Amphetamine-Dextroamphetamine-induced cardiomyopathy has become an emerging cause of heart failure in teenage and young adult populations. With its increasingly widespread use for the treatment of attention-deficit/hyperactivity disorder (ADHD) as well as misuse as a “study drug” to increase concentration for educational performance, more patients are at risk of this cardiac manifestation, especially those without knowledge of these risks. It becomes vital to highlight the correlation of amphetamine-dextroamphetamine use and heart failure in order to increase awareness of this condition. This case study highlights the manifestation of tachycardia-induced cardiomyopathy in a 38-year-old female patient with long-standing amphetamine-dextroamphetamine use for refractory narcolepsy. Our patient was evaluated utilizing a thyroid panel, lipid profiles, EKG, Holter monitoring, stress echocardiography, and left heart catheterization, revealing an unremarkable thyroid panel, a left ventricular ejection fraction (LVEF) of 20-25% from 35% to 40% and normal coronary vessels. Amphetamine-dextroamphetamine was discontinued with the introduction of metoprolol, aspirin, and atorvastatin. The mainstay of treatment includes cessation of amphetamine-dextroamphetamine. It is important that physicians continue to recognize the implication of amphetamine-dextroamphetamine in the diagnosis of non-ischemic cardiomyopathy in young patients presenting with heart failure like symptomology and to attain a comprehensive history in order to establish this diagnosis.  Stimulant medications such as amphetamine-dextroamphetamine have known cardiovascular effects by catecholamine-mediated effects such as the induction of tachycardia, vasoconstriction, vasospasm, hypertension, and direct cardiac toxicity . An uncoThe patient is a 38-year-old female with generalized anxiety disorder, narcolepsy, heart failure secondary to non-ischemic dilated cardiomyopathy, mitral and aortic regurgitation, restless leg syndrome, and tobacco use disorder (one pack per day). The workup of her heart failure diagnosis initially manifested from the evidence of possible bi-atrial enlargement, borderline right axis deviation, and sinus tachycardia with occasional premature ventricular complexes (PVCs) noted on the electrocardiogram during her evaluation of post-traumatic stress disorder (PTSD) in 2020 at an out-of-state facility. An ensuing echocardiogram at that time revealed a left ventricular ejection fraction of 35-40% with global hypokinesis, a normal left ventricular and right ventricular chamber diameter, mild right ventricular hypertrophy, and moderate aortic and mitral regurgitation in the absence of pulmonary hypertension. Stress testing throughout that time revealed a metabolic equivalent (METS) of 10.3 , a Duke Treadmill score of 0.72 , denoting a medium risk for ischemic events. She then underwent myocardial perfusion imaging with gated single-photon emission computed tomography (SPECT) imaging demonstrating global hypokinesis with a left ventricular fraction of 38%. She reportedly had a Holter monitor diary revealing for skipped beats but did not have the Holter monitor results. She had been managed with ivabradine 5 mg for concerns of cardiomyopathy by the preceding cardiology team.The patient indicated that she often experienced substernal chest pain, longstanding in nature and pressure-based, with intermittent radiation to the right upper extremity. The pain would self-resolve with no identified alleviating factors. The patient reported that her heart rate was usually within the 90s, but without her medications, when emotionally stressed, anxious, or physically active, she would be tachycardic with heart rates as high as the 130s. She did complain of palpitations. She mentioned the use of more pillows in order to sleep due to orthopnea manifesting a few weeks prior to her presentation.She had a social history including tobacco smoking of one pack per day of cigarettes, and she denied any use of alcohol or recreational drugs such as cocaine or intravenous drug usage. The patient did have children prior and had no miscarriages or recent childbirths. No prior history was noted of post-partum cardiomyopathy, Takotsubo cardiomyopathy, or myocarditis. Her family history did include stroke, hypertension, and diabetes, though she denied any genetic or autoimmune conditions. She had a longstanding history of anxiety and PTSD as well. Regarding her history of narcolepsy, per the patient, she did not respond to standard treatments and was prescribed amphetamine-dextroamphetamine for a number of years for management.Evaluation during the initial consultation for tachycardia, palpitations, and prior documented cardiomyopathy with this treating team revealed tachycardia with a heart rate of 133 and a regular rhythm. No murmurs were appreciated. She had fine rales within the midlung and bases bilaterally and traces of non-pitting bilateral lower extremity edema. ECG revealed sinus tachycardia of 108 beats per minute and suggested bi-atrial enlargement /mL, normal 0.350-4.940 u (IU)/mL) and normal lipid panel (low density lipoprotein (LDL) of 50 mg/dL, high density lipoprotein (HDL) of 53 mg/dL, triglycerides of 113 mg/dL, total cholesterol of 121 mg/dL). The brain natriuretic peptide was 16.0 pg/mL . The ensuing stress transthoracic echocardiogram (TTE) revealed a left ventricular ejection fraction of 20-25%, systolic left ventricular internal dimension (LVID) of 4.4 cm , and diastolic LVID of 4.5 cm , where elevations indicate a higher likelihood of heart failure. The TTE also showed mild to moderate aortic regurgitation, mild mitral regurgitation, and a Duke Treadmill score of 3.42 with an intermediate risk for future cardiac events. She was placed on a 48-hour Holter monitor, which revealed sinus rhythm with rates of 42-106 beats per minute (bpm), averaging 59 bpm, rare ventricular and supraventricular ectopy without significant pauses, and no significant diurnal variations. Subsequently, she underwent a left heart catheterization, which revealed angiographically normal coronary vessels, further reaffirming the diagnosis of non-ischemic cardiomyopathy. Amphetamine-dextroamphetamine had then been discontinued. An automated implantable cardioverter defibrillator (AICD) was not considered, as some patients with methamphetamine-induced cardiomyopathy recover simply with cessation, as further discussed below. Upon one month follow-up with the patient, she did have some improvement in her symptoms.The medication known as amphetamine-dextroamphetamine has been a pharmaceutical option for treating attention-deficit/hyperactivity disorder for over two decades. It belongs to a class of medications known as stimulants. The medication is composed of a combination of amphetamine salts, including amphetamine and dextroamphetamine, which act by altering catecholamine levels in the nervous system to induce increased neurocognitive stimulation , euphoriThrough catecholamine-mediated signaling, the cardiovascular system responds to stimulant use via vasoconstriction, vasospasm tachycardia, and hypertension . StimulaPatients may present as young teenagers or adults with chest pain, tachycardia, palpitations, or overt signs of heart failure such as orthopnea, paroxysmal nocturnal dyspnea, or peripheral edema without any other known underlying risk factors. It is important to garner a thorough history and evaluation pertaining to the use of any stimulants, any drug use history, recent viral illnesses, family history or personal history of autoimmune conditions or prior underlying or congenital cardiac diseases . It is eThe mainstay of treatment is the cessation of amphetamine-dextroamphetamine. Improvements in the patient’s condition occur with cessation, with some studies revealing improvement of the LVEF by 7% in as little as seven days . Other rWith the manifestation of cardiomyopathy and heart failure in young patients, amphetamine-dextroamphetamine-induced cardiomyopathy must be considered as a differential diagnosis. It is important to explore any history of the medication’s use during the evaluation of young patient’s presenting with concerns of heart failure given the drug’s widespread prescribed use and misuse. The mainstay of treatment lies within the cessation and avoidance of medication. As part of the therapeutic decision-making process of physicians treating ADHD, the importance of seeking alternative adjunctive strategies to address the prevalence and burden of the use of amphetamine-dextroamphetamine cannot be understated. As this becomes a developing concern, it is important for physicians to continue to recognize the likelihood of this occurrence in their patients in order to be proactive in their management.


