Thus, the aim of this study was to derive a VO2peak/THV ratio and to test the hypothesis that this ratio can be used to distinguish patients with HF from healthy volunteers and endurance athletes. Thirty-one patients with HF of different etiologies were retrospectively included and 131 control subjects  were prospectively enrolled. Peak oxygen uptake was determined by maximal exercise test and THV was determined by cardiovascular magnetic resonance. The VO2peak/THV ratio was then derived and tested.An early sign of heart failure (HF) is a decreased cardiac reserve or inability to adequately increase cardiac output during exercise. Under normal circumstances maximal cardiac output is closely related to peak oxygen uptake  in the control subjects, but not for the patients . The VO2peak/THV ratio differed significantly between control subjects and patients, even in patients with normal ejection fraction and after normalizing for hemoglobin levels (p < 0.001). In a multivariate analysis the VO2peak/THV ratio was the only independent predictor of presence of HF (p < 0.001).Peak oxygen uptake was strongly correlated to THV (r2peak/THV ratio can be used to distinguish patients with clinically diagnosed HF from healthy volunteers and athletes, even in patients with preserved systolic left ventricular function and after normalizing for hemoglobin levels.The VO Heart failure (HF) is a complex syndrome associated with a variety of etiologies and clinical presentations  which im2peak), shown to be closely correlated to maximal cardiac output [2peak is closely correlated to the total heart volume (THV). Hence, a physiologically enlarged heart has a proportionally increased VO2peak. A decreased cardiac reserve and inability to increase cardiac output to meet the metabolic requirements during exercise might be the first sign of HF [Cardiac performance can be assessed by maximal exercise testing with measurements of respiratory gas exchange to determine peak oxygen uptake  is well suited for determination of the THV, given the completely three dimensional nature of the technique. CMR is also considered the gold standard for determination of cardiac function and dimensions .2peak/THV-index as a novel measure of the cardiac reserve and to test if this can be used to distinguish patients with HF from healthy volunteers and endurance athletes with physiologically enlarged hearts.Therefore, the aim of this study was to use maximal exercise testing with measurements of respiratory gas exchange and CMR to derive a VOThis study follows the Declaration of Helsinki and was approved by the regional ethics committee. All study subjects gave their informed consent to participate in the study.Thirty-one patients  who had been clinically diagnosed with HF with varying etiology were retrospectively enrolled and compared with 60 healthy volunteers  from the local community and 71 elite athletes  prospectively enrolled in the study. All underwent both CMR and maximal incremental exercise testing on ergometer cycle, with measurement of respiratory gas exchange, within a month for the patients and within a week for the healthy volunteers and athletes. Hemoglobin level was assessed within 2 weeks of the exercise test in patients and on the day of the exercise test in healthy volunteers and athletes who gave their consent for blood sampling.CMR was performed on a 1.5 T system  with a cardiac synergy coil. All subjects were placed in supine position. Cine short-axis gradient-recalled echo images covering the entire heart from base of the atria to the ventricular apex were acquired using a steady state free precession sequence - slice thickness = 8 mm, field-of-view = 340 mm, repetition time = 3.14 ms, echo time = 1.58 ms.For viability assessment in the patients, late gadolinium enhancement (LGE) images were acquired 20--30 minutes after intravenous injection of an extracellular gadolinium-based contrast agent . An inversion-recovery (IR) sequence was applied in the corresponding short-axis planes as for the cine images. Typical IR sequence parameters were: slice thickness = 8 mm, repetition time = 3.9 ms, echo time = 1.2 ms, in-plane resolution = 1.5 × 1.5 mm and flip angle = 15° with acquisition every heartbeat. The inversion time, typically 200--300 ms, was manually adjusted to null the signal from remote myocardium .http://segment.heiberg.se) [Total heart volume was measured in the cine short-axis images by planimetry as previously described . In shorberg.se) . The sumberg.se) ,17-21.Furthermore, endocardial borders of the left ventricular (LV) myocardium were manually delineated in end-diastolic and end-systolic short-axis images, enabling calculation of LV end-diastolic and end-systolic volumes (LVEDV and LVESV) as well as LV ejection fraction (LVEF). In addition, the epicardial borders of the left ventricle were delineated for determination of LV mass (LVM).Myocardial scar/fibrosis was assessed by manual delineation of the hyperenhanced myocardium in the LGE short-axis images.-1 (VO2peak) and ml min-1 kg-1 (VO2peakkg).A maximal incremental exercise test was performed using an electronically braked cycle ergometer  with respiratory gas analysis equipment . The test protocols were chosen to yield exercise duration of approximately 8-12 minutes, yielding starting stress between 10-150 W with 10-30 W increment per minute. Peak oxygen uptake was defined as the highest value reached at the end of exercise and expressed both as ml minA 12-lead ECG was acquired throughout the test. Blood pressure was measured by sphygmanometer in the supine position before exercise, every two minutes during exercise on the ergometer cycle and in the supine position at rest after exercise.2peak and THV was derived. Furthermore, the ratio was also normalized to hemoglobin levels to partly compensate for differences in oxygen delivery capacity in peripheral tissue in the presence of anemia. The VO2peak/THV ratio was also compared to levels of plasma amino terminal pro-brain natriuretic peptide (pro-BNP) for the patients who had a pro-BNP taken within 4 months of the exercise test.A ratio between VO2peak and THV as well as body weight. Unpaired T-test was used to assess differences between variables where normal distribution was assumed. The Mann-Whitney test was used to assess differences where normal distribution could not be assumed. Forward stepwise multivariate regression analysis was performed to assess the independent predictive values of THV, LVEF, LVEDV, VO2peak, VO2peakkg and the VO2peak/THV ratio for presence of HF. Receiver operating characteristic (ROC) analysis was performed to test the ability of the VO2peak/THV ratio to distinguish between HF patients and controls. All statistical analysis was performed using SPSS 16.0 . A p-value of <0.05 was considered statistically significant.Values are shown as mean ± standard deviation. Univariate linear regression analysis was used to assess the correlation between VOSubject characteristics are seen in Table 2 = 0.96, p < 0.001).The inter-observer variabililty for measuring THV was -5±37 ml  between VO2peak and THV for the control subjects  but no correlation  for HF patients  between VO2peak and body weight in the control subjects with a considerable variation in VO2peak for a given body weight.There was a strong correlation  than the other subject groups, even after normalizing for hemoglobin levels . However, there was a considerable overlap between the two groups   Figure . The LVE2peak/THV ratio and increasing pro-BNP .In 68% (21/31) of the HF patients a pro-BNP was taken 11 ± 25 days from the exercise test. There was a significant correlation between decreasing VO2peak/THV ratio was the only independent predictor of HF  functional classification ,23 is of2peak/THV ratio could potentially complement commonly used cardiac diagnostic biomarkers such as ECG and biochemical markers. A commonly used biochemical marker for severity of HF is pro-BNP, which has been shown to correlate with the severity of HF [2peak/THV ratio was shown to correlate with pro-BNP, indicating that the ratio can potentially serve as a measure for severity of HF.The clinical use a VOty of HF ,25. In t2peak are usually determined in relation to body weight and used to determine if a patient is suitable for heart transplantation or not [2peak for a given body weight  is negligible compared to the decrease in VO2peak/THV ratio found in the HF patients.There was a significant difference in mean age between the patient population and the control groups. However, the slight decrease in VO2peak can not be obtained in HF patients with acute decompensation, the VO2peak/THV ratio can not be used in these patients. The VO2peak/THV ratio might, however, be of significant benefit when the HF diagnosis is uncertain, such as in the situation of stage A HF or if the progression of the disease is less clear.Since VO2peak/THV ratio also remains to be determined in prospective follow-up studies of different patient groups with established HF or at risk for developing HF.Furthermore, the prognostic value of the VO2peak/THV ratio can be used to distinguish patients with known HF from healthy volunteers and athletes, even in patients with preserved systolic LV function and after normalizing for hemoglobin levels.The VOThe authors declare that they have no competing interests.HE, KS, MC, and HA have made substantial contributions to conception and design of the study. HE, KS, MC, TB, BE, HM, and BH, were responsible for acquisition of data. HE, KS, MC, BE, and HA were responsible for analysis and interpretation of the data. All authors have been involved in drafting the manuscript and revising it critically for important intellectual content. Furthermore, all authors have given final approval of the current version to be published.


