Lower respiratory illnesses in childhood are associated with the presence of air trapping in early adulthood.

Several factors occurring in early life, including lower respiratory tract illnesses (LRIs), are involved in determining lung structure and function in adulthood, but the effects of these factors on lung development remain largely unknown. Hereby, we evaluated the parameters from computed tomography (CT) scans performed at the age of 26 years in 39 subjects from the birth cohort of the Tucson Children's Respiratory Study (TCRS) in order to determine the relationship between early childhood factors and lung structural changes in young adult life. We found that participants with LRIs in childhood had increased air trapping at the age of 26 suggesting an association between childhood infections and lung development.

Distinct Coordination Chemistry of Fe(III)-Based MRI Probes.

Contrast agents are used in approximately 40% of all magnetic resonance imaging (MRI) procedures to improve the quality of the images based on the distribution and dynamic clearance of the agent. To date, all clinically approved contrast agents are Gd(III) coordination complexes that serve to shorten the longitudinal (T1) and transverse (T2) proton relaxation times of water. Recent interest in replacing Gd with biologically relevant metal ions such as Mn or Fe has led to increased interest in the aqueous coordination chemistry of their complexes. In this Account, we focus on high-spin Fe(III) complexes that have been recently reported as MRI contrast agents or probes in our laboratory.The highly Lewis acidic Fe(III) center has distinct coordination chemistry in aqueous solutions, facilitating alternative strategies in the design of MRI probes. To illustrate this, we describe different classes of Fe(III) MRI probes with a focus on macrocyclic complexes and multinuclear complexes such as self-assembled metal organic polyhedra (MOP). Our initial efforts focused on macrocyclic complexes of Fe(III) in order to tune spin and oxidation states with the goal of stabilizing high-spin Fe(III) in reducing biological environments. Our probes feature six-coordinate Fe(III) complexes of 1,4,7-triazacyclononane with hydroxypropyl, phosphonate, or carboxylate pendant groups to produce Fe(III) complexes that shorten proton T1 times predominantly from second-sphere or outer-sphere interactions at neutral pH. Analogues with pentadentate macrocyclic ligands have an inner-sphere water that does not exchange rapidly on the NMR time scale, yet these complexes are effective relaxation agents. Fe(III) macrocyclic complexes in this class can be modified to modulate their biodistribution and pharmacokinetic clearance in mice. The goal of these studies is for the Fe(III) agents to clear as extracellular fluid agents and produce profiles similar to those of Gd agents. Finally, studies of multimeric Fe(III) complexes are of interest to produce probes that give large proton relaxivity. In this approach the two Fe(III) centers are connected through aryl linkers as demonstrated for several macrocyclic complexes. Even more tightly connected Fe(III) centers are produced in a Fe(III) self-assembled cage with relaxivity of 21 mM-1 s-1 at 4.7 T, 37 °C in the presence of serum albumin to which it is tightly bound. This cage enhances contrast of the vasculature as a blood pool agent and accumulates in tumors. Finally, we present our perspectives on the further development of Fe(III) complexes for various applications in MRI.

Alveolar to arterial gas exchange during constant-load exercise in healthy active men and women.

Inadequate hyperventilation and inefficient alveolar to arterial gas exchange are gas exchange challenges that can limit capacity and cause exercise-induced arterial hypoxaemia (EIAH). This work evaluated if the prevalence of gas exchange inefficiencies, defined as AaDO2>25 mmHg, PaCO2>38 mmHg, and/or ΔPaO2>-10 mmHg at any point during constant-load exercise in healthy, active, but not highly trained, individuals suggested an innate sex difference that would make females more susceptible to EIAH. Sixty-four healthy, active males and females completed 18-min of cycling exercise (moderate and vigorous intensity, 9 min/stage). Arterial blood gases were measured at rest and every 3-min during exercise, while constantly assessing gas exchange. Both sexes demonstrated similar levels of AaDO2 widening until the final 3 min of vigorous exercise, where females demonstrated a trend for greater widening than males (16.3±6.2 mmHg vs. 19.1±6.0 mmHg, p=0.07). Males demonstrated a blunted ventilatory response to moderate exercise with higher PaCO2 (38.5±2.6 vs. 36.5±2.4, p=0.002) and a lower ventilation when corrected for workload (0.42±0.1 vs. 0.48±0.1, p=0.002). No significant arterial hypoxaemia occurred, but in 6 M and 5 F SaO2 dropped by ≥2%. There was no difference in prevalence of pulmonary gas exchange inefficiencies between sexes, but the type of inefficiency was influenced by sex.Abbreviations: AaDO2: alveolar-arterial oxygen difference; BP: blood pressure; EIAH: exercise-induced arterial hypoxaemia; F: females; HR: heart rate; M: males; Q: cardiac output; PaCO2: arterial partial pressure of carbon dioxide; PaO2: arterial partial pressure of oxygen; ΔPaO2: change in arterial partial pressure of oxygen; PAO2: alveolar partial pressure of oxygen; RPE: rating of perceived exertion; SaO2: arterial oxygen saturation; VE: ventilation; VE/VCO2: ventilatory equivalent for carbon dioxide; VO2PEAK: peak oxygen consumption; WMAX: workload maximum.

