High-Risk Pulmonary Hypertension Does Not Worsen Outcomes in Heart Transplantation.

Pulmonary hypertension (PH) is a relative contraindication to heart transplantation (HT). Multiple studies showed increased mortality in patients with PH. Advances in care may have led to improved outcomes in the modern era. We analyzed patients who underwent HT at our institution between 2014 and 2018. We divided patients into 2 groups based on the presence of high-risk PH defined as either pulmonary vascular resistance >3 Wood units or transpulmonary gradient >15 mm Hg. The primary outcome was survival. Secondary outcomes were post-HT morbidity and changes in hemodynamics. Subsequently, we analyzed national trends of single organ HT recipients with a high-risk PH between 1994 and 2018 from the United Network for Organ Sharing registry. Of 98 patients who underwent HT at our center, 32% had PH. In patients without and with PH, the survival was 100% at 30 days, 87%, and 81% at 3 years (p = 0.96). In both groups, pulmonary vascular resistance and trans-pulmonary gradient decreased after HT. Nationwide data revealed 30-day survival without and with PH at 97% and 98% (p = 0.47) and 3-year survival at 86% and 87% (p = 0.84), respectively, in 2018. The proportion of recipients with PH decreased from 25% in 1994 to 19% in 2018. Recipients of HT with and without high-risk PH had similar early and late mortality in a single-center and nationwide analysis. PH improved immediately after transplant. The United Network for Organ Sharing registry analysis demonstrates continued improvement in survival in patients with PH in the modern era, whereas the relative percentage of recipients with PH decreased over time.

Large differences in collateral blood vessel abundance among individuals arise from multiple genetic variants.

Collateral blood flow varies greatly among humans for reasons that remain unclear, resulting in significant differences in ischemic tissue damage. A similarly large variation has also been found in mice that is caused by genetic background-dependent differences in the extent of collateral formation, termed collaterogenesis-a unique angiogenic process that occurs during development and determines collateral number and diameter in the adult. Previous studies have identified several quantitative trait loci (QTL) linked to this variation. However, understanding has been hampered by the use of closely related inbred strains that do not model the wide genetic variation present in the "outbred" human population. The Collaborative Cross (CC) multiparent mouse genetic reference panel was developed to address this limitation. Herein we measured the number and average diameter of cerebral collaterals in 60 CC strains, their 8 founder strains, 8 F1 crosses of CC strains selected for abundant versus sparse collaterals, and 2 intercross populations created from the latter. Collateral number evidenced 47-fold variation among the 60 CC strains, with 14% having poor, 25% poor-to-intermediate, 47% intermediate-to-good, and 13% good collateral abundance, that was associated with large differences in post-stroke infarct volume. Collateral number in skeletal muscle and intestine of selected high- and low-collateral strains evidenced the same relative abundance as in brain. Genome-wide mapping demonstrated that collateral abundance is a highly polymorphic trait. Subsequent analysis identified: 6 novel QTL circumscribing 28 high-priority candidate genes harboring putative loss-of-function polymorphisms (SNPs) associated with low collateral number; 335 predicted-deleterious SNPs present in their human orthologs; and 32 genes associated with vascular development but lacking protein coding variants. Six additional suggestive QTL (LOD > 4.5) were also identified in CC-wide QTL mapping. This study provides a comprehensive set of candidate genes for future investigations aimed at identifying signaling proteins within the collaterogenesis pathway whose variants potentially underlie genetic-dependent collateral insufficiency in brain and other tissues.

Large differences in collateral blood vessel abundance among individuals arise from multiple genetic variants.

Collateral blood flow varies greatly among humans for reasons that remain unclear, resulting in significant differences in ischemic tissue damage. A similarly large variation has also been found in mice that is caused by genetic background-dependent differences in the extent of collateral formation, termed collaterogenesis-a unique angiogenic process that occurs during development and determines collateral number and diameter in the adult. Previous studies have identified several quantitative trait loci (QTL) linked to this variation. However, understanding has been hampered by the use of closely related inbred strains that do not model the wide genetic variation present in the "outbred" human population. The Collaborative Cross (CC) multiparent mouse genetic reference panel was developed to address this limitation. Herein we measured the number and average diameter of cerebral collaterals in 60 CC strains, their 8 founder strains, 8 F1 crosses of CC strains selected for abundant versus sparse collaterals, and 2 intercross populations created from the latter. Collateral number evidenced 47-fold variation among the 60 CC strains, with 14% having poor, 25% poor-to-intermediate, 47% intermediate-to-good, and 13% good collateral abundance, that was associated with large differences in post-stroke infarct volume. Genome-wide mapping demonstrated that collateral abundance is a highly polymorphic trait. Subsequent analysis identified: 6 novel QTL circumscribing 28 high-priority candidate genes harboring putative loss-of-function polymorphisms (SNPs) associated with low collateral number; 335 predicted-deleterious SNPs present in their human orthologs; and 32 genes associated with vascular development but lacking protein coding variants. This study provides a comprehensive set of candidate genes for future investigations aimed at identifying signaling proteins within the collaterogenesis pathway whose variants potentially underlie genetic-dependent collateral insufficiency in brain and other tissues.

