ABSTRACT
Sacubitril-valsartan, an angiotensin receptor-neprilysin inhibitor, reduces all-cause mortality and the rate of heart failure hospitalizations in patients with heart failure with reduced ejection fraction. This study aimed to elucidate the benefits of initiating sacubitril-valsartan on ventricular remodeling in patients previously optimized on guideline-directed medical therapy. In this prospective, single-arm longitudinal study, 40 patients with heart failure with reduced ejection fraction who were optimized on guideline-directed medical therapy were transitioned to sacubitril-valsartan. The primary end point was the change in left ventricular (LV) volume at 1 year as assessed by 3-dimensional transthoracic echocardiography. Other echocardiographic end points included change in LV-function and change in right ventricular (RV) size and function. The mean age was 55 ± 12 years, and 63% were male. At 1 year, LV end-diastolic volume decreased from 242 ± 71 to 157 ± 57 ml (p <0.001) with a corresponding increase in LV ejection fraction from 32 ± 7% to 44 ± 9% (p <0.001). RV end-diastolic volume decreased from 151 ± 51 to 105 ±45 ml (p <0.001). Although RV ejection fraction did not change (51 ± 8 vs 51 ± 10; p = 0.35), RV global longitudinal strain improved from -14.9 ± 3.4 % to -19.3 ± 4.3% (p <0.001). When added to standard medical therapy for heart failure, sacubitril-valsartan induces significant remodeling of both the right and left ventricles as assessed by 3-dimensional echocardiography.
Subject(s)
Heart Failure , Ventricular Dysfunction, Left , Humans , Male , Adult , Middle Aged , Aged , Female , Longitudinal Studies , Prospective Studies , Tetrazoles/therapeutic use , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin Receptor Antagonists/pharmacology , Treatment Outcome , Valsartan/pharmacology , Heart Failure/diagnostic imaging , Heart Failure/drug therapy , Aminobutyrates/therapeutic use , Aminobutyrates/pharmacology , Drug Combinations , Ventricular Function, Left , Stroke VolumeABSTRACT
BACKGROUND: Silicone breast implants with smooth outer shells are associated with higher rates of capsular contracture, whereas textured implants have been linked to the development of breast implant-associated anaplastic large cell lymphoma. By assessing the gene expression profile of fibrous capsules formed in response to smooth and textured implants, insight into the development of breast implant-associated abnormalities can be gained. METHODS: Miniature smooth or textured silicone implants were surgically inserted into female rats ( n = 10) and harvested for the surrounding capsules at postoperative week 6. RNA sequencing and quantitative polymerase chain reaction were performed to identify genes differentially expressed between smooth and textured capsules. For clinical correlation, the expression of candidate genes was assayed in implant capsules harvested from human patients with and without capsular contracture. RESULTS: Of 18,555 differentially expressed transcripts identified, three candidate genes were selected: matrix metalloproteinase-3 ( MMP3 ), troponin-T3 ( TNNT3 ), and neuregulin-1 ( NRG1 ). In textured capsules, relative gene expression and immunostaining of MMP3 and TNNT3 was up-regulated, whereas NRG1 was down-regulated compared to smooth capsules [mean relative fold change, 8.79 ( P = 0.0059), 4.81 ( P = 0.0056), and 0.40 ( P < 0.0001), respectively]. Immunostaining of human specimens with capsular contracture revealed similar gene expression patterns to those of animal-derived smooth capsules. CONCLUSIONS: An expression pattern of low MMP3 /low TNNT3 /high NRG1 is specifically associated with smooth implant capsules and human implant capsules with capsular contracture. The authors' clinically relevant breast implant rat model provides a strong foundation to further explore the molecular genetics of implant texture and its effect on breast implant-associated abnormalities. CLINICAL RELEVANCE STATEMENT: The authors have demonstrated that there are distinct gene expression profiles in response to smooth versus textured breast implants. Since surface texture may be linked to implant-related pathology, further molecular analysis of periprosthetic capsules may yield strategies to mitigate implant-related complications.