Left ventricular assist device implantation and clinical outcomes in the Netherlands in this issue by Damman et al. marks a journey that started 30 years ago with the first implantation of a pulsatile implantable left ventricular assist device (LVAD) as bridge to heart transplantation (BTT) [The article on (BTT) . FollowiThe first pulsatile implantable LVADs were voluminous, noisy, and technically vulnerable devices. They were associated with serious complications such as infections, bleeding issues, pump thrombosis and thrombo-embolic events. Nevertheless, the first experience with these devices in Utrecht showed promising outcomes by successfully supporting patients until heart transplantation. However, adverse events as well as technical dysfunction were limiting factors for survival beyond 6–12 months of support. This became evident in a study randomising end-stage heart failure patients for either MCS or optimal medical treatment  [In the Netherlands, the introduction in 2006 of a 2nd generation non-pulsatile LVAD, the HeartMate 2 axial flow pump, was an important step forward. This device proved to be technically more reliable, resulting in a 2-year survival around 70% paired with a better quality of life . AdverseThe article of Damman et al. is unique being the first combined outcome report of all Dutch VAD implanting centres.The HeartMate 3 with almost two-thirds of implants is the most used VAD in their study. It has been claimed that this VAD is more haemocompatible due to its bearing-less, magnetically levitated impeller, thereby reducing stress on blood cells and preventing stasis and blood clot formation in the pump.The outcomes in the study support that claim reporting a significant lower pump thrombosis and cerebrovascular event rate for the HeartMate 3 compared with the HVAD and HeartMate 2  . The HeaOverall survival irrespective of device strategy  is comparable with previously mentioned studies , 5. It shttps://unos.org>news >2022). The competing outcome statistics show that presently around 50% of US patients on devices may expect to receive a heart transplant within 3 years [In the discussion, the authors indicate the high annual number of VAD implants in the Netherlands in contrast to the United States, where it has dropped by 23.5% in 2021  and wher 3 years . In the


The health benefits of regular physical activity (PA) are well documented. However, several people in both developed and developing countries do not meet PA recommendations. Health professionals are believed to be potential PA promoters. The purpose of this study is to gain insight into general and specialist practitioners’ knowledge, practices and PA prescription-related factors in private and public hospitals in Kinshasa.A multicenter cross-sectional analytical study was conducted among general and specialist practitioners in the Democratic Republic of the Congo’s capital using a declarative and anonymous questionnaire.p = 0.055), being an SP increased the likelihood by sixfold , being an internist increase the likelihood by sixfold , being cardiologist by a factor of 12  and knowing the benefits of PA by a factor of 2 . The most common reason given for a lack of interest in patients’ PA, followed by a lack of knowledge about current PA prescribing recommendations and a lack of time.Overall, 40.2% of the participants were interested in their patient’s PA, 2.3% prescribed PA, and 0.9% did it correctly. Specialist physicians (SPs) prescribed PA more frequently than general practitioners (GP), and private hospital physicians prescribed PA more frequently than public hospital physicians. Five factors were independently associated with participants in prescribing PA: being in a private hospital increased the likelihood of prescribing PA by twofold (aOR, 1.83; 95% CI, 0.99–3.39; SPs and professionals in the private health sector were the most interested in their patients’ PA. A small portion of them actually prescribed it, and only a tiny proportion did it correctly. This bleak picture highlights a need to rethink the undergraduate medical curricula, especially about teachings on the importance and use of PA as a medicine in its own right in disease prevention and treatment. Regular physical activity (PA) has been shown to be beneficial in the areas of all-cause mortality, cancer, cardiovascular health, musculoskeletal health, metabolic health and neurocognitive health . As a reBrief interventions in primary care settings, according to randomized controlled trials, effectively improve patients’ PA , 5. BeyoSo far, studies evaluating the participation of health professionals in promoting PA have primarily focused on GPs. The few studies involving specialists physicians (SPs) have not compared these specialists and GPs. Ezgi Agadayı et al.  comparedThis cross-sectional analytical study was conducted between April 1 and June 30, 2022, in both PH and PrH of the city-province of Kinshasa. From the Ministry of Health registers, 5 PrH and 5 PH were randomly selected. The participants were randomly selected from the lists of physicians from the selected hospitals.A sample size of 367 was estimated taking the population size of 8000 physicians registered with the National Medical Council, working in the Province City of Kinshasa (confidence level = 95% and margin of error = 5%).Participants in this study had to be a GP or SP registered with the National Medical Council, working in the Province City of Kinshasa and willing to answer the study questionnaire. Participants who did not complete or returned the questionnaire were excluded from the study.In the beginning, 342 people were chosen to participate in the study, including 279 from PH and 63 from PrH. There were 123 SPs and 219 GPs among them; 14 were lost during follow-up (did not submit the completed questionnaire) and 17 were excluded due to incomplete questionnaires. The selection process is summarized in Fig. A declarative and anonymous questionnaire was created in collaboration with physical medicine specialists and the statistics department of Kinshasa’s School of Public Health. This questionnaire included 21 open or closed questions with single or multiple-choice answers based on international PA prescription recommendations. It has been designed to have a response time of no more than 5–10 min. The respondent’s age and gender, qualifications, area of practice (PrH or PH), knowledge of PA practice and prescribing recommendations and barriers to prescribing PA were all questioned. The questionnaire had previously been tested with eight participants: two PrH GPs, two PH GPs, two PrH SPs, and two PH SPs. This pre-test made it possible to improve and refine the questionnaire, considering some difficulties encountered by the participants and statistician for collected data exploitation.Selection biases were minimized through the following precautions: the sampling was probabilistic, and the nonresponse rate was globally minimized by the interest aroused by the study and the sufficiently long delay (24 h with possible extension up to 48 h) given to everyone to complete their questionnaire.To minimize classification bias, the protocol was developed considering various precautions: the concepts were clearly defined, and highly confidential data were avoided. To minimize nonresponse, a prior appointment was obtained, the participants had firm promise of confidentiality, and the participants were free to choose the moment and place  to complete their questionnaire under the least stressful conditions possible. In addition, essential cooperation of each participant was reiterated for the success of the survey.Following the usual administrative approvals, a team of trained researchers comprised finalists was mobilized to contact the physicians of the selected hospitals. The questionnaire was a two-page hard copy that was personally delivered to each physician who met the eligibility criteria. The same researcher was in charge of retrieving and delivering the completed questionnaire from the respondent to the principal investigator. When a participant did not submit their completed questionnaire within 24 h, they were given another 24 h. If the questionnaire was not returned within 24 h, the candidate was dropped from the study.In this analysis, the following definitions were used:PA interest was defined by responding ‘always’ or ‘often’ to the question, ‘do you ask your patients if they participate in regular PA?’Non-interest in PA was defined as ‘rarely’ or ‘never’ responding ‘rarely’ or ‘never’ to the question ‘Do you ask your patients if they engage in regular PA?’Knowledge of PA benefits was defined by marking all proposed PA benefits claims.When participants flagged all statements about PA indications, they were considered to be aware of them.A correct PA prescription was defined as one that includes information on the frequency, duration, intensity, and type of activities to be performed.Good knowledge of weekly PA volume recommendations was defined by verifying the first statement related to this question (150 min of moderate-intensity PA per week).SD, whereas those with non-normal distributions were presented as median (extreme). The qualitative variables were expressed as a percentage. The Chi-square test, Student t test, and Mann–Whitney Wilcoxon test were used to compare proportions, medians, and means, respectively. Logistic regression using the step-by-step method (backward method) was used to identify independent determinants of PA prescription. The variables that emerged significantly in the bivariate analysis were retained in the multivariate model. Collinear variables  were separately introduced into the multivariate analysis. Thus, three models were made based on collinear variables. In the first model , internist and knowledge about the benefits of PA were the covariates. In the second model , cardiologist and knowledge about the benefits of PA were the covariates. Finally, in the third model , the specialist and knowledge about the benefits of PA were the variables. Odds ratio (OR) and adjusted odds ratio (aOR) with their confidence intervals were calculated to estimate the degree of association. A p value of < 0.05 was considered statistically significant.EpiInfo7 software was used to enter data into a computer, and SPSS Statistics for Windows  was used to perform all statistical analyses. Tables or graphs were used to present results as needed. Continuous quantitative variables with Gaussian distributions were presented as mean ± The questionnaire was administered anonymously, in accordance with the Helsinki III Declaration, and the information obtained was used while respecting the respondents’ confidentiality and privacy. The participants’ data were also manipulated and statistically anonymously and confidentially. Study approval was obtained with waiver of written informed consent from the « comité national d’éthique de la santé » , No. 415/CNES/BN/PMMF/2022.The study population consisted of 311 physicians, including 215 men and 96 women, with a sex ratio of 2.2 (in favor of men).The sociodemographic characteristics of the study population as a whole and by sector of practice are shown in Table As shown in Table Table Table In addition, the tools used varied significantly depending on the health sector; the pedometer and the IPAQ Questionnaire were being used more in PH than in PrH, whereas the Marshall questionnaire and self-report activity diaries were more often used in PrHr than in PH.Table Only 77 (24.8%) participants had a good knowledge of the benefits of PA. No statistically significant difference was found between GPs and SPs in this knowledge of the benefits of PA .Table Concerning the knowledge of the average weekly duration recommended for the practice of PA, only 137 (44%) participants were informed about it, and considerably more SPs than GPs were informed about it.In general, obesity, followed by hypertension and diabetes mellitus were situations that were most often identified by the participants as requiring PA prescription. These same situations, in addition to being elderly and living with disabilities, were more often identified by SPs than by GPs.As shown in Tables Forgetting and lack of knowledge about the recommendations regarding PA prescription were the reasons most often cited to justify PA nonprescription by all participants. Forgetting was more often mentioned by SPs than by GPs, whereas more GPs often mentioned a lack of knowledge about recommendations.Table Following univariate analysis Table , five faThis study aims to describe physicians’ knowledge and practices regarding PA prescription in the Province City of Kinshasa.This study is the first of its kind to highlight the influence of the health sector (private/public), qualification , and specialty area of physicians on their knowledge and practice of the physical activity prescription. Indeed, ours showed for the first time that SP and PrH physicians, on the other hand, were more interested in their patients’ PA than GP or PH physicians. On the other hand, being a specialist, internist, cardiologist and knowing the benefits of PA was significantly associated with prescribing PA.In addition, the present study depicted that only a small percentage of participants (40.2%) were interested in their patients’ PA, and only 2.3% said they would recommend PA by medical prescription Furthermore, the present study showed that forgetting was the most frequently cited reason for not prescribing PA, followed by a lack of knowledge about current PA prescribing recommendations.According to the literature, the percentage of physicians who are interested in their patients’ PA varies widely. One of the rare, if not the only, African studies have addressed the question of the prescription of PA focused on South African general practitioners (GPs). This study by Roos et al.  found suThe profile of the physicians and patients interviewed may explain the large disparity in the proportion of physicians interested in PA. In this study, respondents were physicians of various qualifications and specializations, both of PrH and PH, who cared for patients with various pathologies. Methodological diversity could also be considered: We used a hard-copy declarative and anonymous questionnaire delivered manually to each respondent, whereas others used a self-administered electronic questionnaire without the interviewers and respondents having ever physically met. Still, others proceeded by direct interview. It is also possible that the existence or absence of a public health policy governing doctors’ involvement of in PA promotion plays a significant role. It appears that the highest proportions are found in studies conducted in countries with public health policies, such as “prescription physical activity” , 18–24. Self-report diaries use real-time AP recording to collect the most detailed data , giving Specialist physician appears to be more interested in the patient’s PA than GP in the current study. Furthermore, physicians in PrH, whether SP or GP, appear to be more concerned with their