Missense and Non-Missense Lamin A/C Gene Mutations Are Similarly Associated with Major Arrhythmic Cardiac Events: A 20-Year Single-Centre Experience.

Arrhythmic risk stratification in patients with Lamin A/C gene (LMNA)-related cardiomyopathy influences clinical decisions. An implantable cardioverter defibrillator (ICD) should be considered in patients with an estimated 5-year risk of malignant ventricular arrhythmia (MVA) of ≥10%. The risk prediction score for MVA includes non-missense LMNA mutations, despite their role as an established risk factor for sudden cardiac death (SCD) has been questioned in several studies. The purpose of this study is to investigate cardiac features and find gene-phenotype correlations that would contribute to the evidence on the prognostic implications of non-missense vs. missense mutations in a cohort of LMNA mutant patients. An observational, prospective study was conducted in which 54 patients positive for a Lamin A/C mutation were enrolled, and 20 probands (37%) were included. The median age at first clinical manifestation was 41 (IQR 19) years. The median follow-up was 8 years (IQR 8). The type of LMNA gene mutation was distributed as follows: missense in 26 patients (48%), non-frameshift insertions in 16 (30%), frameshift deletions in 5 (9%), and nonsense in 7 (13%). Among the missense mutation carriers, two (8%) died and four (15%) were admitted onto the heart transplant list or underwent transplantation, with a major adverse cardiovascular event (MACE) rate of 35%. No statistically significant differences in MACE prevalence were identified according to the missense and non-missense mutation groups (p value = 0.847). Our data shift the spotlight on this considerable topic and could suggest that some missense mutations may deserve attention regarding SCD risk stratification in real-world clinical settings.

Accelerated stenotic flow in the left anterior descending coronary artery explains the causes of impaired coronary flow reserve: an integrated transthoracic enhanced Doppler study.

Background: Accelerated stenotic flow (AsF) in the entire left anterior descending coronary artery (LAD), assessed by transthoracic enhanced color Doppler (E-Doppler TTE), can reveal coronary stenosis (CS) and its severity, enabling a distinction between the microcirculatory and epicardial causes of coronary flow reserve (CFR) impairment. Methods: Eighty-four consecutive patients with a CFR <2.0 (1.5 ± 0.4), as assessed by E-Doppler TTE, scheduled for coronary angiography (CA) and eventually intracoronary ultrasounds (IVUS), were studied. CFR was calculated by the ratio of peak diastolic flow velocities: during i.v. adenosine (140 mcg/Kg/m) over resting; AsF was calculated as the percentage increase of localized maximal velocity in relation to a reference velocity. Results: CA showed ≥50% lumen diameter narrowing of the LAD (critical CS) in 68% of patients (57/84) vs. non-critical CS in 32% (27/84). Based on the established CA/IVUS criteria, the non-critical CS subgroup was further subdivided into 2 groups: subcritical/diffuse [16/27 pts (57%)] and no atherosclerosis [11/27 pts (43%)]. CFR was similar in the three groups: 1.4 ± 0.3 in critical CS, 1.5 ± 0.4 in subcritical/diffuse CS, and 1.6 ± 0.4 in no atherosclerosis (p = ns). Overall, at least one segment of accelerated stenotic flow in the LAD was found in 73 patients (87%), while in 11 (13%) it was not. The AsF was very predictive of coronary segmental narrowing in both angio subgroups of atherosclerosis but as expected with the usage of different cutoffs. On the basis of the ROC curve, the optimal cutoff was 109% and 16% AsF % increment to successfully distinguish critical from non-critical CS (area under the curve [AUC] = 0.99, p < 0.001) and diffuse/subcritical from no CS (AUC = 0.91%, p < 0.001). Sensitivity and specificity were 96% and 100% and 82% and 100%, respectively. Conclusion: E-Doppler TTE is highly feasible and reliable in detecting the CS of any grade of severity, distinguishing epicardial athero from microvascular causes of a severe CFR reduction.

Assessment of the Severity of Left Anterior Descending Coronary Artery Stenoses by Enhanced Transthoracic Doppler Echocardiography: Validation of a Method Based on the Continuity Equation.