Acute myopericarditis due to human granulocytic anaplasmosis.

We present a case of a 54-year-old gentleman with a history of hypertension and chronic HIV who presented with fever and epigastric pain, found to have elevated troponin-I levels and diffuse ST-segement elevations on ECG without clinical evidence of ischemia concerning for myopericarditis. Initial laboratory findings also included thrombocytopenia and elevated aminotransferases as well as computed tomography imaging revealing splenic infarcts. Given plausible exposure to ticks, this led to the eventual diagnosis of anaplasmosis confirmed on PCR assay. Cardiac MRI images confirmed myocardial involvement, which resolved with antibiotic treatment. While rare, cardiac involvement is possible sequelae of anaplasmosis infection as illustrated by this case.

A "Grave" Case of Mitral Regurgitation: Cardio-Obstetric Approach to Severe Mitral Regurgitation With Cardiogenic Shock.

A 26-year-old woman presented at 26 weeks of pregnancy with severe mitral regurgitation (MR) and cardiogenic shock in the setting of profound hyperthyroidism. An intra-aortic balloon pump was placed, and surgical intervention was considered. However, with management of thyrotoxicosis and delivery, complete resolution of MR and cardiogenic shock was achieved. (Level of Difficulty: Intermediate.).

Differences in Social Hardships in Women and Men with Acute Myocardial Infarction: Impact on 30-Day Readmission.

Background: Studies have shown that women with acute myocardial infarction (AMI) have a higher prevalence of unfavorable social variables then men and have a worse outcome. Less is known regarding the impact of these social variables on 30-day readmission after AMI. Materials and Methods: We analyzed adult patients with AMI enrolled in a Quality Improvement Program intended to improve the peri-discharge care of patients with an AMI, and decrease all-cause 30-day unplanned readmissions. We compared clinical and social variables by gender. Multivariate logistic regression, with separate adjustment for clinical and for social variable, was used to measure adjusted odds for readmission by gender. Results: Among 208 patients included in our project 68 (32.7%) were women. Only 30.9% of women were married or had domestic partner at the time of the interview and only 16.2% were employed. Nearly half of women (48.5%) needed help with medical care, and 39.7% of women did not speak English as their first language. These variables were significantly different by gender. Rates of 30-day readmissions were higher in women than men (22.1% vs. 7.8%, p = 0.024). After adjusting for clinical variables this difference by gender in 30-day readmissions remained significant (odds ratio [OR] 3.34 95% confidence interval [CI] 1.1-11.1, p = 0.049). However, when adjusting for social variables, this difference was no longer noted (OR 0.87 95% CI 0.27-2.78, p = 0.822). Conclusion: Women with AMI are more likely than men to have unfavorable social factors that can impact recovery from AMI and women have a higher 30-day readmission rate. The higher 30-day readmissions in women appears to be influenced by these social factors. Health care interventions aimed at reducing 30-day readmission after AMI should focus on eliciting a detailed social history and providing aid for those requiring additional social support at home.

Use of coronary artery calcium and coronary tomography angiography in the evaluation of ischemic heart disease.

Over the years, significant technological advances have been made in the field of cardiac CT imaging which has led to the widespread use of the modality in the evaluation of ischemic and structural heart disease. The advent of newer scanning techniques has led to a reduction in scanning time as well as a reduction in the radiation and contrast media dose required - making these scans both convenient and safer to perform. Research has shown that coronary CT angiography has a high negative predictive value in the evaluation of patients with coronary artery disease. There is more recent evidence that coronary CTA has a positive impact on clinical outcomes as well. In this review article, we discuss the clinical applications of coronary CTA in the evaluation of patients with stable ischemic heart disease, the most recent studies evaluating the efficacy and limitations of the modality, the role of coronary calcium in cardiovascular risk prediction in asymptomatic patients and the future applications of the modality.

