A smartphone application toward detection of systolic hypertension in underserved populations.

High systolic blood pressure (BP) is the most important modifiable risk factor for cardiovascular disease. Managing systolic hypertension is especially difficult in underserved populations wherein access to cuff BP devices is limited. We showed that ubiquitous smartphones without force sensing can be converted into absolute pulse pressure (PP) monitors. The concept is for the user to perform guided thumb and hand maneuvers with the phone to induce cuff-like actuation and allow built-in sensors to make cuff-like measurements for computing PP. We developed an Android smartphone PP application. The 'app' could be learned by volunteers and yielded PP with total error < 8 mmHg against cuff PP (N = 24). We also analyzed a large population-level database comprising adults less than 65 years old to show that PP plus other basic information can detect systolic hypertension with ROC AUC of 0.9. The smartphone PP app could ultimately help reduce the burden of systolic hypertension in underserved populations and thus health disparities.

Comparative Analysis of Bilateral Open Inguinal Hernia Repair and Rives-Stoppa Repair: A Comprehensive Review.

Inguinal hernias present a significant healthcare burden globally, necessitating effective surgical management. This comprehensive review evaluates two primary surgical techniques for managing bilateral inguinal hernias: bilateral open inguinal hernia and Rives-Stoppa repair. This review aims to provide insights into optimal surgical approaches through a comparative analysis of these techniques, including examining advantages, disadvantages, outcomes, and factors influencing technique selection. Bilateral open inguinal hernia repair offers simplicity and familiarity, while Rives-Stoppa repair may provide advantages such as reduced recurrence rates and postoperative complications. The findings underscore the importance of considering patient-specific factors, surgeon expertise, and hospital resources when selecting the optimal approach. Further research is warranted to conduct long-term comparative studies and explore innovations in surgical techniques and materials, ultimately enhancing patient outcomes and advancing inguinal hernia repair practices.

Significance of Serum Lactate Dehydrogenase as a Prognostic Marker and Outcome Predictor in Patients With Breast Cancer.

Background Breast carcinoma has been the most prevalent cancer in women, with research-based evidence showing a significant rise in the incidence of cancer and related morbidity and mortality in the Indian subcontinent. The predictive value of plasmatic lactate dehydrogenase (LDH) levels has been studied in breast cancer. Numerous studies have connected high LDH values to a poor prognosis, increased risk of incidence, recurrence, and associated mortality in patients with breast carcinoma. This study aimed to assess the clinical profile of breast carcinoma and determine the correlation of serum lactate dehydrogenase levels with the stage of the disease and assessment of high-risk features using histopathology and immunohistochemistry. Methods A total of 75 patients with carcinoma breast were enrolled for this study and classified into two groups: upfront surgery and post-adjuvant therapy. Serum LDH levels were estimated a day before the surgery (baseline) and on postoperative days 1, 7, 14, and 30. The clinical tumor, node, metastasis (cTNM) staging was correlated with pathological tumor, node, metastasis TNM (pTNM) staging and immunohistochemistry findings. Results The clinical characteristics of breast cancer, serum LDH levels, and stage of the disease were collected and analyzed. A significant decreasing trend was noted in LDH values post-op days, and statistically significant higher LDH values were noted in the triple-negative group, positive lymph nodes, and positive lymphovascular invasion patients. Conclusion Regularly elevated levels or an unanticipated rise in serum LDH might indicate poor outcomes. Hence, this non-specific enzyme marker can be suggested to be used routinely to assess disease outcomes.

Nonlinear Viscoelastic Modeling of Finger Arteries: Toward Smartphone-Based Blood Pressure Monitoring via the Oscillometric Finger Pressing Method.

OBJECTIVE: Oscillometric finger pressing is a smartphone-based blood pressure (BP) monitoring method. Finger photoplethysmography (PPG) oscillations and pressure are measured during a steady increase in finger pressure, and an algorithm computes systolic BP (SP) and diastolic BP (DP) from the measurements. The objective was to assess the impact of finger artery viscoelasticity on the BP computation. METHODS: Nonlinear viscoelastic models relating transmural pressure (finger BP - applied pressure) to PPG oscillations during finger pressing were developed. The output of each model to a measured transmural pressure input was fitted to measured PPG oscillations from 15 participants. A parametric sensitivity analysis was performed via model simulations to elucidate the viscoelastic effect on the derivative-based BP computation algorithm. RESULTS: A Wiener viscoelastic model comprising a first-order transfer function followed by a static sigmoidal function fitted the measured PPG oscillations better than an elastic model containing only the static function (median (IQR) error of 30.5% (25.6%-34.0%) vs 50.9% (46.7%-53.7%); p<0.01). In Wiener model simulations, the derivative algorithm underestimated SP, especially with high pulse pressure and low transfer function cutoff frequency (i.e., greater viscoelasticity). The mean of the normalized PPG waveform at the maximum oscillation beat was found to correlate with the cutoff frequency (r = -0.8) and could thus possibly be used to compensate for viscoelasticity. CONCLUSION: Finger artery viscoelasticity negatively impacts oscillometric BP computation algorithms but can potentially be compensated for using available measurements. SIGNIFICANCE: These findings may help in converting smartphones into truly cuffless BP monitors for improving hypertension awareness and control.

