Transthyretin V142I Genetic Variant and Cardiac Remodeling, Injury, and Heart Failure Risk in Black Adults.

OBJECTIVES: This study evaluated the association of transthyretin (TTR) gene variant, in which isoleucine substitutes for valine at position 122 (V142I), with cardiac structure, function, and heart failure (HF) risk among middle-aged Black adults. BACKGROUND: The valine-to-isoleucine substitution in the TTR protein is prevalent in Black individuals and causes cardiac amyloidosis. METHODS: Jackson Heart Study participants without HF at baseline who had available data on the TTR V142I variant were included. The association of the TTR V142I variant with baseline echocardiographic parameters and repeated measures of high-sensitivity cardiac troponin-I (hs-cTnI) was assessed using adjusted linear regression models and linear mixed models, respectively. Adjusted Cox models, restricted mean survival time analysis, and Anderson-Gill models were constructed to determine the association of TTR V142I variant with the risk of incident HF, survival free of HF, and total HF hospitalizations. RESULTS: A total of 119 of 2,960 participants (4%) were heterozygous carriers of the TTR V142I variant. The TTR V142I variant was not associated with measures of cardiac parameters at baseline but was associated with a greater increase in high-sensitivity troponin I (hs-TnI) levels over time. In adjusted Cox models, TTR V142I variant carriers had significantly higher risk of incident HF (HR: 1.80; 95% CI: 1.07-3.05; P = 0.03), lower survival free of HF (mean difference: 4.0 year; 95% CI: 0.6-6.2 years); P = 0.02), and higher risk of overall HF hospitalizations (HR: 2.12; 95% CI: 1.23-3.63; P = 0.007). CONCLUSIONS: The TTR V142I variant in middle-aged Black adults is not associated with adverse cardiac remodeling but was associated with a significantly higher burden of chronic myocardial injury, and greater risk of incident HF and overall HF hospitalizations.

Admission respiratory status predicts mortality in COVID-19.

COVID-19 has significant case fatality. Glucocorticoids are the only treatment shown to improve survival, but only among patients requiring supplemental oxygen. WHO advises patients to seek medical care for "trouble breathing," but hypoxemic patients frequently have no respiratory symptoms. Our cohort study of hospitalized COVID-19 patients shows that respiratory symptoms are uncommon and not associated with mortality. By contrast, objective signs of respiratory compromise-oxygen saturation and respiratory rate-are associated with markedly elevated mortality. Our findings support expanding guidelines to include at-home assessment of oxygen saturation and respiratory rate in order to expedite life-saving treatments patients to high-risk COVID-19 patients.

Mitochondrial Substrate Utilization Regulates Cardiomyocyte Cell Cycle Progression.

The neonatal mammalian heart is capable of regeneration for a brief window of time after birth. However, this regenerative capacity is lost within the first week of life, which coincides with a postnatal shift from anaerobic glycolysis to mitochondrial oxidative phosphorylation, particularly towards fatty-acid utilization. Despite the energy advantage of fatty-acid beta-oxidation, cardiac mitochondria produce elevated rates of reactive oxygen species when utilizing fatty acids, which is thought to play a role in cardiomyocyte cell-cycle arrest through induction of DNA damage and activation of DNA-damage response (DDR) pathway. Here we show that inhibiting fatty-acid utilization promotes cardiomyocyte proliferation in the postnatatal heart. First, neonatal mice fed fatty-acid deficient milk showed prolongation of the postnatal cardiomyocyte proliferative window, however cell cycle arrest eventually ensued. Next, we generated a tamoxifen-inducible cardiomyocyte-specific, pyruvate dehydrogenase kinase 4 (PDK4) knockout mouse model to selectively enhance oxidation of glycolytically derived pyruvate in cardiomyocytes. Conditional PDK4 deletion resulted in an increase in pyruvate dehydrogenase activity and consequently an increase in glucose relative to fatty-acid oxidation. Loss of PDK4 also resulted in decreased cardiomyocyte size, decreased DNA damage and expression of DDR markers and an increase in cardiomyocyte proliferation. Following myocardial infarction, inducible deletion of PDK4 improved left ventricular function and decreased remodelling. Collectively, inhibition of fatty-acid utilization in cardiomyocytes promotes proliferation, and may be a viable target for cardiac regenerative therapies.

A calcineurin-Hoxb13 axis regulates growth mode of mammalian cardiomyocytes.

A major factor in the progression to heart failure in humans is the inability of the adult heart to repair itself after injury. We recently demonstrated that the early postnatal mammalian heart is capable of regeneration following injury through proliferation of preexisting cardiomyocytes1,2 and that Meis1, a three amino acid loop extension (TALE) family homeodomain transcription factor, translocates to cardiomyocyte nuclei shortly after birth and mediates postnatal cell cycle arrest3. Here we report that Hoxb13 acts as a cofactor of Meis1 in postnatal cardiomyocytes. Cardiomyocyte-specific deletion of Hoxb13 can extend the postnatal window of cardiomyocyte proliferation and reactivate the cardiomyocyte cell cycle in the adult heart. Moreover, adult Meis1-Hoxb13 double-knockout hearts display widespread cardiomyocyte mitosis, sarcomere disassembly and improved left ventricular systolic function following myocardial infarction, as demonstrated by echocardiography and magnetic resonance imaging. Chromatin immunoprecipitation with sequencing demonstrates that Meis1 and Hoxb13 act cooperatively to regulate cardiomyocyte maturation and cell cycle. Finally, we show that the calcium-activated protein phosphatase calcineurin dephosphorylates Hoxb13 at serine-204, resulting in its nuclear localization and cell cycle arrest. These results demonstrate that Meis1 and Hoxb13 act cooperatively to regulate cardiomyocyte maturation and proliferation and provide mechanistic insights into the link between hyperplastic and hypertrophic growth of cardiomyocytes.

