Andrew Koutnik - Academia.edu (original) (raw)

Papers by Andrew Koutnik

Cancers are one of the leading causes of morbidity and mortality worldwide, accounting for 8.8 mi... more Cancers are one of the leading causes of morbidity and mortality worldwide, accounting for 8.8 million deaths in 2015 [1, 2]. In the US, it is estimated that 1,688,780 new cancers will be diagnosed in 2017 [3] and 600,920 people will die from this disease in 2017. Gliomas are a
highly heterogeneous tumor, refractory to treatment and the most frequently diagnosed primary brain tumor. In 2017, an estimated 23,800 new cases of brain tumors will be diagnosed, and 16,700 will die from a brain tumor, most attributed to glioma [3]. Gliomas are neuroepithelial
tumors that originate from the supporting glial cells of the central nervous system (CNS). Glial tumors mostly consist of astrocytomas and oligodendrogliomas. The 2016 WHO classification of CNS tumors uses molecular genetic parameters in addition to histology to define many tumor entities [4]. The routine assessment of isocitrate dehydrogenase (IDH) mutation status, which are frequent in grade II and III infiltrating gliomas and small subset of glioblastomas (GBM) improves histological diagnostic accuracy and has been observed to have a favorable prognostic implication for all glial tumors [5-7] and to be predictive for chemotherapeutic responses in anaplastic oligodendrogliomas with codeletion of 1p/19q chromosomes. Glial tumors that contain chromosomal codeletion of 1p/19q, also defined as tumors of oligodendroglial lineage, have favorable prognosis. GBM typically lack IDH mutations and are instead characterized by EGFR, PTEN, TP53, PDGFRA, NF1, and CDKN2A/B alternations and TERT prompter mutations [5]. The revised classification thus provides a model that reflects malignant characteristics based on histopathlogical and molecular features of the tumors, offering additional opportunities for improved diagnosis, treatment, and estimating prognosis in
the molecular era. Lower grade diffuse gliomas (LGGs) (WHO Grade II-III) have fewer malignant characteristics than high-grade gliomas (WHO Grade IV), and a relatively better clinical prognosis. However, the majority of LGGs eventually progress to high grade gliomas
(HGG, WHO Grade III or IV), with death an inevitable outcome [8]. The life expectancymfollowing diagnosis with Grade IV glioblastoma multiforme is 2-4 months without treatment. Survival at 5 years for patients with GBM who receive treatment with concurrentchemoradiotherapy followed by maintenance temozolomide is around 8-14% [9]. Progression free survival for low grade glioma with standard treatment (LGG, WHO Grade I or II) is 8-35 months depending on patient age, tumor size, functional scores, and symptoms [8]. Treatment for LGG includes surgical resection followed by either radiation and chemotherapy or chemotherapy alone, but average survival is still approximately seven (7) years from diagnosis
[8]. Although LGG have a less aggressive course than do high-grade gliomas, both tumor, its treatment and the ultimate poor prognosis contribute to increased patient burden with disabling morbidity including decline in neurocognitive functions, seizures and compromised quality of life [8]. Significant gaps exist in how best to manage LGG during active surveillance, a period when patients report significant anxiety, eagerness to reduce disease progression, treatment-related symptoms, and demonstrate significant interest in interventions that can extend their years and quality of survival. Patients with LGG may thus represent an ideal cohort for the evaluation of interventions for secondary chemoprevention and symptom management. Although the current WHO grading system (2016) [4] demonstrates promise towards
identifying novel treatment modalities and better prediction of prognosis over time, to date, existing targeted and mono therapy approaches have failed to elicit a robust impact on disease progression and patient survival. It is possible that tumor heterogeneity as well as specifically
targeted agents fail because redundant molecular pathways in the tumor make it refractory to such approaches. Additionally, the underlying metabolic pathology, which is significantly altered during neoplastic transformation and tumor progression, is unaccounted for. Although LGG have a less aggressive course than do high-grade gliomas, both tumor and its treatment contribute to increased patient burden with disabling morbidity including decline in neurocognitive functions, seizures and ultimately to progression to HGG. There is thus an
urgent need and opportunity for the development of novel, adjunct, secondary chemopreventative strategies targeting patients with LGG to slow or halt progression of LGG to HGG. The recognition and broad applicability of the concepts described by Hanahan and Weinberg [10] – identifying the hallmarks of cancer – has transformed the landscape of cancer prevention and treatment. The hallmarks of cancer constitute an organizing principle for rationalizing the complexities and multi-step development of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling
replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Additional hallmarks include genome instability, which underlies these hallmarks and generates the genetic diversity that is permissive for their acquisition, and inflammation, which fosters
multiple hallmark functions. Based on the conceptual progress made in the last decade, two emerging hallmarks of potential generality were added to this list: reprogramming energy metabolism and evading immune destruction [11]. Abnormal energy metabolism is a consistent
feature of most tumor cells across all tissue types [12]. The characteristic metabolic phenotype of tumor cells as compared to non-transformed cells has been well documented. In the 1930s, Otto Warburg observed that tumors exhibit a unique metabolic phenotype characterized by high rates of aerobic glycolysis, or fermentation in the presence of oxygen [13]. Following glycolysis, pyruvate is primarily fermented to lactate despite availability of oxygen. This feature, known as the Warburg effect, is characterized by tumor hypoxia, genetic mutations, and mitochondrial abnormalities within proliferating cancer cells [14]. The rapid and unbridled proliferation characteristic of tumor growth is an energy and resource-consuming process, and thus
predictably, metabolism is significantly altered during neoplastic transformation and tumor progression [15]. The Warburg effect confers multiple growth promoting effects onto the tumor, including provision of ATP in the face of hypoxia, acidification of the tumor microenvironment,
regeneration of endogenous antioxidants, and provision of carbon sources for biomass production, among others [15].