Fetal Origins of Asthma: A Longitudinal Study from Birth to Age 36 Years.

Rationale: Deficits in infant lung function-including the ratio of the time to reach peak tidal expiratory flow to the total expiratory time (tptef/te) and maximal expiratory flow at FRC (V̇maxFRC)-have been linked to increased risk for childhood asthma.Objectives: To examine the individual and combined effects of tptef/te and V̇maxFRC in infancy on risk for asthma and abnormalities of airway structure into mid-adult life.Methods: One hundred eighty participants in the Tucson Children's Respiratory Study birth cohort had lung function measured by the chest-compression technique in infancy (mean age ± SD: 2.0 ± 1.2 mo). Active asthma was assessed in up to 12 questionnaires between ages 6 and 36 years. Spirometry and chest high-resolution computed tomographic (HRCT) imaging were completed in a subset of participants at age 26. The relations of infant tptef/te and V̇maxFRC to active asthma and airway structural abnormalities into adult life were tested in multivariable mixed models.Measurements and Main Results: After adjustment for covariates, a 1-SD decrease in infant tptef/te and V̇maxFRC was associated with a 70% (P = 0.001) and 55% (P = 0.005) increased risk of active asthma, respectively. These effects were partly independent, and two out of three infants who were in the lowest tertile for both tptef/te and V̇maxFRC developed active asthma by mid-adult life. Infant V̇maxFRC predicted reduced airflow and infant tptef/te reduced HRCT airway caliber at age 26.Conclusions: These findings underscore the long-lasting effects of the fetal origins of asthma, support independent contributions by infant tptef/te and V̇maxFRC to development of asthma, and link deficits at birth in tptef/te with HRCT-assessed structural airway abnormalities in adult life.

ACE2 and COVID-19: using antihypertensive medications and pharmacogenetic considerations.

COVID-19 utilizes the ACE2 pathway as a means of infection. Early data on COVID-19 suggest heterogeneity in the severity of symptoms during transmission and infection ranging from no symptoms to death. The source of this heterogeneity is likely multifaceted and may have a genetic component. Demographic and clinical comorbidities associated with the severity of infection suggest that possible variants known to influence the renin-angiotensin-aldosterone (RAAS) system pathway (particularly those that influence ACE2) may contribute to the heterogenous infection response. ACE2 and Ang(1-7) (the product of ACE2) seem to have a protective effect on the pulmonary and cardiac systems. Hypertension medication modulation, may alter ACE2 and Ang(1-7), particularly in variants that have been shown to influence RAAS system function, which could be clinically useful in patients with COVID-19.

Binding and Release of FeIII Complexes from Glucan Particles for the Delivery of T1 MRI Contrast Agents.

Yeast-derived ß-glucan particles (GPs) are a class of microcarriers under development for the delivery of drugs and imaging agents to immune-system cells for theranostic approaches. However, the encapsulation of hydrophilic imaging agents in the porous GPs is challenging. Here, we show that the unique coordination chemistry of FeIII -based macrocyclic T1 MRI contrast agents permits facile encapsulation in GPs. Remarkably, GPs labeled with the simple FeIII complexes are stable under physiologically relevant conditions, despite the absence of amphiphilic groups. In contrast to the free FeIII coordination complex, the labeled FeIII -GPs have lowered T1 relaxivity and act as a silenced form of the contrast agent. Addition of a fluorescent tag to the FeIII complex produces a bimodal agent to further enable tracking of the nanoparticles and to monitor release. Treatment of the iron-labeled GPs with a maltol chelator or with mildly acidic conditions releases the intact iron complex and restores enhanced T1 relaxation of the water protons.

Predictors of long-distance race performance in master runners.