patients’ PA rather than PH, which has not been previously reported in the literature. This difference could be explained by doctors in PrH being more motivated (well paid) than those in the PH. When compared with GPs, SPs appeared to be more interested in PA and prescribed it more frequently and folded correctly than GPs. This discovery could be explained by SPs’ understanding of the benefits of PA, as well as increased remuneration. Aside from remuneration, lessons on nonpharmacological measures, particularly the role of PA in the treatment of chronic noncommunicable diseases, may not yet be well inserted in the curriculum of physician training in the Democratic Republic of the Congo.In this study, 38% of the study participants gave practical instructions on PA, and only 2% formulated these instructions in the form of a prescription. This proportion is lower than that found in a Nigerian study conducted by Ale et al. . Accordiors who appeared to know the exact content of a PA prescription reflects a deficit in the training on PA prescription in the training course of the doctors surveyed.Only 0.9% appeared to get it right, specifying the type of exercise, intensity, duration, and frequency of the prescribed PA. To the best of our knowledge, this study is the first to look into these aspects of prescribing among the surveyed physicians. It was important to get an idea of how doctors prescribe PA, that is to say the content of their prescription, which should normally specify, as for a prescription of a pharmacological treatment, the type of PA to be practiced (molecule), its intensity (dosage), frequency (frequency of taking the drug), and duration of each session. The very low percentage of doctOn the contrary, five factors were found to be independently associated with the prescription of PA. Being a cardiologist was the most important determinant of prescribing PA, increasing the likelihood of prescribing PA by a factor of 12. Being an SP and an internist increased this likelihood by eightfold and knowing the benefits of PA increased it by sixfold, respectively. Other authors have mentioned the physician’s level of PA as a factor. Physicians who are physically active are more likely to recommend PA to their patients , 41.The most common reason for not prescribing PA was forgetting, followed by a lack of knowledge about current PA prescribing recommendations and lack of time. Our findings on barriers to PA prescribing are consistent with those of other authors –47. NautConsulting in PrH, being an SP, an internist, and a cardiologist, and knowing the PA benefits were the determinants of PA prescribing in this study. To our knowledge, no previous study has investigated the determinants of PA prescription. Consulting in PrH as a determinant of PA prescription probably reflects the effort often made in PrH to provide the best service to patients, mainly for commercial reasons. However, some studies have demonstrated better medical service in PrH than in PH , 49. BeiThe interpretation of the findings of this study must take into account some methodological limitations, primarily the small sample size and the use of a declarative questionnaire. As a result, the current study’s findings may be skewed due to cognitive and/or affective bias. Despite its methodological limitations, this study has some strengths. This is the first study in RDC and Sub-Saharan Africa on physicians’ knowledge and practices in promoting PA. Almost all studies on the subject in the world have primarily focused mainly on GPs. By contrast, our research focused on the distinctions between GPs and specialists on the one hand and PrH physicians and PH physicians on the other.SPs and PrH professionals were the most interested in their patients’ PA levels. However, only a small percentage of them prescribed it, and an even tinier fraction did so correctly. This bleak picture highlights a need to  rethink


Our objective is to compare the right/left ventricular blood pool T1 ratio (RVT1/LVT1), and right/left ventricular blood pool T2 ratio (RVT2/LVT2) on Cardiac Magnetic Resonance Imaging (CMR) between patients with pulmonary hypertension (PH) and normal controls, to analyze the correlation of RVT1/LVT1, RVT2/LVT2 and hemodynamics measured with right heart catheterization (RHC) in patients with PH.Forty two patients with PH and 40 gender-and age-matched healthy controls were prospectively included. All patients underwent RHC and CMR within 24 h. The right and left ventricular blood pool T1 and T2 values were respectively measured, and RVT1/LVT1 and RVT2/LVT2 between the PH group and the healthy control were compared. Meanwhile, the correlation between RVT1/LVT1, RV/LVT2 ratio and hemodynamic parameters in patients with PH respectively was analyzed.t = 6.782, p < 0.001) while RVT1 also was lower than LVT1 . In patients with PH, RVT2 was significantly lower than LVT2  while RVT1 was similar to LVT1 . RVT2/LVT2 in the PH group was significantly lower than that in the control group (p < 0.001). RVT1/LVT1 in PH patients increased in comparison with the control group (p < 0.001). RVT2/LVT2 negatively correlated with pulmonary vascular resistance (r =  − 0.506) and positively correlated with cardiac index (r = 0.521), blood oxygen saturation in Superior vena cava, right atrium, right ventricle and pulmonary artery .In the control group, RVT2 was significantly lower than LVT2 (RVT2/LVT2 on T2 mapping could be an additional CMR imaging marker that may assist to evaluate the severity of PH. Ventricular blood pool T1 and T2 values on T1 and T2 Mapping on four-chamber slice have good repeatability.LVT2 is higher than RVT2 in both normal control and PH patients. However, RVT2 in PH patients has a significant reduction, compared with the normal control.RVT2/LVT2 ratio in PH patients correlated with hemodynamics such as PVR, CI, blood oxygen saturation in SVC, right atrium, right ventricle and pulmonary artery Pulmonary hypertension (PH) is a complex chronic disorder of the pulmonary circulation that defined as an increase in mean pulmonary arterial pressure (MPAP) > 20 mmHg and pulmonary vascular resistance (PVR) > 2Wu at rest as assessed by right heart catheterization (RHC). Currently, RHC is the "gold standard" for the diagnosis and evaluation of pulmonary hypertension . As the T1 and T2 mapping is a quantitative technique for measuring spin–lattice and transverse relaxation time (T2) of magnetic resonance imaging (MRI). Both T1 and T2 values are the physiological tissue property that can be exploited with MRI to generate contrast between normal and diseased tissues. To date, Tissue characterization by native T1 mapping can serve as a non-invasive method for the assessment of myocardial fibrosis on CMR , 6. GarcThis study complied with the Declaration of Helsinki and was approved by the ethics committee of our hospital (IRB No. 2022-KY-048). Informed consent was obtained from all participants or their families. From January 2020 to January 2022, patients with chronic thromboembolic pulmonary hypertension (CTEPH)  and gender- and age-matched healthy volunteers as the control group  were prospectively included. CTEPH was diagnosed by RHC with a radionuclide pulmonary ventilation-perfusion scan and computed tomography pulmonary angiography (CTPA). CMR and RHC were finished within 24 h. Patients who were older than 18 years and less than 70 years were included. Patients with congenital heart diseases or malignancies were excluded. Patients without complete hemodynamic data of RHC or patients whose mean pulmonary artery pressure (MPAP) < 20 mmHg were excluded. Patients who did not complete CMR or had poor imaging quality were also excluded.All participants underwent CMR within 24 h before RHC using a 1.5 Tesla clinical scanners  in the supine position with an 18-channel body coil without supplemental oxygen. CMR was acquired during end-expiratory breath holds with retrospective electrocardiographic gating. Using a balanced steady-state free precession sequence with ECG gating, a true steady-state precession fast imaging sequence (TrueFISP T2 Map) was used to scan short-axis slices and long-axis four-chamber slice with the scanning parameters: TE/TR = 193.27 ms/1.06 ms, Flip angle 70°, Slice thickness 8.0 mm, voxel = 1.9 × 1.9 × 8.0 mm3. Field of view = 360 × 256 mm, GRAPPA = 2, T2 preparation: 0 ms, 25 ms, 55 ms, cardiac delay time TD = 517 ms, phase partial Fourier 7/8. Each slice was 8-mm thick with a 2-mm gap.3, Field of view = 360 × 256 mm, GRAPPA = 2, 24 reference lines, cardiac delay time TD = 435 ms, and phase partial Fourier 7/8. Each slice was 8-mm thick with a 2-mm gap. 2 inversions pulses with 5 and 3 images were acquired after each inversion pulse respectively and 3 heart beats to recover before the 2nd inversion If necessary, shimming and center frequency adjustments were performed to generate images free from off-resonance artifacts.T1-mapping was obtained with a modified look-locker inversion-recovery (MOLLI) sequence with a single-shot balanced steady-state free precession (bSSFP) readout including the short-axis slices and long-axis four-chamber slice as T2 Map using the following parameters: TE/TR = 280.56/1.14 ms, Flip angle = 35°, Voxel size = 1.4 × 1.4 × 8 mmRight and left ventricular blood pool T1 and T2 values were respectively measured on the four-chamber slice of T1 map and T2 map with an Argus . Region of interest (ROI) of the left and right ventricular blood pool were delineated along the endomyocardium on the four-chamber T1 Map and T2 Map , pulmonary arterial wedge pressure (PAWP) and pulmonary vascular resistance (PVR). Cardiac Output (CO) and Cardiac Index (CI) were determined using the Fick method.p < 0.05 means the difference is statistically significant.Statistical analysis was performed using SPSS v26.0 . Normally distributed measurement data were described as mean ± standard deviation (SD). Non-normally distributed data were described by the median and interquartile range (IQR). Bland–Altman plot and intraclass correlation coefficient were used to assess the reproducibility of right and left ventricular blood pool T1  and T2 . The RV/LV T2 ratio was compared between the CTPEH and the control groups by t or U tests. Spearman's rank correlation analysis was performed between RV/LV T2 ratio and hemodynamic data in CTEPH patients. Eighty two participants , including 42 patients in the PH group  and 40 healthy volunteers in the control group  enrolled this study. Table A Bland–Altman plot of LVT1 is shown in Fig. A Bland–Altman plot of LVT2 is shown in Fig. t = 9.802, p < 0.001) while RVT1 was similar to LVT1 in patients with PH . In normal control group, RVT2 was significantly lower than LVT2  while RVT1 also was lower than LVT1 .Figure p = 0.591) while LVT1 in the PH group was lower than LVT1 in the control group (p < 0.001). RVT1/LVT1ratio in PH patients increased in comparison with the control group (p < 0.001). RVT2 in PH patients significantly decreased in comparison with RVT2 in the control (p < 0.001), however, there was no significant difference in LVT2 values between the two groups (p = 0.328). The RVT2/LVT2 ratio in the PH group were significantly lower than that in the control group (p < 0.001). The alteration of ventricular blood pool T1 and T2 is shown in Fig. Table r = − 0.310), DPAP (r =  − 0.372), MPAP (r =  − 0.343), PVR . It was positively correlated with CO (r = 0.489), CI (r = 0.521), SVC oxygen saturation (r = 0.564), right atrial oxygen saturation (r = 0.603), right ventricular oxygen saturation (r = 0.648), and pulmonary artery oxygen saturation (r = 0.582). RVT1/LVT1ratio only had a weak negative correlation with PAWP (r =  − 0.311).As shown in Table There are several major findings in the present study. (I) Ventricular blood pool T1 and T2 measurements with T1 and T2 Mapping on CMR four-chamber view have good repeatability. (II). LVT2 is higher than RVT2 in both normal control and PH patients. However, RVT2 in PH patients has a significant reduction, compared with the normal control. (III) RVT2/LVT2 ratio in PH patients correlated with hemodynamics such as PVR, SVC, right heart and pulmonary artery oxygen saturation. (IV). In normal control, LVT1 is more than RVT1. Compared with the normal control, LVT1 decreased in patients with PH, however, RVT1/LVT1 ratio only has a weak correlation with PAWP.Although myocardial T1 and T2 mapping have been proven excellent repeatability and is widely used to assess myocardial injury under various pathological conditions, we first studied T1 and T2 value of ventricular blood pool in patients with CTEPH. To accurately measure RV and LV blood pool T1 and T2, outlining the ventricular blood pool must avoid the muscle trabecula and papillary muscle. In the current study, blood pool T1 and T2 demonstrate better repeatability, which is the foundation of further research.2]  , 18. The2] , 19–21. 2] . In healIn PH patients, pulmonary vascular remodeling leads to a progressive increase in pulmonary vascular resistance and a worsening right heart function, resulting in a further reduced blood oxygen saturation and evaluated deoxyhemoglobin in the erythrocyte of SVC, the right atrium and right ventricle, pulmonary artery. Thus, RVT2 in PH patients significantly decreased compared with healthy control. However, in patients with precapillary PH, blood oxygen saturation and intracellular hemoglobin content in the erythrocyte of the left atrium and ventricle is less affected. Our patients with CTEPH belong to precapillary PH. That explains why LVT2 in normal control is comparable to LVT2 in CTEPH patients.Emrich et al.  reportedT1 map showed that LVT1 was more than RVT1 in the normal control. Unexpectedly, compared with the normal control, LVT1 in patients with PH has a significant decrease while RVT1 between the PH group and normal control is comparable, and RVT1/LVT1 only has a weak correlation with PAWP. This suggested hemodynamics may have less effect on the ventricular blood pool T1. The possible mechanism which affects LVT1 but not RVT1 remains unclear.First, this was a single-center study performed at a large tertiary hospital, so the inherent limitations of this study design cannot be avoided. Second, our study only included patients with CTEPH, so further studies are needed to determine the relationship between ventricular blood pool T2 and hemodynamics, cardiac function and the prognosis in patients with other etiologies of PH. A non-contrast CMR protocol was applied, therefore, post-contrast T1 mapping could not be assessed. Since we cannot obtain the hemodynamics of healthy people with RHC, the cutoff value of blood pool RVT2/LVT2 for predicting PVR and MPAP remains unknown. Finally, all included patients with CTPEH underwent PEA, the correlation of the ventricular blood pool T2 value with the progress and prognosis of CTEPH patients remains for further research.Ventricular blood pool RVT2/LVT2 ratio on T2 mapping could be an additional new CMR imaging biomarker in addition to conventional CMR functional metrics that may assist to evaluate the severity of PH.