A haemodynamic conundrum: a case report of a patient with concurrent pulmonary arterial hypertension and hypertrophic obstructive cardiomyopathy.

BACKGROUND: The co-existence of hypertrophic obstructive cardiomyopathy (HOCM) and pulmonary arterial hypertension (PAH) is extremely rare and poses a management conundrum. This is the first case report in the published literature to describe the diagnosis and management of a patient with both conditions. CASE SUMMARY: A 49-year-old female with a history of HOCM and recently diagnosed scleroderma presented to the clinic with progressive dyspnoea. Transthoracic echocardiogram demonstrated left ventricular outflow tract (LVOT) obstruction at rest, and elevated pulmonary artery (PA) pressure. Cardiac catheterization (CC) demonstrated an LVOT gradient of 150 mmHg, PA pressure of 88/32 mmHg, pulmonary capillary wedge pressure (PCWP) 12 mmHg, pulmonary vascular resistance 14.8 Wu, and a cardiac index of 1.6 L/min/m2. The differential diagnosis for the dyspnoea included combined pre- and post-capillary pulmonary hypertension from longstanding HOCM vs. scleroderma associated PAH. Tadalafil was added to the patient's medical regimen of metoprolol but it was stopped because the patient developed pulmonary oedema. Alcohol septal ablation was undertaken with improvement in the LVOT gradient, but only a modest improvement in her dyspnoea. Repeat CC demonstrated worsening PAH. Vasodilatory testing with nitric oxide led to an improvement in the PA pressure with minimal increase of the PCWP. Hence, she was started on treprostinil and macitentan, with significant improvement in her dyspnoea on follow-up. CONCLUSION: In patients with concurrent HOCM and advanced PAH, a multidisciplinary treatment approach is needed to rapidly and safely optimize the background of HOCM in order to permit the use of PAH-specific medications.

Hypoxia induces de novo formation of cerebral collaterals and lessens the severity of ischemic stroke.

Pial collaterals provide protection in stroke. Evidence suggests their formation late during gestation (collaterogenesis) is driven by reduced oxygen levels in the cerebral watersheds. The purpose of this study was to determine if collaterogenesis can be re-activated in the adult to induce formation of additional collaterals ("neo-collateral formation", NCF). Mice were gradually acclimated to reduced inspired oxygen (FIO2) and maintained at 12, 10, 8.5 or 7% for two-to-eight weeks. Hypoxemia induced "dose"-dependent NCF and remodeling of native collaterals, and decreased infarct volume after permanent MCA occlusion. In contrast, no formation occurred of addition collateral-like intra-tree anastomoses, PComs, or branches within the MCA tree. Hypoxic NCF, remodeling and infarct protection were durable, i.e. retained for at least six weeks after return to normoxia. Hypoxia increased expression of Hif2α, Vegfa, Rabep2, Angpt2, Tie2 and Cxcr4. Neo-collateral formation was abolished in mice lacking Rabep2, a novel gene involved in VEGFA→Flk1 signaling and required for formation of collaterals during development, and inhibited by knockdown of Vegfa, Flk1 and Cxcr4. Rabep2-dependent NCF was also induced by permanent MCA occlusion. This is the first report that hypoxia induces new pial collaterals to form. Hypoxia- and occlusion-induced neo-collateral formation provide models to study collaterogenesis in the adult.

Genetic and Environmental Contributions to Variation in the Posterior Communicating Collaterals of the Circle of Willis.

Variation in blood flow mediated by the posterior communicating collateral arteries (PComs) contributes to variation in the severity of tissue injury in obstructive disease. Evidence in animals and humans indicates that differences in the extent of PComs, i.e., their anatomic lumen diameter and whether they are present bilaterally, unilaterally, or absent, are a major factor. These differences arise during development since they are present at birth. However, the causal mechanisms are unknown. We used angiography after maximal dilation to examine involvement of genetic, environmental, and stochastic factors. The extent of PComs varied widely among seven genetically diverse strains of mice. Like pial collaterals in the microcirculation, aging and hypertension reduced PCom diameter, while in contrast, obesity, hyperlipidemia, metabolic syndrome, and diabetes mellitus had no effect. Naturally occurring intrauterine growth restriction had no effect on extent of PCom or pial collaterals in the adult. The number and diameter of PComs evidenced much larger apparent stochastic-dependent variation than pial collaterals. In addition, both PComs underwent flow-mediated outward remodeling after unilateral permanent MCA occlusion that varied with genetic background and was greater on the ipsilesional side. These findings indicate that variation in the number and diameter of PCom collateral arteries arises from stochastic factors and naturally occurring genetic variants that differ from those that cause variation in pial collateral arterioles. Environmental factors also contribute: aging and hypertension reduce PCom diameter. Our results suggest possible sources of variation of PComs in humans and provide information relevant when studying mouse models of occlusive cerebrovascular disease.