The Effect of Hypoxia on Cardiovascular Disease: Friend or Foe?

Savla, Jainy J., Benjamin D. Levine, and Hesham A. Sadek. The effect of hypoxia on cardiovascular disease: Friend or foe? High Alt Med Biol. 19:124-130, 2018.-Over 140 million people reside at altitudes exceeding 2500 m across the world, resulting in exposure to atmospheric (hypobaric) hypoxia. Whether this chronic exposure is beneficial or detrimental to the cardiovascular system, however, is uncertain. On one hand, multiple studies have suggested a protective effect of living at moderate and high altitudes for cardiovascular risk factors and cardiovascular disease (CVD) events. Conversely, residence at high altitude comes at the tradeoff of developing diseases such as chronic mountain sickness and high-altitude pulmonary hypertension and worsens outcomes for diseases such as chronic obstructive pulmonary disease. Interestingly, recently published data show a potential role for severe hypoxia as a unique and unexpected therapy after myocardial infarction. In this review, we will discuss the current literature evaluating the effects of altitude exposure and the accompanying hypoxia on health and the potential therapeutic applications of hypoxia on CVD.

Induced pluripotent stem cells for the study of cardiovascular disease.

Groundbreaking advances in stem cell research have led to techniques for the creation of human cardiomyocytes from cells procured from a variety of sources, including a simple skin biopsy. Since the advent of this technology, most research has focused on utilizing these cells for therapeutic purposes. However, recent studies have demonstrated that stem cell-derived cardiomyocytes generated from patients with inherited cardiovascular disorders recapitulate key phenotypic features of disease in vitro. Furthermore, these cells can be maintained in culture for prolonged periods of time and used for extensive biochemical and physiological analysis. By serving as models of inherited cardiac disorders, these systems have the potential to fundamentally change the manner in which cardiovascular disease is studied and new therapies are developed.

Cardiomyocyte proliferation contributes to heart growth in young humans.

The human heart is believed to grow by enlargement but not proliferation of cardiomyocytes (heart muscle cells) during postnatal development. However, recent studies have shown that cardiomyocyte proliferation is a mechanism of cardiac growth and regeneration in animals. Combined with evidence for cardiomyocyte turnover in adult humans, this suggests that cardiomyocyte proliferation may play an unrecognized role during the period of developmental heart growth between birth and adolescence. We tested this hypothesis by examining the cellular growth mechanisms of the left ventricle on a set of healthy hearts from humans aged 0-59 y (n = 36). The percentages of cardiomyocytes in mitosis and cytokinesis were highest in infants, decreasing to low levels by 20 y. Although cardiomyocyte mitosis was detectable throughout life, cardiomyocyte cytokinesis was not evident after 20 y. Between the first year and 20 y of life, the number of cardiomyocytes in the left ventricle increased 3.4-fold, which was consistent with our predictions based on measured cardiomyocyte cell cycle activity. Our findings show that cardiomyocyte proliferation contributes to developmental heart growth in young humans. This suggests that children and adolescents may be able to regenerate myocardium, that abnormal cardiomyocyte proliferation may be involved in myocardial diseases that affect this population, and that these diseases might be treatable through stimulation of cardiomyocyte proliferation.

Thoracic duct ligation for persistent chylothorax after pediatric cardiothoracic surgery.

BACKGROUND: There is considerable literature on incidence and medical management of postsurgical chylothorax in children but little is known about outcomes of thoracic duct ligation (TDL) for patients refractory to medical therapy. METHODS: A retrospective review of patients undergoing TDL after cardiothoracic surgery (1992 through 2007) was done. Data on demographics including cardiac morphology, characteristics of chylous drainage, medical management, and post-TDL course were collected. When available, imaging studies of the upper body venous drainage vessels were examined. RESULTS: Twenty patients (median age, 0.65 years; range, 0.03 to 11 years; weight, 7.0 kg; range, 2.6 to 30 kg) had a diagnosis of chylothorax made 8.5 days (range, 2 to 118 days) after initial operation. Median duration of pre-TDL medical management was 17.5 days (range, 7 to 69 days). Median drainage for 5 days preceding TDL was 34.5 mL x kg(-1) x d(-1) (range, 15 to 135 mL x kg(-1) x d(-1)) with maximal output of 65 mL x kg(-1) x d(-1) (range, 30 to 200 mL x kg(-1) x d(-1)). After TDL, there was a decrease in median drainage to 13 mL x kg(-1) x d(-1) (range, 4 to 160 mL x kg(-1) x d(-1); p = 0.003). Chest tubes were removed 8.5 days (range, 4 to 34 days) after TDL. There were 4 deaths (none attributed to TDL), 2 treatment failures (post-TDL chest tube drainage > 2 mL x kg(-1) x d(-1) > 14 days), and 2 recurrences (after initial chylothorax resolution and hospital discharge). Three patients had documented upper body venous thrombosis. Univariate analysis demonstrated thrombosis of upper body venous vessels (p = 0.02) and prolonged post-TDL chest tube drainage (p = 0.01) were risk factors for death, treatment failure, or chylothorax recurrence. CONCLUSIONS: Thoracic duct ligation leads to a major reduction in chest tube drainage and prompt tube removal in most pediatric patients and should be considered early in refractory postoperative chylothorax. Patients with upper body venous thrombosis associated with chylothorax are at a high risk for failure of TDL and mortality.