Melatonin against pulmonary arterial hypertension: is it ready for testing in patients?

Pulmonary arterial hypertension (PAH) is a fatal disease defined as a mean pulmonary artery pressure exceeding 25 mmHg when diagnosed with right heart catheterisation. Its pathophysiology involves multiple molecular pathways, including key components leading to an inflammatory and oxidative stress environment that ultimately causes right ventricular hypertrophy and failure. Compared to the developed world, the overall PAH prevalence is higher in developing countries, including Africa, where it is mostly associated with left heart disease, obstructive/restrictive pulmonary disease, HIV and rheumatic heart disease. Current targeted PAH treatments are expensive, not always available in developing countries, and have a limited impact on PAH progression and mortality rate. Therefore, there is an urgent need for effective and affordable medications that can be used as adjunct therapy against PAH in developing countries. Recently, there have been mounting pre-clinical and clinical data suggesting that melatonin may provide health benefits against PAH.

Cardiopulmonary Testing before Pediatric Adenotonsillectomy for Severe and Very Severe Obstructive Sleep Apnea Syndrome.

OBJECTIVES/HYPOTHESIS: Adenotonsillectomy is first-line treatment for pediatric obstructive sleep apnea syndrome (OSAS) when not otherwise contraindicated. There is concern severe OSAS increases risk of comorbid cardiopulmonary abnormalities, such as ventricular hypertrophy or pulmonary hypertension, which preoperative testing could detect. Our objective is to determine if there is a severity of pediatric OSAS where previously undetected cardiopulmonary comorbidities are likely. STUDY DESIGN: Retrospective chart review. METHODS: We performed a retrospective review of 358 patients ≤21 years with severe OSAS who underwent adenotonsillectomy at a tertiary hospital June 1, 2016 to June 1, 2018. We extracted demographics, comorbidities, polysomnography, and preoperative tests. Wilcoxon rank-sum and logistic regression estimated associations of OSAS severity (based on obstructive apnea-hypopnea index [OAHI], hypoxia, hypercarbia) with preoperative echocardiograms and chest X-rays (CXRs). RESULTS: Mean age was 5.9 (±3.6) years and 52% were male. Mean OAHI and oxygen saturation nadir were 30.3 (±23.8) and 80.7% (±9.2), respectively. OAHI ≥60 was associated with having a preoperative echocardiogram (OR, 3.8; 95% CI, 1.7-8.5) or CXR (OR, 3.0; 95% CI, 1.4-6.8) compared to OAHI 10-59. There were no significant associations between OSAS severity and test abnormalities. The presence of previously diagnosed cardiopulmonary comorbidities was associated with abnormalities on echocardiogram (OR, 36; 95% CI, 4.1-320.1) and CXR (OR, 4.1; 95% CI, 1.2-14.4). CONCLUSIONS: Although pediatric patients with very severe OSAS (OAHI ≥60) underwent more pre-adenotonsillectomy cardiopulmonary tests, OSAS severity did not predict abnormal findings. Known cardiopulmonary comorbidities may be a better indication for cardiopulmonary testing than polysomnographic parameters, which could streamline pre-adenotonsillectomy evaluation and reduce cost. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:2361-2368, 2021.

Fetal cardiac findings and hemodynamic changes associated with severe lower urinary tract obstruction in utero.