Clinicians use presence of Q waves as a sign of transmural infarction although this is an imperfect marker to predict lack of myocardial viability (MV). We hypothesized that presence of R waves as a marker of electrical activity on surface electrocardiogram (ECG) may be a sensitive marker for presence of MV as determined by delayed enhanced cardiac magnetic resonance (DE-CMR) imaging.Retrospective study of 105 patients referred for assessment of MV by CMR with prior diagnosis of CAD and LV dysfunction. Cine steady state-free precession (SSFP) sequences and DE-CMR images were performed using standard protocols. Baseline ECG's were analyzed blinded to DE-CMR in 2 ways: presence of any R waves in ≥ 2 contiguous anterior , inferior  and lateral leads  and ≥ 3 contiguous lead in a similar fashion. ECG's were also analyzed for presence of Q waves and QR complexes in a similar fashion. DE was quantified using a standard 17-segment model. Anterior wall was considered viable when > 3 out of 7 segments had <50 % DE in each segment and > 2 out of 5 segments had < 50 % DE in the inferior and lateral walls.Mean age of the cohort was 63.2 ± 11.6 years and mean left ventricular ejection fraction was 33.5 ±13.6 %. With our viability definition, 83.8 % patients had viability in the anterior and inferior segments along with 95.2 % in the lateral segments. Sensitivity of any R wave to predict viability in the anterior wall was 96.5 % with a positive predictive value of 85.0 % but a poor specificity of 13.3%. Sensitivity of R waves for the inferior and lateral wall was 94.3 % and 100.0 % each. There was no substantial difference in sensitivity or PPV using both methods of R wave presence. (Table Presence of R waves on surface 12 lead ECG in patients with ischemic cardiomyopathy is a highly sensitive and simple tool to predict MV in all 3 major coronary artery territories with excellent positive predictive value. Clinicians could use this simple ECG tool to potentially channelize patients to further confirmatory viability testing when decision for revascularization based on left ventircular dysfunction is unclear.None


Recently Cardrase (6-ethoxyzolamide), a CA inhibitor, was found to prevent and revert agonist-stimulated cardiac hypertrophy (CH) in cultured cardiomyocytes. Our goal thus was to determine whether hypertrophied human hearts have altered expression of CA isoforms.Carbonic anhydrase enzymes (CA) catalyze the reversible hydration of carbon dioxide to bicarbonate in mammalian cells. Trans-membrane transport of CA-produced bicarbonate contributes significantly to cellular pH regulation. A body of evidence implicates pH-regulatory processes in the hypertrophic growth pathway characteristic of hearts as they fail. In particular, NaWe measured CA expression in hypertrophied human hearts to begin to examine the role of carbonic anhydrase in progression of human heart failure. Ventricular biopsies were obtained from patients undergoing cardiac surgery , or heart transplantation . CS patients presented mild/moderate concentric left ventricular hypertrophy and normal right ventricles, with preserved ventricular function; ejection fractions were ~60%. Conversely, HT patients with failing hearts presented CH or ventricular dilation accompanied by ventricular dysfunction and EF values of 20%. Non-hypertrophic, non-dilated ventricular samples served as controls.Expression of atrial and brain natriuretic peptide (ANP and BNP) were markers of CH. Hypertrophic ventricles presented increased expression of CAII, CAIV, ANP, and BNP, mRNA levels, which increased in failing hearts, measured by quantitative real-time PCR. CAII, CAIV, and ANP protein expression also increased approximately two-fold in hypertrophic/dilated ventricles.in vitro data that CA inhibition prevents and reverts CH, suggest that increased carbonic anhydrase expression is a prognostic molecular marker of cardiac hypertrophy.These results, combined with  Indeed, experimental and clinical studies demonstrated the pathophysiological implications of increased NHE1 activity during an ischemic episode and in hypertrophy [+ load, leading to elevated intracellular Ca2+ through the action of Na+/Ca2+ exchanger, NCX1. In some studies, increased cardiac expression of NHE1 protein appears to be involved in the subsequent pathological changes [Heart failure places an increasingly heavy disease burden on populations world-wide, leading to a need to understand basic mechanisms underlying the disease . Identifertrophy -4. NHE1  changes . In huma changes .-/HCO3- exchange mediated by AE3, since NHE activity alkalinizes the cell, resulting in self inactivation through a cytosolic modifier site [3- and H+ substrate for the two transporters [++ transients induced by pro-hypertrophic hormones, indicating that CA has a role in the elevated Ca++ found in the hypertrophic heart [Sustained NHE1 activity requires an acidifying pathway, such as Clier site ,8. Hyperier site . Maximalsporters -12. Treasporters . ETZ alsic heart . The ideic heart , may be Beneficial effects of NHE inhibition in the failing heart have been suggested on the basis of cellular signalling mechanisms and experimental studies ,15. HereThe study was approved the Human Research Ethics Board, Faculty of Medicine and Dentistry, University of Alberta and all patients gave written informed consent. To avoid possible disease-specific confounding factors, only samples from patients with early-stage hypertrophy  were used.later®  for storage.End-stage failing hearts , were biopsied following explantation associated with cardiac transplant surgery. Samples were collected from right or left free ventricular wall as indicated. Endomyocardial biopsy samples (EMBs), from patients who were referred to the University of Alberta Hospital for evaluation of cardiomyopathy, were collected by needle biopsy (average diameter 3 mm), and immediately placed into microcentrifuge tubes containing 4°C RNAhttp://www.chtn.nci.nih.gov/)), and used as a control) with RNeasy Micro kit , according to the manufacturer’s instructions. Isolated RNA was treated with DNase I  at 22°C, 15 min. RNA integrity was confirmed by agarose gel electrophoresis.RNA was isolated from human heart ventricles and human brain cortex (from Cooperative Human Tissue Network (http://www.ncbi.nlm.nih.gov/). Primers were designed with the Oligo software of the DNA Star program (http://frodo.wi.mit.edu/cgi-bin/primer3/primer3.cgi). In conventional RT-PCR, all primers generated only one amplification band visualized by agarose gel electrophoresis. Sequences for all PCR primers are presented in Additional file cDNA synthesis was carried out with Superscript III reverse transcriptase , according to the manufacturer’s instructions. cDNA sequences were obtained from the GenBank sequence database of the National Centre for Biotechnology Information . Real time PCR reaction contained 25 μL with 12.5 μL of 2X Platinum® SYBR® Green qPCR SuperMix-UDG (Invitrogen), 5 pmol/primer and 5 μL of template and cDNA prepared from 100 ng total RNA. Cycle threshold values (Ct) were obtained for CAII, CAIV, CAXIV, ANP, BNP, and GAPDH. GAPDH, assumed not to vary between samples, was used to normalize for differences in the efficiency of mRNA isolation from the samples as follows. Ct values were corrected for each sample by addition or subtraction of cycles so that GAPDH Ct values were the same.later® and stored at 4°C. Tissue was disrupted in PBS Buffer , containing protease inhibitors . After disruption, ventricular lysates were prepared by addition of SDS-PAGE sample buffer, heated at 70°C, 3 min, and centrifuged 10 min at 16,110 x g.Explanted heart samples were rapidly placed in RNA2 (19:1) environment in DMEM, with 5% (v/v) fetal bovine serum and 5% (v/v) calf serum. Two days post-transfection, HEK293 cells were washed in PBS buffer and cell lysates were prepared by addition of 150 μl SDS-PAGE sample buffer to each 60 mm tissue culture dish. Protein samples were transferred to PVDF membranes and then incubated with rabbit anti-human CAII , goat anti-CAIV antibody , goat anti-CAXIV antibody , goat anti-atrial natriuretic factor antibody , or rabbit anti-α-actinin antibody . Immunoblots were then incubated with donkey anti-rabbit IgG conjugated to horseradish peroxidase (HRP), mouse anti-goat IgG conjugated to HRP, or sheep anti-mouse IgG conjugated to HRP , as appropriate. Blots were visualized and quantified using ECL reagent and a Kodak Image Station.Expression constructs of human CAII, rabbit CAIV, and mouse CAXIV, have been described previously -18. HEK2Adult mice were anesthetized with sodium pentobarbital, 150 mg/kg i.p. Animal protocols were approved by the University of Alberta Animal Policy and Welfare Committee and performed in accordance with Canadian Council on Animal Care guidelines. Hearts were excised, and ventricular myocytes obtained by enzymatic dissociation .Data are expressed as mean ± SEM. Student Paired t-test or one-way ANOVA followed by Neuwman-Keuls Multiple Comparison post-test analysis, when appropriate, were used to compare data. P < 0.05 was considered of statistical significance.Clinical conditions of two patient cohorts are summarized. Patients undergoing cardiac interventions had good prognosis and good cardiac contractility measured by left ventricular ejection fraction values of 59 ± 3% , and ventricular slices, respectively, from 27 human samples. An average of 1 mg of total RNA, isolated from each EMB, was subjected to reverse transcription and quantification of transcript abundance by real-time PCR. To verify the specificity of the real-time RT-PCR data, we performed RT-PCR using the designed pair primers  values in real time-PCR were used as a measure of transcript abundance, where higher threshold values correspond to lower mRNA abundance and each change of 1 cycle threshold corresponds to a two-fold difference in message abundance. To correct for differences in total RNA abundance between samples, each sample was analyzed for ANP, BNP and the CA genes, and for GAPDH .In the failing hearts, CAII, CAIV, and ANP protein expression increased in ventricles without signs of hypertrophy or dilation compared to hypertrophic or dilated ventricles, demonstrating that these genes increased under hypertrophic conditions independent of the contractile performance of the heart. Conversely, failing explanted heart, showed no differences in CAII, CAIV, CAXIV, and ANP protein expression, in non-hypertrophic non-dilated right ventricles, compared to non-hypertrophic non-dilated left ventricles  . FurtherIn the human heart, the right ventricle has important anatomical and functional differences from the left ventricle. The right ventricle is a thin-walled, low-pressure structure that unlike the left ventricle receives most of its blood supply during systole. It has a complex, crescent shape in contrast to the left ventricle with a simple ellipsoid form. Differences between the two ventricles are, however, mostly related to their functions. As the left ventricle must pump blood much further and with more resistance than the right does, the muscular wall of the left ventricle is far thicker to produce the necessary force. Differences in the message and protein for CAs, ANP, and BNP genes expressed in healthy left ventricles compared to healthy right ventricles have not been evaluated here. We were unable to complete this analysis since we could not obtain comparable non-diseased ventricular material.