Misconceptions and Facts About Takotsubo Syndrome.

Takotsubo syndrome, initially described in the 1990s by Sato, has been increasingly recognized around the world. Pathophysiology is directed towards central role of catecholamine surge , but other aspects like microvascular endothelial dysfunction and vasospasm have also been described. Dyspnea and chest pain are most common manifestations, but syncope can also be seen. Right ventricular involvement is not uncommon, and left ventricular outflow tract obstruction is a frequent complication. EKG can differentiate between Takotsubo syndrome and myocardial infarction, but coronary angiography should always be performed. Although treatment has been angiotensin converting enzyme inhibitors and betablockers, recent evidence from nonrandomized studies shows no benefit on betablockers regarding outcomes.

Aerobic exercise prevents rarefaction of pial collaterals and increased stroke severity that occur with aging.

Variation in extent of the brain's collateral circulation is an important determinant of variation in the severity of stroke and efficacy of revascularization therapies. However, the number and diameter of pial collateral "arterioles" decrease with aging in associated with reduced eNOS and increased oxidative stress. We tested whether exercise reduces this aging-induced rarefaction. Twelve-month-old mice were randomized to sedentary or voluntary wheel-running. At 26 months' age, permanent MCA occlusion was followed 72 h later by determination of infarct volume and vascular casting after maximal dilation. The decline in collateral number and diameter and 2.4-fold increase in infarct volume evident in 26-versus 3-month-old sedentary mice were prevented by exercise-training. In contrast, number and diameter of the posterior communicating collateral "arteries" were unaffected by aging or exercise. Interestingly, diameter of the primary intracranial arteries increased with aging. Mechanistically, genetic overexpression of eNOS inhibited age-induced collateral rarefaction, and exercise increased eNOS and SOD2 and decreased the inflammatory marker NFkB assessed in hindlimb arteries. In conclusion, exercise prevented age-induced rarefaction of pial collaterals and reduced infarct volume. Aging also promoted outward remodeling of intracranial arteries. These effects were associated with increased eNOS and reduced markers of inflammation and aging in the vascular wall.

Detecting Mycobacterium tuberculosis complex DNA, based on post-mortem examination of hilar lymph nodes with real-time PCR: initial study.

INTRODUCTION: According to the WHO, almost a third of the world population are thought to be infected with Mycobacterium tuberculosis. Some studies of the prevalence of latent tuberculosis infection (LTBI) have already been performed in Poland, showing that almost a quarter of the Mazovia population could be infected. It also indicated a higher prevalence of LTBI among seniors. Those studies were based on indirect diagnostic methods. MATERIAL AND METHODS: We randomly collected hilar lymph nodes from decedents aged 40 years and older during post-mortem examination. We excluded patients with previous confirmed tuberculosis. In addition, an autopsy was performed in all patients. Finally, we used real-time PCR Xpert MTB/RIF (Cepheid, USA) for the specific capture of mycobacterial DNA. RESULTS: Twenty-two of 23 patients had a negative result of the real-time PCR examination and no signs of caseous necrosis in hilar lymph nodes. We found the only positive sample in a patient with histopathological signs of tuberculosis (the presence of caseous necrosis in the specimens obtained from lymph nodes and lung). Due to the change of cartridges from version G3 to G4, further reactions were inhibited and no more post-mortem samples were tested. CONCLUSIONS: Real-time PCR Xpert MTB/RIF was capable of detecting M. tuberculosis complex DNA in a patient with tuberculosis recognised on autopsy. In the remaining patients, no M. tuberculosis complex DNA was found, in accordance with negative results of histological examination. Since the technology of cartridges has changed, it is no longer possible to use real-time PCR Xpert MTB/RIF (Cepheid USA) on post-mortem material.