Andrew P. Koutnik

Sympathetic vasomotor tone is associated with depressive symptoms in young females: a potential link between depression and cardiovascular disease.

BACKGROUND 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. METHODS 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. RESULTS Hierarchical multiple regression analyses indicated that LFSBP at BASE was a stronger predictor of CES-D variance than BP and HRV indices, with LFSBP uniquely accounting for 8.1% of variance in CES-D scores during laboratory beat-by-beat BP assessments and 44.7% in ABP assessments. Individuals with acute depression scores (n = 12; CES-D ≥ 16) had significantly higher (P < 0.001) mean LFSBP values (6.66 ± 2.54 mm Hg(2)) than the remaining sample (3.32 ± 2.2 mm Hg(2)), whereas no other significant differences were detected in any of the other cardiovascular variables. Cardiovascular responses to CPT did not predict CES-D scores. CONCLUSIONS These findings suggest that LFSBP could be a biomarker of neurovascular functioning with potential clinical implications for understanding the interaction between MDD and CVD.

The Effects of Short Term L-Citrulline Supplementation on Wave Reflection Responses to Cold Exposure With Concurrent Isometric Exercise

BACKGROUND 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. METHODS 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. After initial measurements in cold conditions, subjects were randomized to receive either a placebo (Maltodextrin, PL) or L-cit (100mg/kg) for 14 days, followed by a 14-day washout period and then a 14-day regimen of the other agent. Subjects were re-evaluated after each treatment period. RESULTS At RES, there was a significant treatment-by-time interaction for brachial systolic BP (BSBP; P < 0.01), aortic systolic BP (ASBP; P < 0.01), and AIx (P < 0.05), such that L-cit decreased BSBP (-11±2mm Hg; P < 0.01), ASBP (-10±2mm Hg; P < 0.05), and AIx (-2±2%; P < 0.05) as compared with their respective values before the intervention. During IHG, BSBP, ASBP, and AIx were increased (P < 0.05) as compared with their values at RES, but these responses were unaffected by either of the study treatments. CONCLUSIONS L-citrulline may be a feasible adjuvant treatment for decrease the BP and AIx responses induced by cold. Further research is warranted to evaluate the impact of cold exposure and exercise on cardiovascular risk in clinical populations.

School burnout and cardiovascular functioning in young adult males: a hemodynamic perspective

Abstract 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.

Long term ablation of protein Kinase a (PKA)-mediated cardiac troponin I phosphorylation leads to excitation-contraction uncoupling and diastolic dysfunction in a knock-in mouse model of hypertrophic cardiomyopathy

Background: The R21C mutation in cardiac troponin I (cTnI) prevents PKA-mediated phosphorylation of serines 23 and 24 of cTnI in vivo. Results: Myofilament function is uncoupled from the intracellular [Ca2+] and delays muscle relaxation. Conclusion: Long term ablation of cTnI phosphorylation leads to hypertrophy, diastolic dysfunction, and dysautonomia in mice. Significance: Restoration of phosphorylated cTnI may prevent hypertrophic cardiomyopathy and diastolic dysfunction. The cardiac troponin I (cTnI) R21C (cTnI-R21C) mutation has been linked to hypertrophic cardiomyopathy and renders cTnI incapable of phosphorylation by PKA in vivo. Echocardiographic imaging of homozygous knock-in mice expressing the cTnI-R21C mutation shows that they develop hypertrophy after 12 months of age and have abnormal diastolic function that is characterized by longer filling times and impaired relaxation. Electrocardiographic analyses show that older R21C mice have elevated heart rates and reduced cardiovagal tone. Cardiac myocytes isolated from older R21C mice demonstrate that in the presence of isoproterenol, significant delays in Ca2+ decay and sarcomere relaxation occur that are not present at 6 months of age. Although isoproterenol and stepwise increases in stimulation frequency accelerate Ca2+-transient and sarcomere shortening kinetics in R21C myocytes from older mice, they are unable to attain the corresponding WT values. When R21C myocytes from older mice are treated with isoproterenol, evidence of excitation-contraction uncoupling is indicated by an elevation in diastolic calcium that is frequency-dissociated and not coupled to shorter diastolic sarcomere lengths. Myocytes from older mice have smaller Ca2+ transient amplitudes (2.3-fold) that are associated with reductions (2.9-fold) in sarcoplasmic reticulum Ca2+ content. This abnormal Ca2+ handling within the cell may be attributed to a reduction (2.4-fold) in calsequestrin expression in conjunction with an up-regulation (1.5-fold) of Na+-Ca2+ exchanger. Incubation of permeabilized cardiac fibers from R21C mice with PKA confirmed that the mutation prevents facilitation of mechanical relaxation. Altogether, these results indicate that the inability to enhance myofilament relaxation through cTnI phosphorylation predisposes the heart to abnormal diastolic function, reduced accessibility of cardiac reserves, dysautonomia, and hypertrophy.

