Single-cell RNA sequencing analysis of SARS-CoV-2 entry receptors in human organoids.

Coronavirus disease-2019 (COVID-19) is a global pandemic and caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has resulted in millions of deaths worldwide. Reports denote SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2), transmembrane serine protease 2 (TMPRSS2) as its primary entry point into the host cell. However, understanding the biology behind this viral replication, disease mechanism and drug discovery efforts are limited due to the lack of a suitable experimental model. Here, we used single-cell RNA sequencing data of human organoids to analyze expressions of ACE2 and TMPRSS2, in addition to an array of RNA receptors to examine their role in SARS-CoV-2 pathogenesis. ACE2 is abundant in all organoids, except the prostate and brain, and TMPRSS2 is omnipresent. Innate immune pathways are upregulated in ACE2(+) cells of all organoids, except the lungs. Besides this, the expression of low-density lipoprotein receptor is highly enriched in ACE2(+) cells in intestinal, lung, and retinal organoids, with the highest expression in lung organoids. Collectively, this study demonstrates that the organoids can be used as an experimental platform to explore this novel virus disease mechanism and for drug development.

Differential Mitochondrial Function in Remodeled Right and Nonremodeled Left Ventricles in Pulmonary Hypertension.

OBJECTIVES: Right ventricular failure is the primary reason for mortality in pulmonary hypertension (PH), but little is understood about the energetics of the failing right myocardium. Our aim was to examine mitochondrial function and proteomic signatures in paired remodeled right (RM-RV) and non-remodeled left (NRM-LV) ventricular tissue samples procured during heart-lung transplantation. METHODS AND RESULTS: Contractile dysfunction in RM-RV and preserved contractile function in NRM-LV were determined clinically and by echocardiography. Mitochondria were isolated from fresh paired RV and LV wall specimens of explanted hearts. Respiratory states in response to 4 substrates and an uncoupler were analyzed. Proteomic analysis on the mitochondrial isolates was performed with the use of liquid chromatography-mass spectrometry. The RM-RV mitochondria exhibited higher succinate state 4 levels with lower respiratory control ratio (RCR) compared with state 4 levels for pyruvate-malate (PM) and glutamate-malate (GM). RM-RV mitochondria also exhibited lower state 3 for palmitoyl-carnitine (PC) and state 4 for all complex I substrates compared with NRM-LV. The mean RCR were greater in RM-RVs than in NRM-LVs for PM and GM, which is consistent with tight coupling (low state 4 rates, higher RCRs); however, low RM-RV state 3 rates suggest concurrent substrate-dependent impairment in respiratory capacity. Mitochondrial proteomics revealed greater levels of mitochondrial ADP-ATP translocase and proteins of ATP synthesis, mitochondrial pyruvate and short branched chain acyl-CoA metabolism in RM-RV. CONCLUSIONS: The mitochondrial respiration and proteomics in RM-RV are different from NRM-LV. These results have important implications in expanding our understanding of RV metabolism and future management of RV failure.

Acquired and Hereditary Hypercoagulable States in Patients with Continuous Flow Left Ventricular Assist Devices: Prevalence and Thrombotic Complications.

BACKGROUND: Thrombotic events in patients with continuous flow left ventricular assist devices (CF-LVADs) are associated with significant morbidity and mortality. The objective of this study was to delineate the frequency, clinical characteristics, and outcomes of patients with hypercoagulable states who undergo CF-LVAD implantation. METHODS: We performed a retrospective review of 168 consecutive patients who underwent CF-LVAD implantation between 2010 and 2013. Chart and laboratory data were reviewed for the presence of a hereditary and/or acquired hypercoagulable state. Adverse outcomes were defined as death, confirmed pump thrombosis, aortic root clot, stroke, deep vein thrombosis, and pulmonary embolism. Fisher's exact test and Kaplan-Meier estimate were used to analyze frequency of adverse outcomes and event free survival, respectively. RESULTS: A hypercoagulable state was identified in 20 patients (11.9%). There were 18 patients with acquired, 1 with a congenital, and 1 with both congenital and acquired hypercoagulable states. The median follow-up was 429 days and 475 days in patients with and without hypercoagulable states, respectively. During the study period, 15% (3/20) of the patients with a hypercoagulable state had a diagnosis of deep vein thrombosis vs 3% (4/148) of the patients without a hypercoagulable state (P = .030). Only patients with a hypercoagulable state had a subarachnoid hemorrhage (3/20 vs 0/148; P < .01). The event-free survival was lower in the patients with hypercoagulable states (P = .005). CONCLUSION: Hypercoagulable states are not uncommon in patients with CF-LVADs and may be associated with increased morbidity. Prospective studies are needed to more accurately identify the incidence, prevalence, and significance of hypercoagulable states in patients being considered for CF-LVAD.