Subject(s)
Breast Diseases , Breast Implants , Contracture , Humans , Female , Rats , Animals , Breast Implants/adverse effects , Matrix Metalloproteinase 3 , Capsules , Postoperative Complications , Silicones , Gene ExpressionABSTRACT
BACKGROUND: Measuring an accurate blood pressure (BP) in ambulatory patients is critical for therapeutic decisions. An accurate noninvasive device that measures BP continuously could provide a more comprehensive assessment of BP. The aim of this study was to determine whether the LiveOne device, a cuffless wristband that provides continuous BP measurements, is accurate in comparison to an invasive arterial line (A-line). METHODS: We enrolled hospitalized patients and healthy volunteers in this multicenter study. All patients had an invasive A-line. Waveforms were simultaneously downloaded from the A-line and LiveOne device. The primary outcome was the correlation between the LiveOne device and the A-line for systolic BP (SBP) and diastolic BP (DBP). RESULTS: Thirty-four patients with 233 measurement periods were included. Mean age was 60.7 ± 15.2 years, and 15 (44%) were female. The correlation for SBP was 0.91 and for DBP was 0.85. The mean band error was 0.0 ± 6.9 mm Hg for SBP and 1.2 ± 5.7 mm Hg for DBP. The mean absolute error was 8.2 ± 5.8 mm Hg for SBP and 6.4 ± 3.9 mm Hg for DBP. For SBP, 98% of LiveOne measurements were within 15 mm Hg and for DBP, 92% of LiveOne measurements were within 10 mm Hg. CONCLUSIONS: The LiveOne device provides continuous, noninvasive BP measurements that are accurate in comparison to A-line measurements. The portability and unobtrusive nature of this device and the ability to provide continuous BP measurements may offer advantages over currently available BP monitors. CLINICAL TRIALS REGISTRATION: Trial Number NCT03919136.
Subject(s)
Blood Pressure Determination , Hypertension , Aged , Blood Pressure/physiology , Female , Humans , Male , Middle Aged , Sphygmomanometers , WristABSTRACT
BACKGROUND: Elevated lactic acid (LA) levels carry a poor prognosis in patients with shock. Data are lacking on the significance of LA levels in patients with acute decompensated heart failure (ADHF). HYPOTHESIS: This study assessed the relationship between LA levels, hemodynamics and clinical outcomes. METHODS: This was a retrospective analysis of registry data of 100 advanced heart failure patients presenting for right heart catheterization (RHC) for concern of ADHF. LA levels (normal ≤2.1 mmol/L) were obtained prior to RHC; no significant changes in therapy were made between LA collection and RHC. RESULTS: Median age was 58 (47.3, 64.8) years; 57% were receiving inotropes prior to RHC. Median pulmonary capillary wedge pressure (PCWP) and cardiac index (CI) were 28 (21, 35) mmHg and 2.0 (1.7, 2.5) L/min/m2 , respectively. Eighty patients had normal LA prior to RHC. There was no correlation between LA levels and PCWP (R = 0.09, p = .38); 63% of the normal LA group had a PCWP >24 mmHg. There was a moderate inverse correlation between LA and CI (R = - 0.40; p < .001); 58% of the normal LA group had a CI <2.2 L/min/m2 . Thirty-day survival free of death/hospice, inotrope dependence, progression to heart transplant/left-ventricular assist device implant was comparable between the normal and elevated LA groups (28% vs. 20%; p = .17). CONCLUSION: In patients presenting with ADHF, normal LA levels do not exclude the presence of depressed CI (a hemodynamic criteria for cardiogenic shock) and may not offer accurate risk stratification. Invasive hemodynamics should not be delayed based on normal LA levels alone.