Trait anxiety mimics age-related cardiovascular autonomic modulation in young adults

Anxiety produces maladaptive cardiovascular changes and accelerates biological aging. We evaluated cardiovascular reactivity in young and middle-aged individuals with varying anxiety scores to test the hypothesis that anxiety mimics cardiovascular aging by influencing cardiovascular autonomic modulation. The State-Trait Anxiety Inventory was used to classify healthy young individuals (20–29 years) into high (YHA, n=22;10 men) and low (YLA, n=21;10 men) anxiety, and to identify middle-aged individuals (50–60 years) with low anxiety (MLA, n=22;11 men). Heart rate, blood pressure (BP) and their variability (HRV and BPV, respectively) and baroreflex function were analyzed from beat-to-beat finger BP and electrocardiogram recordings collected during 5-min baseline, 6-min speech task (ST) and 3-min post ST recovery. Analyses of covariance showed significant differences (P<0.05) at baseline for HRV, BPV and barorelfex, and low-frequency power of systolic BP variability (LFSBP) was lower, whereas baroreflex and high frequency (HF) normalized units were higher in the YLA compared with YHA and MLA groups. Compared with YLA, YHA and MLA displayed attenuated vagal withdraw response (HF) to ST. BP and LFSBP responses to ST in YHA and MLA were higher compared with the YLA group. These findings suggest that anxiety could be linked to cardiovascular aging as it attenuates cardiac reactivity and exaggerates vascular responses to stress.

Depressive Symptoms Contribute to Increased Wave Reflection During Cold Pressor Test in Young Adult Men

BACKGROUND 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. METHODS 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. RESULTS 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 significant group-by-time interaction for aortic mean blood pressure (HDS vs. LDS = 107±3mm Hg vs. 96±3mm Hg; P = 0.008); augmentation index (HDS vs. LDS =19% ± 3% vs. 11% ± 2%; P = 0.02), a surrogate of wave reflection; and systolic time interval (HDS vs. LDS = 2295±78mm Hg/s.min(-1) vs. 1919±74mm Hg/s.min(-1); P = 0.001), a marker of myocardial work, such that the HDS group had significantly higher responses than the LDS group. CONCLUSIONS HDS may be associated with cardiac hyperactivity during sympatho-stimulation, contributing to increased central blood pressure, wave reflection, and myocardial work. Prospective studies to unveil mechanisms explaining increased AH in healthy individuals with high depressive symptomatology are warranted.

Impact of negative affectivity and trait forgiveness on aortic blood pressure and coronary circulation

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.

Pathogenesis of depression- and anxiety-like behavior in an animal model of hypertrophic cardiomyopathy

Cardiovascular dysfunction is highly comorbid with mood disorders, such as anxiety and depression. However, the mechanisms linking cardiovascular dysfunction with the core behavioral features of mood disorder remain poorly understood. In this study, we used mice bearing a knock‐in sarcomeric mutation, which is exhibited in human hypertrophic cardiomyopathy (HCM), to investigate the influence of HCM over the development of anxiety and depression. We employed behavioral, MRI, and biochemical techniques in young (3–4 mo) and aged adult (7–8 mo) female mice to examine the effects of HCM on the development of anxiety‐ and depression‐like behaviors. We focused on females because in both humans and rodents, they experience a 2‐fold increase in mood disorder prevalence vs. males. Our results showed that young and aged HCM mice displayed echocardiographic characteristics of the heart disease condition, yet only aged HCM females displayed anxiety‐ and depression‐like behaviors. Electrocardiographic parameters of sympathetic nervous system activation were increased in aged HCM females vs. controls and correlated with mood disorder–related symptoms. In addition, when compared with controls, aged HCM females exhibited adrenal gland hypertrophy, reduced volume in mood‐related brain regions, and reduced hippocampal signaling proteins, such as brain‐derived neurotrophic factor and its downstream targets vs. controls. In conclusion, prolonged systemic HCM stress can lead to development of mood disorders, possibly through inducing structural and functional brain changes, and thus, mood disorders in patients with heart disease should not be considered solely a psychologic or situational condition.—Dossat, A. M., Sanchez‐Gonzalez, M. A., Koutnik, A. P., Leitner, S., Ruiz, E. L., Griffin, B., Rosenberg, J. T., Grant, S. C., Fincham, F. D., Pinto, J. R. Kabbaj, M. Pathogenesis of depression‐ and anxiety‐like behavior in an animal model of hypertrophic cardiomyopathy. FASEB J. 31, 2492–2506 (2017). www.fasebj.org

Impact of psychological distress on cardiovagal reactivation after a speech task.

Cardiovascular disease (CVD) is more prevalent in individuals with Type-D personality(distressed) who tend to avoid confrontation in social situations (social inhibition) and have a greater tendency to experience negative emotions (negative affectivity). Although psychological distress is associated with increased risk of adverse cardiovascular outcomes and impaired heart rate (HR) modulation, studies examining cardiac autonomic modulation in distressed individuals through heart rate variability (HRV) and baroreflex functioning during, and more importantly, after stress are scarce. Accordingly, we investigated blood pressure (BP), baroreflex sensitivity (BRS) and HRV responses before, during and after an interpersonal speech task (ST) in individuals with high distress scores (HD) and low distress scores (LD).