks earlier than did control ELPCs. Microarray-based gene ontology analysis of the right ventricle revealed that a number of MCT-altered genes and neurotransmitter pathways (dopamine, serotonin, and γ-aminobutyric acid) were restored after ELPC-based prostacyclin gene therapy. CONCLUSIONS: Cyclooxygenase isoform 1-prostacyclin synthase-expressing ELPCs reversed MCT-induced PAH. A single jugular vein injection offered survival benefits for at least 4 weeks and may provide a promising option for PAH patients.

Subjective assessment of right ventricle enlargement from computed tomography pulmonary angiography images.

To retrospectively evaluate prognostic accuracy of subjective assessment of right ventricle (RV) enlargement on CT pulmonary angiography (CTPA) images in comparison with objective measures of RV enlargement in patients with acute pulmonary embolism (PE). For 200 consecutive patients with acute PE, two readers blinded to patient outcomes subjectively determined whether the maximum RV diameter was greater than that of the left ventricle (LV) using axial CTPA images. For the objective measurements, RV/LV diameter ratios were calculated using axial images and 4-chamber reformatted images. For all assessments, sensitivities and specificities for predicting PE-related death within 30-days and a composite outcome including PE-related death or the need for intensive therapies were compared. The agreement between two readers was 91.5% (kappa = 0.83) and all other assessments had pair-wise agreement over 75% (kappa = 0.53-0.72). There was no significant difference in sensitivity between the subjective and objective methods for predicting both outcomes. The specificity for subjective RV enlargement (55.4-67.7%) was significantly higher than objective measures (45.8-53.1%), except for the 4-chamber views where, for one reader, the specificity of the subjective evaluation was higher but did not reach statistical significance. Complex measurements of RV/LV diameter ratios may not be needed to maximize the prognostic value from CTPA. The radiologist who interprets the CTPA images should report RV enlargement when the RV diameter subjectively appears larger than the LV.

A low mortality model of chronic pulmonary hypertension in sheep.

BACKGROUND: Pulmonary hypertension and right ventricular failure are major contributors to morbidity and mortality in chronic lung disease. Therefore, large animal models of pulmonary hypertension and right ventricular hypertrophy are needed to study underlying disease mechanisms and test new treatment modalities. The objective of this study was to create a low-mortality model of chronic pulmonary hypertension and right ventricular hypertrophy in sheep. METHODS: The vena cavae of nine sheep weighing 62 ± 2 (SEM) kg were injected with 0.375 g of dextran beads (sephadex) every day for 60 d. Pulmonary hemodynamics were assessed via pulmonary artery catheterization prior to the first injection and again on d 14, 28, 35, 42, 49, and 56. At the end of the experiment, the heart was removed, dissected, and weighed to determine the ratio of right ventricular mass to left ventricle plus septal mass (RV:LV+S). RESULTS: All sheep survived to 60 d. The average pulmonary artery pressure rose from 17 ± 1 mmHg at baseline to 35 ± 3 mmHg on d 56 with no significant change in cardiac output (8.7 ± 0.7 to 9.8 ± 0.7 L/min, P = 0.89). The RV:LV+S was significantly higher (0.42 ± 0.01, P < 0.001) than a historic group of untreated normal animals (0.35 ± 0.01, n = 13). CONCLUSION: This study provides a low-mortality large animal model of moderate chronic pulmonary hypertension and right ventricular hypertrophy.

Clinical and prognostic relevance of echocardiographic evaluation of right ventricular geometry in patients with idiopathic pulmonary arterial hypertension.

The aim of the present study was to assess the clinical and prognostic significance of right ventricular (RV) dilation and RV hypertrophy at echocardiography in patients with idiopathic pulmonary arterial hypertension. Echocardiography and right heart catheterization were performed in 72 consecutive patients with idiopathic pulmonary arterial hypertension admitted to our institution. The median follow-up period was 38 months. The patients were grouped according to the median value of RV wall thickness (6.6 mm) and the median value of the RV diameter (36.5 mm). On multivariate analysis, the mean pulmonary artery pressure (p = 0.018) was the only independent predictor of RV wall thickness, and age (p = 0.011) and moderate to severe tricuspid regurgitation (p = 0.027) were the independent predictors of RV diameter. During follow-up, 22 patients died. The death rate was greater in the patients with a RV diameter >36.5 mm than in patients with a RV diameter ≤36.5 mm: 15.9 (95% confidence interval 9.4 to 26.8) vs 6.6 (95% confidence interval 3.3 to 13.2) events per 100-person years (p = 0.0442). In contrast, the death rate was similar in patients with RV wall thickness above or below the median value. However, among the patients with a RV wall thickness >6.6 mm, a RV diameter >36 mm was not associated with a poorer prognosis (p = 0.6837). In conclusion, in patients with idiopathic pulmonary arterial hypertension, a larger RV diameter is a marker of a poor prognosis but a greater RV wall thickness reduces the risk of death associated with a dilated right ventricle.

Outcome in stable patients with acute pulmonary embolism who had right ventricular enlargement and/or elevated levels of troponin I.