BACKGROUND: To verify whether the severity of coronary stenosis could be non-invasively assessed by enhanced transthoracic coronary echo Doppler in convergent color Doppler mode (E-Doppler TTE) over a wide range of values (from mild to severe). METHODS: Color-guided pulsed wave Doppler sampling in the left anterior descending coronary artery (LAD) was performed in 103 diseased LAD segments (corresponding to 94 patients examined) as assessed by quantitative coronary angiography (QCA) or intracoronary ultrasound (IVUS). The E-Doppler TTE examinations consisted of measuring the velocity (vel) at the stenosis site and a reference adjacent segment. Then the continuity equation (C-Eq) was applied to calculate the percent cross-sectional area reduction (%CSA) at the stenosis site. The applied formula was: %CSA = 100 × (1 - [TVIref × 0.5]/TVIs). TVI = the time velocity integral at the stenosis [s] and the reference site [ref], respectively); 0.5 = the correcting factor for a parabolic profile was used only when the % accelerated stenotic flow was >122% (AsF = diastolic peak vel at first site - diastolic peak vel at second site/diastolic peak vel at second site × 100). RESULTS: E-Doppler TTE feasibility was 100%. Doppler and QCA/IVUS-derived %CSA stenosis showed very good agreement over a large range of values (from mild to severe), with no significant bias; the maximum difference between QCA/IVUS and transthoracic Doppler %CSA was mostly around 20% with a few patients exceeding this limit (limits of agreement = -27.53 to 23.5%). The scattering was slightly larger for the non-significant stenoses. The correlation was strong (r = 0.89, p < 0.001). CONCLUSION: E-Doppler TTE is a feasible and reliable method for assessing the severity of LAD stenosis by applying the C-Eq.

Free Radicals and Obesity-Related Chronic Inflammation Contrasted by Antioxidants: A New Perspective in Coronary Artery Disease.

We are surrounded by factors called free radicals (FR), which attach to the molecules our body is made of, first among them the endothelium. Even though FR are to a certain extent a normal factor, nowadays we face an escalating increase in these biologically aggressive molecules. The escalating formation of FR is linked to the increased usage of man-made chemicals for personal care (toothpaste, shampoo, bubble bath, etc.), domestic laundry and dish-washer detergents, and also an ever wider usage of drugs (both prescription and over the counter), especially if they are to be used long-term (years). In addition, tobacco smoking, processed foods, pesticides, various chronic infectious microbes, nutritional deficiencies, lack of sun exposure, and, finally, with a markedly increasing impact, electromagnetic pollution (a terribly destructive factor), can increase the risk of cancer, as well as endothelial dysfunction, owing to the increased production of FR that they cause. All these factors create endothelial damage, but the organism may be able to repair such damage thanks to the intervention of the immune system supported by antioxidants. However, one other factor can perpetuate the state of inflammation, namely obesity and metabolic syndrome with associated hyperinsulinemia. In this review, the role of FR, with a special emphasis on their origin, and of antioxidants, is explored from the perspective of their role in causing atherosclerosis, in particular at the coronary level.

Case report: Diagnosis of apical hypertrophic cardiomyopathy that escaped clinical and echocardiographic investigations for twenty years: Reasons and clinical implications.

Background: Apical hypertrophic cardiomyopathy (ApHCM) is a rare form of hypertrophic cardiomyopathy which predominantly affects the apex of the left ventricle. The diagnosis can be challenging due to several factors, ranging from no typical clinical and electrocardiogram (EKG) findings to potential difficulties in executing and interpreting the echocardiographic examination. Case presentation: We report the case of an 84-year-old woman who came to our echo-lab to undergo a routine echocardiogram. She had a history of permanent atrial fibrillation, paced rhythm and previous episodes of heart failure (HF), allegedly explained by a diagnosis of hypertensive heart disease that had been confirmed many times over the previous 20 years. The clinical examination and the EKG were unremarkable. The echocardiographic images were poor quality. But a senior cardiologist, expert in imaging and echocardiography, noted the lack of delineation of the endocardial border of the left ventricular (LV) apex region. Contrast echocardiography was performed and severe apical hypertrophy discovered. Conclusion: ApHCM can be a challenging diagnosis. Contrast echocardiography must always be applied in cases of poor delineation of the LV apical endocardial border at baseline echocardiography. Timely detection and appropriate lifestyle intervention might slow the development of LV hypertrophy, and possibly minimize and delay heart failure (HF) related symptoms and arrhythmias. The prognosis remains relatively benign during long term follow-up.

Heart Rate Lowering Significantly Increases Feasibility in Doppler Recording Blood Flow Velocity in Coronaries during Transthoracic Doppler Echocardiography.