The robust glycolytic metabolism of glioblastoma multiforme (GBM) has proven them susceptible to ... more The robust glycolytic metabolism of glioblastoma multiforme (GBM) has proven them susceptible to increases in oxidative metabolism induced by the pyruvate mimetic dichloroace-tate (DCA). Recent reports demonstrate that the anti-diabetic drug metformin enhances the damaging oxidative stress associated with DCA treatment in cancer cells. We sought to elucidate the role of metformin's reported activity as a mitochondrial complex I inhibitor in the enhancement of DCA cytotoxicity in VM-M3 GBM cells. Metformin potentiated DCA-induced superoxide production, which was required for enhanced cytotoxicity towards VM-M3 cells observed with the combination. Similarly, rotenone enhanced oxidative stress resultant from DCA treatment and this too was required for the noted augmentation of cytotoxicity. Adeno-sine monophosphate kinase (AMPK) activation was not observed with the concentration of metformin required to enhance DCA activity. Moreover, addition of an activator of AMPK did not enhance DCA cytotoxicity, whereas an inhibitor of AMPK heightened the cytotoxicity of the combination. Our data indicate that metformin enhancement of DCA cytotoxicity is dependent on complex I inhibition. Particularly, that complex I inhibition cooperates with DCA-induction of glucose oxidation to enhance cytotoxic oxidative stress in VM-M3 GBM cells.

Global metabolomics analysis was performed on blood plasma from treated and untreated animals. Ad... more Global metabolomics analysis was performed on blood plasma from treated and untreated animals. Additionally, the time to paralysis of TDP-43 ALS C. elegans treated with and without the individual and combination DP supplements was measured. Results 30 and 49 biochemicals were significantly altered in the plasma of LOW and HIGH groups, respectively. Metabolites associated with mitochondrial energy metabolism , arginine metabolism, as well as long-and medium-chain fatty acids, GABA and related intermediates were elevated in response to DP. Elements of DP, arginine and alpha-ketoglutarate, GABA, and MCTs prolonged the rate of final paralysis of C. elegans TDP-43 disease models. Conclusion Targeting energy metabolism with the DP supplement as a metabolic therapy produces a change in the global metabolic profile of ALS mice that support the role of the DP for enhanced mitochondrial energy metabolism and prolongs time to paralysis of ALS C. elegans.

