Initiation and Up-titration of Guideline-directed Medical Therapy for Patients with Heart Failure: Better, Faster, Stronger!

Treatment for heart failure has experienced a major revolution in recent years, and current evidence shows that a combination of four medications (angiotensin receptor-neprilysin inhibitors + ß-blockers + mineralocorticoid receptor antagonists + sodium.glucose cotransporter 2 inhibitors) offer the greatest benefit to our patients with significant reductions in cardiovascular mortality, heart failure hospitalisations and all-cause mortality. Unfortunately, despite their proven benefits, the implementation of these therapies is still low. Clinical inertia, and unfounded fear of using these drugs might contribute to this. Recently, evidence from randomised clinical trials has shown that intensive implementation of these therapies in patients with heart failure is safe and effective. In this review, we attempt to tackle some of these misconceptions/fears regarding medical therapy for heart failure and discuss the available evidence showing the best strategies for implementation of these therapies.

NUAK1 coordinates growth factor-dependent activation of mTORC2 and Akt signaling.

BACKGROUND: mTORC2 is a critical regulator of cytoskeleton organization, cell proliferation, and cancer cell survival. Activated mTORC2 induces maximal activation of Akt by phosphorylation of Ser-473, but regulation of Akt activity and signaling crosstalk upon growth factor stimulation are still unclear. RESULTS: We identified that NUAK1 regulates growth factor-dependent activation of Akt by two mechanisms. NUAK1 interacts with mTORC2 components and regulates mTORC2-dependent activation of Akt by controlling lysosome positioning and mTOR association with this organelle. A second mechanism involves NUAK1 directly phosphorylating Akt at Ser-473. The effect of NUAK1 correlated with a growth factor-dependent activation of specific Akt substrates. NUAK1 induced the Akt-dependent phosphorylation of FOXO1/3a (Thr-24/Thr-32) but not of TSC2 (Thr-1462). According to a subcellular compartmentalization that could explain NUAK1's differential effect on the Akt substrates, we found that NUAK1 is associated with early endosomes but not with plasma membrane, late endosomes, or lysosomes. NUAK1 was required for the Akt/FOXO1/3a axis, regulating p21CIP1, p27KIP1, and FoxM1 expression and cancer cell survival upon EGFR stimulation. Pharmacological inhibition of NUAK1 potentiated the cell death effect induced by Akt or mTOR pharmacological blockage. Analysis of human tissue data revealed that NUAK1 expression positively correlates with EGFR expression and Akt Ser-473 phosphorylation in several human cancers. CONCLUSIONS: Our results showed that NUAK1 kinase controls mTOR subcellular localization and induces Akt phosphorylation, demonstrating that NUAK1 regulates the growth factor-dependent activation of Akt signaling. Therefore, targeting NUAK1, or co-targeting it with Akt or mTOR inhibitors, may be effective in cancers with hyperactivated Akt signaling.

Echocardiographic manifestations during the first 3 months after an episode of COVID-19 and their relationship with disease severity and persistence of symptoms.

BACKGROUND: Cardiovascular manifestations in patients with COVID-19 are associated with dire outcomes. Long COVID syndrome is the persistence of symptoms after acute disease and is found in up to 40% of subjects. There is little information regarding subacute echocardiographic manifestations after COVID-19, and no study has included a Mexican mestizo population. METHODS: This cross-sectional study included subjects older than 18 with an episode of COVID-19 in the last 3 months. Those with previously known cardiovascular disease were excluded. The patient´s medical history and COVID-19 information were obtained from clinical charts. We performed a transthoracic echocardiogram in every subject and determined left ventricular (LV) index mass, LV ejection fraction (LVEF), left ventricular global longitudinal strain (LV GLS), right ventricular (RV) GLS, and tricuspid annular plane systolic excursion (TAPSE). A descriptive and comparative analysis was performed based on symptom severity and persistence. RESULTS: One hundred subjects were included; 63% were classified with mild and 37% with moderate to severe COVID-19. The median of LVEF was 60% (55-60), LV GLS and RV GLS was impaired in 34% and 74% of patients, respectively. Patients with moderate to severe disease had significantly lower LVEF (Mean Difference: -3.3), TAPSE (mean difference: -1.8), and higher (worse) LV GLS (Mean Difference: 2.5) and RV GLS (mean difference: 2.9). Persistent symptoms were associated with lower TAPSE and higher RVGLS. CONCLUSIONS: Patients who recover from COVID-19 have a high prevalence of subtle RV and LV dysfunction using GLS analysis. A moderate to severe episode was associated with worse RV and LV function measured by RV GLS, TAPSE, and LV GLS. Subjects with persistent symptoms had worse RVGLS and TAPSE.