OBJECTIVES: To describe fetal echocardiographic findings associated with lower urinary tract obstruction (LUTO) and to compare anatomic and hemodynamic measurements between fetuses with LUTO and gestational age (GA)-matched controls, with an emphasis on quantitative indices of diastolic function and cardiac output. METHODS: This was a retrospective cohort study of fetuses diagnosed with severe LUTO with giant bladder, which underwent at least one fetal echocardiogram at our center between January 2005 and June 2018. Fetuses with major congenital heart disease were excluded. Control fetuses did not have any structural or functional abnormalities and were GA-matched to the LUTO fetuses based on the time of the first fetal echocardiogram. Cardiac anatomy and hemodynamic measurements were compared between fetuses with LUTO and controls. In infants with LUTO, serial fetal and postnatal echocardiographic data were assessed, when available, and clinical outcomes were reviewed. RESULTS: Twenty-six fetuses with LUTO and at least one fetal echocardiogram available were identified, one of which was excluded due to hypoplastic left heart syndrome, leaving 25 LUTO fetuses in the final cohort. The mean GA at the first fetal echocardiogram was 25.4 ± 5.1 weeks in the LUTO group and 25.3 ± 5.0 weeks in the control group. Common findings in fetuses with LUTO included cardiomegaly (40%), pericardial effusion (44%), right ventricular (RV) hypertrophy (64%) and left ventricular (LV) hypertrophy (48%). Compared with GA-matched controls, LUTO fetuses had lower ascending aorta Z-score (-0.10 ± 0.94 vs -0.93 ± 1.03; P = 0.02) and aortic isthmus Z-score (-0.14 ± 0.86 vs -1.62 ± 1.11; P < 0.001), shorter mitral valve inflow time indexed to cardiac cycle length (0.46 ± 0.04 vs 0.41 ± 0.06; P = 0.002), and worse (increased) LV myocardial performance index (0.39 ± 0.03 vs 0.44 ± 0.04; P < 0.001). In addition, the ratio of RV to LV cardiac index was higher in LUTO fetuses compared with controls (1.62 ± 0.13 vs 1.33 ± 0.11; P < 0.001). Of the 25 LUTO pregnancies, two were lost to follow-up, three underwent elective termination of pregnancy and three ended in intrauterine fetal demise. Four (16%) patients had mildly hypoplastic left-heart structures, comprising two with aortic arch hypoplasia and two with mitral and aortic stenosis. CONCLUSION: In addition to presenting with cardiomegaly, pericardial effusion and ventricular hypertrophy, fetuses with LUTO demonstrate LV diastolic dysfunction and appear to redistribute cardiac output as compared to control fetuses, which may contribute to the development of left-heart hypoplasia. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

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.

Right atrium enlargement predicts clinically significant supraventricular arrhythmia in patients with pulmonary arterial hypertension.

BACKGROUND: Right atrial (RA) enlargement is a common finding in patients with pulmonary arterial hypertension (PAH) and an important predictor of mortality, however its relation to the risk of atrial arrhythmias has not been assessed. OBJECTIVES: To assess whether RA enlargement is associated with supraventricular arrhythmias (SVA) and whether it predicts new clinically significant SVA (csSVA). METHODS: Patients with PAH were recruited between January 2010 and December 2014 and followed until January 2017. csSVA was diagnosed if it resulted in hospitalization. To assess predictors of new csSVA, only patients without a history of SVA at baseline were analyzed. RESULTS: Among 97 patients, any SVA was observed in 45 (46.4%) and included permanent atrial fibrillation(AF, n = 8), paroxysmal AF (n = 10), permanent atrial flutter (AFl, n = 1), paroxysmal AFl (n = 2) or other types of supraventricular tachycardia (n = 24). Patients with SVA as compared to patients without SVA were characterized by older age, lower distance in a 6-minute test, higher NT-proBNP, higher RA area index (RAai), left atrial area index, mean right atrial pressure (mRAP) and were more commonly treated with ß-blocker. Eighty five patients who were in sinus rhythm at baseline assessment and had no history of significant SVA were observed for 37 ± 19.9 months. During that time csSVA occurred in 15.3%. In univariate models, the occurrence of csSVA were predicted by age, right ventricular ejection fraction, right ventricular end diastolic index, RAai and mRAP, but in multivariate model only RAai remained significant predictor for csSVA (HR of 1.23, 95%CI: 1.11-1.36, p < 0.001). The optimal threshold for RA enlargement as discriminator of csSVA was 21.7 cm2/m2. CONCLUSIONS: In PAH patients RA enlargement is associated with increased prevalence of SVA. RAai is an independent predictor of hospitalization due to csSVA.