Mitral annulus disjunction (MAD) is defined as a systolic displacement between the ventricular myocardium and the posterior mitral annulus supporting the posterior mitral leaflet. This structural abnormality is associated with the loss of mechanical annular function manifested as an abnormal systolic excursion of the leaflet hinge point into the left atrium but with maintained electrical function, separating the left atrium and ventricle electrophysiologically. The mitro-aortic fibrous continuity limits MAD anteriorly, between the aortic cusps and the anterior leaflet of the mitral valve. Consequently, MAD has been observed only at the insertion of the posterior leaflet. It can extend preferentially at the central posterior scallop. The first diagnostic modality aiding the diagnosis is transthoracic echocardiography (TTE), although in some cases adjunctive cardiac imaging modality might be suggested. MAD carries a strong association with malignant ventricular arrhythmogenesis and a profound predisposition for sudden cardiac death (SCD). In this context, a thorough investigation of this morphological and functional abnormality is vital in estimating the risk assessment and stratification for optimal management and elimination of the risk of the patient for SCD. Based on the current scientific data and literature, we will discuss the diagnosis, clinical implications, risk stratification, and therapeutic management of MAD. Mitral valve prolapse (MVP) is the most frequent cause of primary or degenerative mitral regurgitation (MR) with estimated prevalence up to 3% in the general population , 2. MitrThe clinical significance of MAD in the absence of mitral valve disease is unknown, although it has been shown that the prevalence of ventricular arrhythmias in MAD with concomitant MVP and isolated MAD was not significantly different, which suggests the arrhythmogenicity of MAD alone , 6. MAD At first, MAD was described in autopsy studies to be present in approximately 6% of human hearts , 8. The In arrhythmic MVP syndrome, MAD prevalence is reported between 34%  in patieThe cornerstone for the diagnosis of MAD is cardiac imaging modalities. MAD can be detected easily in the long-axis views during end-systole using transthoracic echocardiography (TTE) –5, 10, aMAD is widely known as a common abnormality in MVP. The disjunctive annulus is paradoxically functionally decoupled from the left ventricle and coupled more to the left atrium, consequently leading to paradoxical annulus dynamics with systolic expansion and annulus flattening. As a result, the abnormal mechanical stress and disjunctive annular dynamics exerted on the mitral valve and subvalvular apparatus accelerate the degenerative processes .Excluding pseudo-MAD phenotype is of great importance. Pseudo-MAD refers to the juxtaposition of the posterior leaflet of the mitral valve on the atrial wall in systole mimicking MAD , 16. ParDue to the high prevalence of MAD in normal subjects, an acceptable cut-off value of separation ≥5 mm) between the posterior leaflet insertion and the atrioventricular junction  is approved based on a histologic  and an e mm betweThe proposed mechanism of arrhythmias in MAD is related to a combination of papillary muscle fibrosis- anatomical substrate and mechanical stretch of the myocardium, which has been supported by CMR imaging findings , 21, 22.All patients with MVP should be mandatory stratified for sudden cardiac death (SCD) risk. Risk stratification of patients with MVP includes focused history, 12-lead ECG, extended ECG monitoring, and detailed echocardiography. The use of CMR and implantation of a loop recorder are more selective depending on the probability of VAs. Risk stratification involves two phases based on the clinical and imaging context and the detected arrhythmia . Even thSeveral phenotypic risk features of MVP have been identified including young age, female sex, high burden of ventricular ectopy (VE), bileaflet myxomatous MV degeneration, MR severity, and flail leaflet , 25.More malignant risk factors of arrhythmia in MAD are younger age, high burden of VE, longer longitudinal distance of MAD, and evidence of papillary muscle fibrosis-anatomical substrate on CMR , 13. In A 31-year-old Caucasian with a known medical history of bronchial asthma, mild MVP, autonomic dysregulation of sinus and atrioventricular node, smoking, and a family history with MVP and SCD was transferred to the emergency department of our hospital, following an episode of out-of-hospital cardiac arrest due to ventricular fibrillation. After the restoration of spontaneous circulation, a thorough clinical examination showed unremarkable findings, and a bedside FOCUS TTE on presentation showed a severely depressed LVEF and coronary angiography excluded obstructive coronary artery disease (CAD). Repeated TTE and TOE showed improved LV function (50% EF) and evidence of bileaflet MVP, severe mitral regurgitation, and MAD approximately 16 mm, not clearly visualized on initial imaging . The CMRMYOM1 gene, classified as a variant of unknown significance (VUS). No specific relation between this mutation and MAD has been described.A genetic test was performed with a next generation sequencing panel and revealed a very rare genetic variant in the The patient was discharged after receiving a secondary prevention implantable cardioverter defibrillator (ICD) and was referred for mitral valve repair. The post-operation follow-up with a cardiac event monitor showed a subtle arrhythmogenic activity VE burden (approximately 1.0%) and mild mitral regurgitation on transthoracic echocardiogram. He remained stable and asymptomatic.A 50-year-old Caucasian man has been transferred to our clinic from another hospital, in an emergency manner for emergency coronary angiography due to persistent monomorphic ventricular tachycardia. While evaluating the patient, the patient collapsed abruptly due to ventricular fibrillation. He was successfully resuscitated from cardiac arrest and transferred fully consciousness for emergency coronary angiography. The clinical evaluation prior to the coronary angiography showed no significant clinical findings.His past medical history was smoking in a habitual manner and former drug user (drug test upon admission was negative), reporting abstinence for 3 years now. He mentioned occasional palpitations without any further investigation. Collecting data from his family history, one case of sudden death was reported in the family at the age of 60 in a second-degree relative. Family history was negative for primary electrical diseases and MVP. He was not taking any medications or drugs at the time of presentation.The coronary angiography excluded obstructive coronary artery disease as the cause of cardiac arrest and revealed a moderately impaired LV systolic function by left ventriculography.The FOCUS echocardiographic assessment showed a moderately impaired LV systolic function, gross estimation LVEF: 40%, without pericardial effusion, and intact proximal ascending aorta. A complete TTE and TEE study that followed revealed a mildly dilated LV with borderline normal LVEF and MAD .The cardiac magnetic resonance report an unveiled annular disjunction of the posterior LV wall, measuring a longitudinal MAD distance of 8 mm , with laA multidisciplinary heart team suggested an ICD implantation as a secondary prevention for SCD and no further surgical intervention due to limited data in the current literature.ANK2 and TTN. Both variants have no specific relation with MAD.A genetic investigation with next generation sequencing panel revealed two variants of unknown significance (VUS) in The patient is currently asymptomatic and without any worrying arrhythmic findings on follow-up cardiac rhythm monitoring 2 months after. His ICD check is also without any remarkable arrhythmic activity.Beyond the first part of the diagnostic algorithm with clinical approach, imaging, electrocardiographic, and cardiac event monitoring, asymptomatic patients with MAD—with or without MVP—require a close follow-up with repeated 2D-transthoracic echocardiography over the years, to explore MAD development over time and for routine rhythm surveillance, as MAD is an independent risk factor for arrhythmias . AdditioCurrent literature regarding the medical management of AMVP patients is scanty. The medical management should be addressed to the specific presentation by aiming the symptomatic improvement and improving survival .The American Heart Association/European Society of Cardiology guidelines for ventricular arrhythmias and SCD have no distinctive criteria or recommendations for the secondary prevention of SCD and the management of ventricular arrhythmias in significant mitral valvulopathy , 28.The pivotal challenge of SCD prevention mandates the establishment of primary and secondary preventive methods such as screening programs, technological measures , and a fundamental risk stratification strategy with the use of CMR, treadmill exercise test, and a serial rhythm monitoring. In the case where MVP had been diagnosed in a random order or screening (relatives of SCD victims or athletes), a risk stratification strategy may be essential depending on the existence of high-risk criteria. It is essential to thoroughly evaluate with electrophysiological study, CMR, and echocardiography, particularly the young individuals, for the proper selection of candidates for ICD implantation .According to the latest data from the expert consensus, patients with AMVP and a documented history of VF or hemodynamically not tolerated VT, in the absence of reversible causes, should receive an ICD. MVP with LVEF <35% and symptomatic HF despite ≥3 months of OMT should receive an ICD.Ablation of PVCs in patients with frequent PVCs who are symptomatic or have decreased LV function is advised. Ablation of VA in MVP patients should be performed in experienced centers with expertise in VA ablation and interventional and surgical treatment of MV regurgitation. Ablation of PVCs is reasonable if triggering VF, particularly if not controlled by medications. Ablation of sustained monomorphic VT despite antiarrhythmic treatment or if antiarrhythmic treatment is not desired, or contraindicated, should be performed in MVP patients with recurrent ICD therapies. Mitral valve surgery may reduce the burden of malignant VAs in MVP patients and severe MR .The promising potential of biomarkers and genetic studies for the determination of high-risk individuals, particularly after the latest correlating with familial clustering, is likely to be further tested in the coming future , 30.A case report emphasized and illustrated the need to maintain alertness in malignant MVP patients and signified the role of mitral valve repair in the treatment of ventricular arrhythmias resulting from malignant MVP as a potential treatment option and secondary preventive method for SCD . CurrentMAD is an anatomical, congenital variation associated frequently with MVP. Distinct anatomic characteristics of this potentially lethal entity may increase the risk of malignant ventricular arrhythmia and SCD. A suggestive therapeutic approach with ICD implantation and mitral valve repair might be necessary for this appropriate group. Large cohorts with long-term follow-up are required to better define MAD without MVP and its outcome and consequences. Future prospective studies evaluating ECG features, ventricular arrhythmia burden and morphology, and electrophysiological findings may provide further information. In individuals with different MAD phenotypes, further evidence could clarify its arrhythmogenic role and specify the effectiveness of antiarrhythmic therapy, the potential use of early catheter ablation in refractory ventricular arrhythmias, and the surgical approach in managing ventricular arrhythmia in patients with MVP .