Blocking the Farnesyl Pocket of PDEδ Reduces Rheb-Dependent mTORC1 Activation and Survival of Tsc2-Null Cells.

Rheb is a small GTPase member of the Ras superfamily and an activator of mTORC1, a protein complex master regulator of cell metabolism, growth, and proliferation. Rheb/mTORC1 pathway is hyperactivated in proliferative diseases, such as Tuberous Sclerosis Complex syndrome and cancer. Therefore, targeting Rheb-dependent signaling is a rational strategy for developing new drug therapies. Rheb activates mTORC1 in the cytosolic surface of lysosomal membranes. Rheb's farnesylation allows its anchorage on membranes, while its proper localization depends on the prenyl-binding chaperone PDEδ. Recently, the use of PDEδ inhibitors has been proposed as anticancer agents because they interrupted KRas signaling leading to antiproliferative effects in KRas-dependent pancreatic cancer cells. However, the effect of PDEδ inhibition on the Rheb/mTORC1 pathway has been poorly investigated. Here, we evaluated the impact of a new PDEδ inhibitor, called Deltasonamide 1, in Tsc2-null MEFs, a Rheb-dependent overactivated mTORC1 cell line. By using a yeast two-hybrid assay, we first validated that Deltasonamide 1 disrupts Rheb-PDEδ interaction. Accordingly, we found that Deltasonamide 1 reduces mTORC1 targets activation. In addition, our results showed that Deltasonamide 1 has antiproliferative and cytotoxic effects on Tsc2-null MEFs but has less effect on Tsc2-wild type MEFs viability. This work proposes the pharmacological PDEδ inhibition as a new approach to target the abnormal Rheb/mTORC1 activation in Tuberous Sclerosis Complex cells.

The Heart in Diabetic Ketoacidosis: A Narrative Review Focusing on the Acute Cardiac Effects and Electrocardiographic Abnormalities.

Diabetic ketoacidosis (DKA) is a serious complication of diabetes mellitus. Hyperglycemia, acidosis, and electrolyte imbalances can directly affect the heart by inducing toxicity, impairing myocardial blood flow, autonomic dysfunction, and altering activation and conduction of electrical impulses throughout the heart, increasing the risk of arrhythmias and ischemia. The electrocardiogram is useful in monitoring patients during and after an episode of DKA, as it allows the detection of arrhythmias and guides metabolic correction. Unfortunately, reports on electrocardiographic abnormalities in patients with DKA are lacking. We found two electrocardiographic patterns that are frequently reported in the literature: a pseudo-myocardial infarction and a Brugada Phenocopy. Both are associated with DKA metabolic anomalies and they resolve after treatment. Because of their clinical relevance and the challenge they represent for clinicians, we analyzed the clinical characteristics of these patients and the mechanisms involved in these electrocardiographic findings.

Echocardiographic Manifestations in COVID-19: A Review.

COVID-19 has rapidly spread around the world and threatened global health. Although this disease mainly affects the respiratory system, there is increasing evidence that SARS-CoV-2 also has effects on the cardiovascular system. Echocardiography is a valuable tool in the assessment of cardiovascular disease. It is cost-effective, widely available and provides information that can influence management. Given the risk of personnel infection and equipment contamination during echocardiography, leading world societies have recommended performing echocardiography only when a clinical benefit is likely, favouring focussed evaluations and using smaller portable equipment. In the past months, multiple reports have described a wide pattern of echocardiographic abnormalities in patients with COVID-19. This review summarises these findings and discusses the possible mechanisms involved.