Background: Coronary blood flow Doppler recording by Transthoracic Doppler in convergent mode (E-Doppler TTE) might be further improved by lowering heart rate (HRL) down to <60 bpm, since low HR < 60 b/m causes a disproportional lengthening of the diastole, so the coronaries are still for a longer time, very much improving the Doppler signal/noise ratio. Methods: A group of 26 patients underwent E-Doppler TTE before and after HR lowering in four branches of the coronary tree, namely, the left main (LMCA); left anterior descending (LAD), subdivided into three segments: proximal, mid and distal; proximal left circumflex (LCx); and obtuse marginal (OM). Color and PW coronary Doppler signal was judged by two expert observers as undetectable (SCORE 1), weak or with clutter artifacts (SCORE 2), or well delineated (SCORE 3). In addition, local accelerated stenotic flow (AsF) was measured in the LAD before and after HRL. Results: Beta-blockers significantly decreased the mean HR from 76 ± 5 to 57 ± 6 bpm (p < 0.001). Before HRL, the Doppler quality was very poor in the proximal and mid-LAD segments (median score value = 1 in both), while in the distal LAD, it was significantly better but still suboptimal (median score value = 1.5, p = 0.009 vs. proximal and mid-LAD score). After HRL, blood flow Doppler recording in the three LAD segments was strikingly improved (median score value = 3, 3 and 3, p = ns), so the effect of HRL was more efficacious in the two more proximal LAD segments. In 10 patients undergoing coronary angiography (CA), no AsF as expression of transtenotic velocity was detected at baseline. After HRL, thanks to the better quality and length of color flow, ASF was detected in five patients while in five others, it was not in perfect agreement with CA (Spearman correlation coefficient = 1, p < 0.01). The color flow in the proximal LCx and OM was extremely poor at baseline (color flow length 0 and 0, median (interquartile range) mm, respectively) and improved considerably after HRL (color flow length 23 [13.5] and 25 [12.0] mm, respectively, p < 0.001). Conclusions: HRL greatly improved the success rate of blood flow Doppler recording in coronaries, not only in the LAD, but also in the LCx. Therefore, AsF for stenosis detection and coronary flow reserve assessment can have wider clinical applications. However, further studies with larger samples are needed to confirm these results.

Hidden Coronary Atherosclerosis Assessment but Not Coronary Flow Reserve Helps to Explain the Slow Coronary Flow Phenomenon in Patients with Angiographically Normal Coronary Arteries.

The significance of the slow coronary flow phenomenon (SCFph), as visualized in patients (pts) with angiographically normal coronary arteries, is controversial. Absolute coronary flow reserve (CFR) in the left anterior descending coronary artery (LAD), non-invasively assessed by a transthoracic color-guided pulsed-wave Doppler (E-Doppler TTE), is a reliable parameter to assess coronary microcirculatory dysfunction (CMD). Mild and angiographically hidden epicardial atherosclerosis (Hath), as visualized by intracoronary ultrasound (IVUS), which could be the clue to atherosclerotic coronary microvascular involvement, has never been investigated together with CFR in patients. This study was aimed at assessing the value of CFR and HA in explaining the SCFph. Methods. Both non-invasive assessment of CFR in the LAD and corrected TIMI frame count assessment of the coronary contrast runoff were performed in 124 pts with angiographically normal coronary arteries. Among the whole group, 32 patients also underwent intracoronary ultrasounds in the LMCA and LAD, and the maximal plaque burden was assessed (Lesion external elastic (EEM) cross sectional area (CSA)­Lesion Lumen CSA/Lesion EEM CSA * 100). We found that 24 of the 124 pts (group 1) had the SCFph and the remaining 100 had a normal runoff (group 2). CFR, evaluated in both groups, was not significantly different, being 2.79 ± 0.79 (Mean ± SD) in group 1 and 2.90 ± 0.8 in group 2 (p = ns); in the pts also examined by IVUS (32 pts), the SCFph was always associated with hidden atherosclerosis, and a plaque burden of ≥33%. On the contrary, in the normal runoff group, any grade of PB was observed (from no athero to a PB > 70%) and remarkably, 10 pts had no signs of athero or just a minimal plaque burden. This resulted in a ROC curve analysis in which PB < 33% had a high negative predictive value (100%) in ruling out the SCFph. In addition, considering a CFR value < 2.21 as an index of coronary microcirculatory dysfunction, we found CMD in 15 pts (15%) in group 1 and in 7 pts (29%) in group 2 (p = ns). In conclusion, the SCFph is strongly connected to epicardial athero to the extent that the absence of hidden coronary athero has a very high negative predictive power in ruling out SCFph. CFR that is based on an endothelium-independent mechanism remains fairly normal in this condition. An endothelium-dependent microcirculatory constriction at rest due to atherosclerotic involvement of the coronary microvascular network is a possible explanation of the SCFph.