Peak aerobic power (V .O2peak) and parameters related to training are associated with long-distance running performance in master athletes. Running economy (RE) predicts performance in younger runners, but its relationship to racing ability in older athletes is unclear. Allometrically scaled RE (alloV .O2; ml kg -0.66 min-1), energy cost (EC; kcal kg-1 km-1), and percent of V .O2peak (%V .O2peak) required in a submaximal bout represent RE more accurately than V .O2 does. The VDOT score, estimating V .O2peak and RE, can be used to compare races of different distances. Purpose: To determine predictors of temperature-converted VDOT in master runners training for a long-distance race (10-26.2 mi). Methods: Twenty-three master runners (age 57±9 years; eight females) performed treadmill marathon-intensity-effort (MIE) and V .O2peak tests within four weeks of their goal race. The MIE occurred at 88% of predicted maximum heart rate, which corresponds to estimated marathon intensity. Participants completed online training-history surveys. Forward stepwise multiple linear regression was used to find key predictors of VDOT. The alpha level for significance was .05. Results: Converted VDOT was significantly associated with three-year peak weekly training distance (3YP) (r = 0.454, p = .039), V .O2peak (r = 0.845, p = .000), alloV .O2 (r = 0.623, p = .005), and EC (r = -0.528, p = .018). The best-fitting model included V .O2peak and 3YP (r = 0.898). Conclusion: Physiological and training factors are related to race performance in master runners. The best predictors of VDOT are V .O2peak and 3YP. Training to enhance these variables may improve distance-running performance in masters.

A Class of FeIII Macrocyclic Complexes with Alcohol Donor Groups as Effective T1 MRI Contrast Agents.

Early studies suggested that FeIII complexes cannot compete with GdIII complexes as T1 MRI contrast agents. Now it is shown that one member of a class of high-spin macrocyclic FeIII complexes produces more intense contrast in mice kidneys and liver at 30 minutes post-injection than does a commercially used GdIII agent and also produces similar T1 relaxivity in serum phantoms at 4.7 T and 37 °C. Comparison of four different FeIII macrocyclic complexes elucidates the factors that contribute to relaxivity in vivo including solution speciation. Variable-temperature 17 O NMR studies suggest that none of the complexes has a single, integral inner-sphere water that exchanges rapidly on the NMR timescale. MRI studies in mice show large in vivo differences of three of the FeIII complexes that correspond, in part, to their r1 relaxivity in phantoms. Changes in overall charge of the complex modulate contrast enhancement, especially of the kidneys.

Effects of marathon training on maximal aerobic capacity and running economy in experienced marathon runners.

Maximal aerobic capacity (VO2max) and running economy (RE) are markers of running performance. A valid evaluation of RE may occur through allometric scaling of body mass (alloVO2; ml kg-0.66 min-1), energy cost (EC; kcal kg-1 km-1), or percent of VO2max (%VO2max). Little is known about physiological changes that occur in competitive runners over a marathon training cycle. The VDOT score, incorporating VO2max and RE, enables comparison of race performances under different temperature conditions. This study's purpose was to determine whether VO2max and measures of RE change with marathon training, and to evaluate the relationship between these variables and VDOT. Eight runners (age 34±2 years; marathon <3:00 males, <3:30 females; five females) completed treadmill marathon-intensity-effort (MIE) and VO2max tests at 10 and 1-2 weeks pre-marathon. Body composition (%BF) was determined using hydrostatic weighing. Paired t-tests were used to compare pre- and post-training values. The alpha level for significance was set at 0.05. Body fat decreased from 18.7±1.5% to 16.7±1.6%, VO2max increased from 51.6±2.4 to 63.9±1.1 ml kg-1 min-1, and %VO2max during the MIE decreased from 82.1±2.0 to 72.3±3.2% (p < 0.05 for all). VDOT was significantly associated with alloVO2 (r = -0.779, p = 0.039) but not with VO2max (r = 0.071, p = 0.867). Experienced competitive runners may increase VO2max and decrease %BF after a marathon-specific training cycle. The decrease in %VO2max in a MIE is likely due to a higher VO2max, as other measures of RE did not change significantly. In this cohort, alloVO2 was negatively correlated with race performance.

Foam rolling is an effective recovery tool in trained distance runners.