Echocardiographic Characteristics of Subjects With COVID-19: A Case Series.

Although coronavirus disease 2019 (COVID-19) manifests in most cases with respiratory symptoms, other presentations can occur. Direct damage to the cardiovascular system has been reported and recently, acute myocardial injury has been identified as a risk factor for mortality. Transthoracic echocardiography is a non-invasive tool that allows the detection of myocardial damage with validated markers (left ventricular ejection fraction and global longitudinal strain). Herein, we present the echocardiographic findings in four patients with COVID-19. All cases had acute respiratory distress syndrome (100%). Three out of four had elevated levels of creatine kinase and creatine kinase myocardial band. One case had ventricular concentric remodeling (25%). All cases (100%) had altered ventricular function: two had a reduced ejection fraction (50%) and, of those available for global longitudinal strain analysis, all had abnormal global longitudinal strain (100%). One case was found to have a tricuspid vegetation of 12 × 10 mm with no other manifestation of endocarditis. All of our cases had left ventricular dysfunction as assessed by echocardiography. One of our patients had a vegetation in the tricuspid valve. Two of our cases had a reduced ejection fraction. The importance of acute cardiac injury in COVID-19 has recently been established. A recent study found it to be an independent risk factor for mortality in patients with this disease. Information regarding echocardiographic characteristics of this population is scarce. Further research to elucidate the impact of these characteristics on morbidity and mortality is urgently needed.

Toluene toxicity presenting with hypokalemia, profound weakness and U waves in the electrocardiogram.

We present the case of a 25-year-old man with progressive limb weakness. His electrocardiogram showed prominent U waves which made us consider hypokalemia. The final diagnosis was toluene intoxication with severe hypokalemia and metabolic acidosis. Intravenous potassium administration and hydration effectively corrected the electrolyte and acid-base alterations; weakness resolved and the patient was discharged. The approach to a patient with acute weakness can be challenging. This case reminds us that the electrocardiogram can be a valuable tool in the evaluation and differential diagnosis of patients presenting to the emergency department with these conditions.

Pseudomyocardial Infarction in a Patient with Severe Diabetic Ketoacidosis and Mild Hyperkalemia.

A 48-year-old male with a prior diagnosis of diabetes mellitus presented to the emergency department with malaise and nausea. On work-up, he was found with hyperglycemia and high anion gap metabolic acidosis, with a blood pH < 6.94. A diagnosis of severe diabetic ketoacidosis was established; serum electrolyte analysis showed mild hyperkalemia. On work-up, a 12-lead electrocardiogram was obtained, and it showed an ST-segment elevation on anterior leads that completely resolved with diabetic ketoacidosis treatment. ST-segment elevation myocardial infarction can be a precipitant factor for diabetic ketoacidosis, and evaluation of diabetic patients with suspected myocardial infarction can be challenging since they can present with atypical or little symptoms. Hyperkalemia, which usually accompanies diabetic ketoacidosis, can cause electrocardiographic alterations that are well described, but ST-segment elevation is uncommon. A pseudomyocardial infarction pattern has been described in patients with diabetic ketoacidosis; of note, most of these patients presented severe hyperkalemia. We believe this is of great importance for clinicians because they must be able to recognize those patients that present with electrocardiographic abnormalities secondary to the metabolic alterations and those that can be experiencing actual ongoing ischemia, in order to establish an appropriate and prompt treatment.

Periodontal Disease, Systemic Inflammation and the Risk of Cardiovascular Disease.