-/HCO3- exchanger and NHE1 Na+/H+ exchanger to promote cardiomyocyte hypertrophy, as is found in heart failure  produces HCO3- and H+ for efflux by AE3, and NHE1, respectively  maximizes the transmembrane [HCO3- gradient, which enhances the rate of HCO3- transport. We propose that AE3, and NHE1, CAII, and CAIV work together to promote cardiac hypertrophy , blocks the reabsorption of sodium and potassium by inhibiting CA in the renal tubule , and wasClinical relevance of the present study includes: 1) Carbonic anhydrase expression levels, in particular CAII and CAIV, increase during progression of cardiac hypertrophy. The prognostic value of biomarkers as clinical predictor factors in heart failure is well-established -47 and tThis study suggests that ventricular hypertrophy/failure and the augmented expression of the CA in the ventricle may be induced by a common mechanism. Ventricular stretch arising from an increased ventricular load leads to the induction of CA gene expression. In this paper we have presented evidence of elevated CA as biomarkers for early detection of cardiac hypertrophy and heart failure, and proposing a mechanism that could improve the cardiac performance, by CA inhibition. The ability to distinguish individual patients at the early stage of heart disease, by detecting elevation of CA expression, might help to improve their functional status and prevent further circulatory collapse that will require cardiac transplantation.AE3: Anion exchanger isoform 3; ACTZ: Acetazolamide; ANP: Atrial natriuretic peptide; BNP: Brain natriuretic peptide; CA: Carbonic anhydrase enzyme; CAII: Carbonic anhydrase isoform II; CAIV: Carbonic anhydrase isoform IV; CAVI: Carbonic anhydrase isoform VI; CAXIV: Carbonic anhydrase isoform XIV; CH: Cardiac hypertrophy; CS: Cardiac surgery; Ct: Cycle threshold; EMB: Endomyocardial biopsy; ETZ: 6-ethoxyzolamide; HT: Heart transplant; HTM: Hypertrophic transport metabolon; HRP: Horse radish peroxidase; NHE: Sodium/proton exchange; PI: Protease inhibitors; qPCR: Quantitative polymerase chain reaction; SHHF: Spontaneous hypertension and heart failure.The authors declare that they have no competing interests.BV- Manuscript drafting, data acquisition, data analysis. ALQ- data aquisition. JM- data aquisition. JRC- Manuscript drafting, data analysis. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2261/13/2/prepub Sequence of primers used in real time polymerase chain reaction.Click here for file Clinical details of patients undergoing cardiac interventions, who provided endomyocardial biopsy samples.Click here for file Clinical details of patients undergoing cardiac transplant surgery.Click here for file


Working together is success.”Henry FordThe story of developing cardiac pacemakers is a story of team work. Very much like many great medical inventions developed in the Twentieth Century.During the Eighteenth Century, Scientists were fascinated by electricity and many experiments were conducted to study this new exciting field. In 1775, the Danish physicist Nickolev Abildgaard placed electrodes on the sides of a hen’s head and applied an electric discharge, which made the hen fall dead. When the electrodes were applied over the hen’s chest, it staggered onto its feet and walked away! It was like a magical revival of the dead. Great minds, such as Luigi Galvani (1737 – 1798) and Alessandro Volta (1745 – 1827) in Italy, Charles-Augustine de Coulomb (1736 – 1806) and André-Marie Ampère (1775 – 1836) in France, George Ohm (1789 – 1854) in Germany, and Michael Faraday (1791 – 1867) in England, were conducting important experiments, which established the basic understanding of electricity. Doctors were also involved in such research very early.In 1786, Luigi Galvani (1737 – 1798) an Italian professor of medicine, found that when the leg of a dead frog was touched by a metal knife, the leg twitched violently. Galvani thought that the muscles of the frog contained electricity, and he wrote about ‘animal electricity’. By 1792, another Italian scientist, Alessandro Volta, realized that the main factors in Galvani’s discovery were the two different metals, the steel knife and the tin plate upon which the frog was lying. Volta showed that when moisture comes between two different metals, electricity is generated. This led him to invent the first electric battery, the voltaic pile. In this way, a new kind of electricity was discovered, electricity that flowed steadily like a current, instead of discharging itself in a single spark. The instrument for measuring and recording electricity is named ‘Galvanometer’ after Galvani, and ECG is essentially a sensitive galvanometer. The unit of electrical potential, the Volt, is named after Volta.An essay upon the recovery of the apparently dead” he reported the use of an electrostatic generator (Layden jar) in the resuscitation of a three-year-old girl who was supposed to be dead after falling out of a window. In his own words he described the event: “with the consent of the parents, very humanely tried the effects of electricity. Twenty minutes had at least elapsed before I could apply the shock, which I gave to various parts of the body without any apparent success; but at length, on transmitting a few shocks through the thorax, I perceived a small pulsation; soon after that the child began to breathe, though with great difficulty. In about 10 minutes she vomited. A kind of stupor she remained for some days, but the child was restored to perfect health and spirit in about a week.” He went on to present his sound scientific vision in declaring that: “…electricity is the most powerful stimulus we can apply…if it is able so powerfully to excite the action of the external muscles, it will be capable of reproducing the motion of the heart which is infinitely more irritable, and by that means accomplish our great desideratum, the renewal of the circulation.”John Hunter (1728 – 1793), a Scottish surgeon who is one of the most distinguished pioneers of experimental surgery, in 1776, recommended that electric stimulation should be tried in the resuscitation of drowning victims. In London, Charles Kite attempted that in 1788. In “Tambora’s 1815 outburst in Indonesia was the largest volcanic eruption in recorded history. The explosion was heard more than 2,000 km away. The death toll was at least 71,000 people (the most deadly eruption in recorded history). The eruption created global climate changes that included the phenomenon known as ‘volcanic winter’: 1816 became known as the ‘Year without summer’ because of the cooling effect on North American and European weather. Agriculturai crops failed and livestock died in much of the Northern Hemisphere, resulting in the worst famine of the Nineteenth century. During that dreadful summer of 1816, Mary Shelley, aged 18, and her lover (and later husband) Percy Shelley, visited Lord Byron in Switzerland. Among other subjects, conversations turned to galvanism and the feasibility of returning a corpse or assembled body parts to life, and to the experiments of the eighteenth-century natural philosopher and poet Erasmus Darwin, who was said to have revived dead matter. Inspired by this situation, the young writer Mary Shelley came up with the horrific science fiction novel ‘Frankenstein,’ which was published in 1818. The novel told the story of Victor Frankenstein, the bioscientist who managed to assemble parts of dead human bodies and ‘bring them back to life’ by lightning, to create the famous nameless monster that was mistakenly named later after the name of the ‘mad’ scientist… Frankenstein!In 1899, Jean-Louis Prévost (1838 – 1927) and Frederic Batelli in Geneva demonstrated that electrical currents could cause ventricular fibrillation, which could often be reversed by another powerful stimulus of either alternating or direct current to the canine heart, thereby inventing the first electrical defibrillator. John A. McWilliam (1857 – 1937) of Scotland published a series of articles, between 1887 and 1899, on cardiac electrophysiology in mammals, in which he identified an area of the sino-atrial node, studied the development and progression of ventricular fibrillation, postulated that sudden death in humans could be the result of ventricular fibrillation, and proved that it was possible to evoke cardiac contractions by electric stimuli applied directly to the heart. Louise Robinovitch, a pioneer woman in American medicine, a graduate of the Women’s Medical College of Pennsylvania in 1889, continued her studies and research in France in the 1900s. She discovered that pulsed electrical stimuli could be used for cardiac resuscitation. She designed equipment, which was the forerunner of the automatic defibrillator. She published a series of reports from 1906 through 1909, designed the first portable electrical resuscitative apparatus for ambulances and almost came up with an external pacemaker device. Interestingly, the significance of these sporadic experimental and clinical reports was not well appreciated at the time because of the lack of understanding of ventricular fibrillation. Electric defibrillation was considered impractical and applications of either cardiac pacing or electrical defibrillation were delayed.In 1938 – 1939, impressive research on electrophysiology was performed by the pioneer Naum Lazarevich Gurvich (1905 – 1981), in Moscow. He investigated the effects of alternating (AC) and direct (DC) electric currents on the heart. His study was published in English in 1945. He demonstrated the advantages of DC over AC shock, and even proposed the biphasic waveform defibrillation at that early time. His defibrillator was used clinically in cardiac operations in 1952, in USSR. His biphasic waveform defibrillation had to wait another 50 years before it was clinically applied in external and implantable defibrillators. Gurvich was awarded the National Award of USSR in 1970.It was not until the efforts of William Kounwenhowen (1932), Naum Gurvich (1939), and Carl J. Wiggers and Claude Beck (1947) that electrical defibrillation became widely used. A boy, 14 years of age, was operated by the American cardiac surgeon Claude Schaeffer Beck (1894 – 1971), for repair of severe funnel chest. During the closure of the chest incision, the pulse suddenly stopped and blood pressure could not be recorded. The patient was apparently dead. The wound was reopened and cardiac massage was initiated. Cardiac massage was continuously given for 35 minutes, at the end of which the electrocardiogram was characteristic of ventricular fibrillation. A first electric shock applied directly to the heart was unsuccessful. Procaine hydrochloride was injected into the right atrium, the heart massaged and a second series of shocks given. The heart then was in standstill. However, feeble, regular, and fairly rapid cardiac contractions appeared. Cardiac massage was continued for five more minutes, at which time it was obvious that the contractions became coordinated and fairly vigorous, although still fast. The electrocardiogram at this time revealed supraventricular tachycardia at a rate of 175. The heart gradually increased in vigor and brachial blood pressure was 50. This was a report of the first case, published in 1947, with complete recovery after prolonged ventricular fibrillation. Beck suggested that operating rooms should be equipped with electric shock devices to treat cases of sudden ventricular fibrillation, and that personnel should be trained in the method. He also recommended that speed and precision in the technique were important!I think I recognized at that time that a new field of electric cardiac stimulation had begun”.These early defibrillators were successful, but they had a great disadvantage: the paddles had to be applied directly to the heart, which of