Wellens' Syndrome from COVID-19 Infection Assessed by Enhanced Transthoracic Coronary Echo Doppler: A Case Report.

Wellens' syndrome (WS) is a preinfarction state caused by a sub-occlusion of the proximal left anterior descending coronary artery (LAD). In this case report, for the first time, we describe how this syndrome can be caused by COVID-19 infection and, most importantly, that it can be assessed bedside by enhanced transthoracic coronary echo Doppler (E-Doppler TTE). This seasoned technique allows blood flow Doppler to be recorded in the coronaries and at the stenosis site but has never been tested in an acute setting. Two weeks after clinical recovery from bronchitis allegedly caused by COVID-19 infection on the basis of epidemiologic criteria (no swab performed during the acute phase but only during recovery, at which time it was negative), our patient developed typical angina for the first time, mainly during effort but also at rest. He was admitted to our tertiary center, where pharyngeal swabs tested positive for COVID-19. A typical EKG finding supporting WS prompted an assessment of the left main coronary artery (LMCA) and the whole LAD blood flow velocity by E-Doppler TTE. Localized high velocity (transtenotic velocity) (100 cm/s) was recorded in the proximal LAD, with the reference velocity being 20 cm/s. This indicated severe stenosis with 90% area narrowing according to the continuity equation, as confirmed by coronary angiography. During follow-up after successful stenting, E-Doppler TTE showed a decrease in the transtenotic acceleration, confirming stent patency and a normal coronary flow reserve (3.2) and illustrating a normal microcirculatory function. Conclusion: COVID infection can trigger a coronary syndrome like WS. E-Doppler TTE, an ionizing radiation-free method, allows safe and rapid bedside management of the syndrome. This new strategy can be pivotal in distinguishing true WS from pseudo-WS. In cases of pseudo-WS, coronary angiography can be avoided. If E-Doppler TTE confirms the stenosis and PCI (percutaneous coronary intervention) is performed, the same method can allow assessment over time of the precise residual stenosis after stenting and verify the microvasculature status by evaluating coronary flow reserve.

Cardiorenal Syndrome Triggered by Slowly Progressive Drugs Toxicity-Induced Renal Failure along with Minimal Mitral Disease: A Case Report.

BACKGROUND: We report the case of a 93-year-old patient with normal left ventricular function and severe mitral annulus calcification, with mild mitral steno-insufficiency. CASE PRESENTATION: She had developed creeping drugs-induced renal toxicity that is generally totally overlooked, due mainly to statins, a proton pump inhibitor, and aspirin. The Na and fluid retention, along with hypertension that ensued, although not severe, caused acute heart failure (sub-pulmonary edema) by worsening the mitral insufficiency. This occurred due to a less efficient calcific mitral annulus contraction during systole and an increasing mitral transvalvular gradient, as the transvalvular mitral gradient has an exponential relation to flow. After the suspension of the nephrotoxic drugs and starting intravenous furosemide, she rapidly improved. At 6 months follow-up, she is stable, in an NYHA 1-2 functional class, despite the only partial recovery of the renal function. CONCLUSION: Progressive renal failure can functionally worsen even minimal mitral valvulopathy. Drug-induced nephrotoxicity can always be suspected in case of renal failure of unknown etiology. The suspension of the culprit drugs can improve renal function and dramatically improve the clinical symptoms even in a nonagenarian.

Predictors of Exercise Capacity in Dilated Cardiomyopathy with Focus on Pulmonary Venous Flow Recorded with Transesophageal Eco-Doppler.