Subject(s)
Heart Failure , Hemodynamics , Lactic Acid , Female , Heart Failure/diagnosis , Heart Failure/therapy , Humans , Lactic Acid/blood , Male , Middle Aged , Pulmonary Wedge Pressure , Retrospective Studies , Shock, Cardiogenic/diagnosis , Shock, Cardiogenic/therapySubject(s)
Coinfection/diagnosis , Darier Disease/pathology , Leishmaniasis, Diffuse Cutaneous/pathology , Skin Diseases, Parasitic/pathology , Adult , Amphotericin B/administration & dosage , Amphotericin B/therapeutic use , Antiprotozoal Agents/administration & dosage , Darier Disease/diagnosis , Drug Therapy, Combination , HIV Infections/complications , HIV Infections/virology , Humans , Infusions, Intravenous/methods , Leishmaniasis, Diffuse Cutaneous/complications , Leishmaniasis, Diffuse Cutaneous/drug therapy , Leishmaniasis, Diffuse Cutaneous/parasitology , Male , Phosphorylcholine/administration & dosage , Phosphorylcholine/analogs & derivatives , Phosphorylcholine/therapeutic use , Treatment Outcome , Trypanosoma cruzi/isolation & purificationABSTRACT
AIMS: Aortic pulsatility index (API), calculated as (systolic-diastolic blood pressure)/pulmonary capillary wedge pressure (PCWP), is a novel haemodynamic measurement representing both cardiac filling pressures and contractility. We hypothesized that API would better predict clinical outcomes than traditional haemodynamic metrics of cardiac function. METHODS AND RESULTS: The Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial individual-level data were used. Routine haemodynamic measurements, including Fick cardiac index (CI), and the advanced haemodynamic metrics of API, cardiac power output (CPO), and pulmonary artery pulsatility index (PAPI) were calculated after final haemodynamic-monitored optimization. The primary outcome was a composite endpoint of death or need for orthotopic heart transplant (OHT) or left ventricular assist device (LVAD) at 6 months. A total of 433 participants were enrolled in the ESCAPE trial of which 145 had final haemodynamic data. Final API measurements predicted the primary outcome, OR 0.47 (95% CI 0.32-0.70, P < 0.001), while CI, CPO, and PAPI did not. Receiver operator characteristic analyses of final advanced haemodynamic measurements indicated API best predicted the primary outcome with a cutoff of 2.9 (sensitivity 76.2%, specificity 55.3%, correctly classified 61.4%, area-under-the-curve 0.71), compared with CPO, CI, and PAPI. Kaplan-Meier analyses indicated API ≥ 2.9 was associated with greater freedom from the primary outcome (83.5%), compared with API < 2.9 (58.4%), P = 0.001. While PAPI was also significantly associated, CI and CPO were not. CONCLUSIONS: The novel haemodynamic measurement API better predicted clinical outcomes in the ESCAPE trial when compared with traditional invasive haemodynamic metrics of cardiac function.
Subject(s)
Heart Failure , Heart-Assist Devices , Catheterization, Swan-Ganz , Heart Failure/diagnosis , Heart Failure/therapy , Humans , Pulmonary Artery/diagnostic imaging , Pulmonary Wedge PressureABSTRACT
Ventricular arrhythmias are common following left ventricular assist device implantation (LVAD), and the effects of ventricular tachycardia (VT) ablation on thrombosis and embolic events are unknown. We aimed to assess LVAD thrombosis, stroke, and embolic event rates after VT ablation. Left ventricular assist device implantation patients from two academic centers who underwent endocardial VT ablation between 2009 and 2016 were compared to a control group with VT who were not ablated and followed for one year. The primary composite outcome was confirmed or suspected LVAD thrombosis, stroke, or other embolic event. Survival analysis was conducted with Kaplan-Meier curves, log-rank tests, and Cox regression. Forty-three LVAD patients underwent VT ablation, and 73 LVAD patients had VT but were not ablated. Patients who were ablated were more likely have VT prior to LVAD (p = 0.04), monomorphic VT (p < 0.01), and to be on antiarrhythmics (p < 0.01). Fifty-eight percent of the patients in the ablation group experienced the primary composite outcome (11% had confirmed device thrombosis [DT], 41% suspected DT, 39% had a stroke or embolic event) compared to 30% in the control group (12% with confirmed DT, 11% with suspected DT, 14% with stroke or embolic event) (p = 0.002). In multivariable regression, ablation was an independent predictor of the primary composite outcome (hazard ratios, 2.24; 95% confidence interval, 1.09-4.61; p = 0.03). Patients with LVADs referred for endocardial VT ablation had elevated rates of DT and embolic events.