Editorial on the Research TopicResearch topic for frontiers in cardiovascular medicine: non-invasive sensing and imaging techniques for cardiometabolic diseasesManagement of cardiometabolic diseases consists one of the biggest challenges in medicine. The heterogeneity of such diseases renders their clinical management complex and the development of tools for assessment of specific treatment effects necessary. Non-invasive sensing or imaging techniques play an important role in the in evaluating novel treatment options such as anti-inflammatory regimens or cell-based therapies. In fact, by directly assessing the affected organs and tissues such techniques frequently offer better specificity than routine blood analyses. For example, the diagnosis of several heart conditions is based mainly on the interpretation of electrocardiographic or echocardiographic readouts. Also, the detection and stratification of non-alcoholic fatty liver disease relies on direct imaging of the liver.The Research Topic “Non-invasive Sensing and Imaging Techniques for Cardiometabolic Diseases”, with five original articles and two reviews, covered several clinical and translational aspects of the techniques already used or show potential to be used in the management of cardiometabolic diseases .Wang et al. explores the connection between preinfraction angina (PIA) and the morphological characteristics of the vulnerable coronary plaque in patients with ST-segment elevation myocardial infraction (STEMI). Optical coherence tomography (OCT), an intravascular high-resolution (10–20 um) imaging technique, revealed a lower rate of plaque rupture and increased lipid content in vulnerable plaques in patients with STEMI and PIA, compared to patients with STEMI but no PIA. The study not only provides insights into the pathophysiology of STEMI, by implying different pathophysiologic mechanisms between the two groups, but has also clinical implications by demonstrating that the absence of PIA is an independent predictor of plaque rupture in STEMI patients.The study of Zhao et al. is addressed the echocardiographic differentiation between hypertrophic cardiomyopathy (HCM) and hypertensive left ventricular hypertrophy (H-LVH): two conditions with different pathophysiology, prognosis and treatment. To this end, the ultrasound-based non-invasive myocardial work index (NMWI)—an index derived from several pressure-strain-loops-based parameters, such as the global myocardial work index (GWI) and global constructive work (GCW)—was compared to other conventional echocardiographic readouts, such as the inter-ventricular septum thickness (IVST) and left ventricular posterior wall thickness (LVPWT), in 40 patients with HCM and 35 patients with H-LVH. It was shown that NMWI is characterized by a significant difference between the two groups, offering possibly novel insights into the pathophysiology of both diseases. Moreover, even if both IVST/LVPWT and GCW were proven to be predictors for discriminating the two forms of hypertrophy, combining these two parameters provided higher predictive accuracy than using each parameter on its own. This finding further highlights the clinical implications of the study in distinguishing between HCM and H-LVH based purely on echocardiography-extracted measurements.In the work of Xie et al. investigate the relationship between the fragmented QRS (f-QRS) complex of the surface ECG signals with the functional status of the myocardium in patients with previously diagnosed Danon disease (DD): a genetic metabolic disorder associated with cardiomyopathy. N = 15 patients in total underwent 12-lead ECG for the assessment of the f-QRS complex and heart magnetic resonance imaging (CMR) to evaluate the cardiac functional status via parameters, such as the left ventricular ejection fraction (LVEF) and the late gadolinium enhancement (LGE), a characteristic of irreversible myocardial fibrosis or scarring and, thus, loss of functionality. The results showed that the f-QRS were commonly seen in patients with DD and associated with a higher level of myocardial fibrosis, as described by LGE > 35% in CMR. Finally, the f-QRS showed in general a positive correlation with myocardial fibrosis, as described by LGE, and a negative correlation with myocardial functionality, as described by LVEF.Lohr et al. aim at characterizing the myocardial microstructure and function in a small animal model of obesity-associated heart dysfunction. Male C57BL/6N mice were either fed with a high-fat diet  or normal control diet  for 15 weeks. Mouse hearts were assessed both functionally  and microanatomically by means of ex vivo diffusion tensor magnetic resonance imaging (DT-MRI), a technique that offers a resolution of 100 um. The latter allowed for a depth analysis of myocardial deformation, diffusion metrics and fiber tract geometry of the myocardium. DT-MRI revealed distorted myocardial diffusion properties in the HFD group but no changes in the three-dimensional (3D) arrangement of the myocardial fibers of the left ventricle (LV). Furthermore, obesity was correlated with reduced longitudinal strain and mean diffusivity in the basal region of the LV, compared to the control group. The study highlights the high potential of DT-MRI as a novel tool in the assessment and diagnostics of heart dysfunction in obesity.In another interesting study, Chamtouri et al. it is shown that high severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as reflected in computed tomography (CT), is associated with higher possibility to develop subclinical heart damage, as described in echocardiographic measurements. More specifically, N = 111 subjects recovered from COVID-19 were included in the study. All subjects underwent a chest CT scan and, based on this, were categorized in subjects with mild CT scan lesions (<50%) and with severe CT scan lesions (≥50%). Finally, after three months all participants underwent blood analysis to estimate the levels of high-sensitivity cardiac troponin (hs-cTn) and transthoracic echocardiography (TTE) to measure the global longitudinal strain (GLS) of the myocardium: a parameter reflecting the function of the longitudinal fibers in the subendocardium. The outcomes showed that subjects with severe CT scan lesions are more prone to develop subclinical myocardial damage, possibly leading to the useful clinical recommendation that patients recovering from COVID-19 could undergo a TTE examination to check for silent cardiac lesions.In the original research paper of Chalet et al. the authors provide an overview of the methods used in imaging of ischemic penumbra, the severely hypoperfused but not yet infarcted brain region after an acute ischemic stroke (AIS), while exploring future directions. Imaging the penumbra is critical for guiding the acute actions which might allow for achieving reperfusion and improving the functional outcome. Apart from 15O-positron emission tomography (15O-PET), the current gold standard method, the use of multiparametric magnetic resonance imaging (MRI) and computed tomography (CT) are also presented and thoroughly discussed. The evolution of penumbra imaging is described over time and in correlation with the main therapeutic strategies, i.e., thrombolysis and thrombectomy. While highlighting the role of imaging within the clinical emergency settings, the authors provide insights into promising clinical imaging biomarkers/methods and potential research targets, such as the MR-based CMRO2  and the MR vascular fingerprinting method.Furthermore, two review papers are published in this research topic. In the study of Kampaktsis et al. provide a comprehensive overview of applications of artificial intelligence (AI) in the management of atherosclerosis, a condition strongly related to cardiometabolic disease. First, the key concepts of AI applications are described from a clinical point of view. Second, a detailed overview of AI applications is given for four main categories of atherosclerotic cardiovascular disease (ASCVD): coronary artery disease (CAD), peripheral arterial disease (PAD), abdominal aortic aneurysm (AAA), and carotid artery disease. For each type of ASCVD, Kampaktsis et al. focus on the main imaging modalities employed in clinical practice as well as the key aim of the applied AI techniques, i.e., disease detection, phenotyping, prediction of outcome and assistance of clinical decision process. Finally, advantages and disadvantages of current AI approaches are discussed and future perspectives are provided.In the second review paper, To summarize, the current Research Topic for Frontiers in Cardiovascular Medicine: Non-invasive Sensing and Imaging Techniques for Cardiometabolic Diseases provides the reader with a comprehensive overview of sensing and imaging applications in preclinical and translational research and clinical management of cardiometabolic diseases. Non-invasive imaging approaches will play a major role in driving the research, optimising diagnosis and personalising the therapy of the patient with cardiometabolic disease. Clearly, imaging may provide a high-resolution assessment, both in space and in time, of cardiometabolic alterations and the effects of novel targeted therapies. Therefore, further development, evaluation and clinical translation of such techniques is important to foster advances in the diagnosis and treatment of cardiovascular disease.