Grand Challenges at the Interface of Engineering and Medicine.

Over the past two decades Biomedical Engineering has emerged as a major discipline that bridges societal needs of human health care with the development of novel technologies. Every medical institution is now equipped at varying degrees of sophistication with the ability to monitor human health in both non-invasive and invasive modes. The multiple scales at which human physiology can be interrogated provide a profound perspective on health and disease. We are at the nexus of creating "avatars" (herein defined as an extension of "digital twins") of human patho/physiology to serve as paradigms for interrogation and potential intervention. Motivated by the emergence of these new capabilities, the IEEE Engineering in Medicine and Biology Society, the Departments of Biomedical Engineering at Johns Hopkins University and Bioengineering at University of California at San Diego sponsored an interdisciplinary workshop to define the grand challenges that face biomedical engineering and the mechanisms to address these challenges. The Workshop identified five grand challenges with cross-cutting themes and provided a roadmap for new technologies, identified new training needs, and defined the types of interdisciplinary teams needed for addressing these challenges. The themes presented in this paper include: 1) accumedicine through creation of avatars of cells, tissues, organs and whole human; 2) development of smart and responsive devices for human function augmentation; 3) exocortical technologies to understand brain function and treat neuropathologies; 4) the development of approaches to harness the human immune system for health and wellness; and 5) new strategies to engineer genomes and cells.

Atypical Psuedo-Demons-Meigs Syndrome Presenting As Acute Dyspnoea With Pseudomembranous Colitis.

Demons-Meigs syndrome is a rare clinical presentation of benign ovarian mass with hydrothorax and ascites. As ascites can be present in any ovarian mass, hydrothorax is a salient feature of the syndrome. The syndrome is subtyped as atypical in the absence of ascites from the triad. Nevertheless, it is labeled as pseudo-Demons-Meigs syndrome if the ovarian tumor is neoplastic rather than benign. The management of Demons-Meigs syndrome is complex and could be misleading due to pleural effusion and ascites, so an understanding of the syndrome is important. This case report is unique as it has two rare findings of neoplastic tumor and absence of ascites. Furthermore, this case is distinct as both ovaries are involved in malignant granulosa theca cell tumor with right-sided pleural effusion without ascites.

European Society of Hypertension recommendations for the validation of cuffless blood pressure measuring devices: European Society of Hypertension Working Group on Blood Pressure Monitoring and Cardiovascular Variability.

BACKGROUND: There is intense effort to develop cuffless blood pressure (BP) measuring devices, and several are already on the market claiming that they provide accurate measurements. These devices are heterogeneous in measurement principle, intended use, functions, and calibration, and have special accuracy issues requiring different validation than classic cuff BP monitors. To date, there are no generally accepted protocols for their validation to ensure adequate accuracy for clinical use. OBJECTIVE: This statement by the European Society of Hypertension (ESH) Working Group on BP Monitoring and Cardiovascular Variability recommends procedures for validating intermittent cuffless BP devices (providing measurements every >30 sec and usually 30-60 min, or upon user initiation), which are most common. VALIDATION PROCEDURES: Six validation tests are defined for evaluating different aspects of intermittent cuffless devices: static test (absolute BP accuracy); device position test (hydrostatic pressure effect robustness); treatment test (BP decrease accuracy); awake/asleep test (BP change accuracy); exercise test (BP increase accuracy); and recalibration test (cuff calibration stability over time). Not all these tests are required for a given device. The necessary tests depend on whether the device requires individual user calibration, measures automatically or manually, and takes measurements in more than one position. CONCLUSION: The validation of cuffless BP devices is complex and needs to be tailored according to their functions and calibration. These ESH recommendations present specific, clinically meaningful, and pragmatic validation procedures for different types of intermittent cuffless devices to ensure that only accurate devices will be used in the evaluation and management of hypertension.