Association between electrocardiographic and echocardiographic right ventricular hypertrophy in a military cohort in Taiwan: The CHIEF study: ECG criteria for RVH.

We compared electrocardiographic and echocardiographic right ventricular hypertrophy (RVH) in 264 military members in Taiwan. The correlations of the Myers et al. and Sokolow-Lyon criteria with RV wall thickness were low (r<0.1). Our data supported the American guidance that RVH voltage criteria violations should not receive further echocardiographic investigation.

Symptoms, diagnoses, and sporting consequences among athletes referred to a Danish sports cardiology clinic.

As the number of recreational athletes performing exercise and participating in competitions at a high-level increases, exercise-induced cardiac symptoms may become a more common problem, not least because recreational athletes often continue high-level exercise programs into advanced ages. We investigated the prevalence of cardiac symptoms and diagnoses among 201 athletes referred for cardiac evaluation at a Sports Cardiology Clinic in Denmark. To our knowledge, this is the first systematic study of athletes referred for suspected cardiac disease. The athletes were all well-trained recreational to elite athletes who participated in various sports with different training loads and a wide age span (13-66 years). All patients were referred by physicians, primarily their general practitioner (38%), and palpitations were the most common cardiac symptom (40%). Cardiac symptoms had a sensitivity of 86% in detecting cardiac disease and a specificity of 13%. Cardiac disease was diagnosed in 44% of the patients, and atrial fibrillation was the most prevalent diagnosis (7.5%). Cardiac diseases with therapeutic- or sports-related consequences for the patients were diagnosed in 28% of the population, but only 1% received a recommendation to avoid high-level sports indefinitely.

Sex-Specific Association of Sleep Apnea Severity With Subclinical Myocardial Injury, Ventricular Hypertrophy, and Heart Failure Risk in a Community-Dwelling Cohort: The Atherosclerosis Risk in Communities-Sleep Heart Health Study.

BACKGROUND: Risk factors for obstructive sleep apnea (OSA) and the development of subsequent cardiovascular (CV) complications differ by sex. We hypothesize that the relationship between OSA and high-sensitivity troponin T (hs-TnT), cardiac structure, and CV outcomes differs by sex. METHODS AND RESULTS: Seven hundred fifty-two men and 893 women free of CV disease participating in both the Atherosclerosis Risk in the Communities and the Sleep Heart Health Studies were included. All participants (mean age, 62.5 ± 5.5 years) underwent polysomnography and measurement of hs-TnT. OSA severity was defined by using established clinical categories. Subjects were followed for 13.6 ± 3.2 years for incident coronary disease, heart failure, and CV and all-cause mortality. Surviving subjects underwent echocardiography after 15.2 ± 0.8 years. OSA was independently associated with hs-TnT among women (P=0.03) but not in men (P=0.94). Similarly, OSA was associated with incident heart failure or death in women (P=0.01) but not men (P=0.10). This association was no longer significant after adjusting for hs-TnT (P=0.09). Among surviving participants without an incident CV event, OSA assessed in midlife was independently associated with higher left ventricle mass index only among women (P=0.001). CONCLUSIONS: Sex-specific differences exist in the relationship between OSA and CV disease. OSA, assessed in midlife, is independently associated with higher levels of concomitantly measured hs-TnT among women but not men, in whom other comorbidities associated with OSA may play a more important role. During 13-year follow-up, OSA was associated with incident heart failure or death only among women, and, among those without an incident event, it was independently associated with left ventricular hypertrophy only in women.

Right ventricular hypertrophy is associated with cardiovascular events in hypertrophic cardiomyopathy: evidence from study with magnetic resonance imaging.