Periodontal and cardiovascular disease are both major health issues. Poor oral health has long been associated with the development of systemic diseases, with the typical example being the risk of endocarditis posterior to dental procedures. Through the years, the association of periodontal disease with other non-infectious systemic diseases has been brought to attention. One of the most interesting associations is the one that exists with the development of cardiovascular disease. Many studies, including systematic reviews and meta-analyses, suggest an important association between periodontal disease and ischaemic heart disease, cerebrovascular disease, heart failure, atrial fibrillation and peripheral artery disease. Among the proposed mechanisms of this relationship, systemic inflammation appears to play a major role. Evidence suggests that periodontal inflammation triggers a systemic inflammatory state that, added to the damage mediated by antibodies that cross react between periodontal pathogens and components of the intimal wall, and the direct lesion of the intima by bacteria entering the circulation, promotes atheroma plaque development and progression. There are other studies that show a clear relationship between periodontal disease severity, elevations of inflammatory markers, and the presence of atherosclerosis. Here, we give a review of the available evidence supporting this association, and the possible mechanisms involved.

Thermal burn resulting from prolonged transcutaneous pacing in a patient with complete heart block.

Temporary transcutaneous pacing devices are used to treat symptomatic bradyarrhythmias that are unresponsive to medical therapy until it resolves or a more stable pacing device is established. Pain is the most common complication. Skin burns as a complication are uncommon. A female patient presented with a complete atrioventricular block that caused altered mental status and required orotracheal intubation. A temporary transcutaneous pacing device was used to treat the bradyarrhythmia and maintained for 12 h until a temporary transvenous pacemaker was placed. The patient developed a third degree skin burn in the area where the anterior pacing patch was placed. Bradycardia is a common complaint in the emergency department. Temporary transcutaneous cardiac pacing is a widely available treatment modality that serves as initial management for these cases and allows us to keep patients stable until a more stable pacing solution is available. Burns as a complication of transcutaneous pacing are uncommon.

Global longitudinal strain as a biomarker in diabetic cardiomyopathy. A comparative study with Gal-3 in patients with preserved ejection fraction / Deformación longitudinal global como un biomarcador en miocardiopatía diabética. Estudio comparativo con galectina-3 en pacientes con fracción de eyección preservada

Abstract: Objectives: To establish a relationship between global longitudinal strain (GLS) and Galectin-3 in pre-clinical heart failure in diabetic patients. Galectin-3 is a biomarker in heart failure with depressed ejection fraction (HFdEF). The hypothesis is presented that Galectin-3 is related to GLS and can detect left ventricular dysfunction in heart failure with preserved ejection fraction. Methods: Galectin-3 and GLS were measured in 121 asymptomatic individuals: 14 diabetics with mild depressed ejection fraction (mdEF) (LVEF 47.0 ± 6.9); 76 diabetics with preserved ejection fraction (LVEF 61 ± 5.5), and 31 controls (61.7 ± 5.1). Results: Galectin-3 was elevated in all diabetics vs controls (3.46 ± 1.36 ng/ml vs 2.78 ± 0.91 ng/ml; p = .003). It was also elevated in mdEF (3.76 ± 1.12 ng/ml vs 2.78 ± 0.9 ng/ml; p = .009) and pEF subjects (3.41 ± 1.40 ng/ml vs 2.78 ± 0.9 ng/ml; p = .058), respectively, vs controls. No difference in Gal-3 was found between diabetic groups (p = .603). Diabetics had lower GLS than controls (-18.5 ± 3.9 vs -20 ± 2.6; p = .022). Diabetics with mdEF had lower GLS than those with pEF (-13.3 ± 3.41 vs -19 ± 3.2; P<.001). There was no difference in GLS with pEF compared to controls (-19.4 ± 3.2 vs -20 ± 2.6; p = .70). Conclusions: Galectin-3 is elevated in diabetic patients with mdEF, and is associated with a diminished GLS. GLS could be an early marker of left ventricular dysfunction as well as evidence of diabetic cardiomyopathy.