The aim of this study was to clarify the relative contribution of elevated left ventricle (LV) filling pressure (FP) estimated by pulmonary venous (PV) and mitral flow, transesophageal Doppler recording (TEE), and other extracardiac factors like obesity and renal insufficiency (KI) to exercise capacity (ExC) evaluated by cardiopulmonary exercise testing (CPX) in patients with dilated cardiomyopathy (DCM). During the CPX test, 119 patients (pts) with DCM underwent both peak VO2 consumption and then TEE with color-guided pulsed-wave Doppler recording of PVF and transmitral flow. In 78 patients (65%), peak VO2 was normal or mildly reduced (>14 mL/kg/min) (group 1) while it was markedly reduced (≤14 mL/kg/min) in 41 (group 2). In univariate analysis, systolic fraction (S Fract), a predictor of elevated pre-a LV diastolic FP, appeared to be the best diastolic parameter predicting a significantly reduced peak VO2. Logistic regression analysis identified five parameters yielding a unique, statistically significant contribution in predicting reduced ExC: creatinine clearance < 52 mL/min (odds ratio (OR) = 7.4, p = 0.007); female gender (OR = 7.1, p = 0.004); BMI > 28 (OR = 5.8, p = 0.029), age > 62 years (OR = 5.5, p = 0.03), S Fract < 59% (OR = 4.9, p = 0.02). Conclusion: KI was the strongest predictor of reduced ExC. The other modifiable factors were obesity and severe LV diastolic dysfunction expressed by blunted systolic venous flow. Contrarily, LV ejection fraction was not predictive, confirming other previous studies. This has important clinical implications.

Coronary Flow and Reserve by Enhanced Transthoracic Doppler Trumps Coronary Anatomy by Computed Tomography in Assessing Coronary Artery Stenosis.

We report the case of a 71-year-old patient with many risk factors for coronary atherosclerosis, who underwent computed coronary angiography (CTA), in accordance with the guidelines, for recent onset atypical chest pain. CTA revealed critical (>50% lumen diameter narrowing) stenosis of the proximal anterior descending coronary, and the patient was scheduled for invasive coronary angiography (ICA). Before ICA he underwent enhanced transthoracic echo-Doppler (E-Doppler TTE) for coronary flow detection by color-guided pulsed-wave Doppler recording of the left main (LMCA) and whole left anterior descending coronary artery (LAD,) along with coronary flow reserve (CFR) in the distal LAD calculated as the ratio, of peak flow velocity during i.v. adenosine (140 mcg/Kg/m) to resting flow velocity. E-Doppler TTE mapping revealed only mild stenosis (28% area narrowing) of the mid LAD and a CFR of 3.20, in perfect agreement with the color mapping showing no flow limiting stenosis in the LMCA and LAD. ICA revealed only a very mild stenosis in the mid LAD and mild atherosclerosis in the other coronaries (intimal irregularities). Thus, coronary stenosis was better predicted by E-Doppler TTE than by CTA. Coronary flow and reserve as assessed by E-Doppler TTE trumps coronary anatomy as assessed by CTA, without exposing the patient to harmful radiation and iodinated contrast medium.

A Novel Clinical Perspective on New Masses after Lead Extraction (Ghosts) by Means of Intracardiac Echocardiography.

BACKGROUND: A lead-reactive fibrous capsule (FC) identified by ultrasounds as an atrial or ventricular lead thickness of more than 1 mm above the vendor-declared lead diameter (TL) and its local fibrotic attachment to the cardiac wall (FAC) have never been investigated in vivo, so their relationship with post-extraction masses (ghost) is not known. METHODS: Intracardiac echocardiography (ICE) was performed twice during the same extraction procedure in 40 consecutive patients: before and immediately after infected lead extraction Results: The ghost detection rate was high: 60% (24/40 patients); ICE could identify both TL and FAC, TL being noted in 25/40 (62%) patients and FAC in 12/40 patients (30%). Both TL and FAC were significantly associated with ghosts (p < 0.001 and p = 0.002, respectively), but TL had a higher prediction power. The specificity was similar: 94% (15/16) and 100% (16/16), respectively, but TL showed a much higher sensitivity: 100%, (24/24) vs 50% (12/24) (p = 0.016). The ghost group did not show a higher event rate in the follow-up (mean follow-up time = 20 ± 17 months). CONCLUSION: ICE is able to evaluate both TL and FAC in vivo; ghosts are mostly benign remnants of fibrotic lead capsule cut off during extraction and retained inside the heart by FAC.

A case of suspected eosinophilic myocarditis recognized by a fully noninvasive approach and safely treated with corticosteroids despite underlying hepatitis C virus-related hepatitis.

Hypereosinophilic syndrome can lead to acute myocarditis with a potentially severe systolic dysfunction and serious complications. A 75-year-old patient suffering from Hepatitis C virus (HCV) related-hepatitis came to our observation for idiopatic hypereosinophilic syndrome and acute severe cardiac systolic dysfunction without coronaropathy. Cardiac magnetic resonance showed a 'patchy' subendocardial and intramyocardial late gadolinium enhancement pattern often seen in eosinophilic myocarditis (EM). Assuming EM, appropriate corticosteroid therapy was initiated and it led to clinical remission. Despite endomyocardial biopsy (EMB) is the diagnostic gold standard for EM, in this case only a noninvasive integrated imaging approach was successfully attempted. Given an adequate clinical context, in our opinion EM can be correctly recognized without EMB and so promptly and safely treated with corticosteroids, even when an underling mild HCV-hepatitis is present.