Persistent blood stream infection in patients supported with a continuous-flow left ventricular assist device is associated with an increased risk of cerebrovascular accidents.

BACKGROUND: Common adverse events in patients supported with Continuous-flow left ventricular assist devices (CF-LVAD) include infections and cerebrovascular accidents (CVA). Some studies have suggested a possible association between blood stream infection (BSI) and CVA. METHODS AND RESULTS: Medical records of patients who received Heartmate II (HMII) CF-LVADs in 2008-2012 at a single center were reviewed. CVA was categorized as either hemorrhagic (HCVA) or ischemic (ICVA). BSI was divided into persistent (pBSI) and nonpersistent (non-pBSI). pBSI was defined as BSI with the same organism on repeated blood culture >72 hours from initial blood culture despite antibiotics. Univariate and multivariate analyses were performed to determine predictors. A total of 149 patients had HMII implanted; 76% were male, and the overall mean age was 55.4 ± 13 years. There were a total of 19 (13%) patients who had CVA (7 HCVA and 12 ICVA) at a median of 295 days (range 5-1,096 days) after implantation. There were a total of 28 (19%) patients with pBSI and 17 (11%) patients with non-pBSI. Patients with pBSI had a trend toward greater BMI (31 kg/m(2) vs 27 kg/m(2); P = .09), and longer duration of support (1,019 d vs 371 d; P < .001) compared with those with non-pBSI. Persistent BSI was associated with an increased risk of mortality and with all-cause CVA on multivariate analysis (odds ratio [OR] 5.97; P = .003) as well as persistent Pseudomonas aeruginosa infection (OR 4.54; P = .048). CONCLUSIONS: Persistent BSI is not uncommon in patients supported by CF-LVAD and is highly associated with all-cause CVA and increased all-cause mortality.

Ventricular assist devices: a review of psychosocial risk factors and their impact on outcomes.

BACKGROUND: Psychosocial contraindications for ventricular assist devices (VADs) remain particularly nebulous and are driven by institution-specific practices. Our multi-institutional, multidisciplinary workgroup conducted a review with the goal of addressing the following research question: How are preoperative psychosocial domains predictive of or associated with postoperative VAD-related outcomes? Answers to this question could contribute to the development of treatment-specific (contra) indications for patients under consideration for mechanical devices. METHODS AND RESULTS: We identified 5 studies that examined psychosocial factors and their relationship to postoperative VAD-related outcomes. Our results suggest that 3 psychosocial variables are possibly associated with VAD-related outcomes: depression, functional status, and self-care. Of the few studies that exist, the generalizability of findings is constrained by a lack of methodologic rigor, inconsistent terminology, and a lack of conceptual clarity. CONCLUSIONS: This review should serve as a call for research. Efforts to minimize psychosocial risk before device placement can only be successful insofar as VAD programs can clearly identify who is at risk for suboptimal outcomes.

Cardiovascular magnetic resonance characterization of left ventricular non-compaction provides independent prognostic information in patients with incident heart failure or suspected cardiomyopathy.