BACKGROUND: Although left ventricular (LV) morphology and function have been well studied in hypertrophic cardiomyopathy (HCM), few data exist regarding the right ventricle. Accordingly, we studied right ventricular (RV) morphology and function and their effect on cardiovascular events in HCM using cardiac magnetic resonance (CMR) imaging. METHODS: This retrospective study included 106 HCM patients (age 61.6 ± 14.5 years) examined using CMR imaging during January 2008 to September 2014. RV hypertrophy (RVH) was defined as RV maximal wall thickness > 5 mm. RESULTS: RVH was observed in 30 of the 106 patients (RVH group), with the remaining 76 patients assigned to the non-RVH group. The RVH group had higher brain natriuretic peptide levels (461.6 ± 699.8 pg/mL vs. 225.3 ± 254.5 pg/mL; P = 0.01) and also showed a reduced RV end-diastolic volume index (43.4 ± 16.0 mL/m2 vs. 56.6±15.2 mL/m2; P = 0.0001), in keeping with a greater LV mass index (109.1 ± 24.9 g/m2 vs. 78.6 ± 23.0 g/m2; P < 0.0001). The RVH group was prominently associated with RV late gadolinium enhancement compared with the non-RVH group (33.3% vs. 0%; P < 0.0001). After CMR imaging, 15 patients developed cardiovascular events that included admission for heart failure, ventricular tachyarrhythmia/fibrillation, stroke, and sudden cardiac death. Cox proportional hazard analysis revealed that RVH was an independent predictor of the occurrence of cardiovascular events after adjustments by sex, age, LV mass index, LV ejection fraction, and LV outflow tract obstruction (hazard ratio, 5.42; 95% confidence interval, 1.16-25.3; P = 0.03). CONCLUSIONS: These results suggest that HCM patients with RVH on CMR images have a greater incidence of cardiovascular events than non-RVH patients. Further work is needed to confirm this observation and assess its clinical importance.

Effect of the 2010 task force criteria on reclassification of cardiovascular magnetic resonance criteria for arrhythmogenic right ventricular cardiomyopathy.

BACKGROUND: We sought to evaluate the effect of application of the revised 2010 Task Force Criteria (TFC) on the prevalence of major and minor Cardiovascular Magnetic Resonance (CMR) criteria for Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) versus application of the original 1994 TFC. We also assessed the utility of MRI to identify alternative diagnoses for patients referred for ARVC evaluation. METHODS: 968 consecutive patients referred to our institution for CMR with clinical suspicion of ARVC from 1995 to 2010, were evaluated for the presence of major and minor CMR criteria per the 1994 and 2010 ARVC TFC. CMR criteria included right ventricle (RV) dilatation, reduced RV ejection fraction, RV aneurysm, or regional RV wall motion abnormalities. When quantitative measures of RV size and function were not available, and in whom abnormal size or function was reported, a repeat quantitative analysis by 2 qualified CMR physicians in consensus. RESULTS: Of 968 patients, 220 (22.7%) fulfilled either a major or a minor 1994 TFC, and 25 (2.6%) fulfilled any of the 2010 TFC criterion. Among patients meeting any 1994 criteria, only 25 (11.4%) met at least one 2010 criterion. All patients who fulfilled a 2010 criteria also satisfied at least one 1994 criterion. Per the 2010 TFC, 21 (2.2%) patients met major criteria and 4 (0.4%) patients fulfilled at least one minor criterion. Eight patients meeting 1994 minor criteria were reclassified as satisfying 2010 major criteria, while 4 patients fulfilling 1994 major criteria were reclassified to only minor or no criteria under the 2010 TFC.Eighty-nine (9.2%) patients had alternative cardiac diagnoses, including 43 (4.4%) with clinically significant potential ARVC mimics. These included cardiac sarcoidosis, RV volume overload conditions, and other cardiomyopathies. CONCLUSIONS: Application of the 2010 TFC resulted in reduction of total patients meeting any diagnostic CMR criteria for ARVC from 22.7% to 2.6% versus the 1994 TFC. CMR identified alternative cardiac diagnoses in 9.2% of patients, and 4.4% of the diagnoses were potential mimics of ARVC.