course required major surgery. The first successful ‘closed chest’ defibrillation was performed by the American cardiologist Paul Maurice Zoll (1911 – 1999), of Boston in 1956, using a device with a large rechargeable battery. Zoll’s achievement was based on research in dogs and clinical research on external pacing. He later described the first time he had observed stimulation of the canine ventricle by application of electric current to the chest, “The biphasic waveform was first developed by the Russian scientist Naum L Gurvich in the 1930s, after years of research in animals. It was not until the 1980s that research in the west indicated its superiority to the Lown waveform introduced by Bernard Lown in 1959. The Lown waveform was the standard for defibrillation until the late 1980s, when numerous studies showed that a biphasic truncated waveform (BTE) was better. The major advantage of biphasic over the Lown waveform was that it required less energy, which made it safer, with reduced risk of burns and muscle damage. The reduced power requirement also enabled the manufacture of lighter, more portable machines.The BTE waveform, combined with automatic measurement of transthoracic impedance is the basis for modern defibrillators. Defibrillators have come a long way in the last half-century, and now save lives on the streets and even in the air, as well as in hospitals and ambulances. Their success in preventing deaths in cases of sudden cardiac arrest has led to the installation of defibrillation machines in airports, railway stations, restaurants, sports centers, and many other public places.In 1882, Hugo von Ziemssen (1829 – 1902) in Germany described a case of a 42-year-old lady who had a postoperative defect in the anterior left chest wall. The heart was covered only by a thin layer of skin and was directly palpable. von Ziemssen noted that application of electrodes to the heart resulted in rhythmic stimulation only if the rate of stimulation was greater than that of the spontaneous heart rate. Slower stimulation produced erratic and sometimes slower heart rate. He also noted that the most sensitive area for stimulation was in the region of atrioventricular groove. Interestingly, this observation was made more than a decade before the description of the location of the atrioventricular node and bundle by Wilhelm His (1863 – 1934).One pole was applied to a skin pad soaked in strong salt solution,” while the other pole “consisted of a needle insulated except at its point, and was plunged into the appropriate cardiac chamber. The pacemaker rate was variable from about 80 to 120 pulses per minute, and likewise the voltage was variable from 1.5 to 120 volts”. In 1928, the apparatus was used to revive a stillborn infant whose heart continued “to beat on its own accordt the end of 10 minutes of stimulation”.In 1926, the Australian anesthesiologist Mark C. Lidwill (1878 – 1968), devised a portable apparatus in which “In 1932, the American physiologist Albert S. Hyman (1893 – 1972) described an electro-mechanical instrument of his own, powered by a spring-wound, hand-cranked motor. Hyman coined the term ‘artificial pacemaker’, in 1932, to describe this electric device that could pace the heart and lead it like an artificial maestro! The delay in publication and application of this research was attributed to the public perception of interfering with nature by ‘reviving the dead’ and ‘prolongation of life and interfering with the will of God’. In those days, death was defined as the arrest of cardiac activity and absence of pulse. Hyman did not publish data on the use of his pacemaker in humans because of adverse publicity, both among his fellow physicians, and due to newspaper reporting at the time. Lidwill may have been aware of such resistance and did not proceed with his experiments in humans.Out of interest and desperation,” recalls Bigelow, “I gave the left ventricle a good poke with a probe I was holding…All the four chambers of heart responded to it and further pokes clearly indicated that the heart was beating normally with good blood pressure”. He discussed this event with Dr. Callaghan. Using dogs and rabbits, they studied the most effective safe electric current, and presented movies of their experiments at the Annual Surgical Congress of the American College of Surgeons, in 1950. The external pacemaker was designed and built by the Canadian electrical engineer John Hopps (1919 – 1998) based on observations by cardiothoracic surgeon Wilfred Bigelow at the Toronto General Hospital. The device was a large electrical machine with vacuum tube technology, to provide transcutaneous pacing. It was somewhat crude and painful to the patient, and being powered from an AC outlet; it carried a potential hazard of electrocution of the patient when inducing ventricular fibrillation. John Hopps himself later became a pacemaker recipient. In the cold war era, it was difficult for them to be aware of the brilliant earlier research done in the Soviet Union (USSR).Wilfred G. Bigelow (1913 – 2005), John A. Callaghan and John Hopps in Canada used transcutaneous electrodes to pace the right atrium in dogs. In 1949, during an experimental operation, a dog’s heart suddenly stopped. “Hopps also designed the first catheter-electrode for cardiac stimulation, which was introduced via the right external jugular vein of the experimental animal. Using his external pacemaker, atrial pacing was achieved and control of the cardiac rate was accomplished. In 1950, Paul M. Zoll began work on an external pacemaker, which was used to stimulate the heart, across the chest wall. The pacemaker current put out a maximum of approximately 150 volts. Output voltage and stimulation rates were controlled from the front panel of the pacemaker. The electrodes were two, one-inch diameter metal disks placed on the right and left sides of the chest, held in place by a rubber strap and made contact via conductive electrode jelly. By 1952, the first articles concerning the pacemaker were published, and revolutionized the concept of resuscitation of the patient with heart block and asystole. External pacing was painful and required sedation. Prolonged stimulation produced local skin burns. The longest period of reported stimulation was 11 days. Zoll also later developed a bulky external transcutaneous pacemaker operated by rechargeable batteries.Earl Bakken (1924 –), an electrical engineer designed the first battery-operated pacemaker. Bakken and his brother-in-law Palmer Hermundslie co-founded Medtronic, in 1949, in a garage in Minneapolis. The company operated mainly as a repair service for hospital electrical equipment. At the time, Clarence Walton Lillehei (1918 – 1999), was starting a successful repair of the congenital heart defect using cross-circulation, and later on, using the heart–lung machine. About one patient in ten developed complete heart block postoperatively. Drugs such as adrenaline, atropine or isoprenaline, were helpful in the short-term, but proved disappointing over a longer period of time and could not prevent a sudden recurrence of heart block. Another solution had to be found. It was thought that temporary pacing could keep patients alive until recovery of the conducting system. The external pacing developed by Zoll was clearly inappropriate as the high voltage pacing delivered transcutaneously would be far too traumatic on these young children.Lillehei and his co-workers developed a myocardial wire: a stainless steel wire in a Teflon sleeve. One end of this wire was implanted directly into the myocardium and the other end was exteriorized and connected to a stimulator. An indifferent electrode was buried under the skin to complete the circuit. Effective pacing needed only 1.5 volts as there was direct contact with the myocardium. There was no rejection and no damage to the beating heart and the wire could be removed easily once normal conduction resumed. The first myocardial wire was implanted in 1957, in a three-year old girl, in whom heart block had complicated the repair of Fallot’s tetralogy. Pacing was successful and the little girl soon regained sinus rhythm and survived. The myocardial wires were implanted electively in all patients; ready for immediate use should this become necessary.Without any grandiose expectations for the device, I was moderately optimistic about what it might eventually do for Lillehei’s patients. I drove the device over to the University’s animal lab where it could be tested on a dog. Of course it worked. The next day I returned to the hospital to work on another project when I happened to walk past a recovery room and spotted one of Lillehei’s patients. The little girl was wearing the prototype I had delivered only the day before! I was stunned. I quickly tracked down Lillehei and asked him what was going on. In his typical calm, measured, no-nonsense fashion he explained that he’d been told by the lab the pacemaker worked and he didn’t want to waste another minute without it. He said he wouldn’t allow a child to die because we hadn’t used the best technology available.” In modern terms, this was the first VOO external portable pacemaker.Further problems soon became obvious: the stimulator was large and heavy and the system depended totally on external power supply, On October 31, 1957, a municipal power failure lasting three hours resulted in the tragic death of a baby. The day after, Lillehei requested Bakken to see if Medtronic could come up with something better. After only four weeks of experimentation in using the transistor circuit, the first battery-powered pacemaker was put in clinical use! Bakken recounts: “On October 8, 1958, the first implantation of a totally internal pacemaker was performed in Sweden. The system was developed by the surgeon Ake Senning (1915 – 2000), and the physician inventor Rune Elmqvist (1906 – 1996), It was implanted on a 43-year-old engineer called Arne Larsson. This experience was reported at the Second International Conference on Medical Electronics in 1959.Senning was the cardiac surgeon in charge of the Department of Thoracic Surgery at the Karolinska Hospital in Stockholm. He had observed Lillehei’s work with temporary external pacing. Elmqvist was a medical graduate who became an engineer. He designed a portable ECG machine and ink jet printer. These two men began to collaborate closely in 1950 and developed fibrillators and defibrillators for open heart surgery. They realized that the main problem with external pacemakers was the route for ascending infection along the wire, and planned to design a fully implantable system. Silicone transistor technology was used in the circuit. The pulse generator was powered by two rechargeable nickel-cadmium batteries. Recharging was delivered transcutaneously using external induction coils for 12 hours every week.Arne Larsson had been hospitalized with complete heart block and frequent Stokes-Adams attacks for six months. He was having 20 to 30 attacks daily and his prognosis was poor. Treatment was maximized with ephedrine, atropine, isoprenaline, caffeine, digoxin, and whisky without success.I implanted the first pacemaker, but it lasted only eight hours. Presumably, I had damaged the output transistor or capacitance with the catheter and I did not have the other one which was in the lab. I implanted the other one early the next morning”. The second pacemaker functioned well for about one week. In modern terms, this was the first VOO internal pacemaker, The pulse rate was fixed at a constant rate of 70 to 80 beats per minute. The energy need was minimized, as Elmqvist used silicon transistors in the