American journal of hypertension, 2013

Major depressive disorder (MDD) is associated with increased cardiovascular risk. Although cardio... more Major depressive disorder (MDD) is associated with increased cardiovascular risk. Although cardiovascular hyperactivity to stressors (e.g., cold pressor test (CPT)) is common in those with MDD, the aortic hemodynamic (AH) responses to sympatho-stimulation in healthy individuals with higher depressive scores (HDS) are not well understood. We hypothesized that individuals with HDS, compared with those with low depressive scores (LDS), would have greater changes in AH during the CPT. Thirty-five male participants (mean age, 22.3±0.7 years) completed a self-report measure of depressive symptoms and were classified as having an HDS or LDS. Radial waveforms were then obtained by means of applanation tonometry. The testing protocol consisted of a 10-minute seated rest, 5 minutes of baseline measurements, a 3-minute CPT, and a 3-minute recovery period. At baseline, no differences were found between the LDS (n=16) and HDS (n=19) groups on any variables studied. During CPT, there was a signif...

American journal of hypertension, 2013

Although increased sympathetic nervous system (SNS) activity is commonly associated with major de... more Although increased sympathetic nervous system (SNS) activity is commonly associated with major depressive disorder (MDD) and cardiovascular disease (CVD), a biomarker linking these two entities remains elusive. We therefore evaluated the relationship between depressive symptoms and cardiovascular modulation by heart rate variability (HRV), brachial blood pressure (BP), ambulatory BP (ABP), and low frequency component of systolic BP variability (LFSBP), a surrogate of sympathetic vasomotor tone. We hypothesized that LFSBP would be the strongest predictor of depressive symptoms compared with HRV and BP measurements. Eighty young healthy female subjects (20.51 ± 2.82 years) were evaluated for depressive symptoms using the Center for Epidemiologic Studies Depression Scale (CES-D). Data collection was conducted after a 10-minute resting period. Beat-to-beat BPs were recorded for 5-minute at baseline (BASE) followed by a 3-minute cold pressor test (CPT). ABP was obtained for 24 hours. Hie...

American journal of hypertension, 2013

Supplementation with L-citrulline (L-cit) has shown attenuating effects on blood pressure (BP) an... more Supplementation with L-citrulline (L-cit) has shown attenuating effects on blood pressure (BP) and pulse-wave-reflection responses (augmentation index (AIx)) to local exposure to cold, but the potential cardioprotective effects of L-cit during whole-body cold exposure with concurrent exercise are poorly understood. We hypothesized that L-cit would attenuate the BP and AIx responses to cold exposure and isometric handgrip (IHG) exercise. Sixteen healthy males with a mean age of 23±3 years volunteered for a study of the effect of L-cit on the BP and AIx responses to cold exposure and IHG exercise. Experiments were conducted inside an environmental chamber in cold conditions (4 ºC). Radial waveforms were obtained in duplicates and averaged through applanation tonometry. After 5 minutes of measurements made at rest in the supine position (RES), after the finalization of the exercise about the subjects were evaluated in non exercise condition that were basically the same as the RES. Afte...

European Journal of Applied Physiology, 2014

Journal of Biological Chemistry, 2014

Psychophysiology, 2014

Prior research suggests that negative affectivity (NA) may have a direct adverse effect on corona... more Prior research suggests that negative affectivity (NA) may have a direct adverse effect on coronary circulation, whereas forgiveness may provide cardioprotection. This study examined whether NA and forgiveness were independently related to aortic hemodynamics and the subendocardial viability index (SVI), a marker of coronary perfusion. A sample of 131 adults (M = 21.11 years, SD = 2.52) were evaluated for NA (depression, anxiety, and anger symptoms) and forgiveness (Tendency to Forgive Scale; TTF). Aortic hemodynamic parameters via applanation tonometry were assessed at rest and during sympathostimulation (cold pressor test; CPT). Hierarchical multiple regression analyses of resting values showed that NA was related to higher aortic blood pressure (ABP) and lower SVI. After controlling for demographics and for NA, TTF scores were significantly associated with decreased ABP, but increased SVI. CPT changes from baseline indicated that, after controlling for demographics and NA, TTF scores were significantly associated with SVI. Results indicate that NA significantly predicts ABP and decreased SVI. Conversely, forgiveness seems to provide cardioprotection by evoking decreased ABP while improving SVI.