Smartphone-Based Blood Pressure Monitoring via the Oscillometric Finger Pressing Method: Analysis of Oscillation Width Variations Can Improve Diastolic Pressure Computation.

OBJECTIVE: Oscillometric finger pressing is a potential method for absolute blood pressure (BP) monitoring via a smartphone. The user presses their fingertip against a photoplethysmography-force sensor unit on a smartphone to steadily increase the external pressure on the underlying artery. Meanwhile, the phone guides the finger pressing and computes systolic BP (SP) and diastolic BP (DP) from the measured blood volume oscillations and finger pressure. The objective was to develop and evaluate reliable finger oscillometric BP computation algorithms. METHODS: The collapsibility of thin finger arteries was exploited in an oscillometric model to develop simple algorithms for computing BP from the finger pressing measurements. These algorithms extract features from "width" oscillograms (oscillation width versus finger pressure functions) and the conventional "height" oscillogram for markers of DP and SP. Finger pressing measurements were obtained using a custom system along with reference arm cuff BP measurements from 22 subjects. Measurements were also obtained during BP interventions in some subjects for 34 total measurements. RESULTS: An algorithm employing the average of width and height oscillogram features predicted DP with correlation of 0.86 and precision error of 8.6 mmHg with respect to the reference measurements. Analysis of arm oscillometric cuff pressure waveforms from an existing patient database provided evidence that the width oscillogram features are better suited to finger oscillometry. CONCLUSION: Analysis of oscillation width variations during finger pressing can improve DP computation. SIGNIFICANCE: The study findings may help in converting widely available devices into truly cuffless BP monitors for improving hypertension awareness and control.

Subject-specific factors affecting particle residence time distribution of left atrial appendage in atrial fibrillation: A computational model-based study.

Background: Atrial fibrillation (AF) is a prevalent arrhythmia, that causes thrombus formation, ordinarily in the left atrial appendage (LAA). The conventional metric of stroke risk stratification, CHA2DS2-VASc score, does not account for LAA morphology or hemodynamics. We showed in our previous study that residence time distribution (RTD) of blood-borne particles in the LAA and its associated calculated variables (i.e., mean residence time, tm , and asymptotic concentration, C ∞) have the potential to improve CHA2DS2-VASc score. The purpose of this research was to investigate the effects of the following potential confounding factors on LAA tm and C ∞: (1) pulmonary vein flow waveform pulsatility, (2) non-Newtonian blood rheology and hematocrit level, and (3) length of the simulation. Methods: Subject-Specific data including left atrial (LA) and LAA cardiac computed tomography, cardiac output (CO), heart rate, and hematocrit level were gathered from 25 AF subjects. We calculated LAA tm and C ∞ based on series of computational fluid dynamics (CFD) analyses. Results: Both LAA tm and C ∞ are significantly affected by the CO, but not by temporal pattern of the inlet flow. Both LAA tm and C ∞ increase with increasing hematocrit level and both calculated indices are higher for non-Newtonian blood rheology for a given hematocrit level. Further, at least 20,000 s of CFD simulation is needed to calculate LAA tm and C ∞ values reliably. Conclusions: Subject-specific LA and LAA geometries, CO, and hematocrit level are essential to quantify the subject-specific proclivity of blood cell tarrying inside LAA in terms of the RTD function.

Bioengineered 3D Skeletal Muscle Model Reveals Complement 4b as a Cell-Autonomous Mechanism of Impaired Regeneration with Aging.

A mechanistic understanding of cell-autonomous skeletal muscle changes after injury can lead to novel interventions to improve functional recovery in an aged population. However, major knowledge gaps persist owing to limitations of traditional biological aging models. 2D cell culture represents an artificial environment, while aging mammalian models are contaminated by influences from non-muscle cells and other organs. Here, a 3D muscle aging system is created to overcome the limitations of these traditional platforms. It is shown that old muscle constructs (OMC) manifest a sarcopenic phenotype, as evidenced by hypotrophic myotubes, reduced contractile function, and decreased regenerative capacity compared to young muscle constructs. OMC also phenocopy the regenerative responses of aged muscle to two interventions, pharmacological and biological. Interrogation of muscle cell-specific mechanisms that contribute to impaired regeneration over time further reveals that an aging-induced increase of complement component 4b (C4b) delays muscle progenitor cell amplification and impairs functional recovery. However, administration of complement factor I, a C4b inactivator, improves muscle regeneration in vitro and in vivo, indicating that C4b inhibition may be a novel approach to enhance aged muscle repair. Collectively, the model herein exhibits capabilities to study cell-autonomous changes in skeletal muscle during aging, regeneration, and intervention.