circuit. The entire unit was handmade and was encapsulated in a resin that had excellent biocompatibility. The approximate diameter was 55 mm, and thickness 16 mm.To avoid publicity, the implantation of the pacemaker was done in the evening when the operating rooms were empty. Two electrodes were implanted into the myocardium and tunneled to the pacemaker pulse generator placed in the abdominal wall. The first pacemaker implanted functioned only a few hours. Senning recounts: “Rune Elmqvist died in 1997, Ake Senning remained very active in the field of cardiac surgery and died in 2000. The patient Arne Larsson survived both the engineer and the surgeon who had saved his life. He required five lead systems and 22 pulse generators of 11 different models until his death from cancer on December 28, 2001, at the age of 86 years.Wilson Greatbatch (1919), is an electrical engineer who was teaching at the University of Buffalo, where he accidentally discovered the way to make an implantable pacemaker, while working on an oscillator to aid in the recording of tachycardia.It was no accident; the Lord was working through me. The oscillator required a 10 K resistor at the transistor base. I reached into my resistor box for one, but I misread the color coding and got a 1 M resistor by mistake.” When he plugged in the resistor, the circuit started to ‘squeg’ with a 1.8 millisecond pulse followed by a 1 second interval during which the transistor was cut off and drew practically no current. “I stared at the thing in disbelief” he said. Greatbatch realized that this small device could drive a human heart, but it wasn’t easy to find a surgeon who would believe in his idea.Greatbatch describes the event this way: “I seriously doubt if anything I ever do will give me the elation I felt that day when a 2 cubic inch electronic device of my own design controlled a living heart.” Chardack reported the first success in a human with this unit in 1960. The procedure was completed in June 1960 on a 77-year-old man, in complete heart block. Chardack implanted the lead, measured the threshold, and implanted the pulse generator. The patient survived uneventfully for two years. The system was powered by mercury–zinc battery that usually lasted for about five years.William Chardack, was chief of surgery at Buffalo’s Veteran’s Hospital at the time. On May 7, 1958, Greatbatch brought what would become the world’s first implantable pacemaker to the animal laboratory at the hospital. There, Chardack and another surgeon, Andrew Gage, exposed the heart of a dog to which they touched the two pacing wires. The heart proceeded to beat in synchrony with the device. A year later, Greatbatch wrote “In 1961, Chardack, Gage, and Greatbatch reported a series of 15 patients who had implanted pacemakers. Greatbatch later invented the long-life lithium–iodine battery, which powered modern pacemakers.Faulty batteries, body fluids leaking into the case and broken leads caused numerous pacemaker failures that required emergency operation. The main difficulty, however, was the lead. It was obvious that the myocardial wire was unsuitable for long-term use. Stimulation threshold increased after a few weeks until an exit block developed and no more capture was possible. Moreover, the wire could not resist the mechanical stresses. These technical problems contributed to the delay in the widespread use of implanted pacemakers for several years.The technique for inserting permanent transvenous bipolar pacing electrodes was developed in 1962, by Victor Parsonnet (in USA) and by Ekstrom (in Sweden). Transvenous leads replaced myocardial leads. Pacemakers and their leads could be implanted without a thoracotomy and without general anesthesia. Lead designs were improved: ‘tined’ for passive fixation and ‘screw-in’ for active fixation.In the early 1980s steroid-eluting leads were developed to decrease the inflammatory response evoked by the tip. Consequently, the early rise of the capture threshold was resolved and safety was enhanced.The lithium–iodine battery was developed to replace the mercury–zinc battery. This resulted in greatly increased pacemaker longevity.The use of external pacing was reported by Zoll in the late 1950s; however, Zoll’s pacemaker was a fixed system without a demand capability and could cause ‘R on T’-induced ventricular fibrillation. At St. George’s Hospital in London, Aubrey Leatham (1920),and Geoffrey Davies (1924 – 2008) developed the first demand circuit device, which was published in 1956. However, Demand pacemakers were not in clinical use till the late sixties.In 1972, an American-made radioisotope pacemaker was implanted by Parsonnet. These nuclear pacemakers had an expected life of 20 years, but went out of fashion mainly due to the need for extensive regulatory paperwork.Radio-frequency telemetry made pacemakers non-invasively programmable in the mid-70s. Most pacing parameters could be remotely adjusted to follow the changing clinical needs of the patient. Modern telemetry allows follow-up of pacemaker patients anywhere in the world, by the use of telephone lines and mobile phones. Modern pacemakers can store some medical information about the patient, record cardiac events, and ECG, By the end of the ‘70s dual-chamber pacemakers were developed to pace and sense in both the atria and ventricles. Synchronized DDD timing made it possible to preserve the atrial contribution to ventricular filling as well as to track the intrinsic atrial rate. In the mid-1980s, rate-responsive pacemakers were designed.Biventricular pacing for heart failure was introduced and started the revolution of Cardiac Resynchronization Therapy (CRT). An additional lead was introduced via the coronary sinus toward the left ventricle. The right ventricle (via the standard lead) and the left ventricle (via coronary sinus lead) were paced simultaneously to resynchronize their contraction and improve the symptoms and survival of properly selected heart failure patients.The development of the Internal defibrillators (ICD) was pioneered at the Sinai Hospital in Baltimore by a team that included Michel Mirowski (1924 – 1990) and Morton Mower (1933). They started their research in 1969, but it took 11 years before they treated their first patient. More than a decade of research went into the development of an implantable defibrillator that would automatically sense the onset of ventricular fibrillation and deliver an electric counter-shock converting the heart to sinus rhythm.The very rare patient who has frequent bouts of ventricular fibrillation is best treated in a Coronary Care Unit and is better served by an effective antiarrhythmic program or surgical correction of inadequate coronary blood flow or ventricular malfunction. In fact, the implanted defibrillator system represents an imperfect solution in search of a plausible and practical application”. Just eight years later, the first ICD device was implanted in February 1980, at Johns Hopkins Hospital by Levi Watkins. The patient survived for 10 years and died from unrelated causes.Leading experts in the field of arrhythmias and sudden death were skeptical. There was doubt that the idea of an implantable defibrillator would ever become a clinical reality. In 1972, Bernard Lown, the inventor of the Lown waveform, which was the standard for defibrillation until the late 1980s, stated: “Initially, ICDs were implanted via surgical thoracotomy with the defibrillator patches applied directly to the epicardium or pericardium. The leads were attached to the device, which was placed in a large subcutaneous abdominal wall pocket. Most ICDs nowadays, are implanted transvenously with the devices placed in the left pectoral region similar to pacemakers, and can deliver CRT pacing, cardioversion, and defibrillation.Cardiothoracic surgeons were leading pioneers in developing and implementing the clinical use of cardiac pacing and defibrillation. Great pioneers, such as Beck, Bigelow, Lillehei, Senning, Chardack, Parsonnet, Watkins, and others, were leaders in this field. Almost all early clinical applications of cardiac pacing and defibrillation required an operative approach, before further technical advancement allowed transvenous placement under local anesthesia. Young cardiologists and cardiothoracic surgeons may be surprised to know the significant contribution of pioneer surgeons to understanding and treating cardiac arrhythmias. I recall a time when I was a resident in cardiothoracic surgery at the Medical University of South Carolina in 1981, when we used to do all transvenous pacemaker implantation, and started the early clinical trials of dual chamber (DDD) pacemakers. Cardiology fellows had just started to join us then to learn these techniques. Yet, the story of cardiac pacing is a story of success in cooperation in this magnificent century. The collaboration between engineers, cardiologists, cardiothoracic surgeons, and patients was the fundamental driving force for the development of new hope for cardiac patients, and the growth of a significant global industry. The cooperation between these pioneers was a success story of team work; doctors working together, and extending caring hands to help their patients.


As a precursor to overt heart failure, diabetics experience a unique alteration in myocardial architecture marked by diffuse interstitial fibrosis. We hypothesized that the myocardial extracellular volume fraction (MECVF) could be used to detect myocardial matrix remodeling and its relationship to ventricular structure and function in diabetics without cardiovascular disease.Diabetics without any history of MI  or heart failure underwent 3T CMR imaging and assessment of MECVF and assessment of biochemical parameters of insulin sensitivity. 10 volunteers without diabetes, hypertension, or clinical cardiac disease were used for comparison. Cine SSFP, LGE imaging, and myocardial T1 quantitation using a modified Look-Locker sequence were performed. For measurement of MECVF, segmental myocardial T1 was measured once pre-Gd and at least 3 times over 3-20 minutes post-Gd . Regression of myocardial R1 (=1/T1) on R1 in the blood pool was used to determine the Gd partition coefficient, which when multiplied by (1-hematocrit/100), gave MECVF. Left atrial volume index (LAVI) and emptying function, as well as LV and RV volumes and function, were determined by standard techniques.55 recruited patients were predominantly male (62%), with an average age of 54±8 years, systolic blood pressure 126±14 mmHg, body mass index (BMI) 32.4±4 kg/m2, fasting glucose 108±25 mg/dl, and triglycerides 128±69 mg/dl. CMR LVEF averaged 60±5%, LV mass index 45±11 g/m2, LVEDV index 68±14 ml/m2, LAVI 35±9 ml/ m2 . MECVF in diabetics was 0.36±0.05 . MECVF correlated with LAVI , but not with LV mass index, fasting glucose or insulin levels, insulin sensitivity, triglycerides, LVEF, age, BMI, LA function or systolic blood pressure.Well-controlled diabetics with normal ventricular structure, function, and no prior cardiac disease have diffuse interstitial myocardial fibrosis by CMR. Diffuse fibrosis is associated with LAVI, a marker of diastolic function, but not with other markers of clinical or cardio-metabolic risk. Diffuse myocardial damage occurs early in the course of diabetic cardiomyopathy independent of hypertension and obesity, and may be a potential target for early intervention in at-risk diabetic patients with subclinical myocardial disease.RVS was supported by a Post-Doctoral Fellowship Grant from the American Heart Association (11POST000002). RYK, MJ, GKA are supported by grants from the National Institutes of Health.