Biophysical Journal, 2015

Journal of Human Hypertension, 2014

European Journal of Applied Physiology, 2014

This study investigated aortic and brachial hemodynamic functioning that may link school burnout ... more This study investigated aortic and brachial hemodynamic functioning that may link school burnout to cardiovascular risk factors. Methodological improvements from previous research were implemented including (1) statistical control of depressive and anxiety symptoms (2) resting, stress-induced and cardiac recovery condition comparisons and (3) use of pulse wave analysis. Forty undergraduate young adult males completed self-report measures of school burnout, trait anxiety and depressive symptoms. Participants then completed a protocol consisting of a 10-min seated rest, 5-min baseline (BASE), 3-min cold pressor test (CPT) and a 3-min recovery period (REC). Indices of brachial and aortic hemodynamics were obtained by means of pulse wave analysis via applanation tonometry. Controlling for anxiety and depressive symptoms, planned contrasts identified no differences in cardiovascular parameters at BASE between participants in burnout and non-burnout groups. However, negative changes in hemodynamic indices occurred in burnout participants at CPT and REC as evidenced by increased aortic and brachial systolic and diastolic blood pressures, increased left ventricular work and increased myocardial oxygen consumption. Findings suggest that school burnout symptoms are associated with cardiac hyperactivity during conditions of cardiac stress and recovery and therefore may be associated with the early manifestations of cardiovascular disease. Future studies are suggested to reveal underlying autonomic mechanisms explaining hemodynamics functioning in individuals with school burnout symptomatology.

Nutritional ketosis has been proven effective for seizure disorders and other neurological disord... more Nutritional ketosis has been proven effective for seizure disorders and other neurological disorders. The focus of this study was to determine the effects of ketone supplementation on anxiety-related behavior in Sprague-Dawley (SPD) and Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. We tested exogenous ketone supplements added to food and fed chronically for 83 days in SPD rats and administered sub-chronically for 7 days in both rat models by daily intragastric gavage bolus followed by assessment of anxiety measures on elevated plus maze (EPM). The groups included standard diet (SD) or SD + ketone supplementation. Low-dose ketone ester (LKE; 1,3-butanediol-acetoacetate diester, ∼10 g/kg/day, LKE), high dose ketone ester (HKE; ∼25 g/kg/day, HKE), beta-hydroxybutyrate-mineral salt (βHB-S; ∼25 g/kg/day, KS) and βHB-S + medium chain triglyceride (MCT; ∼25 g/kg/day, KSMCT) were used as ketone supplementation for chronic administration. To extend our results, exogenous ketone supplements were also tested sub-chronically on SPD rats (KE, KS and KSMCT; 5 g/kg/day) and on WAG/Rij rats (KE, KS and KSMCT; 2.5 g/kg/day). At the end of treatments behavioral data collection was conducted manually by a blinded observer and with a video-tracking system, after which blood βHB and glucose levels were measured. Ketone supplementation reduced anxiety on EPM as measured by less entries to closed arms (sub-chronic KE and KS: SPD rats and KSMCT: WAG/Rij rats), more time spent in open arms (sub-chronic KE: SPD and KSMCT: WAG/Rij rats; chronic KSMCT: SPD rats), more distance traveled in open arms (chronic KS and KSMCT: SPD rats) and by delayed latency to entrance to closed arms (chronic KSMCT: SPD rats), when compared to control. Our data indicates that chronic and sub-chronic ketone supplementation not only elevated blood βHB levels in both animal models, but reduced anxiety-related behavior. We conclude that ketone supplementation may represent a promising anxiolytic strategy through a novel means of inducing nutritional ketosis.