BACKGROUND: With recent advances in imaging methods, detection of LVNC is increasingly common. Concomitantly, the prognostic importance of LVNC is less clear. METHODS: We followed 42 patients (63% male, age 44 ± 15 years) with incident heart failure or suspected cardiomyopathy, in whom cardiovascular magnetic resonance (CMR) yielded a diagnosis of LVNC, for 27 ± 16 months. RESULTS: LVNC was preferentially distributed among posterolateral segments, with apical predominance. Patients with maximum non-compacted-to-compacted thickness ratio (NC:C) < 3 improved by 0.9 ± 0.7 NYHA Class, compared to 0.3 ± 0.8 for patients with NC:C > 3 (p = 0.001). In 29 patients with baseline LVEF < 0.40, there was an inverse correlation between NC:C ratio, and the change in LVEF during follow-up. Tachyarrhythmias were observed in 42% of patients with LGE, and in 0% of patients without LGE (p = 0.02). In multivariate analysis, arrhythmia incidence was significantly higher in patients with LGE, even when adjusted for LVEF and RVEF. CONCLUSIONS: CMR assessments of myocardial morphology provide important prognostic information for patients with LVNC who present with incident heart failure or suspected cardiomyopathy.

Evaluation, Diagnosis, and Classification of Pulmonary Hypertension.

Pulmonary hypertension (PH) is a rare heterogenous disease characterized by elevated blood pressure in the lungs. Patients with PH require careful evaluation and management at an expert center. Understanding of the mechanisms underlying the development of PH has increased over the past two decades, and several treatment options for pulmonary arterial hypertension have emerged. Despite this progress, PH continues to carry high morbidity and mortality. The 6th World Symposium on Pulmonary Hypertension that occurred in late 2018 modified the clinical classification of PH into five groups. In this review, we focus on the evaluation and diagnosis of PH and discuss the updated clinical classification.

Pulse assessment is important with blood pressure measurement in individuals with continuous flow left ventricular assist devices.

While Doppler and cuff blood pressure techniques are prevalent methods of assessing blood pressure in patients with continuous flow left ventricular assist devices, the impact of pulsatility on measurement is not well established. Retrospective chart analysis of clinical variables including pulse perception, blood pressure (Doppler and standard cuff), and aortic valve opening on echo at clinic visit were abstracted. Stable outpatients on continuous flow left ventricular assist devices support with concomitant portable echo assessment were included. Mean average difference was calculated and Pearson's correlation performed for all those patients who had both Doppler and cuff pressure obtained. In all, 74 Heartmate-II patients with a median time from implant of 380 days were analyzed. A pulse was perceived in 82% of patients with persistent aortic valve opening on portable echo and also in 30% of those who had a persistently closed aortic valve. The mean average difference between the Doppler and systolic cuff pressure was ~13 mmHg (r = 0.5, p = 0.004) when a pulse was present and ~11 mmHg when aortic valve was open (r = 0.68, p < 0.0001). Pulse presence seems to reflect aortic valve opening a majority of the time but not always. In the presence of a prominent pulse or persistent aortic valve opening, the Doppler pressure seems to be more reflective of a systolic pressure than mean perfusion pressure. Hence, assessment of pulsatility needs to be incorporated into blood pressure measurement methods for patients with continuous flow left ventricular assist devices.

Acute phenol poisoning: a life-threatening hazard of chronic pain relief.

BACKGROUND: Phenol (carbolic acid, a higher alcohol) has been used for local analgesic therapy for a long time. Several complications of phenol therapy can occur by exposure through inhalational, oral, and dermal routes. Renal and pulmonary toxicity arising from the exposure to injectable phenol, however, has only been reported in a few case reports. CASE PRESENTATION: A 50-year-old man inadvertently received 10 cc of 89% phenol injection. It resulted in the development of acute respiratory and renal failure requiring intubation and hemodialysis, respectively. He improved clinically with the recovery of renal function. However, the chest x-ray and CT scan showed persistent nodular pulmonary infiltrates which resolved by six months. CONCLUSION: We report here an unusual case of acute respiratory and acute renal failure following accidental overdose of phenol. The case highlights potential development of multiple organ failure with persistence of organ dysfunction, an unusual danger associated with the overdose of injectable phenol for neurolysis.

Echocardiographic Evaluation of Hemodynamics in Patients With Systolic Heart Failure Supported by a Continuous-Flow LVAD.