P < 0.01), ESV and WMSI were higher , and anterior infarct localization was more frequent (P = 0.02) than in the secondary prevention group (n = 29). There were no differences in infarct tissue characteristics between patients treated for primary versus secondary prevention . During 21 ± 9 months of follow-up, 3 (5 %) patients in the primary prevention group and 9 (31 %) in the secondary prevention group experienced appropriate ICD therapy for treatment of ventricular arrhythmia (P < 0.01). There was no difference in infarct tissue characteristics between recipients of ICD for primary versus secondary prevention, while the secondary prevention group showed a higher frequency of applied ICD therapy for ventricular arrhythmia.Knowledge about potential differences in infarct tissue characteristics between patients with prior life-threatening ventricular arrhythmia versus patients receiving prophylactic implantable cardioverter-defibrillator (ICD) might help to improve the current risk stratification in myocardial infarction (MI) patients who are considered for ICD implantation. In a consecutive series of (ICD) recipients for primary and secondary prevention following MI, we used contrast-enhanced (CE) cardiovascular magnetic resonance (CMR) imaging to evaluate differences in infarct tissue characteristics. Cine-CMR measurements included left ventricular end-diastolic and end-systolic volumes , left ventricular ejection fraction (LVEF), wall motion score index (WMSI), and mass. CE-CMR images were analyzed for core, peri, and total infarct size, infarct localization (according to coronary artery territory), and transmural extent. In this study, 95 ICD recipients were included. In the primary prevention group (n = 66), LVEF was lower (23 ± 9 % vs. 31 ± 14 %;  Ventricular arrhythmia (VA) is a major cause of sudden cardiac death (SCD) in patients with prior myocardial infarction (MI) . SeveralCardiovascular magnetic resonance (CMR) imaging in combination with the contrast-enhancement (CE) technique allows the accurate assessment of LV geometry and function as well as tissue characteristics. This permits accurate assessment of size, heterogeneity, and transmurality of the myocardial scar , 9. InfaPrevious studies demonstrated a higher occurrence of VA (and thus a higher incidence of appropriate ICD therapy) in ICD recipients for secondary prevention compared to patients who received an ICD in the setting of primary prevention , 15–18. Therefore, in a consecutive series of ICD recipients for primary and secondary prevention following MI, we used CE-CMR to evaluate potential differences in infarct tissue characteristics.The study was conducted at Medisch Spectrum Twente, Enschede, the Netherlands. A consecutive series of patients with prior MI, who received an ICD for primary or secondary prevention following current guidelines of the Dutch (NVVC) and European society of Cardiology (ESC) in which the LVEF was determined based on echocardiographic findings, was assessed. The referring physicians had no access to the CMR report before defining therapeutic management. Prior to ICD implantation, these patients were referred for CMR to assess left ventricular (LV) dimension and function, and after intravenous injection of gadolinium, characterization of the infarcted tissue. According to current guidelines, the patients who received ICD treatment for primary prevention had an indication based on a LVEF ≤ 35 % (majority of patients) or the presence of spontaneous ventricular tachycardia, even with a somewhat more preserved LV function. Patients were only included in the study if the MI occurred at least 1 month prior to CMR  was not selected based on a particularly low ejection fraction, the mean LVEF of this group may be expected to be higher. To correct for this potential confounder, ICD recipients from both groups with a LVEF ≤ 35 % were separately compared. A comparable subgroup analysis in ICD recipients with a LVEF > 35 % was not performed as the limited number of patients did not permit a meaningful analysis.CMR examination was performed on a 1.5-T whole body scanner  using commercially available software. For signal-reception a five-element cardiac synergy coil was used. Electrocardiogram triggering was performed with a vector-electrocardiogram set-up. Subjects were examined in the supine position. Cine (morphologic) images in the cardiac short-axis, four-chamber, three-chamber, two-chamber long-axis, and LV outflow tract views were acquired by using fast field echo cine images. .Myocardial scar was assessed on CE multislice short- axis, long-axis and four-chamber views, obtained 10 min after intravenous bolus injection of 0.2 mmol gadolinium/kg body weight . A three-dimensional Turbo Field Echo-inversion recovery T1-weighted sequence was used with the following parameters: repetition time 4.0 ms; echo time 1.3 ms; flip angle 15°; inversion time individually optimized to null myocardial signal ; matrix 157; and slice thickness 10 mm.CMR data were analyzed on a workstation using dedicated software . Analysis was performed by reviewers blinded to clinical information.Left ventricular end-diastolic and end-systolic volumes , left ventricular ejection fraction , and end-diastolic wall mass  were calculated from contiguous short-axis loops by segmentation of endocardial and epicardial borders on each frame. Body surface area adjusted EDV (EDVi), ESV (ESVi) and EDWM (EDWMi) were also calculated.The left ventricular wall regions were further divided into 17 segments according to a standardized myocardial segmentation model . Normal Infarcted myocardium was defined as the zone of hyperenhancement on the CE images, in contrast with the dark-gray signal of normal myocardium Fig. . InfarctScar tissue characteristics were further quantified according to location by use of a 17 segmental model . Each setransmural extent of myocardial scar was defined as the number of segments with a scar score 3 or 4 [regional scar score was calculated in order to relate scar size to the territories of the three major coronary arteries as previously described in detail [The e 3 or 4 . In addin detail .Follow-up was performed by our outpatient clinic, including registration of the occurrence of events and survival status. Regular device interrogation was scheduled every 3–6 months. In case of any experienced event, an additional device interrogation was performed. Device therapy was classified as appropriate or inappropriate. Appropriate ICD therapy was defined as anti-tachycardia pacing and/or appropriate shock in response to ventricular tachycardia or ventricular fibrillation. For the purpose of this study, only appropriate device therapies were considered as arrhythmic events. Mortality was reported and causes of death were scored as follows: (1) myocardial infarction, (2) heart failure, (3) cerebrovascular accident, (4) carcinoma, or (5) other causes of death.A major cardiovascular event (MACE) was defined as appropriate ICD therapy and/or death.t test and Mann–Whitney U test were used to compare continuous variables, and Chi-square test and Fisher exact test were used to compare categorical variables. A survival analysis was performed to investigate if the association between infarct tissue characteristics with MACE is different among groups (ICD for primary preventions vs. ICD for secondary prevention). A P value < 0.05 was considered statistically significant.Continuous variables had a normal distribution and were expressed as mean ± SD. Categorical data were expressed as frequencies and percentages. To compare the primary and secondary prevention groups, Student’s P < 0.01). Patient demographics are presented in Table In this study, 95 patients  with a median of 141 (1–434) months after MI were examined. A total of 66 patients received an ICD for primary prevention and 29 patients for secondary prevention. Indication for secondary prevention by ICD implantation was (1) SCD in 14 patients (48 %) or (2) VT episodes in 15 patients (52 %). Time between events and ICD implantation was on average 2 weeks (median). . In general, ICD implantation was performed shortly after CE-CMR assessment; the average (median) within 1 week, the 75th percentile within 1 week and the 90th percentile within 5.4 weeks. Demographics and baseline characteristics did not differ between groups except for diuretic usage  was significantly lower while ESVi  and WMSI  were significantly higher than in the secondary prevention group , size of the peri-infarct , total infarct size  and transmural extent  of the infarct  was significantly higher in the primary prevention group  and a higher WMSI  than the secondary prevention group (n = 14); but there was no significant difference in infarct tissue characteristics . In the primary prevention group, only appropriate shock therapy  was delivered, while in the secondary prevention group both appropriate shock therapy  and antitachycardia pacing (n = 6) were delivered. All but 2 patients with appropriate ICD therapy (both secondary prevention) had a ≤35 %.During 21 ± 9 months of follow-up, 4 patients in the primary prevention group and 4 patients in the secondary prevention group died, respectively. All 8 patients died on heart failure. The frequency of appropriate ICD therapy differed significantly between the primary and secondary prevention group (3/66 (5 %) vs. 9/29 (31 %); P = 0.20), but core infarct size was smaller in patients with events .Patients with appropriate ICD therapy did not differ from patients without event in peri-infarct size .The association between infarct tissue characteristics with MACE did not significantly differ among groups (ICD for primary prevention vs. ICD for secondary prevention)  there was a higher use of diuretics for symptomatic treatment of heart failure. On the other hand, secondary prevention patients—patients who already had a life-threatening VA in the past—showed more appropriate ICD therapies during follow-up, as may be expected based on the difference in indication. Thus, there must be other factors than the studied CMR characteristics involved to make the myocardium prone to the development of life-threatening VA.In the primary prevention group, we found a substantially larger amount of MI tissue in the anterior wall of the LV during CMR assessment. Several clinical studies observed that patients with anterior MI usually have a worse LVEF . The larWith current clinically applied CE-CMR technology, spatial resolution imposes constraints on what type of tissue is concealed within the peri-infarct zone, characterized by intermediate signal intensities . High-reWhile CMR is the gold standard for the assessment of LV function, myocardial viability, extent and transmurality of scar, our findings suggest that infarct tissue analysis with the CE-CMR technique that is currently applied in clinical practice does not appear to have the potential to improve the current practice of risk stratification in MI patients considered for ICD implantation.Our study comprises a limited number of patients; nevertheless, this represents a consecutive series of patients examined with CE-CMR for that indication. While the secondary outcome of defibrillator shocks was prospectively collected and analyzed, the primary comparison of CE-CMR image characteristics was based on a cross-sectional approach. In the light of the duration of clinical follow-up of 21 ± 9 months, event rates in subgroups should be interpreted carefully. In addition, primary aim of the present study was the assessment of potential differences in infarct tissue characteristics between ICD recipients for primary versus secondary prevention.There was no difference in infarct tissue characteristics between recipients of ICD for primary versus secondary prevention, while the secondary prevention group showed a higher frequency of applied ICD therapy for ventricular arrhythmia.