Cancers are one of the leading causes of morbidity and mortality worldwide, accounting for 8.8 mi... more Cancers are one of the leading causes of morbidity and mortality worldwide, accounting for 8.8 million deaths in 2015 [1, 2]. In the US, it is estimated that 1,688,780 new cancers will be diagnosed in 2017 [3] and 600,920 people will die from this disease in 2017. Gliomas are a
highly heterogeneous tumor, refractory to treatment and the most frequently diagnosed primary brain tumor. In 2017, an estimated 23,800 new cases of brain tumors will be diagnosed, and 16,700 will die from a brain tumor, most attributed to glioma [3]. Gliomas are neuroepithelial
tumors that originate from the supporting glial cells of the central nervous system (CNS). Glial tumors mostly consist of astrocytomas and oligodendrogliomas. The 2016 WHO classification of CNS tumors uses molecular genetic parameters in addition to histology to define many tumor entities [4]. The routine assessment of isocitrate dehydrogenase (IDH) mutation status, which are frequent in grade II and III infiltrating gliomas and small subset of glioblastomas (GBM) improves histological diagnostic accuracy and has been observed to have a favorable prognostic implication for all glial tumors [5-7] and to be predictive for chemotherapeutic responses in anaplastic oligodendrogliomas with codeletion of 1p/19q chromosomes. Glial tumors that contain chromosomal codeletion of 1p/19q, also defined as tumors of oligodendroglial lineage, have favorable prognosis. GBM typically lack IDH mutations and are instead characterized by EGFR, PTEN, TP53, PDGFRA, NF1, and CDKN2A/B alternations and TERT prompter mutations [5]. The revised classification thus provides a model that reflects malignant characteristics based on histopathlogical and molecular features of the tumors, offering additional opportunities for improved diagnosis, treatment, and estimating prognosis in
the molecular era. Lower grade diffuse gliomas (LGGs) (WHO Grade II-III) have fewer malignant characteristics than high-grade gliomas (WHO Grade IV), and a relatively better clinical prognosis. However, the majority of LGGs eventually progress to high grade gliomas
(HGG, WHO Grade III or IV), with death an inevitable outcome [8]. The life expectancymfollowing diagnosis with Grade IV glioblastoma multiforme is 2-4 months without treatment. Survival at 5 years for patients with GBM who receive treatment with concurrentchemoradiotherapy followed by maintenance temozolomide is around 8-14% [9]. Progression free survival for low grade glioma with standard treatment (LGG, WHO Grade I or II) is 8-35 months depending on patient age, tumor size, functional scores, and symptoms [8]. Treatment for LGG includes surgical resection followed by either radiation and chemotherapy or chemotherapy alone, but average survival is still approximately seven (7) years from diagnosis
[8]. Although LGG have a less aggressive course than do high-grade gliomas, both tumor, its treatment and the ultimate poor prognosis contribute to increased patient burden with disabling morbidity including decline in neurocognitive functions, seizures and compromised quality of life [8]. Significant gaps exist in how best to manage LGG during active surveillance, a period when patients report significant anxiety, eagerness to reduce disease progression, treatment-related symptoms, and demonstrate significant interest in interventions that can extend their years and quality of survival. Patients with LGG may thus represent an ideal cohort for the evaluation of interventions for secondary chemoprevention and symptom management. Although the current WHO grading system (2016) [4] demonstrates promise towards
identifying novel treatment modalities and better prediction of prognosis over time, to date, existing targeted and mono therapy approaches have failed to elicit a robust impact on disease progression and patient survival. It is possible that tumor heterogeneity as well as specifically
targeted agents fail because redundant molecular pathways in the tumor make it refractory to such approaches. Additionally, the underlying metabolic pathology, which is significantly altered during neoplastic transformation and tumor progression, is unaccounted for. Although LGG have a less aggressive course than do high-grade gliomas, both tumor and its treatment contribute to increased patient burden with disabling morbidity including decline in neurocognitive functions, seizures and ultimately to progression to HGG. There is thus an
urgent need and opportunity for the development of novel, adjunct, secondary chemopreventative strategies targeting patients with LGG to slow or halt progression of LGG to HGG. The recognition and broad applicability of the concepts described by Hanahan and Weinberg [10] – identifying the hallmarks of cancer – has transformed the landscape of cancer prevention and treatment. The hallmarks of cancer constitute an organizing principle for rationalizing the complexities and multi-step development of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling
replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Additional hallmarks include genome instability, which underlies these hallmarks and generates the genetic diversity that is permissive for their acquisition, and inflammation, which fosters
multiple hallmark functions. Based on the conceptual progress made in the last decade, two emerging hallmarks of potential generality were added to this list: reprogramming energy metabolism and evading immune destruction [11]. Abnormal energy metabolism is a consistent
feature of most tumor cells across all tissue types [12]. The characteristic metabolic phenotype of tumor cells as compared to non-transformed cells has been well documented. In the 1930s, Otto Warburg observed that tumors exhibit a unique metabolic phenotype characterized by high rates of aerobic glycolysis, or fermentation in the presence of oxygen [13]. Following glycolysis, pyruvate is primarily fermented to lactate despite availability of oxygen. This feature, known as the Warburg effect, is characterized by tumor hypoxia, genetic mutations, and mitochondrial abnormalities within proliferating cancer cells [14]. The rapid and unbridled proliferation characteristic of tumor growth is an energy and resource-consuming process, and thus
predictably, metabolism is significantly altered during neoplastic transformation and tumor progression [15]. The Warburg effect confers multiple growth promoting effects onto the tumor, including provision of ATP in the face of hypoxia, acidification of the tumor microenvironment,
regeneration of endogenous antioxidants, and provision of carbon sources for biomass production, among others [15].