Relation of electrocardiographic changes in pulmonary embolism to right ventricular enlargement.

The electrocardiographic (ECG) findings in patients with pulmonary embolism (PE) and no previous cardiopulmonary disease are well documented; however, investigation of the relation of ECG abnormalities to right ventricular (RV) enlargement has been limited. The purpose of the present investigation was to assess further the relation of ECG changes in acute PE to RV cavity enlargement (dilation). The records of patients hospitalized from January 2009 to December 2012 with acute PE and no previous cardiopulmonary disease were reviewed. A total of 289 patients were included. RV cavity enlargement was present in 141 patients (49%). Normal ECG findings were less prevalent in patients with PE and RV enlargement than those with PE and no RV enlargement (35 of 141 [25%] vs 56 of 148 [38%]; p = 0.02). One or more of the traditional ECG manifestations of acute cor pulmonale (S1Q3T3, complete right bundle branch block, P pulmonale, or right axis deviation) was found in 18 of 141 patients (13%) with RV enlargement and 13 of 148 (8.8%) with a normal size RV (p = NS). None of the ECG abnormalities was sensitive for RV enlargement. The specificity of P and QRS abnormalities was high. The positive predictive values were ≤83% or had wide 95% confidence intervals. The negative predictive values ranged from 50% to 61%. In conclusion, ECG findings were not useful for the detection or exclusion of RV cavity enlargement in patients with acute PE.

Right ventricular hypertrophy in systemic hypertension: an updated review of clinical studies.

AIM: Experimental and clinical evidence supports the view that right ventricular hypertrophy (RVH) may parallel left ventricular hypertrophy in systemic hypertension; a comprehensive analysis of this issue, however, is lacking. Thus, we analyzed the literature in order to provide an updated information on the right ventricular structural changes associated to systemic hypertension. DESIGN: A literature search using the key words 'right ventricle' 'right ventricular hypertrophy', 'biventricular hypertrophy' 'right and left ventricular hypertrophy'. 'hypertension', 'echocardiography' was performed in order to identify relevant articles. Full articles published in English language in the last three decades reporting studies in adult hypertensive individuals were considered. RESULTS: A total of 13 studies, including 1290 untreated (45%) and treated hypertensive patients and 259 normotensive controls, were considered. Overall, in hypertensive individuals right ventricular wall was thicker than in normotensive counterparts (standardized difference 1.3 mm, P < 0.001). RVH prevalence consistently varied among studies (17.0-80.0%) with an average of 28.6% in the pooled population. This was also the case for LVH prevalence rates (9.0-100%) with an average value of 30.6%. CONCLUSION: Clinical studies consistently indicate that RVH is a common cardiac phenotype in systemic hypertension. As this finding is based on a limited number of cross-sectional studies including small population samples, further investigations are needed to determine the clinical utility and prognostic value of this phenotype in clinical practice.

Significance of electrocardiographic right ventricular hypertrophy in patients with pulmonary hypertension with or without right ventricular systolic dysfunction.

OBJECTIVE: We sought to determine the value of electrocardiographic right ventricular hypertrophy (ECG-RVH) in pulmonary hypertension (PH) patients with right ventricular systolic dysfunction defined by cardiac magnetic resonance (CMR-RVSD). PATIENTS: A total of 31 consecutive patients with PH with a mean pulmonary arterial pressure of >25 mmHg underwent both ECG and CMR studies. Patients were divided into 2 groups according to the presence of RVSD, defined as a RV ejection fraction <35%. Logistic regression modeling was performed to define the association between ECG-RVH and CMR-RVSD. RESULTS: About half of the patients had RVSD (n=15 ; 48%). The R to S wave ratio (p=0.01) or incidence of qR pattern (p=0.002) in lead V(1) was significantly greater in patients with PH complicated by RVSD than in those without RVSD. These 2 patterns were significant predictors of RVSD [odds ratio (OR), 19.3 for qR; OR, 14.0 for R/S>1] and when each of these ECG findings was assigned with a point proportional to OR (score of 2 for qR in lead V(1) and score of 1 for R/S>1 in lead V(1)), the incidence of RVSD increased by the total ECG score. CONCLUSION: The combination of ECG-RVH findings, especially in lead V(1), predicts the presence of RVSD defined by CMR. ECG might be a useful tool for estimating the presence of RVSD in patients with PH.