Ventilatory efficiency is as strong prognostic and an important stratification marker. This paper describes the pulmonary abnormalities at rest and during exercise in the patients with heart failure, highlighting the principal diagnostic tools for evaluation of lungs function, the possible pharmacological interventions, and the parameters that could be useful in prognostic assessment of heart failure patients.Lung function abnormalities both at rest and during exercise are frequently observed in patients with chronic heart failure, also in the absence of respiratory disease. Alterations of respiratory mechanics and of gas exchange capacity are strictly related to heart failure. Severe heart failure patients often show a restrictive respiratory pattern, secondary to heart enlargement and increased lung fluids, and impairment of alveolar-capillary gas diffusion, mainly due to an increased resistance to molecular diffusion across the alveolar capillary membrane. Reduced gas diffusion contributes to exercise intolerance and to a worse prognosis. Cardiopulmonary exercise test is considered the “gold standard” when studying the cardiovascular, pulmonary, and metabolic adaptations to exercise in cardiac patients. During exercise, hyperventilation and consequent reduction of ventilation efficiency are often observed in heart failure patients, resulting in an increased slope of ventilation/carbon dioxide (VE/VCO Not only heart is involved in chronic heart failure but also lung, kidney, peripheral and respiratory muscles, chemo-ergoreceptors, neurohormonal mechanisms, mitochondria, all play a major role in determining the complex clinical syndrome of chronic heart failure. Indeed, energy deficit is a relevant contributor to the development of cardiac and skeletal myopathy. In heart failure several functions of muscle bioenergetics are altered such as oxygen availability, substrate oxidation, ATP production by the mitochondria, and transfer to contractile apparatus . Notably2. The excess of ventilation is due to an increase of dead space/tidal volume (VD/VT) ventilation and of ventilatory drive from peripheral chemo- and ergoreceptors. The reduced ventilatory efficiency during exercise is used more and more as a prognostic marker in heart failure. In addition, an improvement of the efficiency of ventilation is among the goals of heart failure therapy. The following review will examine the role of different mechanisms underlying ventilatory efficiency evaluated with spirometry, lung gas diffusion measurement, and cardiopulmonary exercise test in heart failure patients. Dyspnea, either at rest or during exercise, is one of the main symptoms in heart failure. Indeed, the most often used heart failure grading methodology, the NYHA classification, is based on dyspnea. Dyspnea is the result of a neurological reconstruction of an abnormal physiological condition characterized by hyperventilation and by high ventilation to metabolic demand ratio. This leads to a reduced ventilatory efficiency, which is physiologically defined as the amount of ventilation needed to eliminate a given amount of COPulmonary abnormalities are part of the heart failure syndrome, as both lung mechanics and alveolar-capillary gas exchange are impaired –5. In heSpirometry is the preliminary pulmonary function test to assess respiratory mechanics.Wasserman et al.  showed iAlterations of respiratory mechanics and of gas exchange capacity are strictly related in heart failure patients. Reduction in the pulmonary DLCO is well documented in heart failure , 13–15. Reduced Dm is the main component of impaired pulmonary gas transfer in heart failure . Puri etIn heart failure, the alveolar-capillary membrane surface area available for gas exchange is reduced and partially responsible for low Dm. Furthermore, Dm reduction remains even after correction for alveolar volume (Dm/VA) . In factNevertheless, we must underline that, albeit several heart failure models have been prepared to study the correlation between increased congestion of lung interstitial space and pulmonary function, a reliable model of lung function abnormalities mimicking those present in heart failure does not exist. Studies in healthy humans –26 demonDLCO is a limiting factor for exercise performance , 29, whi2 and ventilation versus CO2 production (VE/VCO2) slope  is the slope, K is constant to adjust for standard temperature pressure dry and body temperature pressure saturated and to convert fractional concentrations to pressures, PaCO2 is partial pressure of CO2 in arterial blood, and VD/VT is the fraction of VT that goes to VD. This equation is linear over a wide range of exercise. 2 slope in a normal subject and in a patient with heart failure. If PaCO2 is driven down by a high ventilatory drive from peripheral chemoreceptors or by ergoreceptors in skeletal muscles, the slope of the VE/VCO2 will increase as well as if VD/VT is high. Little is known about chemosensitivity in heart failure. It has been documented that central hypercapnic chemo-sensitivity is enhanced in patients with heart failure with central sleep apnea [In normal subjects the relation of VE versus VCO, and pH . Clinicac period , albeit proposed  providinequation  conciselep apnea . Chua etep apnea  demonstrep apnea . Piepoliep apnea  showed t2 relationship, for incremental exercise, is normally linear up to the “respiratory compensation point,” when ventilatory compensation begins in response to metabolic (lactic) acidosis. Over the linear phase of the VE/VCO2 relationship, below the respiratory compensation point, the profile of VE/VCO2 closely reflects that of VD/VT, providing information on ventilatory efficiency. In heart failure, hyperventilation is associated with an increased VD/VT and VCO2 and a lower PaCO2 when compared to similar normal subjects at a similar percent of VO2 peak [2 relationship is likely when respiratory comorbidities, such as emphysema, are present [In normal subjects, VE/VCOVO2 peak . PatientVO2 peak , which wVO2 peak  showed tVO2 peak . In hearVO2 peak . A total present , 54.2 at the nadir is between 25 and 35. Normal values for these ventilatory equivalents with an end-tidal of CO2 (PetCO2) of approximately 40 mmHg suggest a normal VD/VT and uniform matching of V/Q [The normal VE/VCOg of V/Q .2 slope has gained notoriety in the heart failure population as an outstanding prognostic marker. Several studies report the VE/VCO2 slope to be prognostically superior to peak VO2 to predict mortality [2 slope to stratify the risk of major cardiovascular events in heart failure. Corrà et al. [2 slope (with a cutoff >34) for efficient prognostic stratification in patients with moderate to severe heart failure (defined as VO2/kg peak 10–18 mL/kg/min). Ponikowski et al. [2 >18 mL/kg/min, abnormal exercise ventilation significantly discriminates survival. Guazzi et al. [2 slope has a remarkable value for risk stratification even in patients with diastolic heart failure. In recent years, the VE/VCOortality –60. Arenortality  built a à et al.  used VE/i et al.  suggeste2 pressure (PetCO2) and VE during the isocapnic buffering period [2 set point and ventilation. PetCO2, equivalent to PaCO2, during the isocapnic buffering period, is around 40 mmHg in normal subjects, higher in athletes [2 (and consequently a low peak PetCO2 and an elevated VD/VT) is a strong independent predictor of mortality in stable heart failure, and that a low peak PaCO2 is the most significant determinant of the prognostic value of a steep VE/VCO2 slope. Another ventilation-related index with a prognostic value in heart failure is Oxygen Uptake Efficiency Slope (OUES). OUES is derived from the relation between oxygen uptake (VO2 L/min) and VE (L/min) during incremental exercise. OUES is determined by the linear relation of VO2 (y-axis) versus the logarithm of VE (x-axis) during exercise [Another way to assess ventilation during exercise is to analyze the relationship between end-tidal COg period , 62. At athletes  and loweathletes  suggesteexercise .2 and VE:a is the constant that represents the rate of increase in VO2 in response to VE. We define the constant “a” as the OUES. Baba et al. [2max(r = 0.941).The following equation was used to determine the relation between VOa et al.  emphasiz2. Davies et al. [2/VE) as the best single predictor of early death (six months), in a cohort of 508 patients with low ejection fraction (>35%), with an Odds ratio for mortality of 13. When OUEP is combined with periodic breathing, the Odds ratio increases to 56.Myers et al. , when des et al.  claimed s et al.  have recPeriodic breathing is a ventilatory pattern, which is present in some heart failure patients both at rest and during exercise. Exercise-induced periodic breathing has been defined by Kremser et al.  as the pSeveral reports showed that the respiratory system can be one of the targets for proper heart failure treatment. On this regard, several therapeutic interventions affect the ventilatory abnormalities both at rest and during exercise in heart failure patients. Indeed, ACE-inhibition improves pulmonary diffusion in heart failure . ACE-inh2 slope, consequent to an increase in the arterial CO2 set point [Also Beta-blockers affect DLCO diffusion. Beta-receptors in the lung are located on the alveoli, mainly Beta2-receptors, and on the airways (mainly Beta1-receptor). Carvedilol reduces DLCO, due to a reduction of membrane diffusion , while Bet point , 78. The2 during exercise at a simulated altitude of 2,000 m [A direct effect of Carvedilol on chemoreceptors activity has been recently suggested . This re 2,000 m . In conclusion, lung abnormalities have a major role in heart failure syndrome. Indeed, lung abnormalities influence the clinical setting being dyspnea, a frequently reported heart failure symptom, affecting exercise performance, providing a tool to grade heart failure severity and to predict its prognosis, and finally being the target of therapy with several drugs commonly used in heart failure.