The robust glycolytic metabolism of glioblastoma multiforme (GBM) has proven them susceptible to ... more The robust glycolytic metabolism of glioblastoma multiforme (GBM) has proven them susceptible to increases in oxidative metabolism induced by the pyruvate mimetic dichloroace-tate (DCA). Recent reports demonstrate that the anti-diabetic drug metformin enhances the damaging oxidative stress associated with DCA treatment in cancer cells. We sought to elucidate the role of metformin's reported activity as a mitochondrial complex I inhibitor in the enhancement of DCA cytotoxicity in VM-M3 GBM cells. Metformin potentiated DCA-induced superoxide production, which was required for enhanced cytotoxicity towards VM-M3 cells observed with the combination. Similarly, rotenone enhanced oxidative stress resultant from DCA treatment and this too was required for the noted augmentation of cytotoxicity. Adeno-sine monophosphate kinase (AMPK) activation was not observed with the concentration of metformin required to enhance DCA activity. Moreover, addition of an activator of AMPK did not enhance DCA cytotoxicity, whereas an inhibitor of AMPK heightened the cytotoxicity of the combination. Our data indicate that metformin enhancement of DCA cytotoxicity is dependent on complex I inhibition. Particularly, that complex I inhibition cooperates with DCA-induction of glucose oxidation to enhance cytotoxic oxidative stress in VM-M3 GBM cells.

Global metabolomics analysis was performed on blood plasma from treated and untreated animals. Ad... more Global metabolomics analysis was performed on blood plasma from treated and untreated animals. Additionally, the time to paralysis of TDP-43 ALS C. elegans treated with and without the individual and combination DP supplements was measured. Results 30 and 49 biochemicals were significantly altered in the plasma of LOW and HIGH groups, respectively. Metabolites associated with mitochondrial energy metabolism , arginine metabolism, as well as long-and medium-chain fatty acids, GABA and related intermediates were elevated in response to DP. Elements of DP, arginine and alpha-ketoglutarate, GABA, and MCTs prolonged the rate of final paralysis of C. elegans TDP-43 disease models. Conclusion Targeting energy metabolism with the DP supplement as a metabolic therapy produces a change in the global metabolic profile of ALS mice that support the role of the DP for enhanced mitochondrial energy metabolism and prolongs time to paralysis of ALS C. elegans.