Subject(s)
Catheter Ablation/adverse effects , Heart-Assist Devices , Tachycardia, Ventricular/surgery , Thrombosis/epidemiology , Thrombosis/etiology , Aged , Female , Heart-Assist Devices/adverse effects , Humans , Male , Middle Aged , Postoperative Complications/epidemiology , Postoperative Complications/etiology , Stroke/epidemiology , Stroke/etiology , Tachycardia, Ventricular/etiology , Thoracic Surgical Procedures/adverse effects , Thoracic Surgical Procedures/methods , Treatment OutcomeABSTRACT
For many years, the University of Chicago administered sulfamethoxazole-trimethoprim sulfate (SMZ-TMP) oral suspension to select immunocompromised mouse colonies via the drinking water. In 2014, SMZ-TMP oral suspension was placed on back-order and medicated diet with a different sulfonamide, sulfadiazine-trimethoprim (SDZ-TMP) was used as a replacement. Months after this transition, sentinel mice from the same room as one of the remaining immunocompromised colonies on this diet were found dead or appeared sick. Necropsies revealed cardiomegaly, and histology confirmed myocardial fibrosis in the first 4 sentinel mice examined, consistent with cardiomyopathy. Subsequent sequential monitoring of 2 sentinel mice via echocardiography showed their progression toward decreased cardiac function. Investigation of the housing room revealed that the sentinel mice had been accidently placed on SDZ-TMP diet upon entering the colony housing room. This case report describes cardiomyopathy in 6 ICR mice after long term consumption of SDZ-TMP medicated feed.
Subject(s)
Anti-Bacterial Agents/adverse effects , Cardiomyopathies/chemically induced , Sulfadiazine/adverse effects , Trimethoprim/adverse effects , Administration, Oral , Animals , Anti-Bacterial Agents/administration & dosage , Cardiomyopathies/pathology , Drug Combinations , Female , Immunocompetence , Mice , Mice, Inbred ICR , Sulfadiazine/administration & dosage , Trimethoprim/administration & dosageSubject(s)
Folliculitis/etiology , Mesotherapy/adverse effects , Adult , Female , Folliculitis/diagnosis , Folliculitis/pathology , HumansABSTRACT
Vascularized lymph node transfer (VLNT) is a promising treatment modality for lymphedema; however, how lymphatic tissue responds to ischemia has not been well defined. This study investigates the cellular changes that occur in lymph nodes in response to ischemia and reperfusion. Lymph node containing superficial epigastric artery-based groin flaps were isolated in Prox-1 EGFP rats which permits real time identification of lymphatic tissue by green fluorescence during flap dissection. Flaps were subjected to ischemia for either 1, 2, 4, or 8 hours, by temporarily occluding the vascular pedicle. Flaps were harvested after 0 hours, 24 hours, or 5 days of reperfusion. Using EGFP signal guidance, lymph nodes were isolated from the flaps and tissue morphology, cell apoptosis, and inflammatory cytokines were quantified and analyzed via histology, immunostaining, and rtPCR. There was a significant increase in collagen deposition and tissue fibrosis in lymph nodes after 4 and 8 hours of ischemia compared to 1 and 2 hours, as assessed by picrosirius red staining. Cell apoptosis significantly increased after 4 hours of ischemia in all harvest times. In tissue subject to 4 hours of ischemia, longer reperfusion periods were associated with increased rates of CD3+ and CD45+ cell apoptosis. rtPCR analysis demonstrated significantly increased expression of CXCL1/GRO-α with 2 hours of ischemia and increased PECAM-1 and TNF-α expression with 1 hour of ischemia. Significant cell death and changes in tissue morphology do not occur until after 4 hours of ischemia; however, analysis of inflammatory biomarkers suggests that ischemia reperfusion injury can occur with as little as 2 hours of ischemia.