Hypocalcemic cardiomyopathy is a rare etiology of heart failure. It is considered highly reversible with a relatively favorable prognosis. This case reports a 52-year-old housewife diagnosed with hypocalcemic cardiomyopathy who presented with acute decompensated heart failure and hypocalcemia symptoms with a history of thyroidectomy. Shortness of breath and edema were relieved after diuresis and prompt electrolyte correction. The left ventricular ejection fraction increased from 27% to 53%, and the left ventricular end-diastolic dimension shortened from 58 to 50 mm in echocardiographic re-examinations, while repeat cardiac magnetic resonance imaging revealed evidence of non-reversible cardiac fibrosis after 1-year follow-up. Cardioprotective agents with close follow-ups were called for in this entity of patients. Within different etiologies, hypocalcemia is one of the causes considered to be relatively benign and reversible, with prompt correction of electrolyte disturbance, diuretic treatment, and other guideline-directed medical therapies for heart failure. However, the recovery of underline pathophysiological change is not clear. Here, we present a case with heart failure and prominent hypocalcemia, who had rapid improvement after replacement therapy. However, cardiac magnetic resonance (CMR) imaging showed persistent evidence of cardiac fibrosis, which may indicate hypocalcemia-induced non-reversible myocardium damage.2.A 52-year-old housewife was admitted to our hospital with the chief complaint of exercise intolerance and severe shortness of breath for 1 month. She received a subtotal thyroidectomy for a goiter 11 years ago. Since then, therapy with levothyroxine and calcium supplement for hypoparathyroidism has been prescribed. The thyroid function or serum calcium level was not tested without regular follow-ups. She had suffered occasional hand and arm twitching after thyroidectomy for 10 years. The patient did not have a medical history of hypertension, coronary heart disease, and diabetes mellitus nor a family history of cardiomyopathy or sudden cardiac death.Upon admission, a physical examination showed tachypnea with a respiratory rate of 28 breaths per minute and tachycardia with a heart rate of 100 beats per minute. The obvious distended jugular vein and lower extremity edema were noted. Respiratory crepitations were heard in bilateral base lungs, and a neurology examination revealed positive Chvostek's sign indicating hypocalcemia.The electrocardiogram showed a prolonged heart rate corrected QT interval (QTc) of 530 ms primarily by prolonging the ST segment and multiple premature atrial complexes with aberrant conduction . The cheA primary diagnosis of hypocalcemic cardiomyopathy (HC) was made in view of the congestive heart failure, the potentially long-existing untreated hypocalcemia resulting from hypoparathyroidism, and the lack of evidence of other etiologies including hypertension, valvular, congenital, or ischemic heart disease. The subject was treated with oxygen inhalation, intravenous diuresis, and electrolyte supplements. Calcitriol was simultaneously started along with guideline-directed medical therapy (GDMT), including metoprolol and perindopril, which were gradually titrated to the maximal tolerated dosage. She was intolerant to spironolactone treatment because of acute kidney injury, with serum creatinine increasing from 96 to 221 µmol/L in 1 week. Serum calcium, magnesium, and potassium were normalized within 2 weeks of initiation. Clinical symptoms were relieved significantly following optimal medical therapy. After stabilization, the patient underwent CMR imaging, which showed signs of cardiac fibrosis in the septal, lateral, and inferior walls of the left ventricle after late gadolinium enhancement (LGE) ,B. The 2Repeated electrocardiography at the 3-month follow-up showed QTc shortened to 491 ms . Transth3.3.1.Hypocalcemia is a rare cause of heart failure with reduced ejection fraction (HFrEF). Postsurgical hypoparathyroidism is the most common cause of hypocalcemia. A recent literature review summarized 61 case reports and described the most common causes of HC as being primary hypoparathyroidism (50%) and post-thyroidectomy hypoparathyroidism 26%) (6% (2). PThe primary treatment of hypoparathyroidism and resulting hypocalcemia includes activated vitamin D analogs plus calcium supplements to raise the calcium level to the lower normal range while avoiding hypercalciuria , 4. Card3.2.The literature has documented the presence of cardiac fibrosis in patients with HC. Altunbas et al. have presented two cases of HC resulting from hypoparathyroidism that were left untreated for extended periods, i.e., 19 and 12 years, respectively. The patients underwent endomyocardial biopsy, which revealed hypertrophic and atrophic changes in conjunction with increased fibrous tissue. The patients showed clinical improvement after treatment with calcium supplements and calcitriol, although no follow-up data were available (The development of myocardial fibrosis may be related to the duration and severity of hypocalcemia. Our patient underwent surgery for hypoparathyroidism 11 years ago, implying prolonged untreated hypocalcemia. Some researchers have also employed CMR imaging in patients with hypoparathyroidism; however, they have not been able to detect LGE. For instance, Valek et al. presented a case of a 26-year-old woman with HC, where CMR imaging did not reveal any evidence of fibrosis , 9.The detailed mechanism underlying the formation of cardiac fibrosis in HC remains unknown. In general, cardiomyocyte death and/or mechanical, ischemic, or metabolic injury may activate fibroblasts and stimulate the formation of fibrosis . CalciumCardiac fibrosis is thought to be related to unfavorable outcomes resulting from cardiac dysfunction, reduced perfusion, and propensity to arrhythmias . Althoug


Nuclear imaging techniques can detect and quantify pathophysiological processes underlying heart failure, complementing evaluation of cardiac structure and function with other imaging modalities. Combined imaging of myocardial perfusion and metabolism can identify left ventricle dysfunction caused by myocardial ischaemia that may be reversible after revascularization in the presence of viable myocardium. High sensitivity of nuclear imaging to detect targeted tracers has enabled assessment of various cellular and subcellular mechanisms of heart failure. Nuclear imaging of active inflammation and amyloid deposition is incorporated into clinical management algorithms of cardiac sarcoidosis and amyloidosis. Innervation imaging has well-documented prognostic value with respect to heart failure progression and arrhythmias. Emerging tracers specific for inflammation and myocardial fibrotic activity are in earlier stages of development but have demonstrated potential value in early characterization of the response to myocardial injury and prediction of adverse left ventricular remodelling. Early detection of disease activity is a key for transition from broad medical treatment of clinically overt heart failure towards a personalized approach aimed at supporting repair and preventing progressive failure. This review outlines the current status of nuclear imaging in phenotyping heart failure and combines it with discussion on novel developments.  Thus, nuclear imaging can provide functional and molecular information about pathophysiological processes underlying heart failure that complements assessment of cardiac structure and function with the use of other imaging modalities.2–4Cardiac imaging is essential in establishing the diagnosis of heart failure, determining its mechanisms and prognosis, identifying the specific causes of cardiac dysfunction as well as planning and monitoring treatment.1 Yet, molecule-targeted radiopharmaceuticals enable studying several biological processes involved in heart failure beyond perfusion, including myocardial metabolism, innervation, inflammation, amyloidosis, and fibrosis.4 Currently, molecular imaging is routinely performed for the clinical diagnosis of cardiac sarcoidosis, cardiac amyloidosis as well as device or prosthetic valve infections.5–7 However, several emerging radiotracers and applications are in earlier stages of preclinical and clinical development for phenotyping heart failure with potential for early detection, improved risk stratification and guiding therapy in individual patients.2–4 This review outlines main applications of nuclear imaging in phenotyping heart failure together with discussion about novel developments.The most common application of nuclear imaging in heart failure is evaluation of inducible myocardial ischaemia and viability to assess ischaemic aetiology of cardiac dysfunction and to predict the potential for recovery after revascularization.4 Hybrid devices and image processing techniques facilitate fusion of PET images with high resolution morphologic images of cardiac structure and function obtained with other imaging modalities.8 This is particularly important for localization and quantification of tracers used for molecular imaging of small targets. Both SPECT and PET scanners are increasingly integrated with either computed tomography (CT) or cardiac magnetic resonance (CMR) systems. The use of state-of-the-art methodology enables integration of CT and nuclear imaging with an acceptable radiation exposure to the patient.8Introduction of new radiotracers for SPECT and PET is central for advancing the role of molecular imaging in a personalized approach towards cardiovascular diseases and heart failure.9 Recent advances in cardiac SPECT technology include developments of detector technology (solid-state detectors and cardio centric collimators), image reconstruction algorithms and dedicated cardiac scanner systems.11 As a result, image quality and resolution have improved, acquisition times have shortened and radiation exposure to the patient has reduced.11 Studies have shown the feasibility of quantification of myocardial blood flow (MBF) with the use of dynamic SPECT imaging with dedicated cardiac systems.13 Furthermore, protocols using simultaneous acquisition of multiple tracers are feasible, potentially improving accuracy of cardiac molecular imaging.14Myocardial perfusion SPECT has been the mainstay of cardiac nuclear imaging as the most common non-invasive functional imaging method to evaluate suspected coronary artery disease (CAD).15 With the use of dynamic PET, it is possible to map myocardial radiotracer concentration and kinetics in the myocardium over time, enabling absolute quantification of many parameters, such as MBF and myocardial oxygen consumption.17 Advances in PET technology include introduction of PET scanners with long axial field of view that enable large anatomical coverage (whole-body PET) and increase in system sensitivity.19 Simultaneous assessment of multiple organs provides new possibilities for studying interactions between the heart and other organs, such as the immune system, haematopoietic system, brain, liver, and kidneys. High sensitivity combined with improved resolution provided by motion correction techniques to reduce artefacts in cardiac PET data is needed in the analysis of signals coming from small targets, such as the coronary arteries.21 The availability of PET has improved due to increase in the number of PET scanners and cyclotrons needed to produce tracers, as well as new radiotracers labelled with isotopes with half-life long enough to allow for distribution to sites without a cyclotron.23Cardiac PET is an advanced nuclear imaging technique with high resolution, sensitivity, and accurate quantification of radioactivity.1 In ischaemic heart failure, left ventricular dysfunction may be reversible and improve after myocardial revascularization.24 Myocardial perfusion imaging with either SPECT or PET is an established modality for the evaluation of the presence and severity of CAD, contributing to the detection of ischaemic aetiology of heart failure.25 Furthermore, perfusion imaging and combined metabolic imaging can detect ischaemic myocardium that is dysfunctional, but viable and has potential for recovery of contractile function upon revascularization.24Ischaemic heart disease is the most common cause of heart