American journal of hypertension, 2013

Major depressive disorder (MDD) is associated with increased cardiovascular risk. Although cardio... more Major depressive disorder (MDD) is associated with increased cardiovascular risk. Although cardiovascular hyperactivity to stressors (e.g., cold pressor test (CPT)) is common in those with MDD, the aortic hemodynamic (AH) responses to sympatho-stimulation in healthy individuals with higher depressive scores (HDS) are not well understood. We hypothesized that individuals with HDS, compared with those with low depressive scores (LDS), would have greater changes in AH during the CPT. Thirty-five male participants (mean age, 22.3±0.7 years) completed a self-report measure of depressive symptoms and were classified as having an HDS or LDS. Radial waveforms were then obtained by means of applanation tonometry. The testing protocol consisted of a 10-minute seated rest, 5 minutes of baseline measurements, a 3-minute CPT, and a 3-minute recovery period. At baseline, no differences were found between the LDS (n=16) and HDS (n=19) groups on any variables studied. During CPT, there was a signif...

American journal of hypertension, 2013

Although increased sympathetic nervous system (SNS) activity is commonly associated with major de... more Although increased sympathetic nervous system (SNS) activity is commonly associated with major depressive disorder (MDD) and cardiovascular disease (CVD), a biomarker linking these two entities remains elusive. We therefore evaluated the relationship between depressive symptoms and cardiovascular modulation by heart rate variability (HRV), brachial blood pressure (BP), ambulatory BP (ABP), and low frequency component of systolic BP variability (LFSBP), a surrogate of sympathetic vasomotor tone. We hypothesized that LFSBP would be the strongest predictor of depressive symptoms compared with HRV and BP measurements. Eighty young healthy female subjects (20.51 ± 2.82 years) were evaluated for depressive symptoms using the Center for Epidemiologic Studies Depression Scale (CES-D). Data collection was conducted after a 10-minute resting period. Beat-to-beat BPs were recorded for 5-minute at baseline (BASE) followed by a 3-minute cold pressor test (CPT). ABP was obtained for 24 hours. Hie...

American journal of hypertension, 2013

Supplementation with L-citrulline (L-cit) has shown attenuating effects on blood pressure (BP) an... more Supplementation with L-citrulline (L-cit) has shown attenuating effects on blood pressure (BP) and pulse-wave-reflection responses (augmentation index (AIx)) to local exposure to cold, but the potential cardioprotective effects of L-cit during whole-body cold exposure with concurrent exercise are poorly understood. We hypothesized that L-cit would attenuate the BP and AIx responses to cold exposure and isometric handgrip (IHG) exercise. Sixteen healthy males with a mean age of 23±3 years volunteered for a study of the effect of L-cit on the BP and AIx responses to cold exposure and IHG exercise. Experiments were conducted inside an environmental chamber in cold conditions (4 ºC). Radial waveforms were obtained in duplicates and averaged through applanation tonometry. After 5 minutes of measurements made at rest in the supine position (RES), after the finalization of the exercise about the subjects were evaluated in non exercise condition that were basically the same as the RES. Afte...

European Journal of Applied Physiology, 2014

Journal of Biological Chemistry, 2014

Psychophysiology, 2014

Prior research suggests that negative affectivity (NA) may have a direct adverse effect on corona... more Prior research suggests that negative affectivity (NA) may have a direct adverse effect on coronary circulation, whereas forgiveness may provide cardioprotection. This study examined whether NA and forgiveness were independently related to aortic hemodynamics and the subendocardial viability index (SVI), a marker of coronary perfusion. A sample of 131 adults (M = 21.11 years, SD = 2.52) were evaluated for NA (depression, anxiety, and anger symptoms) and forgiveness (Tendency to Forgive Scale; TTF). Aortic hemodynamic parameters via applanation tonometry were assessed at rest and during sympathostimulation (cold pressor test; CPT). Hierarchical multiple regression analyses of resting values showed that NA was related to higher aortic blood pressure (ABP) and lower SVI. After controlling for demographics and for NA, TTF scores were significantly associated with decreased ABP, but increased SVI. CPT changes from baseline indicated that, after controlling for demographics and NA, TTF scores were significantly associated with SVI. Results indicate that NA significantly predicts ABP and decreased SVI. Conversely, forgiveness seems to provide cardioprotection by evoking decreased ABP while improving SVI.