Electrocardiogram for the diagnosis of right ventricular hypertrophy and dilation in idiopathic pulmonary arterial hypertension.

BACKGROUND: Currently, there are no data on the association between right ventricular (RV) structure and ECG changes specific for idiopathic pulmonary arterial hypertension (IPAH). Therefore, we aimed to assess the accuracy of the recommended ECG criteria for predicting RV hypertrophy (RVH) and dilation in patients with IPAH. METHODS AND RESULTS: Twelve-lead ECG and cardiovascular magnetic resonance imaging (CMR) were performed in 23 consecutive patients with IPAH aged 49.8±16.3 years. ECG criteria were referred to RV mass index and RV end-diastolic volume index as measured by CMR. Only the ECG voltage criteria based on R wave amplitude in lead V1, R wave amplitude in aVR, P wave amplitude in II and ventricular activation time in V1 were useful for differentiating between patients with and without RVH. A ventricular activation time in lead V1 of <0.01 s excluded RVH, whereas R in V1 >6 mm, R:S in V1 >1, R in aVR >4 mm, R:S in V5 to R:S in V1 <0.04 and P in II >2.5 mm confirmed the diagnosis. Only the ventricular activation time in V1 correlated with RV dilation and when >0.045s confirmed its diagnosis. CONCLUSIONS: Only a few of the recommended ECG criteria proved to be useful in the diagnosis of RVH or RV dilation in patients with IPAH. Changes in the cut-off values improved their accuracy.

Electrocardiographic abnormalities in patients with severe versus mild or moderate chronic obstructive pulmonary disease followed in an academic outpatient pulmonary clinic.

BACKGROUND: The prevalence of some electrocardiographic (ECG) abnormalities in severe versus mild or moderate chronic obstructive pulmonary disease (COPD) has been reported. METHODS: ECGs were interpreted blindly in 63 patients with severe COPD (group 1) versus 83 patients with mild or moderate COPD (group 2). RESULTS: Right atrial enlargement (RAE) occurred in 44% of group 1 and 15% of group 2 patients (P < 0.001). Right ventricular hypertrophy (RVH) occurred in 29% of group 1 and 4% of group 2 patients (P < 0.001). Right bundle branch block (RBBB) occurred in 29% of group 1 and 11% of group 2 patients (P < 0.01). Marked clockwise rotation of heart occurred in 40% of group 1 and 18% of group 2 patients (P < 0.005). Low voltage in limb leads occurred in 24% of group 1 and 11% of group 2 patients (P < 0.05). A QS pattern in leads III and aVF occurred in 16% of group 1 and 4% of group 2 patients (P < 0.01). Left axis deviation (LAD) occurred in 16% of group 1 and 4% of group 2 patients (P < 0.01). Premature atrial complexes (PACs) occurred in 19% of group 1 and 7% of group 2 patients (P < 0.05). Supraventricular tachyarrhythmias (SVTs) occurred in 16% of group 1 and 5% of group 2 patients (P < 0.025). CONCLUSIONS: RAE, RVH, RBBB, marked clockwise rotation of heart, a QS pattern in leads III and aVF, LAD, PACs, and SVTs were significantly more prevalent in patients with severe COPD than in patients with mild or moderate COPD.