The Microsoft Research Aurora Project: Important Findings on Cuffless Blood Pressure Measurement.

Conventional blood pressure (BP) measurement devices based on an inflatable cuff only provide a narrow view of the continuous BP profile. Cuffless BP measuring technologies could permit numerous BP readings throughout daily life and thereby considerably improve the assessment and management of hypertension. Several wearable cuffless BP devices based on pulse wave analysis (applied to a photoplethysmography or tonometry waveform) with or without use of pulse arrival time are now available on the market. The key question is: Can these devices provide accurate measurement of BP? Microsoft Research recently published a complex article describing perhaps the most important and highest resource project to date (Aurora Project) on assessing the accuracy of several pulse wave analysis and pulse wave analysis-pulse arrival time devices. The overall results from 1125 participants were clear-cut negative. The present article motivates and describes emerging cuffless BP devices and then summarizes the Aurora Project. The study methodology and findings are next discussed in the context of regulatory-cleared devices, physiology, and related studies, and the study strengths and limitations are pinpointed thereafter. Finally, the implications of the Aurora Project are briefly stated and recommendations for future work are offered to finally realize the considerable potential of cuffless BP measurement in health care.

Mathematical Modeling of Oscillometric Blood Pressure Measurement: A Complete, Reduced Oscillogram Model.

OBJECTIVE: Oscillogram modeling is a powerful tool for understanding and advancing popular oscillometric blood pressure (BP) measurement. A reduced oscillogram model relating cuff pressure oscillation amplitude ( ∆O) to external cuff pressure of the artery ( Pe) is: [Formula: see text], where g(P) is the arterial compliance versus transmural pressure ( P) curve, Ps and Pd are systolic and diastolic BP, and k is the reciprocal of the cuff compliance. The objective was to determine an optimal functional form for the arterial compliance curve. METHODS: Eight prospective, three-parameter functions of the brachial artery compliance curve were compared. The study data included oscillometric arm cuff pressure waveforms and invasive brachial BP from 122 patients covering a 20-120 mmHg pulse pressure range. The oscillogram measurements were constructed from the cuff pressure waveforms. Reduced oscillogram models, inputted with measured systolic and diastolic BP and each parametric brachial artery compliance curve function, were optimally fitted to the oscillogram measurements in the least squares sense. RESULTS: An exponential-linear function yielded as good or better model fits compared to the other functions, with errors of 7.9±0.3 and 5.1±0.2% for tail-trimmed and lower half-trimmed oscillogram measurements. Importantly, this function was also the most tractable mathematically. CONCLUSION: A three-parameter exponential-linear function is an optimal form for the arterial compliance curve in the reduced oscillogram model and may thus serve as the standard function for this model henceforth. SIGNIFICANCE: The complete, reduced oscillogram model determined herein can potentially improve oscillometric BP measurement accuracy while advancing foundational knowledge.

Abdominal aortic aneurysm monitoring via arterial waveform analysis: towards a convenient point-of-care device.

Abdominal aortic aneurysms (AAAs) are lethal but treatable yet substantially under-diagnosed and under-monitored. Hence, new AAA monitoring devices that are convenient in use and cost are needed. Our hypothesis is that analysis of arterial waveforms, which could be obtained with such a device, can provide information about AAA size. We aim to initially test this hypothesis via tonometric waveforms. We study noninvasive carotid and femoral blood pressure (BP) waveforms and reference image-based maximal aortic diameter measurements from 50 AAA patients as well as the two noninvasive BP waveforms from these patients after endovascular repair (EVAR) and from 50 comparable control patients. We develop linear regression models for predicting the maximal aortic diameter from waveform or non-waveform features. We evaluate the models in out-of-training data in terms of predicting the maximal aortic diameter value and changes induced by EVAR. The best model includes the carotid area ratio (diastolic area divided by systolic area) and normalized carotid-femoral pulse transit time ((age·diastolic BP)/(height/PTT)) as input features with positive model coefficients. This model is explainable based on the early, negative wave reflection in AAA and the Moens-Korteweg equation for relating PTT to vessel diameter. The predicted maximal aortic diameters yield receiver operating characteristic area under the curves of 0.83 ± 0.04 in classifying AAA versus control patients and 0.72 ± 0.04 in classifying AAA patients before versus after EVAR. These results are significantly better than a baseline model excluding waveform features as input. Our findings could potentially translate to convenient devices that serve as an adjunct to imaging.