Resumen: Objetivos: Establecer una asociación entre deformación longitudinal global (DLG) y galectina-3 en insuficiencia cardiaca preclínica en pacientes diabéticos. Galectina-3 es un biomarcador en insuficiencia cardiaca con fracción de eyección deprimida. Nuestra hipótesis es que la DLG y galectina-3 correlacionan y pueden detectar disfunción ventricular en insuficiencia cardiaca con FEVI preservada. Métodos: Se midieron galectina-3 y DLG en 121 individuos asintomáticos: 14 diabéticos con FEVI deprimida leve (FEdl) (FEVI 47 ± 6.9); 76 diabéticos con FEVI preservada (FEp) (FEVI 61 ± 5.5) y 31 sujetos controles (FEVI 61.7 ± 5.1). Resultados: Galectina-3 se encontró elevada en todos los diabéticos vs controles (3.46 ± 1.36 ng/ml vs 2.78 ± 0.91 ng/ml; p = 0.003). Está elevada en sujetos con FEdl (3.76 ± 1.12 vs 2.78 ± 0.9 vs ng/ml p = 0.009) y FEp (3.41 ± 1.40 vs 2.78 ± 0.9 ng/ml p = 0.058), respectivamente vs controles; no encontramos diferencia en galectina-3 en ambos grupos de diabéticos (p = 0.603). Los diabéticos tienen menor DLG que los controles (-18.5 ± 3.9 vs -20 ± 2.6; p = 0.022). Los diabéticos con FEdl tienen DLG más disminuida que aquellos con FEp (-13.3 ± 3.41 vs -19 ± 3.2; p < 0.001). No existe diferencia en DLG con FEp y controles (-19.4 ± 3.2 vs -20 ± 2.6; p = 0.70). Conclusiones: Galectina-3 está elevada en diabéticos con FEdl y correlaciona DLG disminuida. DLG podría ser un marcador temprano de disfunción ventricular y evidencia en miocardiopatía diabética.

Congestive Heart Failure with Preserved Ejection Fraction in a Patient with Light Chain (AL) Amyloidosis and Multiple Myeloma.

BACKGROUND Amyloidosis is characterized by tissue deposition of insoluble fibrillar proteins and it affects almost every organ; there are many types and the heart can be affected in all of them. CASE REPORT Our report describes a middle-aged man who presented to the Emergency Department with congestive heart failure. Clinical, electrocardiographic, and echocardiographic findings suggested the presence of an infiltrative disease, so an abdominal fat tissue biopsy was performed. A final diagnosis of systemic amyloidosis with heart involvement was made. CONCLUSIONS This case highlights the importance of combining clinical, electrocardiographic, and echocardiographic information in the diagnosis of complex diseases like amyloidosis with heart involvement.

Global longitudinal strain as a biomarker in diabetic cardiomyopathy. A comparative study with Gal-3 in patients with preserved ejection fraction.

OBJECTIVES: To establish a relationship between global longitudinal strain (GLS) and Galectin-3 in pre-clinical heart failure in diabetic patients. Galectin-3 is a biomarker in heart failure with depressed ejection fraction (HFdEF). The hypothesis is presented that Galectin-3 is related to GLS and can detect left ventricular dysfunction in heart failure with preserved ejection fraction. METHODS: Galectin-3 and GLS were measured in 121 asymptomatic individuals: 14 diabetics with mild depressed ejection fraction (mdEF) (LVEF 47.0±6.9); 76 diabetics with preserved ejection fraction (LVEF 61±5.5), and 31 controls (61.7±5.1). RESULTS: Galectin-3 was elevated in all diabetics vs controls (3.46±1.36 ng/ml vs 2.78±0.91 ng/ml; p=.003). It was also elevated in mdEF (3.76±1.12 ng/ml vs 2.78±0.9 ng/ml; p=.009) and pEF subjects (3.41±1.40 ng/ml vs 2.78±0.9 ng/ml; p=.058), respectively, vs controls. No difference in Gal-3 was found between diabetic groups (p=.603). Diabetics had lower GLS than controls (-18.5±3.9 vs -20±2.6; p=.022). Diabetics with mdEF had lower GLS than those with pEF (-13.3±3.41 vs -19±3.2; P<.001). There was no difference in GLS with pEF compared to controls (-19.4±3.2 vs -20±2.6; p=.70). CONCLUSIONS: Galectin-3 is elevated in diabetic patients with mdEF, and is associated with a diminished GLS. GLS could be an early marker of left ventricular dysfunction as well as evidence of diabetic cardiomyopathy.