failure.99mTc) labelled radiopharmaceuticals (99mTc-sestamibi and 99mTc-tetrofosmin), whereas myocardial perfusion PET is mainly performed with three flow tracers: rubidium-82 (82Rb), 13N-labeled ammonia (13N-ammonia), and 15O-labeled water (15O-water).16 Short radioactive half-life of perfusion tracers (76 s to 10 min) limits the availability PET perfusion imaging, because an on-site cyclotron or a generator is needed. Perfusion tracers labelled with 18F, which has longer half-life (110 min), have been designed in order to enable delivery to sites without a cyclotron.13 Of the 18F-based PET perfusion radiotracers, 18F-Flurpiridaz showed improved sensitivity and accuracy for the detection of obstructive CAD (>50% stenosis) in comparison to SPECT in a recent Phase III study.27Myocardial perfusion SPECT is performed with technetium-99 m .30 Quantification of MBF provides improved characterization of the extent and severity of ischaemia in multi-vessel disease, such as balanced decreases of MBF in all major coronary artery vascular territories.16 Furthermore, reduced MFR detects coronary microvascular dysfunction in the absence of epicardial CAD.16 Several studies have demonstrated that regional perfusion abnormalities31 as well as impaired MFR32 are strong independent predictors of increased risk of future cardiac events in patients with CAD.Myocardial perfusion imaging detects flow-limiting coronary stenosis defined as abnormal fractional flow reserve (FFR) with high accuracy.33–40 In these conditions, reduced MFR was associated with the severity of systolic and diastolic dysfunction, markers of heart failure severity and poor clinical outcomes.33–40 In a recent study including 1255 patients with heart failure with reduced ejection fraction who underwent 82Rb PET, reduced MFR and stress MBF were associated with a greater risk of all-cause mortality in both ischaemic and non-ischaemic cardiomyopathy that was incremental over clinical risk factors, left ventricular ejection fraction, and the presence of scar or ischaemia.41 Whether coronary microvascular dysfunction in non-ischaemic cardiomyopathy is a cause or an effect of the underlying disease process and whether it can be modified by therapies remains incompletely understood.Coronary microvascular dysfunction often co-exists with epicardial CAD but is also common in the absence of CAD in patients with various forms of cardiomyopathy and heart failure with either reduced or preserved ejection fraction.24 Furthermore, the use of specific imaging protocols, such as administration of nitrate before tracer injection or assessment of residual myocardial glucose uptake with 18F-fluorodeoxyglucose (18F-FDG) PET, can reveal viable myocardium in areas of reduced perfusion.42 A preserved or increased uptake of 18F-FDG in the presence of reduced resting myocardial perfusion, known as flow-metabolism mismatch, showed sensitivity of 92% and specificity of 63% for regional functional recovery after revascularization in a pooled analysis, including 24 studies with a total of 756 patients, who underwent 18F-FDG PET.42Detection of myocardial viability is based on uptake of myocardial perfusion tracers at rest being dependent on cell viability.43 Another observational study found significant interaction with the presence of hibernating myocardium and survival benefit from revascularization, particularly when the extent of hibernating myocardium was extensive (>10% of the left ventricular myocardium).44 However, the randomized Positron Emission Tomography and Recovery Following Revascularization (PARR-2) trial that assigned 430 heart failure patients with an ejection fraction below 35% to either management assisted by 18F-FDG PET imaging or standard care, showed only a non-significant trend toward reduction in cardiac events for 18F-FDG PET assisted management vs. standard care.45 Survival benefit for 18F-FDG PET assisted management was found only in the subgroup of patients whose treatment adhered to the recommendations by imaging.46 The overall results of PARR-2 are in line with analyses in other randomized controlled trials, including Surgical Treatment for Ischemic Heart Failure (STICH), Revascularization for Ischemic Ventricular Dysfunction (REVIVED-BCIS2R), and Heart Failure Revascularization Trial (HEART), in that neither the extent of myocardial viability nor the extent of left ventricular inducible ischaemia evaluated with various imaging modalities appeared to interact with treatment strategies in favourably affecting outcomes in ischaemic cardiomyopathy.47–50The value of viability imaging in guiding revascularization was evaluated in a meta-analysis, including 24 single-centre observational studies with a total of 573 patients with CAD and left ventricular systolic dysfunction (mean ejection fraction 33%), showing that the presence of myocardial viability predicted a large and significant benefit from myocardial revascularization .1 Although the role of routine testing of myocardial ischaemia and viability in ischaemic cardiomyopathy is controversial, it remains an option among comprehensive evaluation of heart failure patients in order to predict the response to revascularization in selected patients with CAD, in whom increased perioperative risk and the absence of typical angina makes decisions on revascularization difficult .51Current guidelines recommend that myocardial revascularization may be considered in patients with chronic ischaemic heart failure with reduced ejection fraction after careful evaluation of the individual risk to benefit ratio.52 In a majority of patients, cardiac sarcoidosis appears to be a slowly progressive cardiomyopathy,53 but ventricular arrhythmias and sudden cardiac death are common.54Cardiac sarcoidosis is a granulomatous inflammatory disease with unknown aetiology, which can occur in the presence or absence of systemic sarcoidosis.54 Endomyocardial biopsy is the gold standard for diagnosis, but it has low sensitivity because of the focal nature of the disease.52 Advanced non-invasive cardiac imaging, including CMR and 18F-FDG PET, play an important role in defining myocardial abnormalities in suspected cardiac sarcoidosis.5 While CMR provides high resolution for identifying the presence and extent of myocardial damage, 18F-FDG PET is a marker of active myocardial inflammation and can reveal extra-cardiac sarcoid lesions that may be targeted for histological diagnosis .55–57Diagnosis of cardiac sarcoidosis and stratifying the risk of ventricular arrhythmias is challenging.18F-FDG, attributed to the high metabolic activity of immune cells, after suppression of physiological myocardial glucose metabolism . In a recent meta-analysis of 26 diagnostic studies , 18F-FDG PET had overall sensitivity and specificity of 82% and 82%, respectively, for cardiac sarcoidosis.57 However, sensitivity was 94% in studies that excluded patients who were already treated with anti-inflammatory therapy before imaging.57 Myocardial perfusion imaging is often combined with 18FDG-PET imaging to identify areas of scar, which commonly coexist with inflammation in cardiac sarcoidosis. The findings of PET have prognostic implications in patients with suspected cardiac sarcoidosis. In a series of 118 patients with known or suspected cardiac sarcoidosis who underwent 82Rb perfusion and 18F-FDG PET imaging, abnormal perfusion and 18F-FDG uptake on PET imaging predicted 2.9-times increased risk of ventricular tachycardia and death compared with normal PET results during follow-up.58Active inflammation in cardiac sarcoidosis shows as focal myocardial uptake of 18F-FDG PET, since both normal myocytes and inflammatory cells take up glucose. Protocols to suppress physiological myocyte 18F-FDG uptake vary among studies, including prolonged fasting, low-carbohydrate meals, and/or intravenous heparin.59 The success of these strategies is variable, and incomplete suppression of physiological myocardial 18F-FDG uptake may significantly impair diagnostic accuracy of PET and in particular, monitoring disease activity in repeated studies.59 Therefore, new tracers have been sought to improve the accuracy of PET imaging in cardiac sarcoidosis. Small clinical studies and experimental studies have demonstrated promising results with 68Ga-DOTANOC or 68Ga-DOTATOC targeting somatostatin receptors on immune cells,61 radiolabelled amino acid 11C-Methionine PET,62 proliferation marker 18F-fluorothymidine (FLT),64 and a tracer targeting Folate receptor β expressed on activated macrophages.65Patient preparation to suppress physiological glucose uptake is essential for the detection of cardiac sarcoidosis by 6 Although a rare disease, recent data suggest that cardiac amyloidosis is underappreciated as an underlying mechanism of heart failure with preserved ejection fraction and hypertrophic cardiomyopathy.66 The introduction of targeted therapies for cardiac amyloidosis has emphasized the need for early diagnosis as discussed elsewhere in this issue.66Cardiac amyloidosis results from the myocardial extracellular deposition of misfolded proteins, known as amyloid fibrils, associated with left ventricular hypertrophy.99mTc-pyrophosphate (PYP), 99mTc-3,3-diphosphono-1,2-propanodiacarboxylic acid (DPD), and 99mTc-hydroxymethylene diphosphonate (HMDP) bind to microcalcification associated with transthyretin fibrils and are used to diagnose cardiac transthyretin amyloidosis (ATTR). Scans are analysed semi-quantitatively or by visual grading, myocardial uptake of the tracer equal or higher than in the ribs (Grades 2 and 3) indicating the presence of ATTR.68 In a multi-centre study of patients with suspected amyloid cardiomyopathy, significant cardiac uptake was shown to have a sensitivity close to 100% and provided that light-chain amyloidosis (AL) was excluded by plasma or urine testing, a specificity and positive predictive value close to 100% for the diagnosis of ATTR.69 In some hereditary forms of the disease, sensitivity of SPECT scintigraphy may, however, be lower.71 Semi-quantitative markers of cardiac tracer uptake correlate with markers of disease severity and mortality.68 However, quantitative measures of amyloid burden are sought to better stratify prognosis, assess subtle cardiac uptake possibly representing early stage of disease, and detect changes in amyloid burden in response to disease-modifying therapy.68 Small studies have found correlation between quantitative SPECT measures of PYP and DPD accumulation and left ventricular mass and myocardial extracellular volume measured by CMR indicating amyloid burden.73Bone avid SPECT radiotracers, 11C-labeled Pittsburgh compound B (11C-PIB),74–76 as well as the 18F-labeled alternatives florbetaben or florbetapir,78 bind to both transthyretin and light-chain amyloid and allow the detection of cardiac AL and ATTR. Amyloid-targeted PET provides quantitative measures of about amyloid burden in the myocardium and other organs, potentially already in early stages of disease.79 The cardiac uptake of 11C-PIB has been found to correlate with the degree of histological myocardial amyloid deposition80 and independently predict outcome in cardiac AL amyloidosis.81 Furthermore, quantification may be relevant for determining response to disease-modifying therapies.75Amyloid-targeted PET tracers are emerging in evaluation of suspected cardiac amyloidosis. The original 65 Provided that AL is excluded by evaluation of a monoclonal immunoglobulin light-chain clone with serum protein and urine protein electrophoresis with immunofixation, and serum-free light-chain ratio, a positive scan is diagnostic for ATTR and biopsy is not needed, and the patient can be referred to disease-modifying targeted therapy.68 Novel tracer-based imaging techniques may in the future help in monitoring the success of such therapies.When cardiac amyloidosis is suggested clinically and supported by echocardiographic or CMR findings, current guidelines recommend SPECT bone scintigraphy for the diagnosis of ATTR.82 The most common approach to study cardiac innervation is by radiolabelled catecholamine analogues targeting presynaptic nerve terminals, including SPECT tracer 123I-metaiodobenzylguanidine (123I-MIBG) and PET tracer 11C-metahydroxyephedrine (11C-HED).82 In heart failure, myocardial norepinephrine circulation becomes