Purpose: Many endurance athletes use foam rolling (FR) to decrease muscle soreness, but it is unclear whether FR effectively treats soreness in this population. Moreover, the effects of FR in highly trained runners are unknown. The aim of this study was to use downhill running (DHR) to induce muscle soreness in runners and to determine the influence of FR on soreness and running performance when compared to sham compression tights. Methods: Participants performed a running economy (RE) test at 75% of 5-km race speed and a 3-km time trial (TT). In a crossover design, subjects then completed DHR followed by either a FR protocol or wearing sham compression tights. Two days post-DHR, subjects repeated the RE and TT tests. Crossover visits occurred 2-4 weeks later. During RE tests, VO2 and rating of perceived exertion (RPE) were recorded. Passive and active soreness were measured on a scale of 0 (no soreness) to 10 (extreme soreness). Results: Eight runners (aged 31 ± 7 years; four females; VO2peak 57 ± 7 ml kg-1 min-1) completed the study. Both treatment conditions experienced passive (p = 0.026) and active soreness (p = 0.012) induced by DHR. Active soreness 2 days postDHR was significantly lower after FR than after sham compression tights (p = 0.025). With tights, there was a trend for an increased RPE compared to pre-DHR (p = 0.056). Conclusions: Foam rolling decreases leg soreness in well-trained runners and attenuates soreness-related increases in perceived exertion during sub-maximal running.

Influence of ß2 adrenergic receptor genotype on risk of nocturnal ventilation in patients with Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease resulting in severe respiratory derangements. As such, DMD patients are at a high risk of nocturnal hypoventilation, thereby requiring nocturnal ventilation (NV). To this end, NV is an important clinical milestone in the management of DMD. Emerging evidence suggests that ß2 adrenergic receptors (ADRB2) may play a role in determining respiratory function, whereby more functional ADRB2 genotype variants (e.g., Gly16) are associated with improved pulmonary function and respiratory muscle strength. These findings suggest that the more functional ADRB2 genotype may help to preserve respiratory function in patients with DMD. The purpose of this study was to identify the influence of ADRB2 genotype on the risk of NV use in DMD. Data from the CINRG Duchenne Natural History Study including 175 DMD patients (3-25 yrs) were analyzed focusing on ADRB2 genotype variants. Time-to-event analyses were used to examine differences in the age at prescription of full-time NV use between genotypes. There were no differences between genotype groups in age, height, weight, corticosteroid use, proportion of ambulatory patients, or age at loss of ambulation. DMD patients expressing the Gly16 polymorphism had a significantly (P < 0.05) lower mean age at NV prescription compared with those patients expressing the Arg16 polymorphism (21.80 ± 0.59 yrs. vs 25.91 ± 1.31 yrs., respectively). In addition, a covariate-adjusted Cox model revealed that the Gly16 variant group possessed a 6.52-fold higher risk of full-time NV use at any given age compared with the Arg16 polymorphism group. These data suggest that genetic variations in the ADRB2 gene may influence the age at which DMD patients are first prescribed NV, whereby patients with the Gly16 polymorphism are more likely to require NV assistance at an earlier age than their Arg16 counterparts.

The Effect of Genetically Guided Mathematical Prediction and the Blood Pressure Response to Pharmacotherapy in Hypertension Patients.

PURPOSE: The purpose of this study was to determine the effectiveness of a simple algorithm to mathematically predict a patients' response to blood pressure (BP) therapy using functional genes in the 3 major organ systems involved in hypertension. METHODS: Eighty-six patients with controlled hypertension completed 1 study visit consisting of a buccal swab collection, measurement of office BP, and a medical chart review for BP history. Genes in the analysis included 14 functional alleles in 11 genes. These genotypes were mathematically summed per organ system to determine whether a patient would likely respond to target therapy. RESULTS: Patients recommended to and taking a diuretic had significantly higher rates of control (<120/<80) than patients recommended but not taking this drug class (0.2 ± 0.1 and 0.03 ± 0.03, respectively). Furthermore, there was a difference between patients genetically recommended and taking an angiotensin receptor blocker (ARB) vs patients recommended but not taking an ARB for the lowest diastolic blood pressure (DBP) and mean arterial pressure (MAP) recorded in the past 2 years (DBP = 66.2 ± 2.9 and 75.3 ± 1.7, MAP = 82.3 ± 2.8 and 89.3 ± 1.5, respectively). In addition, there was a nonsignificant trend for greater reductions in ΔSBP, ΔDBP, and ΔMAP in patients on recommended drug class for beta-blockers, diuretics, and angiotensin II receptor blockers vs patients not on these classes. CONCLUSION: The present study suggests that simple mathematical weighting of functional genotypes known to control BP may be ineffective in predicting control. This study demonstrates the need for a more complex, weighted, multigene algorithm to more accurately predict BP therapy response.