Artificial Intelligence in Breast Cancer Screening and Diagnosis.

Cancer is a disease that continues to plague our modern society. Among all types of cancer, breast cancer is now the most common type of cancer occurring in women worldwide. Various factors, including genetics, lifestyle, and the environment, have contributed to the rise in the prevalence of breast cancer among women of all socioeconomic strata. Therefore, proper screening for early diagnosis and treatment becomes a major factor when fighting the disease. Artificial intelligence (AI) continues to revolutionize various spheres of our lives with its numerous applications. Using AI in the existing screening process makes obtaining results even easier and more convenient. Faster, more accurate results are some of the benefits of AI methods in breast cancer screening. Nonetheless, there are many challenges in the process of the integration of AI that needs to be addressed systematically. The following is a review of the application of AI in breast cancer screening.

A computational approach on studying the regulation of TGF-ß1-stimulated Runx2 expression by MicroRNAs in human breast cancer cells.

BACKGROUND: Transforming growth factor-beta1 (TGF-ß1) acts as a most effective growth inhibitor for normal epithelial cells. Loss of this anti-proliferative factor in breast tissues favors invasion and development of osteolytic metastases, aided by a master transcription factor, runt-related transcription factor 2 (Runx2). Several reports identified Runx2 regulation with the help of non-coding RNAs such as microRNAs (miRNAs) under physiological and pathological conditions. METHODS: Using bioinformatics tools such as miRDB, STarMir, Venny, TarBase, a unique list of miRNAs that putatively target the 3' UTR Runx2 was identified. Further, the expression patterns of those miRNAs at the precursor and mature levels were studied by RT-qPCR analyses. Following this, computational analyses using software like TransmiR and bc-GenExMiner v4.6 were done to speculate the miRNA's other target genes that indirectly regulate Runx2 activity in breast cancer. RESULTS: There were 13 miRNAs that putatively target Runx2 identified using bioinformatics tools. Among these miRNAs, miR-5703 expression was significantly downregulated at both precursor and mature levels upon TGF-ß1-treatment in human breast cancer cells. Computational analyses speculated an indirect targeting of Runx2 by miR-5703 by influencing multiple Runx2 regulatory signaling pathways including Jak/Stat, MAPK, Wnt/ß-Catenin, Notch, BMP, and PKA pathways. Furthermore, a correlation of the expression profiles of the speculated genes and Runx2 with miR-5703 was depicted in triple-negative breast cancer patients. CONCLUSION: Identification of miR-5703 and its network for Runx2 regulation directly or indirectly in breast cancer cells could significantly advance our understanding of breast cancer-mediated bone metastasis. In addition, it would potentially pave the way for miRNAs to be used as biomarkers and therapeutic agents in cancer research.

Subject-Specific Calculation of Left Atrial Appendage Blood-Borne Particle Residence Time Distribution in Atrial Fibrillation.

Atrial fibrillation (AF) is the most common arrhythmia that leads to thrombus formation, mostly in the left atrial appendage (LAA). The current standard of stratifying stroke risk, based on the CHA2DS2-VASc score, does not consider LAA morphology, and the clinically accepted LAA morphology-based classification is highly subjective. The aim of this study was to determine whether LAA blood-borne particle residence time distribution and the proposed quantitative index of LAA 3D geometry can add independent information to the CHA2DS2-VASc score. Data were collected from 16 AF subjects. Subject-specific measurements included left atrial (LA) and LAA 3D geometry obtained by cardiac computed tomography, cardiac output, and heart rate. We quantified 3D LAA appearance in terms of a novel LAA appearance complexity index (LAA-ACI). We employed computational fluid dynamics analysis and a systems-based approach to quantify residence time distribution and associated calculated variable (LAA mean residence time, t m) in each subject. The LAA-ACI captured the subject-specific LAA 3D geometry in terms of a single number. LAA t m varied significantly within a given LAA morphology as defined by the current subjective method and it was not simply a reflection of LAA geometry/appearance. In addition, LAA-ACI and LAA t m varied significantly for a given CHA2DS2-VASc score, indicating that these two indices of stasis are not simply a reflection of the subjects' clinical status. We conclude that LAA-ACI and LAA t m add independent information to the CHA2DS2-VASc score about stasis risk and thereby can potentially enhance its ability to stratify stroke risk in AF patients.