abnormal related to activation of the sympathetic nervous system or damage to presynaptic nerves.The development of radiotracers for non-invasive imaging of cardiac innervation has provided insights into pathophysiology of cardiomyopathies and a non-invasive approach to risk stratify patients with heart failure and at risk of arrhythmias.123I-MIBG is a predictor of poor prognosis in heart failure with different aetiologies.83 Cardiac uptake of 123I-MIBG is typically measured as myocardial activity relative to background mediastinal activity [heart-to-mediastinum (H/M) ratio] or myocardial washout. The prospective, multi-centre trial AdreView Myocardial Imaging for Risk Evaluation in Heart Failure (ADMIRE-HF), which included 961 patients in New York Heart Association functional Class II–III and ejection fraction ≤35% for a 17-month follow-up, showed that late H/M ratio <1.6 was associated with an increased incidence of worsening NYHA class, life-threatening arrhythmias, and cardiac death.85 A H/M ratio >1.6 was associated with 1% incidence of cardiac death per year, whereas H/M ratio <1.2 was associated with almost 10% higher incidence (9.6%). More recently, regional heterogeneity of cardiac innervation has emerged as a risk factor for ventricular arrhythmias.82 Studies suggest that the presence of regions of abnormal innervation with relatively preserved perfusion or viability (innervation/perfusion mismatch), typically located adjacent to scarred regions, can represent a marker of arrhythmic susceptibility in patients with CAD.87 In the Prediction of ARrhythmic Events with Positron Emission Tomography (PAREPET) trial, the extent of regional denervation assessed with quantitative 11C-HED PET was predictor of sudden cardiac arrest (arrhythmic death or intracardiac defibrillator shock for ventricular tachycardia >240/min or ventricular fibrillation) independently of ejection fraction, infarct volume, symptoms, and natriuretic peptide level in CAD patients who were candidates for an implantable cardioverter defibrillator placement for primary prevention of sudden cardiac death.88Many studies have demonstrated that reduced cardiac uptake of 82Despite prognostic evidence of innervation imaging, in the absence of prospective evaluation of the prognostic impact of innervation imaging on clinical decision-making and patient management, it has not been incorporated in clinical practice guidelines to risk stratify heart failure patients. Yet, it might be of value in specific patient groups, such as borderline risk for arrhythmias based on other investigations, as well as in guiding therapeutic interventions, such as catheter ablation of ventricular arrhythmias.90 Myocardial external efficiency describes the ability of myocardium to convert energy into mechanical work.17 This can be evaluated non-invasively as the relation of left ventricular external work  and myocardial oxygen uptake measured by carbon-11 acetate (11C-acetate) PET .92 In order to analyse myocardial substrate metabolism, glucose uptake assessed with 18F-FDG can be measured quantitatively and combined with tracers of fatty acid metabolism, such as fatty acid analogue 18F-fluoro-6-thia-heptadecanoicacid (18F-FTHA) or carbon-11 labelled palmitate .90 Studies using metabolic PET tracers have shown distinct alterations in myocardial substrate metabolism and myocardial external efficiency in heart failure that are related to alterations in systemic metabolism, such as those that occur in obesity and diabetes.90Metabolic PET tracers enable studying myocardial oxygen consumption and substrate metabolism beyond glucose utilization.93–95 Furthermore, it may be reduced in the presence of relatively preserved ejection fraction as shown in patients with hypertrophic cardiomyopathy,96 cardiac amyloidosis,97 and severe valvular heart disease.95 Myocardial efficiency is directly associated with systolic dysfunction and inversely related to afterload, activation of the sympathetic nervous system, increased wall stress and left ventricular hypertrophy,98 the contributions of each varying depending on aetiology, and stage of the underlying cardiac disease. Although myocardial oxygen consumption may be similar or even reduced in heart failure when compared with healthy controls, it is increased in relation to mechanical work.94Reduced myocardial external efficiency is a typical feature of heart failure with reduced ejection fraction.99 Furthermore, impaired myocardial efficiency has been associated with reduced exercise capacity and severity of heart failure symptoms.90 However, it remains unknown to what extent reduced myocardial external efficiency represents a cause or sequence of cardiac dysfunction. Therapies that have been proven beneficial in heart failure, such as beta-blockers, mineralocorticoids, and cardiac resynchronization, have been shown to improve myocardial efficiency.17 However, studies that have addressed the effect of manipulating substrate metabolism have yielded discouraging results.90 For example, acute fatty acid deprivation by blocking lipolysis in patients with idiopathic dilated cardiomyopathy, in contrast to healthy controls, led to reduced stroke volume, but not oxidative metabolism so that myocardial efficiency deteriorated further.100 It remains to be seen whether increased availability of cyclotrons to produce 11C-acetate together with standardized analysis tools97 will result in increased use myocardial external efficiency as a tool to study therapeutic interventions in heart failure.There is currently relatively limited information on prognostic and therapeutic implications of imaging myocardial metabolism and efficiency in heart failure. In a small study, impaired myocardial efficiency was a stronger predictor of survival than ejection fraction in patients with dilated cardiomyopathy.101 Inflammation, fibrosis, and angiogenesis play a role in myocardial repair after acute myocardial injury. However, excessive inflammation may be harmful and diffuse interstitial myocardial fibrosis is a common pathophysiological pathway in different forms of heart failure, the extent of which is associated with mortality.102 New targeted tracers have been evaluated in experimental and translational clinical studies to evaluate the extent, time-course, and prognostic value of these mechanisms in cardiac diseases.Acute myocardial injury, such as myocardial infarction, initiates several maladaptive changes in cardiac myocytes and the extracellular matrix, which can contribute to progressive left ventricular dysfunction, adverse remodelling, and eventual failure.18F-FDG103 and tracers targeting chemokine receptors CXCR4105 and CCR2,106 somatostatin receptors,107 the mitochondrial 18kD translocator protein TSPO,108 and other pro-inflammatory targets.2 These studies have demonstrated increased tracer uptake in the infarcted region early after myocardial infarction, indicating the immune response to myocardial injury. Of note, an overzealous response, as indicated by these imaging markers of early post-infarction inflammation, provides information about the risk of subsequent development of cardiac dysfunction, adverse remodelling, and even patient outcome that may be incremental over standard markers of scar extent.108 Molecular imaging of the immune response to injury may even be used in a ‘theranostic’ setting, for guidance of targeted immunomodulatory drug intervention. In an experimental study, a CXCR4-targeted imaging signal was used to identify optimal timing and candidates for treatment with a CXCR4-blocking drug, which subsequently improved function only when PET indicated high expression of the CXCR4 target in myocardial tissue.104 Other studies have also shown the potential of nuclear imaging to characterize associations between inflammatory response in the myocardium and systemic inflammatory networks,109 such as in the haematopoietic organs107 and the central nervous system.108 Such comprehensive, systems-based information may help even further in personalizing targeted therapies, by accounting for the status of other organs and tissues that interact with the cardiovascular system.Myocardial inflammation following acute myocardial infarction has been studied with 101 Hence, fibrosis and fibrotic activity have emerged as further targets for molecular therapy, and thus also for diagnostic imaging. While CMR provides quantitative measures of extracellular tissue composition, including fibrosis, via T1 and T2 mapping, nuclear imaging approaches focus on the cellular substrate for pro-fibrotic activity. Integrin receptors,111 matrix metalloproteinases,112 neurohormonal activation,113 and myofibroblast activation114 may be identified using targeted tracers, and thereby provide molecular signatures of the individual pro-fibrotic activity. Fibroblast activation protein (FAP), for example, is a membrane-bound serine protease highly expressed by activated myofibroblasts that can be targeted by 68Ga-FAPI PET. In clinical pilot studies, 68Ga-FAPI PET showed strong signal early after acute myocardial infarction that exceeded the infarct region indicating that FAP upregulation plays a role not only in replacement fibrosis in the primary injured region but also in reactive fibrosis that may compromise non-infarcted myocardium .114 Furthermore, the FAP signal was distinct from CMR tissue characterization and its extent correlated with contractile dysfunction at follow-up.115 Activation of fibroblasts as well as inflammation represent early steps in the initiation of myocardial fibrosis and therefore, their imaging may provide an opportunity for an early intervention at a reversible stage before irreversible fibrosis.116 Of note, highly specific molecular therapies are emerging that may be able to reverse interstitial fibrosis in heart failure.117 Such therapies may be guided by FAP-targeted PET or other imaging markers of fibrotic activity, towards the most suitable candidates and timing in the future, in a manner similar to other fields of image-guided, personalized medicine.119Activation of the immune system in response to injury leads to activation of pro-fibrotic mechanisms, which initially contribute to tissue repair, but, if maladjusted, may also contribute to excessive fibrosis limiting myocardial contractile function.Nuclear imaging of myocardial perfusion and viability serves as an established tool for the detection of ischaemic aetiology of heart failure and therapeutic guidance before revascularization . However, the use of nuclear imaging in cardiac diseases has been changing due to advances in molecular imaging as well as advances in other imaging modalities, emerging evidence questioning established approaches to diagnose and risk stratify CAD and the emergence of specific, targeted therapies that require imaging biomarkers for guidance with respect to identifying the right patients and timing. High sensitivity of nuclear imaging together with development of new targeted tracers enables assessment of various cellular mechanisms of heart failure, such as inflammation, infiltration, innervation, metabolism, and fibrosis. Furthermore, recently introduced whole-body scanners provide improved evaluation of systemic distribution of tracers to study the interrelationships between the heart and other organs.Nuclear imaging is now routinely used for the diagnostic evaluation of cardiac sarcoidosis and amyloidosis. Innervation imaging has well-documented potential to predict heart failure progression and risk of arrhythmias, but its specific role in patient management remains to be established and will depend on integration with guidance of therapies. New tracers, such as those specific for inflammation and detecting early activation of fibrotic processes have shown promise as biomarkers to assess functional outcomes after myocardial injury. Molecular imaging of early disease activity has potential to provide tools for transition from current practice of treating heart failure to a future of biomarker-based precision medicine aiming at prevention of heart failure and support of tissue repair. However, clinical implementation requires clear definition of the prognostic value of new imaging techniques beyond existing imaging techniques and demonstration of their ability to guide selection of therapies.