Cystic Fibrosis Transmembrane Conductance Regulator Genotype, Not Circulating Catecholamines, Influences Cardiovascular Function in Patients with Cystic Fibrosis.

BACKGROUND: Cystic fibrosis (CF) is a genetic disease affecting multiple organ systems of the body and is characterized by mutation in the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR). Previous work has shown that a single dose of aß-agonist increases cardiac output (Q) and stroke volume (SV) and decreases systemic vascular resistance (SVR) in healthy subjects. This effect is attenuated in patients with CF; however, the mechanism is unknown. Potential explanations for this decreased cardiovascular response to a ß-agonist in CF include inherent cardiovascular deficits secondary to the CFTR mutation, receptor desensitization from prolonged ß-agonist use as part of clinical care, or inhibited drug delivery to the bloodstream due to mucus buildup in the lungs. This study sought to determine the effects of endogenous epinephrine (EPI) and norepinephrine (NE) on cardiovascular function in CF and to evaluate the relationship between cardiovascular function and CFTR F508del mutation. METHODS: A total of 19 patients with CF and 31 healthy control subjects completed an assessment of Q (C2H2 rebreathing), SV (calculated from Q and heart rate [HR]), Q and SV indexed to body surface area (BSA, QI, and SVI, respectively), SVR (through assessment of Q and mean arterial blood pressure [MAP]), and HR (from 12-lead electrocardiogram [ECG]) at rest along with plasma measures of EPI and NE. We compared subjects by variables of cardiovascular function relative to EPI and NE, and also based on genetic variants of the F508del mutation (homozygous deletion for F508del, heterozygous deletion for F508del, or no deletion of F508del). RESULTS: Cystic fibrosis patients demonstrated significantly lower BSA (CF = 1.71 ± 0.05 m2 vs healthy = 1.84 ± 0.04 m2, P = .03) and SVI (CF = 30.6 ± 2.5 mL/beat/m2 vs healthy = 39.9 ± 2.5 mL/beat/m2, P = .02) when compared with healthy subjects. Cystic fibrosis patients also demonstrated lower Q (CF = 4.58 ± 0.36 L/min vs healthy = 5.71 ± 0.32 L/min, P = .03) and SV (CF = 54 ± 5.5 mL/beat vs healthy = 73.3 ± 4.5 mL/beat, P = .01), and a higher HR (CF = 93.2 ± 3.9 bpm vs healthy = 80.5 ± 2.7 bpm, P < .01) and SVR (CF = 2082 ± 156 dynes*s/cm-5 vs healthy = 1616 ± 74 dynes*s/cm-5, P = .01) compared with healthy subjects. Furthermore, CF patients demonstrated a lower SV (P < .01) corrected for NE when compared with healthy subjects. No significant differences were seen in HR or Q relative to NE, or SVR relative to EPI. Differences were seen in SV (F(2,14) = 7.982, P < .01) and SV index (F(2,14) = 2.913, P = .08) when patients with CF were stratified according to F508del mutation (number of deletions). CONCLUSIONS: Individuals with CF have lower cardiac and peripheral hemodynamic function parameters at rest. Furthermore, these results suggest that impairment in cardiovascular function is likely the result of F508del CFTR genotype, rather than receptor desensitization or inhibited drug delivery.

Relationship between a Weighted Multi-Gene Algorithm and Blood Pressure Control in Hypertension.

Hypertension (HTN) is a complex disease with interactions among multiple organ systems, including the heart, vasculature, and kidney with a strong heritable component. Despite the multifactorial nature of HTN, no clinical guidelines utilize a multi-gene approach to guide blood pressure (BP) therapy. Non-smokers with a family history of HTN were included in the analysis (n = 384; age = 61.0 ± 0.9, 11% non-white). A total of 17 functional genotypes were weighted according to the previous effect size in the literature and entered into an algorithm. Pharmacotherapy was ranked from 1⁻4 as most to least likely to respond based on the algorithmic assessment of individual patient's genotypes. Three-years of data were assessed at six-month intervals for BP and medication history. There was no difference in BP at diagnosis between groups matching the top drug recommendation using the multi-gene weighted algorithm (n = 92) vs. those who did not match (n = 292). However, from diagnosis to nadir, patients who matched the primary recommendation had a significantly greater drop in BP when compared to patients who did not. Further, the difference between diagnosis to current 1-year average BP was lower in the group that matched the top recommendation. These data suggest an association between a weighted multi-gene algorithm on the BP response to pharmacotherapy.