Subject(s)
Lymph Nodes/blood supply , Reperfusion Injury/physiopathology , Surgical Flaps/blood supply , Animals , Dissection , Epigastric Arteries/physiopathology , Epigastric Arteries/surgery , Female , Femoral Artery/physiopathology , Ischemia/physiopathology , Lymph Nodes/physiopathology , Lymphedema/surgery , Male , Rats , Rats, Sprague-Dawley , ReperfusionABSTRACT
BACKGROUND AND OBJECTIVES: Previously, we have shown that 9-cis retinoic acid (9-cis RA) stimulates lymphangiogenesis and limits postsurgical lymphedema in animal models when administered via daily intraperitoneal injections. In this study, we investigate whether a single-use depot 9-cis RA drug delivery system (DDS) implanted at the site of lymphatic injury can mitigate the development of lymphedema in a clinically relevant mouse limb model. METHODS: Hind limb lymphedema was induced via surgical lymphadenectomy and irradiation. Animals were divided into two treatment groups: (1) 9-cis RA DDS, (2) placebo DDS. Outcomes measured included paw thickness, lymphatic clearance and density, epidermal thickness, and collagen deposition. RESULTS: Compared with control animals, 9-cis RA-treated animals had significantly less paw swelling from postoperative week 3 (P = .04) until the final timepoint at week 6 (P = .0007). Moreover, 9-cis RA-treated animals had significantly faster lymphatic clearance (P < .05), increased lymphatic density (P = .04), reduced lymphatic vessel size (P = .02), reduced epidermal hyperplasia (P = .04), and reduced collagen staining (P = .10). CONCLUSIONS: Animals receiving 9-cis RA sustained-release implants at the time of surgery had improved lymphatic function and structure, indicating reduced lymphedema progression. Thus, we demonstrate that 9-cis RA contained within a single-use depot DDS has favorable properties in limiting pathologic responses to lymphatic injury and may be an effective strategy against secondary lymphedema.
Subject(s)
Alitretinoin/administration & dosage , Lymph Node Excision/methods , Lymphedema/prevention & control , Animals , Collagen/metabolism , Delayed-Action Preparations , Epidermis/drug effects , Epidermis/pathology , Female , Green Fluorescent Proteins/biosynthesis , Green Fluorescent Proteins/genetics , Hindlimb , Hyperplasia , Lymph Node Excision/adverse effects , Lymphatic System/drug effects , Lymphatic System/metabolism , Lymphedema/metabolism , Male , Mice , Mice, Transgenic , Postoperative Complications/prevention & controlABSTRACT
BACKGROUND: Historically, invasive hemodynamic guidance was not superior compared to clinical assessment in patients admitted with acute decompensated heart failure (ADHF). This study assessed the accuracy of clinical assessment vs invasive hemodynamics in patients with ADHF. METHODS AND RESULTS: We conducted a prospective cohort study of patients admitted with ADHF. Prior to right-heart catheterization (RHC), physicians categorically predicted right atrial pressure, pulmonary capillary wedge pressure, cardiac index and hemodynamic profile (wet/dry, warm/cold) based on physical examination and clinical data evaluation (warmâ¯=â¯cardiac index > 2.2 L/min/m2; wetâ¯=â¯pulmonary capillary wedge pressure > 18 mmHg). We collected 218 surveys (of 83 cardiology fellows, 55 attending cardiologists, 45 residents, 35 interns) evaluating 97 patients. Of those patients, 46% were receiving inotropes prior to RHC. The positive and negative predictive values of clinical assessment compared to RHC for the cold and wet subgroups were 74.7% and 50.4%. The accuracy of categorical prediction was 43.6% for right atrial pressure, 34.4% for pulmonary capillary wedge pressure and 49.1% for cardiac index, and accuracy did not differ by clinician (P > 0.05 for all). Interprovider agreement was 44.4%. Therapeutic changes following RHC occurred in 71.1% overall (P < 0.001). CONCLUSIONS: Clinical assessment of patients with advanced heart failure presenting with ADHF has low accuracy across all training levels, with exaggerated rates of misrecognition of the most high-risk patients.