A comparative ultrastructural analysis of spermatozoa in Pleurodema (Anura, Leptodactylidae, Leiuperinae).

This study describes the spermatozoa of 10 of the 15 species of the Neotropical frog genus Pleurodema through transmission electron microscopy. The diversity of oviposition modes coupled with a recent phylogenetic hypothesis of Pleurodema makes it an interesting group for the study of ultrastructural sperm evolution in relation to fertilization environment and egg-clutch structure. We found that Pleurodema has an unusual variability in sperm morphology. The more variable structures were the acrosomal complex, the midpiece, and the tail. The acrosomal complex has all the structures commonly reported in hyloid frogs but with different degree of development of the subacrosomal cone. Regarding the midpiece, the variability is given by the presence or absence of the mitochondrial collar. Finally, the tail is the most variable structure, ranging from single (only axoneme) to more complex (presence of paraxonemal rod, cytoplasmic sheath, and undulating membrane), with the absence of the typical axial fiber present in hyloid frogs, also shared with some other genera of Leiuperinae. J. Morphol. 277:957-977, 2016. © 2016 Wiley Periodicals, Inc.

Prevalencia del síndrome intestino irritable en la población adulta venezolana / Prevalence of irritable bowel syndrome in venezuelan adults

El síndrome del intestino irritable (SII) es un trastorno digestivo funcional que afecta del 10 al 20% de la población general. Existen pocos estudios en Latinoamérica que muestren su prevalencia nacional, y en Venezuela no disponemos de investigación que reporte tan importante cifra. Estudio multicéntrico, descriptivo, transversal, durante los meses abril y mayo del 2011. Se utilizó el cuestionario validado de la Fundación Roma, con quienes firmamos convenio como Servicio de Gastroenterología del Hospital Vargas de Caracas. Se seleccionaron al azar 15 estados, en cada uno un municipio, y de estos lugares como iglesias, centros comerciales, reuniones de Consejos Comunales, paradas de autobuses, etc. Los valores obtenidos fueron transcritos en una base de datos en Excel y procesados con EPIDAT 3.1. De 1781 personas encuestadas, 299 presentaron criterios clínicos diagnósticos para SII de acuerdo a Roma III. La prevalencia nacional del SII fue de 16,80%, correspondiendo 81,6% a mujeres (244) y 18,4% a hombres (55). El grupo etario entre 38 y 47 años fue el más afectado (26,43%) y el subtipo mixto el más predominante. La prevalencia del SII en la población adulta venezolana según los criterios de Roma III es de 16,80%

Irritable bowel syndrome (IBS) is a functional digestive disorder that affects 10 to 20% of the general population. Few studies exist in Latin America that shows the national prevalence, and in Venezuela we don´t have investigation resources that support those numbers. Multicenter study, descriptive, transversal, during the months April and May 2011. The validated Roma Foundation questionnaire was used. This Foundation authorized its use by the Service of Gastroenterology Hospital Vargas de Caracas. 15 states were randomly selected, in each state one municipality, and in those places as churches, shopping centers, comunity meeting, bus stops, etc. The values obtained were transcribed into a database in Excel and processed EPIDAT 3.1. Of 1781 people encuested, 299 met the criteria for IBS according to Rome III. The national prevalence of IBS was 16.80%, with 81.6% women (244) and 18.4% men (55). The age group between 38 and 47 years was the most affected (26.43%) and the mix was the most predominant subtype. The prevalence of IBS in the Venezuelan adult population according to Rome III criteria is 16.80%

Case report: Transient success using prolonged treatment with miltefosine for a patient with diffuse cutaneous leishmaniasis infected with Leishmania mexicana mexicana.

Leishmania sp. is an intracellular parasite that causes a variable degree of clinical manifestations, especially in the skin. We present the case of a 38-year-old male with a chronic history of mucocutaneous disease present since childhood that generated deformity, loss of cartilage in the ears and nose, and scarring that limited his range of motion. The parasite was identified as L. mexicana mexicana. The patient was treated with a 3-month course of oral miltefosine with overwhelming results.