Psychological and Genetic Predictors of Pain Tolerance.

Previous studies have shown associations between genetic polymorphisms and pain tolerance, but psychological evaluations are seldom measured. The objective of this study was to determine the independent effects of demographic, psychological, and genetic predictors of cold noxious pain tolerance. Healthy subjects (n = 89) completed the Pain Catastrophizing Scale (PCS) and Fear of Pain Questionnaire (FPQ-III), underwent genotyping for candidate single nucleotide polymorphisms (SNPs), and completed a cold-pressor test in a 1-2°C water bath for a maximum of 3 minutes. The primary outcome measure was pain tolerance, defined as the maximum duration of time subjects left their nondominant hand in the cold-water bath. Cox proportional hazards regression indicated that female sex, Asian race, and increasing PCS and FPQ-III scores were associated with lower pain tolerance. No candidate SNP was significantly associated with pain tolerance. Future genetic studies should include demographic and psychological variables as confounders in experimental pain models.

The relationships between age and running performance variables in master runners.

Purpose: Peak aerobic capacity (V̇O2peak) declines with age, but running economy (RE) may not. We evaluated VO2peak and RE in master runners and determined whether age is associated with these measures. Methods: In a cross-sectional study, runners completed two running tests within four weeks of a goal race of 10-26.2 miles. Subjects ran for five min at 88% of predicted maximum heart rate, approximating a marathon-intensity effort (MIE), then performed a V̇O2peak test. Running economy in the MIE was measured using oxygen cost with body mass scaled allometrically (alloV̇O2); energy cost (EC), determined using caloric equivalents; and percent of V̇O2peak (%V̇O2peak). Pearson's correlations were used to determine relationships between age and running performance variables. Results: Runners (n = 31, 13 females; mean age 54.9 ± 8.4 years) had a mean VO2peak of 52.5 ± 7.9 ml O2 kg-1 min-1. Age was significantly correlated with V̇O2peak (r = - 0.580, p = 0.001) and alloV̇O2 (r = - 0.454, p = 0.034). Age was related to EC in females (r = 0.649, p = 0.042) and MIE V̇O2 in males (r = - 0.600, p = 0.039). Conclusions: In this population, age was negatively associated with V̇O2peak and alloV̇O2. Females showed a positive relationship between age and EC, while males had a negative correlation between age and MIE V̇O2. Aerobic capacity declines with age, but there may be sex differences in age-related alterations to submaximal running.

Economic evaluation of a pharmacogenomic multi-gene panel test to optimize anti-hypertension therapy: simulation study.

AIMS: Hypertension is the strongest modifiable risk factor for cardiovascular disease, affecting 80 million individuals in the US and responsible for ∼360,000 deaths, at total annual costs of $93.5 billion. Antihypertension therapies guided by single genotypes are clinically more effective and may avert more adverse events than the standard of care of layering anti-hypertensive drug therapies, thus potentially decreasing costs. This study aimed to determine the economic benefits of the implementation of multi-gene panel guided therapies for hypertension from the payer perspective within a 3-year time horizon. MATERIALS AND METHODS: A simulation analysis was conducted for a panel of 10 million insured patients categorized clinically as untreated, treated but uncontrolled, and treated and controlled over a 3-year treatment period. Inputs included research data; empirical data from a 11-gene panel with known functional, heart, blood vessel, and kidney genotypes; and therapy efficacy and safety estimates from literature. Cost estimates were categorized as related to genetic testing, evaluation and management, medication, or adverse events. RESULTS: Multi-gene panel guided therapy yielding savings of $6,256,607,500 for evaluation and management, $908,160,000 for medications, and $37,467,508,716 for adverse events, after accounting for incremental genetic testing costs of $2,355,540,000. This represents total 3-year savings of $42,276,736,216, or a 47% reduction, and 3-year savings of $4,228 and annual savings of $1,409 per covered patient. CONCLUSIONS: A precision medicine approach to genetically guided therapy for hypertension patients using a multi-gene panel reduced total 3-year costs by 47%, yielding savings exceeding $42.3 billion in an insured panel of 10 million patients. Importantly, 89% of these savings are generated by averting specific adverse events and, thus, optimizing choice of therapy in function of both safety and efficacy.