Biophysical Journal, 2015

Journal of Human Hypertension, 2014

European Journal of Applied Physiology, 2014

This study investigated aortic and brachial hemodynamic functioning that may link school burnout ... more This study investigated aortic and brachial hemodynamic functioning that may link school burnout to cardiovascular risk factors. Methodological improvements from previous research were implemented including (1) statistical control of depressive and anxiety symptoms (2) resting, stress-induced and cardiac recovery condition comparisons and (3) use of pulse wave analysis. Forty undergraduate young adult males completed self-report measures of school burnout, trait anxiety and depressive symptoms. Participants then completed a protocol consisting of a 10-min seated rest, 5-min baseline (BASE), 3-min cold pressor test (CPT) and a 3-min recovery period (REC). Indices of brachial and aortic hemodynamics were obtained by means of pulse wave analysis via applanation tonometry. Controlling for anxiety and depressive symptoms, planned contrasts identified no differences in cardiovascular parameters at BASE between participants in burnout and non-burnout groups. However, negative changes in hemodynamic indices occurred in burnout participants at CPT and REC as evidenced by increased aortic and brachial systolic and diastolic blood pressures, increased left ventricular work and increased myocardial oxygen consumption. Findings suggest that school burnout symptoms are associated with cardiac hyperactivity during conditions of cardiac stress and recovery and therefore may be associated with the early manifestations of cardiovascular disease. Future studies are suggested to reveal underlying autonomic mechanisms explaining hemodynamics functioning in individuals with school burnout symptomatology.

Nutritional ketosis has been proven effective for seizure disorders and other neurological disord... more Nutritional ketosis has been proven effective for seizure disorders and other neurological disorders. The focus of this study was to determine the effects of ketone supplementation on anxiety-related behavior in Sprague-Dawley (SPD) and Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. We tested exogenous ketone supplements added to food and fed chronically for 83 days in SPD rats and administered sub-chronically for 7 days in both rat models by daily intragastric gavage bolus followed by assessment of anxiety measures on elevated plus maze (EPM). The groups included standard diet (SD) or SD + ketone supplementation. Low-dose ketone ester (LKE; 1,3-butanediol-acetoacetate diester, ∼10 g/kg/day, LKE), high dose ketone ester (HKE; ∼25 g/kg/day, HKE), beta-hydroxybutyrate-mineral salt (βHB-S; ∼25 g/kg/day, KS) and βHB-S + medium chain triglyceride (MCT; ∼25 g/kg/day, KSMCT) were used as ketone supplementation for chronic administration. To extend our results, exogenous ketone supplements were also tested sub-chronically on SPD rats (KE, KS and KSMCT; 5 g/kg/day) and on WAG/Rij rats (KE, KS and KSMCT; 2.5 g/kg/day). At the end of treatments behavioral data collection was conducted manually by a blinded observer and with a video-tracking system, after which blood βHB and glucose levels were measured. Ketone supplementation reduced anxiety on EPM as measured by less entries to closed arms (sub-chronic KE and KS: SPD rats and KSMCT: WAG/Rij rats), more time spent in open arms (sub-chronic KE: SPD and KSMCT: WAG/Rij rats; chronic KSMCT: SPD rats), more distance traveled in open arms (chronic KS and KSMCT: SPD rats) and by delayed latency to entrance to closed arms (chronic KSMCT: SPD rats), when compared to control. Our data indicates that chronic and sub-chronic ketone supplementation not only elevated blood βHB levels in both animal models, but reduced anxiety-related behavior. We conclude that ketone supplementation may represent a promising anxiolytic strategy through a novel means of inducing nutritional ketosis.