A new noninvasive method for assessing mild coronary atherosclerosis: transthoracic convergent color Doppler after heart rate reduction. Validation vs. intracoronary ultrasound.

BACKGROUND: A more sensitive transthoracic color Doppler technology (convergent color Doppler), along with a heart rate (HR) reduction and new tomographic planes, can greatly improve coronary blood flow velocity (BFV) recordings in the left main (LMCA) and left anterior descending (LAD) coronary arteries, allowing the detection of even a slight acceleration of BFV due to mild coronary stenosis. METHODS: A group of 26 patients underwent convergent color Doppler transthoracic echocardiography (CC-Doppler TTE) in the LMCA and in the LAD coronary arteries before and after HR lowering. A second group of 71 patients scheduled for intravascular ultrasound, expanded to 96 with 25 more patients with normal LAD (by angiography/low likelihood of disease), underwent BFV Doppler recordings by CC-Doppler TTE of the whole LAD (specifically the proximal, mid and distal segments) to detect a localized increase in BFV, after attaining maximal and reference BFV in each segment. RESULTS: In the first group, HR reduction dramatically improved the detection of optimal flow in the LMCA and LAD, from 4 to 54% and from 6 to 94% of the segments, respectively (P < 0.001). In the second group intravascular ultrasonography (IVUS) showed mild stenoses in 60 patients. The maximum velocity was higher in the diseased segment than normal segments (49 ± 24 vs. 33 ± 11 cm/s; P < 0.001) and as the reference velocity was similar (32 ± 9 vs. 33 ± 11 cm/s; P = ns), the % increase was also higher (52 ± 52 vs. 0.7 ± 3%; P < 0.001). Using a >21% increase in velocity as a cutoff value, the sensitivity and specificity of CC-Doppler TTE in detecting at least one LAD plaque were 87% (52/60 patients [pts]) and 100% (36/36 pts), respectively. CONCLUSION: CC-Doppler TTE evaluation of LAD BFV is greatly improved after reducing HR, allowing accurate noninvasive assessment of mild LAD stenosis with no radiation exposure.

Minimal Cardiac Perforation by Lead Pacemaker Complicated with Pericardial Effusion and Impending Tamponade: Optimal Management with No Pericardiocentesis Driven by Echocardiography.

We report the case of a 51-year-old patient who underwent the implantation of a bi-ventricular implantable cardioverter defibrillator (ICD) complicated by a sub-acute right ventricular minimal perforation with pericardial effusion and echocardiographic signs of tamponade. A new echocardiographic plane orientation allowed us to diagnose this condition in emergency and to make the right decision without delay, which consisting in unscrewing the active fixation screw under fluoroscopy guidance, while the pericardiocentesis was postponed. Thanks to the intervention focused on eliminating the cause of the postcardiac injury syndrome, the patient recovered rapidly and ultimately avoided the pericardiocentesis procedure.

The Herbicide Glyphosate and Its Apparently Controversial Effect on Human Health: An Updated Clinical Perspective.

BACKGROUND: Glyphosate (G) is the most common weed-killer in the world. Every year tons and tons of G are applied on crop fields. G was first introduced in the mid 1970s and since then its usage has gradually increased to reach a peak since 2005. Now G usage is approximately 100 -fold what it was in 1970. Its impact on human health was considered benign at the beginning. But over the years, evidence of a pervasive negative effect of this pesticide on humans has been mounting. Nonetheless, G usage is allowed by government health control agencies (both in the United States and Europe), that rely upon the evidence produced by the G producer. However, the IARC (International Agency for Research on Cancer) in 2015 has stated that G is probable carcinogenic (class 2A), the second highest class in terms of risk. OBJECTIVE: In this review, we explore the effect of G on human health, focusing in particular on more recent knowledge. RESULTS: We have attempted to untangle the controversy about the dangers of the product for human beings in view of a very recent development, when the so -called Monsanto Papers, consisting of Emails and memos from Monsanto came to light, revealing a coordinated strategy to manipulate the debate about the safety of glyphosate to the company's advantage. CONCLUSION: The story of G is a recurrent one (see the tobacco story), that seriously jeopardizes the credibility of the scientific study in the modern era.