Normotensive patients with acute pulmonary embolism (PE) who have increased troponin levels and right ventricular (RV) dysfunction are thought to be at high risk of death, but the level of risk is unclear. We retrospectively evaluated outcome in 1,273 stable patients with PE who had echocardiographic evaluations of RV size and/or measurement of cardiac troponin I (cTnI). In-hospital all-cause mortality was higher in those with RV enlargement (8.0%, 19 of 237, vs 3.3%, 22 of 663, p = 0.003). With an increased cTnI, irrespective of RV enlargement, all-cause mortality was 8.0% (28 of 330) versus 1.9% (15 of 835) in patients with a normal cTnI (p <0.0001). In patients with an increased cTnI combined with an enlarged right ventricle, all-cause mortality was 10.2% (12 of 118) compared to 1.9% (8 of 421) in patients who had neither (p <0.0001). These data show that increased levels of cTnI and RV enlargement are associated with an adverse outcome in stable patients with acute PE. In conclusion, increased levels of cTnI in combination with RV enlargement might indicate a group who would benefit from intense monitoring and aggressive treatment if subsequently indicated. The outcomes, however, were not extreme enough to warrant routine thrombolytic therapy.

Marcadores genéticos como biomarcadores: hipertrofia cardíaca como exemplo / Genetic markers as biomarkers: cardiac hypertrophy as an example

A hipertrofia do ventrículo esquerdo constitui um dos mais poderosos de risco independentes para morbidade e mortalidade cardiovascular em pacientes de alto risco e na população geral. No mesmo nível de pressão arterial, alguns indivíduos desenvolvem hipertrofia do ventrículo esquerdo enquanto outros não o fazem, indicando uma suscetibilidade genética a essa condição. A hipertrofia do ventrículo esquerdo pode ser primária em doenças como cardiomiopatia hipertrofica ou, ao menos em parte, como um mecanismo compensatório para ativação crônica neuro-humoral e carga hemodinâmica anormal, sendo considerada uma adaptação estrutural do coração. O aumento da espessura da parede reduz o estresse na parede e mantém o desempenho da parede na presença do aumento da carga mecânica. Estudos recentes sugerem a existência de marcadores de suscetibilidade à hipertrofia em diversos genes, como o da enzima conversora de angiotensina, do angiotensinogênio, dos receptores tipo 1 e 2 da angiotensina II, da aldosterona sintetase, do receptor ativado...

Left ventricular hypertrophy is one of the strongest independent risk factors for cardiovascular morbidity and mortality in high risk patients and the general population. At the same blood pressure level, some individuals develop left ventricular hypertrophy while others do not, indicating a genetic susceptibility to this condition. Left ventricular hypertrophy may be primary in diseases such as hypertrophic cardiomyopathy or it may be partially due to a compensatory mechanism for chronic neurohumoral activation and abnormal hemodynamic load, considered as a structural adaptation of heart. Increased wall thickness reduces wall stress and maintains cardiac performance in the presence of increased mechanical load. Recent studies suggest the existence of markers of susceptibility to hypertrophy in several genes such as angiotensin converting enzyme, angiotensinogen, angiotensin II type 1 and type 2 receptors, aldosterone synthetase, peroxisome proliferator-activated receptor and G-protein ß3 subunit. Since it involves multiple environmental, behavior and genetic factors, the study of left ventricular hypertrophy is a challenge. However, the knowledge of molecular and genetic bases of left ventricular hypertrophy may contribute to a more accurate understanding of the pathogenesis of this condition and offers a promising future for its treatment and prevention.

Right ventricular heart failure from pulmonary embolism: key distinctions from chronic pulmonary hypertension.

BACKGROUND: The right ventricle normally operates as a low pressure, high-flow pump connected to a high-capacitance pulmonary vascular circuit. Morbidity and mortality in humans with pulmonary hypertension (PH) from any cause is increased in the presence of right ventricular (RV) dysfunction, but the differences in pathology of RV dysfunction in chronic versus acute occlusive PH are not widely recognized. METHODS AND RESULTS: Chronic PH that develops over weeks to months leads to RV concentric hypertrophy without inflammation that may progress slowly to RV failure. In contrast, pulmonary embolism (PE) results in an abrupt vascular occlusion leading to increased pulmonary artery pressure within minutes to hours that causes immediate deformation of the RV. RV injury is secondary to mechanical stretch, shear force, and ischemia that together provoke a cytokine and chemokine-mediated inflammatory phenotype that amplifies injury. CONCLUSIONS: This review will briefly describe causes of pulmonary embolism and chronic PH, models of experimental study, and pulmonary vascular changes, and will focus on mechanisms of right ventricular dysfunction, contrasting mechanisms of RV adaptation and injury in these 2 settings.

Sildenafil attenuates pulmonary inflammation and fibrin deposition, mortality and right ventricular hypertrophy in neonatal hyperoxic lung injury.