BACKGROUND: Hemodynamics assessment is important for detecting and treating post-implant residual heart failure, but its accuracy is unverified in patients with continuous-flow left ventricular assist devices (CF-LVADs). OBJECTIVES: We determined whether Doppler and 2-dimensional transthoracic echocardiography reliably assess hemodynamics in patients supported with CF-LVADs. METHODS: Simultaneous echocardiography and right heart catheterization were prospectively performed in 50 consecutive patients supported by using the HeartMate II CF-LVAD at baseline pump speeds. The first 40 patients were assessed to determine the accuracy of Doppler and 2-dimensional echocardiography parameters to estimate hemodynamics and to derive a diagnostic algorithm for discrimination between mean pulmonary capillary wedge pressure ≤15 versus >15 mm Hg. Ten patients served as a validation cohort. RESULTS: Doppler echocardiographic and invasive measures of mean right atrial pressure (RAP) (r = 0.863; p < 0.0001), systolic pulmonary artery pressure (sPAP) (r = 0.880; p < 0.0001), right ventricular outflow tract stroke volume (r = 0.660; p < 0.0001), and pulmonary vascular resistance (r = 0.643; p = 0.001) correlated significantly. Several parameters, including mitral ratio of the early to late ventricular filling velocities >2, RAP >10 mm Hg, sPAP >40 mm Hg, left atrial volume index >33 ml/m(2), ratio of mitral inflow early diastolic filling peak velocity to early diastolic mitral annular velocity >14, and pulmonary vascular resistance >2.5 Wood units, accurately identified patients with pulmonary capillary wedge pressure >15 mm Hg (area under the curve: 0.73 to 0.98). An algorithm integrating mitral inflow velocities, RAP, sPAP, and left atrial volume index was 90% accurate in distinguishing normal from elevated left ventricular filling pressures. CONCLUSIONS: Doppler echocardiography accurately estimated intracardiac hemodynamics in these patients supported with CF-LVAD. Our algorithm reliably distinguished normal from elevated left ventricular filling pressures.

The impact of prolonged rotary ventricular assist device support upon ventricular geometry and flow kinetics.

BACKGROUND: The aim of this study was to determine the impact of prolonged left ventricular assist device (VAD) support on cardiac ventricular geometry and VAD flow kinetics. METHODS: Nineteen patients with end-stage heart failure underwent the implantation of HeartMate II rotary flow VADs. Left and right ventricular geometry and VAD flow kinetics were assessed by transthoracic echocardiography early (7 ± 1 days) and late (113 ± 21 days) after VAD implantation. RESULTS: Left ventricular end-diastolic internal dimension decreased by 21% and 35%, respectively, early and late after VAD implantation (n = 19; P < .001 vs before VAD implantation). Right ventricular end-diastolic internal dimension did not decrease at either time. Hemodynamic trends were similar. VAD inflow obstruction by myocardium was observed in eight patients, seven of whom demonstrated significantly increased variation of VAD inflow during the cardiac cycle ("pulsatility") detected by Doppler studies. Medical or surgical intervention returned VAD flow patterns toward baseline in seven of eight patients with VAD obstructions. CONCLUSIONS: Prolonged rotary VAD support unloads the left ventricle, with modest effects on the right ventricle. These changes are often associated with alterations of VAD flow kinetics, requiring therapeutic intervention. These findings indicate the usefulness of echocardiographic surveillance in patients undergoing prolonged VAD support.

Revascularization options in patients with chronic kidney disease.

Cardiovascular disease is the leading cause of death in patients who have chronic kidney disease or end-stage renal disease and are undergoing hemodialysis. Chronic kidney disease is a recognized risk factor for premature atherosclerosis. Unfortunately, most major randomized clinical trials that form the basis for evidence-based use of revascularization procedures exclude patients who have renal insufficiency. Retrospective, observational studies suggest that patients with end-stage renal disease and severe coronary occlusive disease have a lower risk of death if they undergo coronary revascularization rather than medical therapy alone. Due to a lack of prospective studies, however, the relative merits of percutaneous versus surgical revascularization are merely a matter of opinion. Several small, retrospective studies have shown that coronary artery bypass grafting is associated with higher procedural death but better long-term survival than is percutaneous coronary intervention. This difference appears to result from poor long-term results of percutaneous coronary intervention in patients who have chronic kidney disease or end-stage renal disease.Because randomized trials comparing percutaneous coronary intervention and coronary artery bypass grafting have included patients undergoing balloon angioplasty and placement of bare-metal stents, their conclusions are suspect in the era of drug-eluting stents. In this review, we discuss different revascularization options for patients with chronic kidney disease, the outcomes of revascularization procedures, and the risk factors for adverse outcomes.