Subject(s)
Cardiac Catheterization/trends , Clinical Decision-Making , Heart Failure/diagnosis , Heart Failure/physiopathology , Hemodynamics/physiology , Physicians/standards , Aged , Cohort Studies , Female , Heart Failure/therapy , Humans , Male , Middle Aged , Prospective Studies , Surveys and QuestionnairesABSTRACT
Head and neck lymphedema (HNL) is a disfiguring disease affecting over 90% of patients treated for head and neck cancer. Animal models of lymphedema are used to test pharmacologic and microsurgical therapies; however, no animal model for HNL is described in the literature to date. In this study we describe the first reproducible rat model for HNL. Animals were subjected to two surgical protocols: (1) lymphadenectomy plus irradiation; and (2) sham surgery and no irradiation. Head and neck expansion was measured on post-operative days 15, 30 and 60. Magnetic resonance imaging (MRI) was acquired at the same time points. Lymphatic drainage was measured at day 60 via indocyanine green (ICG) lymphography, after which animals were sacrificed for histological analysis. Postsurgical lymphedema was observed 100% of the time. Compared to sham-operated animals, lymphadenectomy animals experienced significantly more head and neck swelling at all timepoints (P < 0.01). Lymphadenectomy animals had significantly slower lymphatic drainage for 6 days post-ICG injection (P < 0.05). Histological analysis of lymphadenectomy animals revealed 83% greater subcutis thickness (P = 0.008), 22% greater collagen deposition (P = 0.001), 110% greater TGFß1+ cell density (P = 0.04), 1.7-fold increase in TGFß1 mRNA expression (P = 0.03), and 114% greater T-cell infiltration (P = 0.005) compared to sham-operated animals. In conclusion, animals subjected to complete lymph node dissection and irradiation developed changes consistent with human clinical postsurgical HNL. This was evidenced by significant increase in all head and neck measurements, slower lymphatic drainage, subcutaneous tissue expansion, increased fibrosis, and increased inflammation compared to sham-operated animals.
Subject(s)
Disease Models, Animal , Lymph Node Excision , Lymphedema/physiopathology , Radiotherapy/adverse effects , Animals , Head/pathology , Head and Neck Neoplasms/complications , Lymphatic System/pathology , Neck/pathology , Rats , Rats, TransgenicABSTRACT
Left ventricular (LV) unloading with a LV assist device (LVAD) reverse remodels the heart and may lead to favorable changes in cellular architecture and LV geometry promoting myocardial recovery. Currently, there are no standardized methods for evaluating myocardial recovery. This study assesses the systolic slope of the LVAD outflow cannula as a marker for myocardial contractility. Doppler echocardiography (transthoracic echocardiogram [TTE]) of the LVAD outflow cannula and TTE of the LV cavity were prospectively collected in 57 patients with LVADs. Systolic acceleration of the LVAD outflow cannula was measured in each patient as the peak change of velocity over time (dv/dt) during systole from continuous-wave Doppler signal acquired from the LVAD outflow cannula. Ventricular volumes were concurrently measured by TTE. In a subset of 10 patients, the systolic slope was measured during each stage of a ramp study to study the properties of this parameter across a variety of loading conditions. The systolic slope of the LVAD outflow cannula was successfully measured in 53 of 57 patients (93%). Systolic slope strongly correlated with ejection fraction (EF) (R = 0.92). Analysis of systolic slope stratified by EF (EF >30%, EF 20-30%, EF 10-20%, and EF <10%) revealed systolic slopes that were significantly different between the groups (1,371 cm/s ± 324; 983 cm/s ± 122; 578 cm/s ± 139; and 495 cm/s ± 107, respectively; p < 0.001). Systolic slope did not change significantly across variable preload and afterload conditions during a ramp study. Systolic slope of the LVAD outflow cannula strongly correlates with EF and can be used to assess underlying myocardial contractility across a variety of LVAD loading conditions.