BACKGROUND: Phosphodiesterase-5 inhibition with sildenafil has been used to treat severe pulmonary hypertension and bronchopulmonary dysplasia (BPD), a chronic lung disease in very preterm infants who were mechanically ventilated for respiratory distress syndrome. METHODS: Sildenafil treatment was investigated in 2 models of experimental BPD: a lethal neonatal model, in which rat pups were continuously exposed to hyperoxia and treated daily with sildenafil (50-150 mg/kg body weight/day; injected subcutaneously) and a neonatal lung injury-recovery model in which rat pups were exposed to hyperoxia for 9 days, followed by 9 days of recovery in room air and started sildenafil treatment on day 6 of hyperoxia exposure. Parameters investigated include survival, histopathology, fibrin deposition, alveolar vascular leakage, right ventricular hypertrophy, and differential mRNA expression in lung and heart tissue. RESULTS: Prophylactic treatment with an optimal dose of sildenafil (2 x 50 mg/kg/day) significantly increased lung cGMP levels, prolonged median survival, reduced fibrin deposition, total protein content in bronchoalveolar lavage fluid, inflammation and septum thickness. Treatment with sildenafil partially corrected the differential mRNA expression of amphiregulin, plasminogen activator inhibitor-1, fibroblast growth factor receptor-4 and vascular endothelial growth factor receptor-2 in the lung and of brain and c-type natriuretic peptides and the natriuretic peptide receptors NPR-A, -B, and -C in the right ventricle. In the lethal and injury-recovery model we demonstrated improved alveolarization and angiogenesis by attenuating mean linear intercept and arteriolar wall thickness and increasing pulmonary blood vessel density, and right ventricular hypertrophy (RVH). CONCLUSION: Sildenafil treatment, started simultaneously with exposure to hyperoxia after birth, prolongs survival, increases pulmonary cGMP levels, reduces the pulmonary inflammatory response, fibrin deposition and RVH, and stimulates alveolarization. Initiation of sildenafil treatment after hyperoxic lung injury and continued during room air recovery improves alveolarization and restores pulmonary angiogenesis and RVH in experimental BPD.

Galphaq-protein carboxyl terminus imitation polypeptide (GCIP)-27 inhibits right ventricular hypertrophy induced by monocrotaline in rats.

This study was to investigate the probable inhibitory effect of Galphaq-protein carboxyl terminus imitation polypeptide-27 (GCIP-27), the optimized form of GCIP, which is a competition candidate of the activated binding sites on Galphaq, on the right ventricular (RV) hypertrophy induced by monocrotaline (MCT) in rats. We have previously shown that GCIP-27, can prevent the hypertrophyc responses in cultured rat cardiomyocytes induced by noradrenaline and angiotensin II. Male Sprague-Dawley rats were given a single dose (50 mg/kg) of MCT subcutaneouly to induce pulmonary hypertension (PH) and RV hypertrophy. GCIP-27 (30, 90 microg/kg) or vehicle was administered (twice daily, intraperitoneally) from day 1 to day 21. GCIP-27 (90 microg/kg) inhibited the elevated pulmonary arteria systolic pressure (PASP) and mean pulmonary arteria pressure induced by MCT, but its dose at 30 microg/kg only reduced the elevated PASP. And no effect could be seen on the pulmonary arteria diastolic pressure at both two doses. On the other hand, the two doses of GCIP-27 improved significantly the weight ratio of RV to left ventricle plus septum, the RV free wall thickness and pulmonary arteria acceleration time (PAAT). In morphometric observation, GCIP-27 (30, 90g/kg) could attenuate cardiomyocytes hypertrophy, interstitium fibrosis, mitochondria swelling and malformation markedly in RVs of MCT-treated rats. Furthermore, GCIP-27 (30, 90 mug/kg) significantly reduced the overexpression of the proliferating cell nuclear antigen (PCNA) induced by MCT in RV cardiocytes. The results suggest that GCIP-27 can effectively attenuate the RV hypertrophy induced by MCT in rats, which may be mediated by both the direct effect on cardiomyocyte and the secondary effect by reducing PH, and may be involved in its influence on the Gq signal pathway.

Cardiac-related findings at autopsy in people with severe mental illness treated with clozapine or risperidone.

Clozapine is a superior agent for treatment-refractory patients with schizophrenia, but is underutilized in the US, likely due to the risk of side effects. This study examined all available autopsy data on cardiac disease and risk factors in people with schizophrenia in a sample of deceased persons with severe mental illness who had received clozapine (N=62) or risperidone (N=42). The mean body mass index (BMI) at the time of death was 31.4+/-8.8 kg/m2 and 27.1+/-8.2 kg/m2 in the clozapine and risperidone groups respectively (t=1.98, df=60, p=0.052). Cardiac related measures examined included: abdominal wall thickness, heart weight, left ventricle thickness, right ventricle thickness, presence of notable cardiac involvement (atherosclerosis, fibrosis and hypertrophy) and number of cardiac arteries occluded. No significant differences in any of the cardiac findings were noted between patients in the clozapine and risperidone groups. Independent of treatment, cardiomyopathy deaths were associated with a higher abdominal wall thickness (p=0.042) and a tendency towards higher BMI (p=0.051) as compared to the other causes of death. The results of this study suggest that while clozapine is associated with weight gain and metabolic abnormalities, there does not appear to be an increased occurrence of cardiac abnormalities in deceased persons who were treated with clozapine as compared to risperidone.