Short- and long-term outcomes of coronary artery bypass grafting or drug-eluting stent implantation for multivessel coronary artery disease in patients with chronic kidney disease.

Coronary artery disease (CAD) is the leading cause of morbidity and mortality in patients with chronic kidney disease (CKD), but no study has yet compared the short- and long-term outcomes of coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) with drug-eluting stents for multivessel CAD among non-hemodialysis-dependent (HD) patients with CKD. In our institution's registry, we identified 812 patients with CKD (glomerular filtration rate <60 ml/min) who had undergone either CABG or PCI for multivessel CAD from May 2003 to December 2006. Of these patients, 725 had non-HD CKD, and 87 were hemodialysis-dependent. The rates of 30-day and long-term mortality, 30-day major adverse cardiovascular events, and hemodialysis dependence after revascularization were compared between these 2 groups by computing the hazard ratios from a Cox proportional hazards model and adjusting them for the baseline covariates and propensity score. After either CABG or PCI, 2.4% of the patients with non-HD CKD were hemodialysis dependent. Compared to PCI, CABG was associated with postoperative hemodialysis dependence (odds ratio 3.2, 95% confidence interval 1.1 to 9.3; p <0.001). However, among patients with non-HD CKD and 3-vessel CAD, those who underwent CABG tended to have a lower long-term mortality rate than those who underwent PCI (hazard ratio 0.61, 95% confidence interval 0.36 to 1.03; p = 0.06). In the patients with non-HD CKD treated for 2-vessel CAD, those who underwent CABG or PCI had a similar long-term mortality risk (hazard ratio 1.12, 95% confidence interval 0.52 to 2.34; p = 0.7). In conclusion, in patients with non-HD CKD and multivessel CAD, CABG led to better survival than PCI with drug-eluting stents, but CABG patients had a greater short-term risk of requiring permanent hemodialysis.

Hearing loss in children with congenital cytomegalovirus infection born to mothers with preexisting immunity.

OBJECTIVE: To define hearing outcomes in children with congenital cytomegalovirus (CMV) infection born to mothers with non-primary CMV infection. STUDY DESIGN: A cohort of 300 children with congenital CMV infection identified by newborn virologic screening at the University of Alabama Hospital and a private community hospital in which the type of maternal infection could be classified constituted the study population. Maternal infections were categorized by analyzing serum samples. Children were followed prospectively and underwent serial audiologic evaluations. RESULTS: The frequency of hearing loss was not different between children born to mothers with non-primary infection (10%) and those with primary infection (11%). Significantly more children in the primary infection group had progressive and severe/profound hearing loss compared with children in the non-primary group. The frequency of bilateral, delayed onset, high-frequency, and fluctuating hearing loss was not different between the 2 groups. The mean age of diagnosis of hearing loss was 39 +/- 53 months for children born to mothers with non-primary infection and 13 +/- 21 months for the primary infection group (P = .16). CONCLUSIONS: Maternal preexisting seroimmunity to CMV does not provide complete protection against hearing loss in infants with congenital CMV infection.

Association between genital tract cytomegalovirus infection and bacterial vaginosis.

Women with sexually transmitted diseases (STDs) and bacterial vaginosis (BV) have increased rates of cytomegalovirus (CMV) seroprevalence and CMV seroconversion. To characterize the association between genital tract CMV infection and BV, vaginal wash specimens from 52 women attending an STD clinic were analyzed. Significantly more women with BV shed CMV in the lower genital tract than did women without BV. In addition, most of the women who were shedding CMV were infected with >1 virus strain. These results suggest that local CMV replication and infection with multiple CMV strains is facilitated by the presence of BV.