Regulation of bone metastasis and metastasis suppressors by non-coding RNAs in breast cancer.

Breast cancer (BC) is a critical health care issue that substantially affects women worldwide. Though surgery and chemotherapy can effectively control tumor growth, metastasis remains a primary concern. Metastatic BC cells predominantly colonize in bone, owing to their rigid osseous nutrient-rich nature. There are recently increasing studies investigating the context-dependent roles of non-coding RNAs (ncRNAs) in metastasis regulation. ncRNAs, including microRNAs, long non-coding RNAs, circular RNAs, and small interference RNAs, control the BC metastasis via altered mechanisms. Additionally, these ncRNAs have been reported in regulating a unique class of genes known as Metastatic suppressors. Metastasis suppressors like BRMS1, NM23, LIFR, and KAI1, etc., have been extensively studied for their role in inducing apoptosis, inhibiting metastasis, and maintaining homeostasis. In this review, we have emphasized the direct regulation of ncRNAs for effectively controlling the distant spread of BC. Furthermore, we have highlighted the ncRNA-mediated modulation of the metastatic suppressors, thereby delineating their indirect influence over metastasis.

The VASP-profilin1 (Pfn1) interaction is critical for efficient cell migration and is regulated by cell-substrate adhesion in a PKA-dependent manner.

Dynamic regulation of the actin cytoskeleton is an essential feature of cell motility. Action of Enabled (Ena)/vasodilator-stimulated phosphoprotein (VASP), a family of conserved actin-elongating proteins, is an important aspect of regulation of the actin cytoskeletal architecture at the leading edge that controls membrane protrusion and cell motility. In this study, we performed mutagenesis experiments in overexpression and knockdown-rescue settings to provide, for the first time, direct evidence of the role of the actin-binding protein profilin1 (Pfn1) in VASP-mediated regulation of cell motility. We found that VASP's interaction with Pfn1 is promoted by cell-substrate adhesion and requires down-regulation of PKA activity. Our experimental data further suggest that PKA-mediated Ser137 phosphorylation of Pfn1 potentially negatively regulates the Pfn1-VASP interaction. Finally, Pfn1's ability to be phosphorylated on Ser137 was partly responsible for the anti-migratory action elicited by exposing cells to a cAMP/PKA agonist. On the basis of these findings, we propose a mechanism of adhesion-protrusion coupling in cell motility that involves dynamic regulation of Pfn1 by PKA activity.

Gene-Targeted Mice with the Human Troponin T R141W Mutation Develop Dilated Cardiomyopathy with Calcium Desensitization.

Most studies of the mechanisms leading to hereditary dilated cardiomyopathy (DCM) have been performed in reconstituted in vitro systems. Genetically engineered murine models offer the opportunity to dissect these mechanisms in vivo. We generated a gene-targeted knock-in murine model of the autosomal dominant Arg141Trp (R141W) mutation in Tnnt2, which was first described in a human family with DCM. Mice heterozygous for the mutation (Tnnt2R141W/+) recapitulated the human phenotype, developing left ventricular dilation and reduced contractility. There was a gene dosage effect, so that the phenotype in Tnnt2R141W/+mice was attenuated by transgenic overexpression of wildtype Tnnt2 mRNA transcript. Male mice exhibited poorer survival than females. Biomechanical studies on skinned fibers from Tnnt2R141W/+ hearts showed a significant decrease in pCa50 (-log[Ca2+] required for generation of 50% of maximal force) relative to wildtype hearts, indicating Ca2+ desensitization. Optical mapping studies of Langendorff-perfused Tnnt2R141W/+ hearts showed marked increases in diastolic and peak systolic intracellular Ca2+ ([Ca2+]i), and prolonged systolic rise and diastolic fall of [Ca2+]i. Perfused Tnnt2R141W/+ hearts had slower intrinsic rates in sinus rhythm and reduced peak heart rates in response to isoproterenol. Tnnt2R141W/+ hearts exhibited a reduction in phosphorylated phospholamban relative to wildtype mice. However, crossing Tnnt2R141W/+ mice with phospholamban knockout (Pln-/-) mice, which exhibit increased Ca2+ transients and contractility, had no effect on the DCM phenotype. We conclude that the Tnnt2 R141W mutation causes a Ca2+ desensitization and mice adapt by increasing Ca2+-transient amplitudes, which impairs Ca2+ handling dynamics, metabolism and responses to ß-adrenergic activation.