To evaluate the presence of myocardial structural alterations and subtle myocardial dysfunction during familial screening in asymptomatic mutation carriers without hypertrophic cardiomyopathy (HCM) phenotype.Sixteen HCM families with pathogenic mutation were studied and 46 patients with phenotype expression (Mut+/Phen+) and 47 patients without phenotype expression (Mut+/Phen−) were observed. Twenty-five control subjects, matched with the Mut+/Phen− group, were recruited for comparison. Echocardiography was performed to evaluate conventional parameters, myocardial structural alteration by calibrated integrated backscatter (cIBS) and global and segmental longitudinal strain by speckle tracking analysis. All 3 groups had similar left ventricular dimensions and ejection fraction. Basal anteroseptal cIBS was the highest in Mut+/Phen+ patients  and was higher in Mut+/Phen− patients as compared to controls  suggesting significant myocardial structural alterations. Global and basal anteroseptal longitudinal strains  were the most impaired in Mut+/Phen+ patients as compared to the other 2 groups. Although global longitudinal strain was similar between Mut+/Phen− group and controls, basal anteroseptal strain was lower in Mut+/Phen− patients  as compared to controls , suggesting a subclinical segmental systolic dysfunction. A combination of >−19.0 dB basal anteroseptal cIBS or >−18.0% basal anteroseptal longitudinal strain had a sensitivity of 98% and a specificity of 72% in differentiating Mut+/Phen− group from controls.The use of cIBS and segmental longitudinal strain can differentiate HCM Mut+/Phen− patients from controls with important clinical implications for the family screening and follow-up of these patients. Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease and is the leading cause of sudden cardiac death in young individuals. Initial studies using tissue Doppler imaging (TDI) showed that mutation carriers without an overt HCM phenotype may have subtle myocardial diastolic dysfunction, as an early marker of the disease. Ultrasonic tissue characterization with calibrated integrated backscatter (IBS) enables the evaluation of myocardial structural alterations in HCM patients, identifying the presence of myocardial disarray and diffuse myocardial fibrosis. st degree relatives were offered genetic screening. The genetic testing protocol was approved by the Internal Review Board of our Institution  and written informed consent was provided from all subjects undergoing genetic testing.A total of 16 unrelated HCM patients with an identified gene mutation referred to the cardio-genetic out-patient clinic of our Department were included and their 1st degree relatives subsequently referred for detailed evaluation including clinical assessment, 12-lead electrocardiography (ECG), exercise testing, Holter monitoring and transthoracic echocardiography.Pathogenic HCM gene mutations were found in 77 1st degree relatives to document the presence of ventricular arrhythmias. Clinical and echocardiographic data were prospectively collected in electronic patient dossier .The echocardiographic examination included conventional LV measures, calibrated IBS for the assessment of myocardial structural alteration and 2D speckle tracking myocardial strain analysis. Ambulatory 24-hour ECG Holter monitoring was also performed in 67 (87%) 1The diagnosis of HCM was based on the criteria proposed by McKenna et al. for adult members of affected families, In addition, 25 individuals matched for age and gender with the Mut+/Phen− group were consecutively selected as a control group from an existing echocardiographic database with this information. These subjects were referred for atypical chest pain, palpitations, or syncope without murmur, and showed normal structural heart on echocardiography.Subsequently, both myocardial structural alteration and systolic dysfunction were compared among these 3 groups.All patients were imaged using a commercially available system . Images were obtained using a 3.5-MHz transducer and digitally stored; offline analysis was performed using EchoPAC version 108.1.5 . Maximum thickness of LV walls was measured in diastole from the basal, mid and apical short-axis views and from the parasternal long-axis view. Evaluation of LV diastolic function was based on recommendation from the American Society of Echocardiography. Calibrated IBS evaluates myocardial ultrasound reflectivity, providing an estimate of myocardial structural alterations and fibrotic content. The measurement of global longitudinal, circumferential and radial strain using 2D speckle tracking analysis has been described previously. The global values of circumferential and radial strain were derived from the average of the peak systolic strain values obtained from the mid-ventricular short-axis view (divided into 6 segments).Continuous variables are presented as mean(standard deviation). Categorical data are presented as frequencies and percentages. One-way analysis of variance (ANOVA) with post-hoc test by Bonferroni was used to examine the differences among groups. Receiver operator characteristic (ROC) curve analysis was performed to determine the accuracy of calibrated IBS, segmental longitudinal strain and È velocity in differentiating Mut+/Phen− patients from the controls. The optimal cut-off value was defined as the maximized value for the sum of sensitivity and specificity. To test the variability of calibrated IBS and regional longitudinal strain, 6 Mut+/phen− and 6 Mut+/Phen− patients were selected. A first observer analyzed a first dataset twice (within 1 month time) to determine intra-observer agreement. To test inter-observer variability, the measurements were repeated by a second experienced observer on the same dataset. The first observer also analyzed a second dataset acquired the same day of the first one in order to evaluate test-retest variability. Bland-Altman analysis was conducted (expressed as mean difference±2SD), and intraclass correlation coefficients (ICC) were calculated as indicators of reproducibility. All statistical analysis were performed using the statistical package SPSS for windows . A p value <0.05 was considered to be statistically significant.Clinical characteristics of all patients and normal controls are summarized in LV dimensions and ejection fraction were similar among all 3 groups . The antAs shown in Global longitudinal, circumferential and radial strain were significantly impaired in the Mut+/Phen+ group as compared to the other 2 groups. On the other hand, Mut+/Phen− group showed similar values as compared to controls .As shown in Similarly, the basal posterior longitudinal strain was impaired in the Mut+/Phen+ group (−16.4±5.5%) as compared to the Mut+/Phen− group  and controls . However, no difference was noted in the basal posterior longitudinal strain between Mut+/Phen− group and controls.The ROC curve was generated to determine the accuracy of basal anteroseptal calibrated IBS, basal anteroseptal strain and È velocity measurements to differentiate the Mut+/Phen− group from controls . All 3 pA combination of >−19.0 dB basal anteroseptal calibrated IBS or >−18.0% basal anteroseptal strain had a sensitivity of 98%, a specificity of 72%, a positive predictive value of 87% and a negative predictive value of 95%.Holter ECG recordings were analyzed taking into account the percentage of premature ventricular contractions and the presence of non-sustained ventricular tachycardia (NSVT) defined as 3 or more consecutive ventricular beats at a rate of >120 beats/min, lasting for <30 s. Among the 47 Mut+/Phen− patients, 43(91%) underwent ECG Holter assessment and 9 patients showed abnormal results defined by premature ventricular contractions >100 per 24 hours (6 patients) and NSVT (3 patients). A greater extent of myocardial structural alterations in the basal anteroseptal wall, estimated by calibrated IBS (−15.3±3.1 dB), was observed in patients with abnormal Holter results as compared to those with normal results . However, no significant difference was observed for calibrated IBS of the basal posterior wall between these 2 groups . Moreover, the segmental strain over the basal anteroseptal wall  and basal posterior wall  were also similar between these 2 groups.Inter-observer and intra-observer variability were evaluated by two independent observers. The mean differences for intra-observer variability for basal anteroseptal calibrated IBS was 0.1±0.2 dB , for basal posterior calibrated IBS was 0.2±0.4 dB , for basal anteroseptal strain was 0.2±0.4%  and for basal posterior anteroseptal strain was 0.2±1.1% .Mean absolute differences for inter-observer variability for basal anteroseptal calibrated IBS was 0.5±1.5 dB , for basal posterior calibrated IBS was 0.3±1.2 dB , for basal anteroseptal strain was 0.6±2.0%  and for basal posterior strain was 1.1±1.0% .Test-retest reproducibility of calibrated IBS and segmental strain were evaluated using a second echocardiographic dataset acquired the same day. Mean absolute differences and coefficients of variations between the 2 examinations were as follows: basal anteroseptal calibrated IBS 0.4±0.2 dB p<0.01, ICC = 0.99); basal posterior calibrated IBS 0.3±0.7 dB ; basal anteroseptal strain 0.5±0.9% ; basal posterior strain 0.7±0.9% .The results of the current study demonstrated that calibrated IBS and 2D speckle tracking derived strain are able to detect myocardial regional structural and functional abnormalities in HCM mutation carriers without phenotype expression. In particular, the combined measure of basal anteroseptal calibrated IBS and longitudinal strain provided a highly sensitive index to distinguish mutation carriers from normal controls.The advent of genetic testing has allowed the detection of pathogenic gene mutations in family members of HCM patients before the development of LVH or any HCM phenotype. In a high percentage of HCM patients, the development of LVH is delayed late into adulthood, especially in families with myosin-binding protein C mutation. Therefore, several studies, using either echocardiography or magnetic resonance imaging Besides the assessment of LV diastolic function, Ho and colleagues have also evaluated LV global systolic function using novel strain and strain rate imaging. The present study showed that Mut+/Phen− patients had a significant increased calibrated IBS of the basal anteroseptal region as compared to controls, suggesting substantial myocardial structural alterations. The altered IBS values of the basal anteroseptal region might reflect an increased myocardial interstitial fibrosis in these patients, as recently suggested by Ho et al., who demonstrated increased myocardial type I collagen synthesis in HCM mutation carriers without overt LVH. In addition, ultrasonic techniques are sensitive to anisotropic myocardial architecture, such as myocardial disarray (myocytes arranged at oblique and perpendicular angles to each other), which characterizes the myocardium of HCM patients. In addition to the structural abnormalities detected by calibrated IBS, the current study showed that Mut+/Phen− patients have also impaired segmental longitudinal strain in the basal anteroseptal region, but not in the basal posterior region. The preserved LV global strain values observed in the present study in Mut+/Phen− patients might be the result of compensation from the remaining myocardial segments with normal function.The subtle segmental structural and functional alterations circumscribed to the anteroseptum observed in Mut+/Phen− patients can be explained by the preferential involvement of the basal anteroseptal region by LVH in HCM disease. Previous studies showed that in up to 96% of HCM patients, the anterior portion of the ventricular septum is the most common site with LVH as assessed by echocardiography. Importantly, the current study showed that combined measurements of basal anteroseptal calibrated IBS or longitudinal strain have a high sensitivity and negative predictive value to distinguish Mut+/Phen− patients versus normal controls, suggesting a new tool helping to identify subjects without mutation among familial of HCM patients.Recent reports have suggested that mutation carriers without clinical overt HCM frequently have risk factors for sudden cardiac death. Majority of patients in the current study had a mutation in the MYBPC3 gene and therefore results cannot be extrapolated to other groups of mutations . Furthermore, although the most likely mechanism behind an increased cIBS in this population is the presence of myocardial structural alterations, histopathological examination of the myocardium was not available in the studied patients and the exact mechanism generating the cIBS signals should be clarified in further specific studies. In addition, the potential variation of cIBS and segmental strain affected by age and coexisting disease, such as hypertension and underlying coronary artery disease, could not be fully evaluated due to the small study population and the relatively low prevalence of these potential confounders. Larger study populations involving HCM familial screening would be required to further delineate the sensitivity and specificity of these techniques to predict the presence of mutation and to confirm the intra- and inter-observer reproducibility on a multi-center setting. In particular, a specific evaluation should be performed to better assess test-retest reproducibility, including multiple examinations over time, and to explore possible differences among vendors. Lastly, prospective follow-up is necessary to evaluate the clinical significance of altered basal anteroseptal calibrated IBS and longitudinal strain in Mut+/Phen− patients.Novel echocardiographic assessments by calibrated IBS and speckle tracking derived strain allow detection of subtle myocardial structural alterations and impaired systolic function in mutation carriers without HCM phenotype. Importantly, the preferential involvement of the basal anteroseptum demonstrated a segmental rather than global involvement of the myocardium in this group of patients. These findings allow identification and monitoring of patients with HCM gene mutations before the development of LVH.